Sample records for adipose tissue macrophage

  1. Novel Role of Endogenous Catalase in Macrophage Polarization in Adipose Tissue.

    PubMed

    Park, Ye Seul; Uddin, Md Jamal; Piao, Lingjuan; Hwang, Inah; Lee, Jung Hwa; Ha, Hunjoo

    2016-01-01

    Macrophages are important components of adipose tissue inflammation, which results in metabolic diseases such as insulin resistance. Notably, obesity induces a proinflammatory phenotypic switch in adipose tissue macrophages, and oxidative stress facilitates this switch. Thus, we examined the role of endogenous catalase, a key regulator of oxidative stress, in the activity of adipose tissue macrophages in obese mice. Catalase knockout (CKO) exacerbated insulin resistance, amplified oxidative stress, and accelerated macrophage infiltration into epididymal white adipose tissue in mice on normal or high-fat diet. Interestingly, catalase deficiency also enhanced classical macrophage activation (M1) and inflammation but suppressed alternative activation (M2) regardless of diet. Similarly, pharmacological inhibition of catalase activity using 3-aminotriazole induced the same phenotypic switch and inflammatory response in RAW264.7 macrophages. Finally, the same phenotypic switch and inflammatory responses were observed in primary bone marrow-derived macrophages from CKO mice. Taken together, the data indicate that endogenous catalase regulates the polarization of adipose tissue macrophages and thereby inhibits inflammation and insulin resistance.

  2. Adipocyte fetuin-A contributes to macrophage migration into adipose tissue and polarization of macrophages.

    PubMed

    Chatterjee, Priyajit; Seal, Soma; Mukherjee, Sandip; Kundu, Rakesh; Mukherjee, Sutapa; Ray, Sukanta; Mukhopadhyay, Satinath; Majumdar, Subeer S; Bhattacharya, Samir

    2013-09-27

    Macrophage infiltration into adipose tissue during obesity and their phenotypic conversion from anti-inflammatory M2 to proinflammatory M1 subtype significantly contributes to develop a link between inflammation and insulin resistance; signaling molecule(s) for these events, however, remains poorly understood. We demonstrate here that excess lipid in the adipose tissue environment may trigger one such signal. Adipose tissue from obese diabetic db/db mice, high fat diet-fed mice, and obese diabetic patients showed significantly elevated fetuin-A (FetA) levels in respect to their controls; partially hepatectomized high fat diet mice did not show noticeable alteration, indicating adipose tissue to be the source of this alteration. In adipocytes, fatty acid induces FetA gene and protein expressions, resulting in its copious release. We found that FetA could act as a chemoattractant for macrophages. To simulate lipid-induced inflammatory conditions when proinflammatory adipose tissue and macrophages create a niche of an altered microenvironment, we set up a transculture system of macrophages and adipocytes; the addition of fatty acid to adipocytes released FetA into the medium, which polarized M2 macrophages to M1. This was further confirmed by direct FetA addition to macrophages. Taken together, lipid-induced FetA from adipocytes is an efficient chemokine for macrophage migration and polarization. These findings open a new dimension for understanding obesity-induced inflammation.

  3. Apoptosis inhibitor of macrophage (AIM) is required for obesity-associated recruitment of inflammatory macrophages into adipose tissue

    PubMed Central

    Kurokawa, Jun; Nagano, Hiromichi; Ohara, Osamu; Kubota, Naoto; Kadowaki, Takashi; Arai, Satoko; Miyazaki, Toru

    2011-01-01

    Infiltration of inflammatory macrophages into adipose tissues with the progression of obesity triggers insulin resistance and obesity-related metabolic diseases. We recently reported that macrophage-derived apoptosis inhibitor of macrophage (AIM) protein is increased in blood in line with obesity progression and is incorporated into adipocytes, thereby inducing lipolysis in adipose tissue. Here we show that such a response is required for the recruitment of adipose tissue macrophages. In vitro, AIM-dependent lipolysis induced an efflux of palmitic and stearic acids from 3T3-L1 adipocytes, thereby stimulating chemokine production in adipocytes via activation of toll-like receptor 4 (TLR4). In vivo administration of recombinant AIM to TLR4-deficient (TLR4−/−) mice resulted in induction of lipolysis without chemokine production in adipose tissues. Consistently, mRNA levels for the chemokines that affect macrophages were far lower in AIM-deficient (AIM−/−) than in wild-type (AIM+/+) obese adipose tissue. This reduction in chemokine production resulted in a marked prevention of inflammatory macrophage infiltration into adipose tissue in obese AIM−/− mice, although these mice showed more advanced obesity than AIM+/+ mice on a high-fat diet. Diminished macrophage infiltration resulted in decreased inflammation locally and systemically in obese AIM−/− mice, thereby protecting them from insulin resistance and glucose intolerance. These results indicate that the increase in blood AIM is a critical event for the initiation of macrophage recruitment into adipose tissue, which is followed by insulin resistance. Thus, AIM suppression might be therapeutically applicable for the prevention of obesity-related metabolic disorders. PMID:21730133

  4. Characteristics of adipose tissue macrophages and macrophage-derived insulin-like growth factor-1 in virus-induced obesity.

    PubMed

    Park, S; Park, H-L; Lee, S-Y; Nam, J-H

    2016-03-01

    Various pathogens are implicated in the induction of obesity. Previous studies have confirmed that human adenovirus 36 (Ad36) is associated with increased adiposity, improved glycemic control and induction of inflammation. The Ad36-induced inflammation is reflected in the infiltration of macrophages into adipose tissue. However, the characteristics and role of adipose tissue macrophages (ATMs) and macrophage-secreted factors in virus-induced obesity (VIO) are unclear. Although insulin-like growth factor-1 (IGF-1) is involved in obesity metabolism, the contribution of IGF secreted by macrophages in VIO has not been studied. Four-week-old male mice were studied 1 week and 12 weeks after Ad36 infection for determining the characteristics of ATMs in VIO and diet-induced obesity (DIO). In addition, macrophage-specific IGF-1-deficient (MIKO) mice were used to study the involvement of IGF-1 in VIO. In the early stage of VIO (1 week after Ad36 infection), the M1 ATM sub-population increased, which increased the M1/M2 ratio, whereas DIO did not cause this change. In the late stage of VIO (12 weeks after Ad36 infection), the M1/M2 ratio did not change because the M1 and M2 ATM sub-populations increased to a similar extent, despite an increase in adiposity. By contrast, DIO increased the M1/M2 ratio. In addition, VIO in wild-type mice upregulated angiogenesis in adipose tissue and improved glycemic control. However, MIKO mice showed no increase in adiposity, angiogenesis, infiltration of macrophages into adipose tissue, or improvement in glycemic control after Ad36 infection. These data suggest that IGF-1 secreted by macrophages may contribute to hyperplasia and hypertrophy in adipose tissue by increasing angiogenesis, which helps to maintain the 'adipose tissue robustness'.

  5. Overexpression of IL-10 in C2D macrophages promotes a macrophage phenotypic switch in adipose tissue environments.

    PubMed

    Xie, Linglin; Fu, Qiang; Ortega, Teresa M; Zhou, Lun; Rasmussen, Dane; O'Keefe, Jacy; Zhang, Ke K; Chapes, Stephen K

    2014-01-01

    Adipose tissue macrophages are a heterogeneous collection of classically activated (M1) and alternatively activated (M2) macrophages. Interleukin 10 (IL-10) is an anti-inflammatory cytokine, secreted by a variety of cell types including M2 macrophages. We generated a macrophage cell line stably overexpressing IL-10 (C2D-IL10) and analyzed the C2D-IL10 cells for several macrophage markers after exposure to adipocytes compared to C2D cells transfected with an empty vector (C2D-vector). C2D-IL10 macrophage cells expressed more CD206 when co-cultured with adipocytes than C2D-vector cells; while the co-cultured cell mixture also expressed higher levels of Il4, Il10, Il1β and Tnf. Since regular C2D cells traffic to adipose tissue after adoptive transfer, we explored the impact of constitutive IL-10 expression on C2D-IL10 macrophages in adipose tissue in vivo. Adipose tissue-isolated C2D-IL10 cells increased the percentage of CD206(+), CD301(+), CD11c(-)CD206(+) (M2) and CD11c(+)CD206(+) (M1b) on their cell surface, compared to isolated C2D-vector cells. These data suggest that the expression of IL-10 remains stable, alters the C2D-IL10 macrophage cell surface phenotype and may play a role in regulating macrophage interactions with the adipose tissue.

  6. Brown adipose tissue macrophages control tissue innervation and homeostatic energy expenditure

    PubMed Central

    Cortese, Nina; Haimon, Zhana; Sar Shalom, Hadas; Kuperman, Yael; Kalchenko, Vyacheslav; Brandis, Alexander; David, Eyal; Segal-Hayoun, Yifat; Chappell-Maor, Louise; Yaron, Avraham; Jung, Steffen

    2017-01-01

    Tissue macrophages provide immune defense and contribute to establishment and maintenance of tissue homeostasis. Here we used constitutive and inducible mutagenesis to delete the nuclear transcription regulator methyl-CpG binding protein 2 (Mecp2) in defined tissue macrophages. Animals lacking the Rett syndrome-associated gene in macrophages did not show signs of neurodevelopmental disorder, but displayed spontaneous obesity, which could be linked to impaired brown adipose tissue (BAT) function. Specifically, mutagenesis of a BAT-resident CX3CR1+ macrophage subpopulation compromised homeostatic, though not acute cold-induced thermogenesis. Mechanistically, BAT malfunction of pre-obese mice harboring mutant macrophages was associated with decreased sympathetic innervation and local norepinephrine titers, resulting in reduced adipocyte expression of thermogenic factors. Mutant macrophages over-expressed PlexinA4, which might contribute to the phenotype by repulsion of Sema6A-expressing sympathetic axons. Collectively, we report a previously unappreciated homeostatic role of macrophages in the control of tissue innervation, disruption of which in BAT results in metabolic imbalance. PMID:28459435

  7. Proinsulin-producing, hyperglycemia-induced adipose tissue macrophages underlie insulin resistance in high fat-fed diabetic mice

    USDA-ARS?s Scientific Manuscript database

    Adipose tissue macrophages play an important role in the pathogenesis of obese type 2 diabetes. High-fat diet-induced obesity has been shown to lead to adipose tissue macrophages accumulation in rodents;however, the impact of hyperglycemia on adipose tissue macrophages dynamics in high-fat diet-fed ...

  8. Biology and function of adipose tissue macrophages, dendritic cells and B cells.

    PubMed

    Ivanov, Stoyan; Merlin, Johanna; Lee, Man Kit Sam; Murphy, Andrew J; Guinamard, Rodolphe R

    2018-04-01

    The increasing incidence of obesity and its socio-economical impact is a global health issue due to its associated co-morbidities, namely diabetes and cardiovascular disease [1-5]. Obesity is characterized by an increase in adipose tissue, which promotes the recruitment of immune cells resulting in low-grade inflammation and dysfunctional metabolism. Macrophages are the most abundant immune cells in the adipose tissue of mice and humans. The adipose tissue also contains other myeloid cells (dendritic cells (DC) and neutrophils) and to a lesser extent lymphocyte populations, including T cells, B cells, Natural Killer (NK) and Natural Killer T (NKT) cells. While the majority of studies have linked adipose tissue macrophages (ATM) to the development of low-grade inflammation and co-morbidities associated with obesity, emerging evidence suggests for a role of other immune cells within the adipose tissue that may act in part by supporting macrophage homeostasis. In this review, we summarize the current knowledge of the functions ATMs, DCs and B cells possess during steady-state and obesity. Copyright © 2018 Elsevier B.V. All rights reserved.

  9. PPAR γ is highly expressed in F4/80hi adipose tissue macrophages and dampens adipose-tissue inflammation

    PubMed Central

    Bassaganya-Riera, Josep; Misyak, Sarah; Guri, Amir J.; Hontecillas, Raquel

    2009-01-01

    Macrophage infiltration into adipose tissue is a hallmark of obesity. We recently reported two phenotypically distinct subsets of adipose tissue macrophages (ATM) based on the surface expression of the glycoprotein F4/80 and responsiveness to treatment with a peroxisome proliferator-activated receptor (PPAR) γ agonist. Hence, we hypothesized that F4/80hi and F4/80lo ATM differentially express PPAR γ. This study phenotypically and functionally characterizes F4/80hi and F4/80lo ATM subsets during obesity. Changes in gene expression were also examined on sorted F4/80lo and F4/80hi ATM by quantitative real-time RT-PCR. We show that while F4/80lo macrophages predominate in adipose tissue of lean mice, obesity causes accumulation of both F4/80lo and F4/80hi ATM. Moreover, accumulation of F4/80hi ATM in adipose tissue is associated with impaired glucose tolerance. Phenotypically, F4/80hi ATM express greater amounts of CD11c, MHC II, CD49b, and CX3CR1 and produce more TNF-α, MCP-1, and IL-10 than F4/80lo ATM. Gene expression analyses of the sorted populations revealed that only the F4/80lo population produced IL-4, whereas the F4/80hi ATM expressed greater amounts of PPAR γ, δ, CD36 and toll-like receptor-4. In addition, the deficiency of PPAR γ in immune cells favors expression of M1 and impairs M2 macrophage marker expression in adipose tissue. Thus, PPAR γ is differentially expressed in F4/80hi versus F4/80low ATM subsets and its deficiency favors a predominance of M1 markers in WAT. PMID:19423085

  10. PPAR gamma is highly expressed in F4/80(hi) adipose tissue macrophages and dampens adipose-tissue inflammation.

    PubMed

    Bassaganya-Riera, Josep; Misyak, Sarah; Guri, Amir J; Hontecillas, Raquel

    2009-01-01

    Macrophage infiltration into adipose tissue is a hallmark of obesity. We recently reported two phenotypically distinct subsets of adipose tissue macrophages (ATM) based on the surface expression of the glycoprotein F4/80 and responsiveness to treatment with a peroxisome proliferator-activated receptor (PPAR) gamma agonist. Hence, we hypothesized that F4/80(hi) and F4/80(lo) ATM differentially express PPAR gamma. This study phenotypically and functionally characterizes F4/80(hi) and F4/80(lo) ATM subsets during obesity. Changes in gene expression were also examined on sorted F4/80(lo) and F4/80(hi) ATM by quantitative real-time RT-PCR. We show that while F4/80(lo) macrophages predominate in adipose tissue of lean mice, obesity causes accumulation of both F4/80(lo) and F4/80(hi) ATM. Moreover, accumulation of F4/80(hi) ATM in adipose tissue is associated with impaired glucose tolerance. Phenotypically, F4/80(hi) ATM express greater amounts of CD11c, MHC II, CD49b, and CX3CR1 and produce more TNF-alpha, MCP-1, and IL-10 than F4/80(lo) ATM. Gene expression analyses of the sorted populations revealed that only the F4/80(lo) population produced IL-4, whereas the F4/80(hi) ATM expressed greater amounts of PPAR gamma, delta, CD36 and toll-like receptor-4. In addition, the deficiency of PPAR gamma in immune cells favors expression of M1 and impairs M2 macrophage marker expression in adipose tissue. Thus, PPAR gamma is differentially expressed in F4/80(hi) versus F4/80(low) ATM subsets and its deficiency favors a predominance of M1 markers in WAT.

  11. Inhibition of M1 macrophage activation in adipose tissue by berberine improves insulin resistance.

    PubMed

    Ye, Lifang; Liang, Shu; Guo, Chao; Yu, Xizhong; Zhao, Juan; Zhang, Hao; Shang, Wenbin

    2016-12-01

    Insulin resistance is associated with a chronic inflammation in adipose tissue which is propagated by a phenotypic switch in adipose tissue macrophage (ATM) polarization. This study aimed to investigate whether berberine, the major alkaloid of rhizoma coptidis, can improve insulin resistance through inhibiting ATM activation and inflammatory response in adipose tissue. High-fat-diet induced obese mice were administered oral with berberine (50mg/kg/day) for 14days. ATMs were analysed using FACS and insulin resistance was evaluated. Expressions of pro-inflammatory cytokines and activation of inflammatory pathways were detected. The chemotaxis of macrophages was measured. Glucose consumption and insulin signalling of adipocytes were examined. Berberine significantly decreased F4/80 + /CD11c + /CD206 - cells in the stromal vascular fraction from adipose tissue and improved glucose tolerance in obsess mice. In addition, berberine reduced the elevated levels of serum TNF-α, IL-6 and MCP-1 and the expressions of TNF-α, IL-6 and MCP-1 and attenuated the phosphorylation of JNK and IKKβ and the expression of NF-κB p65 in the obese adipose tissue, Raw264.7 macrophages and 3T3-L1 adipocytes, respectively. The phosphorylation of IRS-1 (Ser307) was inhibited by berberine in adipose tissue and cultured adipocytes. The phosphorylation of AKT (Ser473) was increased in berberine-treated adipose tissue. Conditioned medium from adipocytes treated with berberine reduced the number of infiltrated macrophages. Berberine partly restored the impaired glucose consumption and the activation of IRS-1 (Ser307) in adipocytes induced by the activation of macrophages. Our findings imply that berberine improves insulin resistance by inhibiting M1 macrophage activation in adipose tissue. Copyright © 2016 Elsevier Inc. All rights reserved.

  12. Adipose tissue macrophages induce hepatic neutrophil recruitment and macrophage accumulation in mice.

    PubMed

    Bijnen, Mitchell; Josefs, Tatjana; Cuijpers, Ilona; Maalsen, Constantijn J; van de Gaar, José; Vroomen, Maria; Wijnands, Erwin; Rensen, Sander S; Greve, Jan Willem M; Hofker, Marten H; Biessen, Erik A L; Stehouwer, Coen D A; Schalkwijk, Casper G; Wouters, Kristiaan

    2017-10-26

    Obesity is a risk factor for non-alcoholic steatohepatitis (NASH). This risk has been attributed to visceral adipose tissue (vAT) expansion associated with increased proinflammatory mediators. Accumulation of CD11c + proinflammatory adipose tissue macrophages (ATM) is an important driver of vAT inflammation. We investigated the role of ATMs in hepatic inflammation during NASH development. vAT isolated from lean, obese or ATM-depleted (using clodronate liposomes) obese mice was transplanted to lean ldlr -/- acceptor mice. Systemic and hepatic inflammation was assessed either after 2 weeks on standard chow or after 8 weeks on high cholesterol diet (HCD) to induce NASH. Transplanting donor vAT from obese mice increased HCD-induced hepatic macrophage content compared with lean-transplanted mice, worsening liver damage. ATM depletion prior to vAT transplantation reduced this increased hepatic macrophage accumulation. On chow, vAT transplantation induced a more pronounced increase in circulating and hepatic neutrophil numbers in obese-transplanted than lean-transplanted mice, while ATM depletion prior to vAT transplantation reversed this effect. Microarray analysis of fluorescence-activated cell sorting of CD11c + and CD11c - macrophages isolated from donor adipose tissue showed that obesity resulted in enhanced expression of neutrophil chemotaxis genes specifically in CD11c + ATMs. Involvement of the neutrophil chemotaxis proteins, CXCL14 and CXCL16, was confirmed by culturing vAT. In humans, CD11c expression in vAT of obese individuals correlated with vAT expression of neutrophil chemotactic genes and with hepatic expression of neutrophil and macrophage marker genes. ATMs from obese vAT induce hepatic macrophage accumulation during NASH development, possibly by enhancing neutrophil recruitment. © Article author(s) (or their employer(s) unless otherwise stated in the text of the article) 2018. All rights reserved. No commercial use is permitted unless otherwise

  13. Fats, inflammation and insulin resistance: insights to the role of macrophage and T-cell accumulation in adipose tissue.

    PubMed

    Harford, Karen A; Reynolds, Clare M; McGillicuddy, Fiona C; Roche, Helen M

    2011-11-01

    High-fat diet-induced obesity is associated with a chronic state of low-grade inflammation, which pre-disposes to insulin resistance (IR), which can subsequently lead to type 2 diabetes mellitus. Macrophages represent a heterogeneous population of cells that are instrumental in initiating the innate immune response. Recent studies have shown that macrophages are key mediators of obesity-induced IR, with a progressive infiltration of macrophages into obese adipose tissue. These adipose tissue macrophages are referred to as classically activated (M1) macrophages. They release cytokines such as IL-1β, IL-6 and TNFα creating a pro-inflammatory environment that blocks adipocyte insulin action, contributing to the development of IR and type 2 diabetes mellitus. In lean individuals macrophages are in an alternatively activated (M2) state. M2 macrophages are involved in wound healing and immunoregulation. Wound-healing macrophages play a major role in tissue repair and homoeostasis, while immunoregulatory macrophages produce IL-10, an anti-inflammatory cytokine, which may protect against inflammation. The functional role of T-cell accumulation has recently been characterised in adipose tissue. Cytotoxic T-cells are effector T-cells and have been implicated in macrophage differentiation, activation and migration. Infiltration of cytotoxic T-cells into obese adipose tissue is thought to precede macrophage accumulation. T-cell-derived cytokines such as interferon γ promote the recruitment and activation of M1 macrophages augmenting adipose tissue inflammation and IR. Manipulating adipose tissue macrophages/T-cell activity and accumulation in vivo through dietary fat modification may attenuate adipose tissue inflammation, representing a therapeutic target for ameliorating obesity-induced IR.

  14. Gut REG3γ-Associated Lactobacillus Induces Anti-inflammatory Macrophages to Maintain Adipose Tissue Homeostasis

    PubMed Central

    Huang, Yugang; Qi, HouBao; Zhang, Zhiqian; Wang, Enlin; Yun, Huan; Yan, Hui; Su, Xiaomin; Liu, Yingquan; Tang, Zenzen; Gao, Yunhuan; Shang, Wencong; Zhou, Jiang; Wang, Tianze; Che, Yongzhe; Zhang, Yuan; Yang, Rongcun

    2017-01-01

    Gut microbiota may not only affect composition of local immune cells but also affect systemic immune cells. However, it is not completely clear how gut microbiota modulate these immune systems. Here, we found that there exist expanded macrophage pools in huREG3γtgIEC mice. REG3γ-associated Lactobacillus, which is homology to Lactobacillus Taiwanese, could enlarge macrophage pools not only in the small intestinal lamina propria but also in the spleen and adipose tissues. STAT3-mediated signal(s) was a critical factor in the Lactobacillus-mediated anti-inflammatory macrophages. We also offered evidence for critical cellular links among REG3γ-associated Lactobacillus, tissue macrophages, and obesity diseases. Anti-inflammatory macrophages in the lamina propria, which are induced by REG3γ-associated Lactobacillus, may migrate into adipose tissues and are involved in resistance against high-fat diet-mediated obesity. Thus, REG3γ-associated Lactobacillus-induced anti-inflammatory macrophages in gut tissues may play a role in adipose tissue homeostasis. PMID:28928739

  15. Lymphocytes and macrophages in adipose tissue in obesity: markers or makers of subclinical inflammation?

    PubMed

    Cinkajzlová, Anna; Mráz, Miloš; Haluzík, Martin

    2017-05-01

    Obesity is accompanied by the development of chronic low-grade inflammation in adipose tissue. The presence of chronic inflammatory response along with metabolically harmful factors released by adipose tissue into the circulation is associated with several metabolic complications of obesity such as type 2 diabetes mellitus or accelerated atherosclerosis. The present review is focused on macrophages and lymphocytes and their possible role in low-grade inflammation in fat. Both macrophages and lymphocytes respond to obesity-induced adipocyte hypertrophy by their migration into adipose tissue. After activation and differentiation, they contribute to the development of local inflammatory response and modulation of endocrine function of adipose tissue. Despite intensive research, the exact role of lymphocytes and macrophages within adipose tissue is only partially clarified and various data obtained by different approaches bring ambiguous information with respect to their polarization and cytokine production. Compared to immunocompetent cells, the role of adipocytes in the obesity-related adipose tissue inflammation is often underestimated despite their abundant production of factors with immunomodulatory actions such as cytokines or adipokines such as leptin, adiponektin, and others. In summary, conflicting evidence together with only partial correlation of in vitro findings with true in vivo situation due to great heterogeneity and molecular complexity of tissue environment calls for intensive research in this rapidly evolving and important area.

  16. Iron homeostasis: a new job for macrophages in adipose tissue?

    PubMed Central

    Hubler, Merla J.; Peterson, Kristin R.; Hasty, Alyssa H.

    2015-01-01

    Elevated serum ferritin and increased cellular iron concentrations are risk factors for diabetes; however, the etiology of this association is unclear. Metabolic tissues such as pancreas, liver, and adipose tissue (AT), as well as the immune cells resident in these tissues, may be involved. Recent studies demonstrate that the polarization status of macrophages has important relevance to their iron handling capabilities. Furthermore, a subset of macrophages in AT have elevated iron concentrations and a gene expression profile indicative of iron handling, a capacity diminished in obesity. Because iron overload in adipocytes increases systemic insulin resistance, iron handling by AT macrophages may have relevance not only to adipocyte iron stores but also to local and systemic insulin sensitivity. PMID:25600948

  17. Alternatively Activated Macrophages Drive Browning of White Adipose Tissue in Burns.

    PubMed

    Abdullahi, Abdikarim; Auger, Christopher; Stanojcic, Mile; Patsouris, David; Parousis, Alexandra; Epelman, Slava; Jeschke, Marc G

    2017-08-16

    The aim of this study was to uncover the mediators and mechanistic events that facilitate the browning of white adipose tissue (WAT) in response to burns. In hypermetabolic patients (eg, burns, cancer), the browning of WAT has presented substantial clinical challenges related to cachexia, atherosclerosis, and poor clinical outcomes. Browning of the adipose tissue has recently been found to induce and sustain hypermetabolism. Although browning appears central in trauma-, burn-, or cancer-induced hypermetabolic catabolism, the mediators are essentially unknown. WAT and blood samples were collected from patients admitted to the Ross Tilley Burn Centre at Sunnybrook Hospital. Wild type, CCR2 KO, and interleukin (IL)-6 KO male mice were purchased from Jax laboratories and subjected to a 30% total body surface area burn injury. WAT and serum collected were analyzed for browning markers, macrophages, and metabolic state via histology, gene expression, and mitochondrial respiration. In the present study, we show that burn-induced browning is associated with an increased macrophage infiltration, with a greater type 2 macrophage profile in the fat of burn patients. Similar to our clinical findings in burn patients, both an increase in macrophage recruitment and a type 2 macrophage profile were also observed in post burn mice. Genetic loss of the chemokine CCR2 responsible for macrophage migration to the adipose impairs burn-induced browning. Mechanistically, we show that macrophages recruited to burn-stressed subcutaneous WAT (sWAT) undergo alternative activation to induce tyrosine hydroxylase expression and catecholamine production mediated by IL-6, factors required for browning of sWAT. Together, our findings uncover macrophages as the key instigators and missing link in trauma-induced browning.

  18. Hematopoietic-to-mesenchymal transition of adipose tissue macrophages is regulated by integrin β1 and fabricated fibrin matrices

    PubMed Central

    Majka, Susan M.; Kohrt, Wendy M.; Miller, Heidi L.; Sullivan, Timothy M.; Klemm, Dwight J.

    2017-01-01

    ABSTRACT Some bona fide adult adipocytes arise de novo from a bone marrow-derived myeloid lineage. These studies further demonstrate that adipose tissue stroma contains a resident population of myeloid cells capable of adipocyte and multilineage mesenchymal differentiation. These resident myeloid cells lack hematopoietic markers and express mesenchymal and progenitor cell markers. Because bone marrow mesenchymal progenitor cells have not been shown to enter the circulation, we hypothesized that myeloid cells acquire mesenchymal differentiation capacity in adipose tissue. We fabricated a 3-dimensional fibrin matrix culture system to define the adipose differentiation potential of adipose tissue-resident myeloid subpopulations, including macrophages, granulocytes and dendritic cells. Our data show that multilineage mesenchymal potential was limited to adipose tissue macrophages, characterized by the acquisition of adipocyte, osteoblast, chondrocyte and skeletal muscle myocyte phenotypes. Fibrin hydrogel matrices stimulated macrophage loss of hematopoietic cell lineage determinants and the expression of mesenchymal and progenitor cell markers, including integrin β1. Ablation of integrin β1 in macrophages inhibited adipocyte specification. Therefore, some bona fide adipocytes are specifically derived from adipose tissue-resident macrophages via an integrin β1-dependent hematopoietic-to-mesenchymal transition, whereby they become capable of multipotent mesenchymal differentiation. The requirement for integrin β1 highlights this molecule as a potential target for controlling the production of marrow-derived adipocytes and their contribution to adipose tissue development and function. PMID:28441086

  19. Alternatively activated macrophages do not synthesize catecholamines or contribute to adipose tissue adaptive thermogenesis

    PubMed Central

    Fischer, Katrin; Ruiz, Henry H.; Jhun, Kevin; Finan, Brian; Oberlin, Douglas J.; van der Heide, Verena; Kalinovich, Anastasia V.; Petrovic, Natasa; Wolf, Yochai; Clemmensen, Christoffer; Shin, Andrew C.; Divanovic, Senad; Brombacher, Frank; Glasmacher, Elke; Keipert, Susanne; Jastroch, Martin; Nagler, Joachim; Schramm, Karl-Werner; Medrikova, Dasa; Collden, Gustav; Woods, Stephen C.; Herzig, Stephan; Homann, Dirk; Jung, Steffen; Nedergaard, Jan; Cannon, Barbara; Tschöp, Matthias H.

    2017-01-01

    Adaptive thermogenesis is the process of heat generation in response to cold stimulation and is under the control of the sympathetic nervous system whose chief effector is the catecholamine norepinephrine (NE). NE enhances thermogenesis through beta3 adrenergic receptors to activate brown adipose tissue and by “browning” white adipose tissue. Recent studies reported that the alternative activation of macrophages in response to IL-4 stimulation induces the expression of tyrosine hydroxylase (TH), a key enzyme in the catecholamine synthesis pathway, and to provide an alternative source of locally produced catecholamines during the thermogenic process. We here report that the deletion of Th in hematopoetic cells of adult mice neither alters energy expenditure upon cold exposure nor reduces browning in inguinal adipose tissue. Bone marrow-derived macrophages did not release NE in response to stimulation with Interleukin-4 (IL-4), and conditioned media from IL-4 stimulated macrophages failed to induce expression of thermogenic genes, such as the one for uncoupling protein 1 (Ucp1) in adipocytes cultured with the conditioned media. Further, chronic IL-4 treatment failed to increase energy expenditure in WT, Ucp1-/- and Il4ra-/- mice. Consistent with these findings, adipose tissue-resident macrophages did not express TH. Thus, we conclude that alternatively activated macrophages do not synthesize relevant amounts of catecholamines and hence are not likely to play a direct role in adipocyte metabolism or adaptive thermogenesis. PMID:28414329

  20. Alternatively activated macrophages do not synthesize catecholamines or contribute to adipose tissue adaptive thermogenesis.

    PubMed

    Fischer, Katrin; Ruiz, Henry H; Jhun, Kevin; Finan, Brian; Oberlin, Douglas J; van der Heide, Verena; Kalinovich, Anastasia V; Petrovic, Natasa; Wolf, Yochai; Clemmensen, Christoffer; Shin, Andrew C; Divanovic, Senad; Brombacher, Frank; Glasmacher, Elke; Keipert, Susanne; Jastroch, Martin; Nagler, Joachim; Schramm, Karl-Werner; Medrikova, Dasa; Collden, Gustav; Woods, Stephen C; Herzig, Stephan; Homann, Dirk; Jung, Steffen; Nedergaard, Jan; Cannon, Barbara; Tschöp, Matthias H; Müller, Timo D; Buettner, Christoph

    2017-05-01

    Adaptive thermogenesis is the process of heat generation in response to cold stimulation. It is under the control of the sympathetic nervous system, whose chief effector is the catecholamine norepinephrine (NE). NE enhances thermogenesis through β3-adrenergic receptors to activate brown adipose tissue and by 'browning' white adipose tissue. Recent studies have reported that alternative activation of macrophages in response to interleukin (IL)-4 stimulation induces the expression of tyrosine hydroxylase (TH), a key enzyme in the catecholamine synthesis pathway, and that this activation provides an alternative source of locally produced catecholamines during the thermogenic process. Here we report that the deletion of Th in hematopoietic cells of adult mice neither alters energy expenditure upon cold exposure nor reduces browning in inguinal adipose tissue. Bone marrow-derived macrophages did not release NE in response to stimulation with IL-4, and conditioned media from IL-4-stimulated macrophages failed to induce expression of thermogenic genes, such as uncoupling protein 1 (Ucp1), in adipocytes cultured with the conditioned media. Furthermore, chronic treatment with IL-4 failed to increase energy expenditure in wild-type, Ucp1 -/- and interleukin-4 receptor-α double-negative (Il4ra -/- ) mice. In agreement with these findings, adipose-tissue-resident macrophages did not express TH. Thus, we conclude that alternatively activated macrophages do not synthesize relevant amounts of catecholamines, and hence, are not likely to have a direct role in adipocyte metabolism or adaptive thermogenesis.

  1. Inactivation of adipose angiotensinogen reduces adipose tissue macrophages and increases metabolic activity.

    PubMed

    LeMieux, Monique J; Ramalingam, Latha; Mynatt, Randall L; Kalupahana, Nishan S; Kim, Jung Han; Moustaïd-Moussa, Naïma

    2016-02-01

    The adipose renin-angiotensin system (RAS) has been linked to obesity-induced inflammation, though mechanisms are not completely understood. In this study, adipose-specific angiotensinogen knockout mice (Agt-KO) were generated to determine whether Agt inactivation reduces inflammation and alters the metabolic profile of the Agt-KO mice compared to wild-type (WT) littermates. Adipose tissue-specific Agt-KO mice were created using the Cre-LoxP system with both Agt-KO and WT littermates fed either a low-fat or high-fat diet to assess metabolic changes. White adipose tissue was used for gene/protein expression analyses and WAT stromal vascular cells for metabolic extracellular flux assays. No significant differences were observed in body weight or fat mass between both genotypes on either diet. However, improved glucose clearance was observed in Agt-KO compared to WT littermates, consistent with higher expression of genes involved in insulin signaling, glucose transport, and fatty acid metabolism. Furthermore, Agt inactivation reduced total macrophage infiltration in Agt-KO mice fed both diets. Lastly, stroma vascular cells from Agt-KO mice revealed higher metabolic activity compared to WT mice. These findings indicate that adipose-specific Agt inactivation leads to reduced adipose inflammation and increased glucose tolerance mediated in part via increased metabolic activity of adipose cells. © 2015 The Obesity Society.

  2. FNDC5 attenuates adipose tissue inflammation and insulin resistance via AMPK-mediated macrophage polarization in obesity.

    PubMed

    Xiong, Xiao-Qing; Geng, Zhi; Zhou, Bing; Zhang, Feng; Han, Ying; Zhou, Ye-Bo; Wang, Jue-Jin; Gao, Xing-Ya; Chen, Qi; Li, Yue-Hua; Kang, Yu-Ming; Zhu, Guo-Qing

    2018-06-01

    Obesity-induced chronic inflammation is critical in the pathogenesis of insulin resistance, and the recruitment and proinflammatory activation of adipose tissue macrophages (ATMs) is important for the development of this process. Here, we examined the effects of fibronectin type III domain-containing 5 (FNDC5) on inflammation and insulin resistance in high-fat diet-induced obese mice. Male wild-type (WT) and FNDC5 -/- mice were fed with standard chow (Ctrl) or high fat diet (HFD) for 20 weeks to induce obesity and insulin resistance. Firstly, effects of FNDC5 gene deletion on obesity, insulin resistance, macrophage accumulation and polarization and adipose tissue inflammation were determined in mice. Secondly, the macrophage polarity shift was further examined with flow cytometry in isolated stromal vascular fraction (SVF). Thirdly, the effects of exogenous FNDC5 on lipopolysaccharide (LPS)-induced macrophage polarization, inflammation and the underlying signaling mechanism were investigated in RAW264.7 macrophages and primary mouse peritoneal cavity macrophages (PMs). Finally, the therapeutic effects of FNDC5 overexpression were examined in HFD-induced obese WT and FNDC5 -/- mice. FNDC5 gene deletion aggravated obesity, insulin resistance, fat accumulation and inflammation accompanied with enhanced AMPK inhibition, macrophages recruitment and M1 polarization in mice fed with HFD. Exogenous FNDC5 inhibited LPS-induced M1 macrophage polarization and inflammatory cytokine production via AMPK phosphorylation in both RAW264.7 macrophages and PMs. FNDC5 overexpression attenuated insulin resistance, AMPK inhibition, M1 macrophage polarization and inflammatory cytokine production in adipose tissue of obese WT and FNDC5 -/- mice. FNDC5 attenuates adipose tissue inflammation and insulin resistance via AMPK-mediated macrophage polarization in HFD-induced obesity. FNDC5 plays several beneficial roles in obesity and may be used as a therapeutic regimen for preventing

  3. Angiogenic Deficiency and Adipose Tissue Dysfunction Are Associated with Macrophage Malfunction in SIRT1−/− Mice

    PubMed Central

    Xu, Fen; Burk, David; Gao, Zhanguo; Yin, Jun; Zhang, Xia

    2012-01-01

    The histone deacetylase sirtuin 1 (SIRT1) inhibits adipocyte differentiation and suppresses inflammation by targeting the transcription factors peroxisome proliferator-activated receptor γ and nuclear factor κB. Although this suggests that adiposity and inflammation should be enhanced when SIRT1 activity is inactivated in the body, this hypothesis has not been tested in SIRT1 null (SIRT1−/−) mice. In this study, we addressed this issue by investigating the adipose tissue in SIRT1−/− mice. Compared with their wild-type littermates, SIRT1 null mice exhibited a significant reduction in body weight. In adipose tissue, the average size of adipocytes was smaller, the content of extracellular matrix was lower, adiponectin and leptin were expressed at 60% of normal level, and adipocyte differentiation was reduced. All of these changes were observed with a 50% reduction in capillary density that was determined using a three-dimensional imaging technique. Except for vascular endothelial growth factor, the expression of several angiogenic factors (Pdgf, Hgf, endothelin, apelin, and Tgf-β) was reduced by about 50%. Macrophage infiltration and inflammatory cytokine expression were 70% less in the adipose tissue of null mice and macrophage differentiation was significantly inhibited in SIRT1−/− mouse embryonic fibroblasts in vitro. In wild-type mice, macrophage deletion led to a reduction in vascular density. These data suggest that SIRT1 controls adipose tissue function through regulation of angiogenesis, whose deficiency is associated with macrophage malfunction in SIRT1−/− mice. The study supports the concept that inflammation regulates angiogenesis in the adipose tissue. PMID:22315447

  4. CTLA-4Ig immunotherapy of obesity-induced insulin resistance by manipulation of macrophage polarization in adipose tissues

    DOE Office of Scientific and Technical Information (OSTI.GOV)

    Fujii, Masakazu, E-mail: masakazu731079@yahoo.co.jp; Inoguchi, Toyoshi, E-mail: toyoshi@intmed3.med.kyushu-u.ac.jp; Innovation Center for Medical Redox Navigation, Kyushu University, 3-1-1 Maidashi, Higashi-ku, Fukuoka 812-8582

    Highlights: •CTLA-4Ig completely alleviates HFD-induced insulin resistance. •CTLA-4Ig reduces epididymal and subcutaneous fat tissue weight and adipocyte size. •CTLA-4Ig alters ATM polarization from inflammatory M1 to anti-inflammatory M2. •CTLA-4Ig may lead to a novel anti-obesity/inflammation/insulin resistance agent. •We identified the mechanism of the novel favorable effects of CTLA-4lg. -- Abstract: It has been established that obesity alters the metabolic and endocrine function of adipose tissue and, together with accumulation of adipose tissue macrophages, contributes to insulin resistance. Although numerous studies have reported that shifting the polarization of macrophages from M1 to M2 can alleviate adipose tissue inflammation, manipulation of macrophagemore » polarization has not been considered as a specific therapy. Here, we determined whether cytotoxic T-lymphocyte-associated antigen-4IgG1 (CTLA-4Ig) can ameliorate insulin resistance by induction of macrophages from proinflammatory M1 to anti-inflammatory M2 polarization in the adipose tissues of high fat diet-induced insulin-resistant mice. CTLA4-Ig treatment prevented insulin resistance by changing gene expression to M2 polarization, which increased the levels of arginase 1. Furthermore, flow cytometric analysis confirmed the alteration of polarization from CD11c (M1)- to CD206 (M2)-positive cells. Concomitantly, CTLA-4Ig treatment resulted in weight reductions of epididymal and subcutaneous adipose tissues, which may be closely related to overexpression of apoptosis inhibitors in macrophages. Moreover, proinflammatory cytokine and chemokine levels decreased significantly. In contrast, CCAAT enhancer binding protein α, peroxisome proliferator-activated receptor γ, and adiponectin expression increased significantly in subcutaneous adipose tissue. This novel mechanism of CTLA-4lg immunotherapy may lead to an ideal anti-obesity/inflammation/insulin resistance agent.« less

  5. Adipose tissue macrophages in non-rodent mammals: a comparative study.

    PubMed

    Ampem, Grace; Azegrouz, Hind; Bacsadi, Árpád; Balogh, Lajos; Schmidt, Susanne; Thuróczy, Julianna; Röszer, Tamás

    2016-02-01

    The stromal vascular fraction (SVF) of adipose tissue in rodents and primates contains mesenchymal stem cells and immune cells. SVF cells have complex metabolic, immune and endocrine functions with biomedical impact. However, in other mammals, the amount of data on SVF stem cells is negligible and whether the SVF hosts immune cells is unknown. In this study, we show that the SVF is rich in immune cells, with a dominance of adipose tissue macrophages (ATMs) in cattle (Bos primigenius taurus), domestic goat (Capra aegagrus hircus), domestic sheep (Ovis aries), domestic cat (Felis catus) and domestic dog (Canis familiaris). ATMs of these species are granulated lysosome-rich cells with lamellipodial protrusions and express the lysosome markers acid phosphatase 5 (ACP-5) and Mac-3/Lamp-2. Using ACP-5 and Mac-3/Lamp-2 as markers, we additionally detected ATMs in other species, such as the domestic horse (Equus ferus caballus), wild boar (Sus scrofa) and red fox (Vulpes vulpes). Feline and canine ATMs also express the murine macrophage marker F4/80 antigen. In the lean condition, the alternative macrophage activation marker CD206 is expressed by feline and canine ATMs and arginase-1 by feline ATMs. Obesity is associated with interleukin-6 and interferon gamma expression and with overt tyrosine nitration in both feline and canine ATMs. This resembles the obesity-induced phenotype switch of murine and human ATMs. Thus, we show, for the first time, that the presence of ATMs is a general trait of mammals. The interaction between the adipose cells and SVF immune cells might be evolutionarily conserved among mammals.

  6. Ghrelin receptor regulates adipose tissue inflammation in aging.

    PubMed

    Lin, Ligen; Lee, Jong Han; Buras, Eric D; Yu, Kaijiang; Wang, Ruitao; Smith, C Wayne; Wu, Huaizhu; Sheikh-Hamad, David; Sun, Yuxiang

    2016-01-01

    Aging is commonly associated with low-grade adipose inflammation, which is closely linked to insulin resistance. Ghrelin is the only circulating orexigenic hormone which is known to increase obesity and insulin resistance. We previously reported that the expression of the ghrelin receptor, growth hormone secretagogue receptor (GHS-R), increases in adipose tissues during aging, and old Ghsr(-/-) mice exhibit a lean and insulin-sensitive phenotype. Macrophages are major mediators of adipose tissue inflammation, which consist of pro-inflammatory M1 and anti-inflammatory M2 subtypes. Here, we show that in aged mice, GHS-R ablation promotes macrophage phenotypical shift toward anti-inflammatory M2. Old Ghsrp(-/-) mice have reduced macrophage infiltration, M1/M2 ratio, and pro-inflammatory cytokine expression in white and brown adipose tissues. We also found that peritoneal macrophages of old Ghsrp(-/-) mice produce higher norepinephrine, which is in line with increased alternatively-activated M2 macrophages. Our data further reveal that GHS-R has cell-autonomous effects in macrophages, and GHS-R antagonist suppresses lipopolysaccharide (LPS)-induced inflammatory responses in macrophages. Collectively, our studies demonstrate that ghrelin signaling has an important role in macrophage polarization and adipose tissue inflammation during aging. GHS-R antagonists may serve as a novel and effective therapeutic option for age-associated adipose tissue inflammation and insulin resistance.

  7. Ghrelin receptor regulates adipose tissue inflammation in aging

    PubMed Central

    Buras, Eric D.; Yu, Kaijiang; Wang, Ruitao; Smith, C. Wayne; Wu, Huaizhu; Sheikh-Hamad, David; Sun, Yuxiang

    2016-01-01

    Aging is commonly associated with low-grade adipose inflammation, which is closely linked to insulin resistance. Ghrelin is the only circulating orexigenic hormone which is known to increase obesity and insulin resistance. We previously reported that the expression of the ghrelin receptor, growth hormone secretagogue receptor (GHS-R), increases in adipose tissues during aging, and old Ghsr−/− mice exhibit a lean and insulin-sensitive phenotype. Macrophages are major mediators of adipose tissue inflammation, which consist of pro-inflammatory M1 and anti-inflammatory M2 subtypes. Here, we show that in aged mice, GHS-R ablation promotes macrophage phenotypical shift toward anti-inflammatory M2. Old Ghsr−/− mice have reduced macrophage infiltration, M1/M2 ratio, and pro-inflammatory cytokine expression in white and brown adipose tissues. We also found that peritoneal macrophages of old Ghsr−/− mice produce higher norepinephrine, which is in line with increased alternatively-activated M2 macrophages. Our data further reveal that GHS-R has cell-autonomous effects in macrophages, and GHS-R antagonist suppresses lipopolysaccharide (LPS)-induced inflammatory responses in macrophages. Collectively, our studies demonstrate that ghrelin signaling has an important role in macrophage polarization and adipose tissue inflammation during aging. GHS-R antagonists may serve as a novel and effective therapeutic option for age-associated adipose tissue inflammation and insulin resistance. PMID:26837433

  8. Start of insulin therapy in patients with type 2 diabetes mellitus promotes the influx of macrophages into subcutaneous adipose tissue.

    PubMed

    Jansen, H J; Stienstra, R; van Diepen, J A; Hijmans, A; van der Laak, J A; Vervoort, G M M; Tack, C J

    2013-12-01

    Insulin therapy in patients with type 2 diabetes mellitus is accompanied by weight gain characterised by an increase in abdominal fat mass. The expansion of adipose tissue mass is generally paralleled by profound morphological and inflammatory changes. We hypothesised that the insulin-associated increase in fat mass would also result in changes in the morphology of human subcutaneous adipose tissue and in increased inflammation, especially when weight gain was excessive. We investigated the effects of weight gain on adipocyte size, macrophage influx, and mRNA expression and protein levels of key inflammatory markers within the adipose tissue in patients with type 2 diabetes mellitus before and 6 months after starting insulin therapy. As expected, insulin therapy significantly increased body weight. At the level of the subcutaneous adipose tissue, insulin treatment led to an influx of macrophages. When comparing patients gaining no or little weight with patients gaining >4% body weight after 6 months of insulin therapy, both subgroups displayed an increase in macrophage influx. However, individuals who had gained weight had higher protein levels of monocyte chemoattractant protein-1, TNF-α and IL-1β after 6 months of insulin therapy compared with those who had not gained weight. We conclude that insulin therapy in patients with type 2 diabetes mellitus improved glycaemic control but also induced body weight gain and an influx of macrophages into the subcutaneous adipose tissue. In patients characterised by a pronounced insulin-associated weight gain, the influx of macrophages into the adipose tissue was accompanied by a more pronounced inflammatory status. ClinicalTrials.gov: NCT00781495. The study was funded by European Foundation for the Study of Diabetes and the Dutch Diabetes Research Foundation.

  9. Dietary cholesterol worsens adipose tissue macrophage accumulation and atherosclerosis in obese LDL receptor-deficient mice

    PubMed Central

    Subramanian, Savitha; Han, Chang Yeop; Chiba, Tsuyoshi; McMillen, Timothy S.; Wang, Shari A.; Haw, Antonio; Kirk, Elizabeth A.; O’Brien, Kevin D.; Chait, Alan

    2009-01-01

    Objective Chronic systemic inflammation accompanies obesity and predicts development of cardiovascular disease. Dietary cholesterol has been shown to increase inflammation and atherosclerosis in LDL receptor-deficient (LDLR-/-) mice. This study was undertaken to determine whether dietary cholesterol and obesity have additive effects on inflammation and atherosclerosis. Methods and Results LDLR-/- mice were fed chow, high fat, high carbohydrate (diabetogenic) diet without (DD) or with added cholesterol (DDC) for 24 weeks. Effects on adipose tissue, inflammatory markers and atherosclerosis were studied. Despite similar weight gain between DD and DDC groups, addition of dietary cholesterol increased insulin resistance relative to DD. Adipocyte hypertrophy, macrophage accumulation and local inflammation were observed in intra-abdominal adipose tissue in DD and DDC, but were significantly higher in the DDC group. Circulating levels of the inflammatory protein serum amyloid A (SAA) were 4.4-fold higher in DD animals and 15-fold higher in DDC animals than controls, suggesting chronic systemic inflammation. Hepatic SAA mRNA levels were similarly elevated. Atherosclerosis was increased in the DD-fed animals and further increased in the DDC group. Conclusions Obesity-induced macrophage accumulation in adipose tissue is exacerbated by dietary cholesterol. These local inflammatory changes in adipose tissue are associated with insulin resistance, systemic inflammation and increased atherosclerosis in this mouse model. PMID:18239153

  10. Silencing CCR2 in Macrophages Alleviates Adipose Tissue Inflammation and the Associated Metabolic Syndrome in Dietary Obese Mice.

    PubMed

    Kim, Jongkil; Chung, Kunho; Choi, Changseon; Beloor, Jagadish; Ullah, Irfan; Kim, Nahyeon; Lee, Kuen Yong; Lee, Sang-Kyung; Kumar, Priti

    2016-01-26

    Adipose tissue macrophage (ATM)-mediated inflammation is a key feature contributing to the adverse metabolic outcomes of dietary obesity. Recruitment of macrophages to obese adipose tissues (AT) can occur through the engagement of CCR2, the receptor for MCP-1 (monocyte chemoattractant protein-1), which is expressed on peripheral monocytes/macrophages. Here, we show that i.p. administration of a rabies virus glycoprotein-derived acetylcholine receptor-binding peptide effectively delivers complexed siRNA into peritoneal macrophages and ATMs in a mouse model of high-fat diet-induced obesity. Treatment with siRNA against CCR2 inhibited macrophage infiltration and accumulation in AT and, therefore, proinflammatory cytokines produced by macrophages. Consequently, the treatment significantly improved glucose tolerance and insulin sensitivity profiles, and also alleviated the associated symptoms of hepatic steatosis and reduced hepatic triglyceride production. These results demonstrate that disruption of macrophage chemotaxis to the AT through cell-targeted gene knockdown strategies can provide a therapeutic intervention for obesity-related metabolic diseases. The study also highlights a siRNA delivery approach for targeting specific monocyte subsets that contribute to obesity-associated inflammation without affecting the function of other tissue-resident macrophages that are essential for host homeostasis and survival.

  11. Regulatory iNKT cells lack PLZF expression and control Treg cell and macrophage homeostasis in adipose tissue

    PubMed Central

    Lynch, Lydia; Michelet, Xavier; Zhang, Sai; Brennan, Patrick J.; Moseman, Ashley; Lester, Chantel; Besra, Gurdyal; Vomhof-Dekrey, Emilie E.; Tighe, Mike; Koay, Hui-Fern; Godfrey, Dale I.; Leadbetter, Elizabeth A.; Sant’Angelo, Derek B.; von Andrian, Ulrich; Brenner, Michael B.

    2015-01-01

    iNKT cells are CD1d-restricted lipid-sensing innate T cells that express the transcription factor PLZF. iNKT cells accumulate in adipose tissue, where they are anti-inflammatory, but the factors that contribute to their anti-inflammatory nature, and their targets in adipose tissue are unknown. Here we report that adipose tissue iNKT cells have a unique transcriptional program and produce interleukin 2 (IL-2) and IL-10. Unlike other iNKT cells, they lack PLZF, but express the transcription factor E4BP4, which controls their IL-10 production. Adipose iNKT cells are a tissue resident population that induces an anti-inflammatory phenotype in macrophages and, through production of IL-2, controls the number, proliferation and suppressor function of adipose regulatory T (Treg) cells. Thus, adipose tissue iNKT cells are unique regulators of immune homeostasis in this tissue. PMID:25436972

  12. Isoliquiritigenin Attenuates Adipose Tissue Inflammation in vitro and Adipose Tissue Fibrosis through Inhibition of Innate Immune Responses in Mice.

    PubMed

    Watanabe, Yasuharu; Nagai, Yoshinori; Honda, Hiroe; Okamoto, Naoki; Yamamoto, Seiji; Hamashima, Takeru; Ishii, Yoko; Tanaka, Miyako; Suganami, Takayoshi; Sasahara, Masakiyo; Miyake, Kensuke; Takatsu, Kiyoshi

    2016-03-15

    Isoliquiritigenin (ILG) is a flavonoid derived from Glycyrrhiza uralensis and potently suppresses NLRP3 inflammasome activation resulting in the improvement of diet-induced adipose tissue inflammation. However, whether ILG affects other pathways besides the inflammasome in adipose tissue inflammation is unknown. We here show that ILG suppresses adipose tissue inflammation by affecting the paracrine loop containing saturated fatty acids and TNF-α by using a co-culture composed of adipocytes and macrophages. ILG suppressed inflammatory changes induced by the co-culture through inhibition of NF-κB activation. This effect was independent of either inhibition of inflammasome activation or activation of peroxisome proliferator-activated receptor-γ. Moreover, ILG suppressed TNF-α-induced activation of adipocytes, coincident with inhibition of IκBα phosphorylation. Additionally, TNF-α-mediated inhibition of Akt phosphorylation under insulin signaling was alleviated by ILG in adipocytes. ILG suppressed palmitic acid-induced activation of macrophages, with decreasing the level of phosphorylated Jnk expression. Intriguingly, ILG improved high fat diet-induced fibrosis in adipose tissue in vivo. Finally, ILG inhibited TLR4- or Mincle-stimulated expression of fibrosis-related genes in stromal vascular fraction from obese adipose tissue and macrophages in vitro. Thus, ILG can suppress adipose tissue inflammation by both inflammasome-dependent and -independent manners and attenuate adipose tissue fibrosis by targeting innate immune sensors.

  13. Blocking CXCR7-mediated adipose tissue macrophages chemotaxis attenuates insulin resistance and inflammation in obesity.

    PubMed

    Peng, Hongxia; Zhang, Hu; Zhu, Honglei

    2016-10-28

    Adipose tissue macrophages (ATMs) have been considered to have a pivotal role in the chronic inflammation development during obesity. Although chemokine-chemokine receptor interaction has been studied in ATMs infiltration, most chemokine receptors remain incompletely understood and little is known about their mechanism of actions that lead to ATMs chemotaxis and pathogenesis of insulin resistance during obesity. In this study, we reported that CXCR7 expression is upregulated in adipose tissue, and specifically in ATMs during obesity. In addition, CXCL11 or CXCL12-induced ATMs chemotaxis is mediated by CXCR7 in obesity but not leanness, whereas CXCR3 and CXCR4 are not involved. Additional mechanism study shows that NF-κB activation is essential in ATMs chemotaxis, and manipulates chemotaxis of ATMs via CXCR7 expression regulation in obesity. Most importantly, CXCR7 neutralizing therapy dose dependently leads to less infiltration of macrophages into adipose tissue and thus reduces inflammation and improves insulin sensitivity in obesity. In conclusion, these findings demonstrated that blocking CXCR7-mediated ATMs chemotaxis ameliorates insulin resistance and inflammation in obesity. Copyright © 2016 Elsevier Inc. All rights reserved.

  14. Omega-3 fatty acids promote fatty acid utilization and production of pro-resolving lipid mediators in alternatively activated adipose tissue macrophages.

    PubMed

    Rombaldova, Martina; Janovska, Petra; Kopecky, Jan; Kuda, Ondrej

    2017-08-26

    It is becoming increasingly apparent that mutual interactions between adipocytes and immune cells are key to the integrated control of adipose tissue inflammation and lipid metabolism in obesity, but little is known about the non-inflammatory functions of adipose tissue macrophages (ATMs) and how they might be impacted by neighboring adipocytes. In the current study we used metabolipidomic analysis to examine the adaptations to lipid overload of M1 or M2 polarized macrophages co-incubated with adipocytes and explored potential benefits of omega-3 polyunsaturated fatty acids (PUFA). Macrophages adjust their metabolism to process excess lipids and M2 macrophages in turn modulate lipolysis and fatty acids (FA) re-esterification of adipocytes. While M1 macrophages tend to store surplus FA as triacylglycerols and cholesteryl esters in lipid droplets, M2 macrophages channel FA toward re-esterification and β-oxidation. Dietary omega-3 PUFA enhance β-oxidation in both M1 and M2. Our data document that ATMs contribute to lipid trafficking in adipose tissue and that omega-3 PUFA could modulate FA metabolism of ATMs. Copyright © 2017 Elsevier Inc. All rights reserved.

  15. Rice bran prevents high-fat diet-induced inflammation and macrophage content in adipose tissue.

    PubMed

    Justo, Maria Luisa; Claro, Carmen; Zeyda, Maximilian; Stulnig, Thomas M; Herrera, María Dolores; Rodríguez-Rodríguez, Rosalía

    2016-09-01

    The inflammatory process associated with obesity mainly arises from white adipose tissue (WAT) alterations. In the last few years, nutritional-based strategies have been positioned as promising alternatives to pharmacological approaches against these pathologies. Our aim was to determine the potential of a rice bran enzymatic extract (RBEE)-supplemented diet in the prevention of metabolic, biochemical and functional adipose tissue and macrophage changes associated with a diet-induced obesity (DIO) in mice. C57BL/6J mice were fed high-fat diet (HF), 1 and 5 % RBEE-supplemented high-fat diet (HF1 % and HF5 %, respectively) and standard diet as control. Serum cardiometabolic parameters, adipocytes size and mRNA expression of pro-inflammatory biomarkers and macrophage polarization-related genes from WAT and liver were evaluated. RBEE administration significantly decreased insulin resistance in obese mice. Serum triglycerides, total cholesterol, glucose, insulin, adiponectin and nitrites from treated mice were partially restored, mainly by 1 % RBEE-enriched diet. The incremented adipocytes size observed in HF group was reduced by RBEE treatment, being 1 % more effective than 5 % RBEE. Pro-inflammatory biomarkers in WAT such as IL-6 and IL-1β were significantly decreased in RBEE-treated mice. Adiponectin, PPARγ, TNF-α, Emr1 or M1/M2 levels were significantly restored in WAT from HF1 % compared to HF mice. RBEE-supplemented diet attenuated insulin resistance, dyslipidemia and morphological and functional alterations of adipose tissue in DIO mice. These benefits were accompanied by a modulating effect in adipocytes secretion and some biomarkers associated with macrophage polarization. Therefore, RBEE may be considered an alternative nutritional complement over metabolic syndrome and its complications.

  16. Obesity alters adipose tissue macrophage iron content and tissue iron distribution.

    PubMed

    Orr, Jeb S; Kennedy, Arion; Anderson-Baucum, Emily K; Webb, Corey D; Fordahl, Steve C; Erikson, Keith M; Zhang, Yaofang; Etzerodt, Anders; Moestrup, Søren K; Hasty, Alyssa H

    2014-02-01

    Adipose tissue (AT) expansion is accompanied by the infiltration and accumulation of AT macrophages (ATMs), as well as a shift in ATM polarization. Several studies have implicated recruited M1 ATMs in the metabolic consequences of obesity; however, little is known regarding the role of alternatively activated resident M2 ATMs in AT homeostasis or how their function is altered in obesity. Herein, we report the discovery of a population of alternatively activated ATMs with elevated cellular iron content and an iron-recycling gene expression profile. These iron-rich ATMs are referred to as MFe(hi), and the remaining ATMs are referred to as MFe(lo). In lean mice, ~25% of the ATMs are MFe(hi); this percentage decreases in obesity owing to the recruitment of MFe(lo) macrophages. Similar to MFe(lo) cells, MFe(hi) ATMs undergo an inflammatory shift in obesity. In vivo, obesity reduces the iron content of MFe(hi) ATMs and the gene expression of iron importers as well as the iron exporter, ferroportin, suggesting an impaired ability to handle iron. In vitro, exposure of primary peritoneal macrophages to saturated fatty acids also alters iron metabolism gene expression. Finally, the impaired MFe(hi) iron handling coincides with adipocyte iron overload in obese mice. In conclusion, in obesity, iron distribution is altered both at the cellular and tissue levels, with AT playing a predominant role in this change. An increased availability of fatty acids during obesity may contribute to the observed changes in MFe(hi) ATM phenotype and their reduced capacity to handle iron.

  17. MFehi adipose tissue macrophages compensate for tissue iron pertubations in mice.

    PubMed

    Hubler, Merla J; Erikson, Keith M; Kennedy, Arion J; Hasty, Alyssa H

    2018-05-16

    Resident adipose tissue macrophages (ATMs) play multiple roles to maintain tissue homeostasis, such as removing excess FFAs and regulation of extracellular matrix. The phagocytic nature and oxidative resiliency of macrophages not only allows them to function as innate immune cells but also to respond to specific tissue needs, such as iron homeostasis. MFe hi ATMs are a subtype of resident ATMs that we recently identified to have twice the intracellular iron content as other ATMs and elevated expression of iron handling genes. While studies have demonstrated iron homeostasis is important for adipocyte health, little is known about how MFe hi ATMs may respond to and influence AT iron availability. Two methodologies were used to address this question - dietary iron supplementation and intraperitoneal iron injection. Upon exposure to high dietary iron, MFe hi ATMs accumulated excess iron, while the iron content of MFe lo ATMs and adipocytes remained unchanged. In this model of chronic iron excess, MFe hi ATMs exhibited increased expression of genes involved in iron storage. In the injection model, MFe hi ATMs incorporated high levels of iron and adipocytes were spared iron overload. This acute model of iron overload was associated with increased numbers of MFe hi ATMs; 17% could be attributed to monocyte recruitment and 83% to MFe lo ATM incorporation into the MFe hi pool. The MFe hi ATM population maintained its low inflammatory profile and iron cycling expression profile. These studies expand the field's understanding of ATMs and confirm that they can respond as a tissue iron sink in models of iron overload.

  18. A macrophage NBR1-MEKK3 complex triggers JNK-mediated adipose-tissue inflammation in obesity

    PubMed Central

    Hernandez, Eloy D.; Lee, Sang Jun; Kim, Ji Young; Duran, Angeles; Linares, Juan F.; Yajima, Tomoko; Müller, Timo D.; Tschöp, Matthias H.; Smith, Steven R.; Diaz-Meco, Maria T.; Moscat, Jorge

    2014-01-01

    SUMMARY The c-Jun NH(2)-terminal kinase (JNK) is a critical determinant of obesity-associated inflammation and glucose intolerance. The upstream mechanisms controlling this pathway are still unknown. Here we report that the levels of the PB1 domain-containing adapter NBR1 correlated with the expression of pro-inflammatory molecules in adipose tissue from human patients with metabolic syndrome, suggesting that NBR1 plays a key role in adipose-tissue inflammation. We also show that NBR1 inactivation in the myeloid compartment impairs the function, M1 polarization and chemotactic activity of macrophages, prevents inflammation of adipose tissue, and improves glucose tolerance in obese mice. Furthermore, we demonstrate that an interaction between the PB1 domains of NBR1 and the mitogen-activated kinase kinase 3 (MEKK3) enables the formation of a signaling complex required for the activation of JNK. Together these discoveries identify an NBR1-MEKK3 complex as a key regulator of JNK signaling and adipose-tissue inflammation in obesity. PMID:25043814

  19. N-acetylcysteine Counteracts Adipose Tissue Macrophage Infiltration and Insulin Resistance Elicited by Advanced Glycated Albumin in Healthy Rats

    PubMed Central

    da Silva, Karolline S.; Pinto, Paula R.; Fabre, Nelly T.; Gomes, Diego J.; Thieme, Karina; Okuda, Ligia S.; Iborra, Rodrigo T.; Freitas, Vanessa G.; Shimizu, Maria H. M.; Teodoro, Walcy R.; Marie, Suely K. N.; Woods, Tom; Brimble, Margaret A.; Pickford, Russell; Rye, Kerry-Anne; Okamoto, Maristela; Catanozi, Sergio; Correa-Giannela, Maria L.; Machado, Ubiratan F.; Passarelli, Marisa

    2017-01-01

    Background: Advanced glycation endproducts elicit inflammation. However, their role in adipocyte macrophage infiltration and in the development of insulin resistance, especially in the absence of the deleterious biochemical pathways that coexist in diabetes mellitus, remains unknown. We investigated the effect of chronic administration of advanced glycated albumin (AGE-albumin) in healthy rats, associated or not with N-acetylcysteine (NAC) treatment, on insulin sensitivity, adipose tissue transcriptome and macrophage infiltration and polarization. Methods: Male Wistar rats were intraperitoneally injected with control (C) or AGE-albumin alone, or, together with NAC in the drinking water. Biochemical parameters, lipid peroxidation, gene expression and protein contents were, respectively, determined by enzymatic techniques, reactive thiobarbituric acid substances, RT-qPCR and immunohistochemistry or immunoblot. Carboxymethyllysine (CML) and pyrraline (PYR) were determined by LC/mass spectrometry (LC-MS/MS) and ELISA. Results: CML and PYR were higher in AGE-albumin as compared to C. Food consumption, body weight, systolic blood pressure, plasma lipids, glucose, hepatic and renal function, adipose tissue relative weight and adipocyte number were similar among groups. In AGE-treated animals, insulin resistance, adipose macrophage infiltration and Col12a1 mRNA were increased with no changes in M1 and M2 phenotypes as compared to C-albumin-treated rats. Total GLUT4 content was reduced by AGE-albumin as compared to C-albumin. NAC improved insulin sensitivity, reduced urine TBARS, adipose macrophage number and Itgam and Mrc mRNA and increased Slc2a4 and Ppara. CD11b, CD206, Ager, Ddost, Cd36, Nfkb1, Il6, Tnf, Adipoq, Retn, Arg, and Il12 expressions were similar among groups. Conclusions: AGE-albumin sensitizes adipose tissue to inflammation due to macrophage infiltration and reduces GLUT4, contributing to insulin resistance in healthy rats. NAC antagonizes AGE-albumin and

  20. N-acetylcysteine Counteracts Adipose Tissue Macrophage Infiltration and Insulin Resistance Elicited by Advanced Glycated Albumin in Healthy Rats.

    PubMed

    da Silva, Karolline S; Pinto, Paula R; Fabre, Nelly T; Gomes, Diego J; Thieme, Karina; Okuda, Ligia S; Iborra, Rodrigo T; Freitas, Vanessa G; Shimizu, Maria H M; Teodoro, Walcy R; Marie, Suely K N; Woods, Tom; Brimble, Margaret A; Pickford, Russell; Rye, Kerry-Anne; Okamoto, Maristela; Catanozi, Sergio; Correa-Giannela, Maria L; Machado, Ubiratan F; Passarelli, Marisa

    2017-01-01

    Background: Advanced glycation endproducts elicit inflammation. However, their role in adipocyte macrophage infiltration and in the development of insulin resistance, especially in the absence of the deleterious biochemical pathways that coexist in diabetes mellitus, remains unknown. We investigated the effect of chronic administration of advanced glycated albumin (AGE-albumin) in healthy rats, associated or not with N-acetylcysteine (NAC) treatment, on insulin sensitivity, adipose tissue transcriptome and macrophage infiltration and polarization. Methods: Male Wistar rats were intraperitoneally injected with control (C) or AGE-albumin alone, or, together with NAC in the drinking water. Biochemical parameters, lipid peroxidation, gene expression and protein contents were, respectively, determined by enzymatic techniques, reactive thiobarbituric acid substances, RT-qPCR and immunohistochemistry or immunoblot. Carboxymethyllysine (CML) and pyrraline (PYR) were determined by LC/mass spectrometry (LC-MS/MS) and ELISA. Results: CML and PYR were higher in AGE-albumin as compared to C. Food consumption, body weight, systolic blood pressure, plasma lipids, glucose, hepatic and renal function, adipose tissue relative weight and adipocyte number were similar among groups. In AGE-treated animals, insulin resistance, adipose macrophage infiltration and Col12a1 mRNA were increased with no changes in M1 and M2 phenotypes as compared to C-albumin-treated rats. Total GLUT4 content was reduced by AGE-albumin as compared to C-albumin. NAC improved insulin sensitivity, reduced urine TBARS, adipose macrophage number and Itgam and Mrc mRNA and increased Slc2a4 and Ppara . CD11b, CD206, Ager, Ddost, Cd36, Nfkb1, Il6, Tnf , Adipoq, Retn, Arg, and Il12 expressions were similar among groups. Conclusions: AGE-albumin sensitizes adipose tissue to inflammation due to macrophage infiltration and reduces GLUT4, contributing to insulin resistance in healthy rats. NAC antagonizes AGE-albumin and

  1. Adipose tissue: cell heterogeneity and functional diversity.

    PubMed

    Esteve Ràfols, Montserrat

    2014-02-01

    There are two types of adipose tissue in the body whose function appears to be clearly differentiated. White adipose tissue stores energy reserves as fat, whereas the metabolic function of brown adipose tissue is lipid oxidation to produce heat. A good balance between them is important to maintain energy homeostasis. The concept of white adipose tissue has radically changed in the past decades, and is now considered as an endocrine organ that secretes many factors with autocrine, paracrine, and endocrine functions. In addition, we can no longer consider white adipose tissue as a single tissue, because it shows different metabolic profiles in its different locations, with also different implications. Although the characteristic cell of adipose tissue is the adipocyte, this is not the only cell type present in adipose tissue, neither the most abundant. Other cell types in adipose tissue described include stem cells, preadipocytes, macrophages, neutrophils, lymphocytes, and endothelial cells. The balance between these different cell types and their expression profile is closely related to maintenance of energy homeostasis. Increases in adipocyte size, number and type of lymphocytes, and infiltrated macrophages are closely related to the metabolic syndrome diseases. The study of regulation of proliferation and differentiation of preadipocytes and stem cells, and understanding of the interrelationship between the different cell types will provide new targets for action against these diseases. Copyright © 2012 SEEN. Published by Elsevier Espana. All rights reserved.

  2. Visceral adipose tissue macrophage-targeted TACE silencing to treat obesity-induced type 2 diabetes.

    PubMed

    Yong, Seok-Beom; Song, Yoonsung; Kim, Yong-Hee

    2017-12-01

    Obesity is an increasingly prevalent global health problem. Due to its close relations with metabolic diseases and cancer, new therapeutic approaches for treating obesity and obesity-induced metabolic diseases are required. Visceral white adipose tissue (WAT) has been closely associated with obesity-induced inflammation and adipose tissue macrophages (ATMs) are responsible for obesity-induced inflammation by releasing inflammatory cytokines such as tumor necrosis factor-α (TNF-α) and interleukin-6. TNF-α converting enzyme (TACE) is a transmembrane enzyme that induces the enzymatic cleavage and release of inflammatory cytokines. In this study, we developed a nonviral gene delivery system consisting of an oligopeptide (ATS-9R) that can selectively target visceral ATMs. In here we shows visceral adipose tissue-dominant inflammatory gene over-expressions in obese mouse and our strategy enabled the preferential delivery of therapeutic genes to visceral ATMs and successfully achieved ATM-targeted gene silencing. Finally, ATS-9R-mediated TACE gene silencing in visceral ATMs alleviated visceral fat inflammation and improved type 2 diabetes by reducing whole body inflammation. Copyright © 2017 Elsevier Ltd. All rights reserved.

  3. Active spice-derived components can inhibit inflammatory responses of adipose tissue in obesity by suppressing inflammatory actions of macrophages and release of monocyte chemoattractant protein-1 from adipocytes.

    PubMed

    Woo, Hae-Mi; Kang, Ji-Hye; Kawada, Teruo; Yoo, Hoon; Sung, Mi-Kyung; Yu, Rina

    2007-02-13

    Inflammation plays a key role in obesity-related pathologies such as cardiovascular disease, type II diabetes, and several types of cancer. Obesity-induced inflammation entails the enhancement of the recruitment of macrophages into adipose tissue and the release of various proinflammatory proteins from fat tissue. Therefore, the modulation of inflammatory responses in obesity may be useful for preventing or ameliorating obesity-related pathologies. Some spice-derived components, which are naturally occurring phytochemicals, elicit antiobesity and antiinflammatory properties. In this study, we investigated whether active spice-derived components can be applied to the suppression of obesity-induced inflammatory responses. Mesenteric adipose tissue was isolated from obese mice fed a high-fat diet and cultured to prepare an adipose tissue-conditioned medium. Raw 264.7 macrophages were treated with the adipose tissue-conditioned medium with or without active spice-derived components (i.e., diallyl disulfide, allyl isothiocyanate, piperine, zingerone and curcumin). Chemotaxis assay was performed to measure the degree of macrophage migration. Macrophage activation was estimated by measuring tumor necrosis factor-alpha (TNF-alpha), nitric oxide, and monocyte chemoattractant protein-1 (MCP-1) concentrations. The active spice-derived components markedly suppressed the migration of macrophages induced by the mesenteric adipose tissue-conditioned medium in a dose-dependent manner. Among the active spice-derived components studied, allyl isothiocyanate, zingerone, and curcumin significantly inhibited the cellular production of proinflammatory mediators such as TNF-alpha and nitric oxide, and significantly inhibited the release of MCP-1 from 3T3-L1 adipocytes. Our findings suggest that the spice-derived components can suppress obesity-induced inflammatory responses by suppressing adipose tissue macrophage accumulation or activation and inhibiting MCP-1 release from adipocytes

  4. Adipose tissue immunity and cancer

    PubMed Central

    Catalán, Victoria; Gómez-Ambrosi, Javier; Rodríguez, Amaia; Frühbeck, Gema

    2013-01-01

    Inflammation and altered immune response are important components of obesity and contribute greatly to the promotion of obesity-related metabolic complications, especially cancer development. Adipose tissue expansion is associated with increased infiltration of various types of immune cells from both the innate and adaptive immune systems. Thus, adipocytes and infiltrating immune cells secrete pro-inflammatory adipokines and cytokines providing a microenvironment favorable for tumor growth. Accumulation of B and T cells in adipose tissue precedes macrophage infiltration causing a chronic low-grade inflammation. Phenotypic switching toward M1 macrophages and Th1 T cells constitutes an important mechanism described in the obese state correlating with increased tumor growth risk. Other possible synergic mechanisms causing a dysfunctional adipose tissue include fatty acid-induced inflammation, oxidative stress, endoplasmic reticulum stress, and hypoxia. Recent investigations have started to unravel the intricacy of the cross-talk between tumor cell/immune cell/adipocyte. In this sense, future therapies should take into account the combination of anti-inflammatory approaches that target the tumor microenvironment with more sophisticated and selective anti-tumoral drugs. PMID:24106481

  5. Effects of prenatal low protein and postnatal high fat diets on visceral adipose tissue macrophage phenotypes and IL-6 expression in Sprague Dawley rat offspring

    USDA-ARS?s Scientific Manuscript database

    Adipose tissue macrophages (ATM) are implicated in adipose tissue inflammation and obesity-related insulin resistance. Maternal low protein models result in fetal programming of obesity. However, it is not known whether maternal undernutrition increases ATM phenotypic expression in F1 offspring. Us...

  6. Aging is associated with an increase in T cells and inflammatory macrophages in visceral adipose tissue1

    PubMed Central

    Lumeng, Carey N.; Liu, Jianhua; Geletka, Lynn; Delaney, Colin; DelProposto, Jennifer; Desai, Anjali; Oatmen, Kelsie; Martinez-Santibanez, Gabriel; Julius, Annabelle; Garg, Sanjay; Yung, Raymond L.

    2011-01-01

    Age-related adiposity has been linked to chronic inflammatory diseases in late-life. To date, the studies on adipose tissue leukocytes and aging have not taken into account the heterogeneity of adipose tissue macrophages (ATMs), nor have they examined how age impacts other leukocytes such as T cell in fat. Therefore, we have performed a detailed examination of ATM subtypes in young and old mice using state of the art techniques. Our results demonstrate qualitative changes in ATMs with aging that generate a decrease in resident Type 2 (M2) ATMs. The profile of ATMs in old fat shifts towards a pro-inflammatory environment with increased numbers of CD206-CD11c- (double negative) ATMs. The mechanism of this aging-induced shift in the phenotypic profile of ATMs was found to be related to a decrease in PPARγ expression in ATMs and alterations in chemokine/chemokine receptor expression profiles. Furthermore, we have revealed a profound and unexpected expansion of adipose tissue T (ATT) cells in visceral fat with aging that includes a significant induction of regulatory T cells (Tregs) in fat. Our findings demonstrate a unique inflammatory cell signature in the physiologic context of aging adipose tissue that differs from those induced in setting of diet-induced obesity. PMID:22075699

  7. Immunomodulatory Effects of Adipose Stromal Vascular Fraction Cells Promote Alternative Activation Macrophages to Repair Tissue Damage.

    PubMed

    Bowles, Annie C; Wise, Rachel M; Gerstein, Brittany Y; Thomas, Robert C; Ogelman, Roberto; Febbo, Isabella; Bunnell, Bruce A

    2017-10-01

    The pathogenesis of many diseases is driven by the interactions between helper T (T H ) cells and macrophages. The phenotypes of these cells are functional dichotomies that are persuaded according to the surrounding milieu. In both multiple sclerosis and the experimental autoimmune encephalomyelitis (EAE) model, T H 1 and T H 17 cells propagate autoimmune signaling and inflammation in the peripheral lymphoid tissues. In turn, this proinflammatory repertoire promotes the classical activation, formerly the M1-type, macrophages. Together, these cells infiltrate into the central nervous system (CNS) tissues and generate inflammatory and demyelinating lesions. Our most recent report demonstrated the immunomodulatory and anti-inflammatory effects of adipose stromal vascular fraction (SVF) cells and adipose-derived stem cells (ASCs) that led to functional, immunological, and pathological improvements in the EAE model. Here, a deeper investigation revealed the induction of regulatory T cells and alternative activation, or M2-type, macrophages in the periphery followed by the presence of alternative activation macrophages, reduced cellular infiltrates, and attenuation of neuroinflammation in CNS tissues following intraperitoneal administration of these treatments. Spleens from treated EAE mice revealed diminished T H 1 and T H 17 cell activities and were markedly higher in the levels of anti-inflammatory cytokine interleukin-10. Interestingly, SVF cells were more effective than ASCs at mediating these beneficial changes, which were attributed to their localization to the spleens after administration. Together, SVF cells rapidly and robustly attenuated the propagation of autoimmune signaling in the periphery that provided a permissive milieu in the CNS for repair and possibly regeneration. Stem Cells 2017;35:2198-2207. © 2017 AlphaMed Press.

  8. Omega-3-derived mediators counteract obesity-induced adipose tissue inflammation.

    PubMed

    Titos, Esther; Clària, Joan

    2013-12-01

    Chronic low-grade inflammation in adipose tissue has been recognized as a key step in the development of obesity-associated complications. In obesity, the accumulation of infiltrating macrophages in adipose tissue and their phenotypic switch to M1-type dysregulate inflammatory adipokine production leading to obesity-linked insulin resistance. Resolvins are potent anti-inflammatory and pro-resolving mediators endogenously generated from omega-3 fatty acids that act as "stop-signals" of the inflammatory response promoting the resolution of inflammation. Recently, a deficit in the production of these endogenous anti-inflammatory signals has been demonstrated in obese adipose tissue. The restoration of their levels by either exogenous administration of these mediators or feeding omega-3-enriched diets, improves the inflammatory status of adipose tissue and ameliorates metabolic dysfunction. Here, we review the current knowledge on the role of these endogenous autacoids in the resolution of adipose tissue inflammation with special emphasis on their functional actions on macrophages. Copyright © 2013 Elsevier Inc. All rights reserved.

  9. Flow cytometry on the stromal-vascular fraction of white adipose tissue

    USDA-ARS?s Scientific Manuscript database

    Adipose tissue contains cell types other than adipocytes that may contribute to complications linked to obesity. For example, macrophages have been shown to infiltrate adipose tissue in response to a high-fat diet. Isolation of the stromal-vascular fraction of adipose tissue allows one to use flow c...

  10. Adipose tissue as an immunological organ

    PubMed Central

    Grant, Ryan W.; Dixit, Vishwa Deep

    2014-01-01

    Objective This review will focus on the immunological aspects of adipose tissue and its potential role in development of chronic inflammation that instigates obesity-associated co-morbidities. Design and Methods The review utilized PubMed searches of current literature to examine adipose tissue leukocytosis. Results The adipose tissue of obese subjects becomes inflamed and contributes to the development of insulin resistance, type 2 diabetes and metabolic syndrome. Numerous immune cells including B cells, T cells, macrophages and neutrophils have been identified in adipose tissue, and obesity influences both the quantity and the nature of immune cell subtypes which emerges as an active immunological organ capable of modifying whole body metabolism through paracrine and endocrine mechanisms. Conclusion Adipose tissue is a large immunologically active organ during obesity that displays hallmarks of both and innate and adaptive immune response. Despite the presence of hematopoietic lineage cells in adipose tissue, it is presently unclear whether the adipose compartment has a direct role in immune-surveillance or host defense. Understanding the interactions between leukocytes and adipocytes may reveal the clinically relevant pathways that control adipose tissue inflammation and is likely to reveal mechanism by which obesity contributes to increased susceptibility to both metabolic and certain infectious disease. PMID:25612251

  11. Serum Progranulin Concentrations May Be Associated With Macrophage Infiltration Into Omental Adipose Tissue

    PubMed Central

    Youn, Byung-Soo; Bang, Sa-Ik; Klöting, Nora; Park, Ji Woo; Lee, Namseok; Oh, Ji-Eun; Pi, Kyung-Bae; Lee, Tae Hee; Ruschke, Karen; Fasshauer, Mathias; Stumvoll, Michael; Blüher, Matthias

    2009-01-01

    OBJECTIVE—Progranulin is an important molecule in inflammatory response. Chronic inflammation is frequently associated with central obesity and associated disturbances; however, the role of circulating progranulin in human obesity, type 2 diabetes, and dyslipidemia is unknown. RESEARCH DESIGN AND METHODS—For the measurement of progranulin serum concentrations, we developed an enzyme-linked immunosorbent assay (ELISA). Using this ELISA, we assessed circulating progranulin in a cross-sectional study of 209 subjects with a wide range of obesity, body fat distribution, insulin sensitivity, and glucose tolerance and in 60 individuals with normal (NGT) or impaired (IGT) glucose tolerance or type 2 diabetes before and after a 4-week physical training program. Progranulin mRNA and protein expression was measured in paired samples of omental and subcutaneous adipose tissue (adipocytes and cells of the stromal vascular fraction) from 55 lean or obese individuals. Measurement of Erk activation and chemotactic activity induced by progranulin in vitro was performed using THP-1–based cell migration assays. RESULTS—Progranulin serum concentrations were significantly higher in individuals with type 2 diabetes compared with NGT and in obese subjects with predominant visceral fat accumulation. Circulating progranulin significantly correlates with BMI, macrophage infiltration in omental adipose tissue, C-reactive protein (CRP) serum concentrations, A1C values, and total cholesterol. Multivariable linear regression analyses revealed CRP levels as the strongest independent predictor of circulating progranulin. The extent of in vitro progranulin-mediated chemotaxis is similar to that of monocyte chemoattractant protein-1 but independent of Gα. Moreover, in type 2 diabetes, but not in IGT and NGT individuals, physical training for 4 weeks resulted in significantly decreased circulating progranulin levels. CONCLUSIONS—Elevated progranulin serum concentrations are associated

  12. Regulatory iNKT cells lack expression of the transcription factor PLZF and control the homeostasis of T(reg) cells and macrophages in adipose tissue.

    PubMed

    Lynch, Lydia; Michelet, Xavier; Zhang, Sai; Brennan, Patrick J; Moseman, Ashley; Lester, Chantel; Besra, Gurdyal; Vomhof-Dekrey, Emilie E; Tighe, Mike; Koay, Hui-Fern; Godfrey, Dale I; Leadbetter, Elizabeth A; Sant'Angelo, Derek B; von Andrian, Ulrich; Brenner, Michael B

    2015-01-01

    Invariant natural killer T cells (iNKT cells) are lipid-sensing innate T cells that are restricted by the antigen-presenting molecule CD1d and express the transcription factor PLZF. iNKT cells accumulate in adipose tissue, where they are anti-inflammatory, but the factors that contribute to their anti-inflammatory nature, as well as their targets in adipose tissue, are unknown. Here we found that iNKT cells in adipose tissue had a unique transcriptional program and produced interleukin 2 (IL-2) and IL-10. Unlike other iNKT cells, they lacked PLZF but expressed the transcription factor E4BP4, which controlled their IL-10 production. The adipose iNKT cells were a tissue-resident population that induced an anti-inflammatory phenotype in macrophages and, through the production of IL-2, controlled the number, proliferation and suppressor function of regulatory T cells (Treg cells) in adipose tissue. Thus, iNKT cells in adipose tissue are unique regulators of immunological homeostasis in this tissue.

  13. Macrophage infiltration in the omental and subcutaneous adipose tissues of dairy cows with displaced abomasum.

    PubMed

    Contreras, G Andres; Kabara, Ed; Brester, Jill; Neuder, Louis; Kiupel, Matti

    2015-09-01

    High concentrations of plasma nonesterified fatty acids (NEFA), a direct measure of lipolysis, are considered a risk factor for displaced abomasum (DA) and other clinical diseases. In nonruminants, uncontrolled lipolysis is commonly associated with adipose tissue macrophage (ATM) infiltration. In dairy cows, recent studies report ATM infiltration in specific adipose depots during the first week of lactation. Depending on their phenotype, ATM can be broadly classified as classically activated (M1) or alternatively activated (M2). The M1 ATM are considered pro-inflammatory, whereas M2 ATM enhance inflammation resolution. Currently, it is not known whether multiparous transition cows with DA have increased ATM infiltration, and the predominant phenotype of these mononuclear cells remains unclear. The objective of this study was to characterize ATM infiltration into different adipose tissue depots in transition cows with DA (days in milk=7.8±4.6 d; body condition score=2.95±0.10; n=6). Serum samples and biopsies from omental (OM) and subcutaneous (SC) fat depots were obtained during corrective surgery for DA. In an effort to compare ATM infiltration in DA cows with that of healthy cows in anabolic state (AS), adipose biopsies and blood samples were collected from nonlactating, nongestating dairy cows at the time of slaughter (body condition score=3.75±0.12; n=6). Adipose tissues were digested and cells from the stromal vascular fraction (SVF) were analyzed using flow cytometry to establish cell surface expression of specific macrophage markers including CD14, CD11c, CD163, and CD172a. Tissue sections were analyzed by immunohistochemistry to assess ATM localization. Cows with DA were ketotic and had plasma NEFA above 1.0 mEq/L. The same group of cows had significant infiltration of ATM in OM characterized by increased numbers of SVF cells expressing CD14 and CD172a. At the same time, expression of CD11c, and CD163 was significantly higher in SVF from OM and SC of DA

  14. Zinc Deficiency Augments Leptin Production and Exacerbates Macrophage Infiltration into Adipose Tissue in Mice Fed a High-Fat Diet123

    PubMed Central

    Liu, Ming-Jie; Bao, Shengying; Bolin, Eric R.; Burris, Dara L.; Xu, Xiaohua; Sun, Qinghua; Killilea, David W.; Shen, Qiwen; Ziouzenkova, Ouliana; Belury, Martha A.; Failla, Mark L.; Knoell, Daren L.

    2013-01-01

    Zinc (Zn) deficiency and obesity are global public health problems. Zn deficiency is associated with obesity and comorbid conditions that include insulin resistance and type 2 diabetes. However, the function of Zn in obesity remains unclear. Using a mouse model of combined high-fat and low-Zn intake (0.5–1.5 mg/kg), we investigated whether Zn deficiency exacerbates the extent of adiposity as well as perturbations in metabolic and immune function. C57BL/6 mice were randomly assigned to receive either a high-fat diet (HFD) or a control (C) diet for 6 wk, followed by further subdivision into 2 additional groups fed Zn-deficient diets (C-Zn, HFD-Zn), along with a C diet and an HFD, for 3 wk (n = 8–9 mice/group). The extent of visceral fat, insulin resistance, or systemic inflammation was unaffected by Zn deficiency. Strikingly, Zn deficiency significantly augmented circulating leptin concentrations (HFD-Zn vs. HFD: 3.15 ± 0.16 vs. 2.59 ± 0.12 μg/L, respectively) and leptin signaling in the liver of obese mice. Furthermore, gene expression of macrophage-specific markers ADAM8 (A disintegrin and metalloproteinase domain-containing protein 8) and CD68 (cluster of differentiation 68) was significantly greater in adipose tissue in the HFD-Zn group than in the HFD group, as confirmed by CD68 protein analysis, indicative of increased macrophage infiltration. Inspection of Zn content and mRNA profiles of all Zn transporters in the adipose tissue revealed alterations of Zn metabolism to obesity and Zn deficiency. Our results demonstrate that Zn deficiency increases leptin production and exacerbates macrophage infiltration into adipose tissue in obese mice, indicating the importance of Zn in metabolic and immune dysregulation in obesity. PMID:23700340

  15. Inhibition of intestinal cholesterol absorption decreases atherosclerosis but not adipose tissue inflammation

    PubMed Central

    Umemoto, Tomio; Subramanian, Savitha; Ding, Yilei; Goodspeed, Leela; Wang, Shari; Han, Chang Yeop; Teresa, Antonio Sta.; Kim, Jinkyu; O'Brien, Kevin D.; Chait, Alan

    2012-01-01

    Adipose tissue inflammation is associated with insulin resistance and increased cardiovascular disease risk in obesity. We previously showed that addition of cholesterol to a diet rich in saturated fat and refined carbohydrate significantly worsens dyslipidemia, insulin resistance, adipose tissue macrophage accumulation, systemic inflammation, and atherosclerosis in LDL receptor-deficient (Ldlr−/−) mice. To test whether inhibition of intestinal cholesterol absorption would improve metabolic abnormalities and adipose tissue inflammation in obesity, we administered ezetimibe, a dietary and endogenous cholesterol absorption inhibitor, to Ldlr−/− mice fed chow or high-fat, high-sucrose (HFHS) diets without or with 0.15% cholesterol (HFHS+C). Ezetimibe blunted weight gain and markedly reduced plasma lipids in the HFHS+C group. Ezetimibe had no effect on glucose homeostasis or visceral adipose tissue macrophage gene expression in the HFHS+C fed mice, although circulating inflammatory markers serum amyloid A (SSA) and serum amyloid P (SSP) levels decreased. Nevertheless, ezetimibe treatment led to a striking (>85%) reduction in atherosclerotic lesion area with reduced lesion lipid and macrophage content in the HFHS+C group. Thus, in the presence of dietary cholesterol, ezetimibe did not improve adipose tissue inflammation in obese Ldlr−/− mice, but it led to a major reduction in atherosclerotic lesions associated with improved plasma lipids and lipoproteins. PMID:22956784

  16. Dynamic M2-like remodeling phenotypes of CD11c+ adipose tissue macrophages during high fat diet-induced obesity in mice

    USDA-ARS?s Scientific Manuscript database

    Chronic inflammation is a pathogenic factor in obesity complications, in particular insulin resistance (IR). A significant advance in our understanding of obesity-associated inflammation and insulin resistance has been the recognition of the underlying role of adipose tissue macrophages (ATM's). The...

  17. Adipose Tissue in HIV Infection.

    PubMed

    Koethe, John R

    2017-09-12

    HIV infection and antiretroviral therapy (ART) treatment exert diverse effects on adipocytes and stromal-vascular fraction cells, leading to changes in adipose tissue quantity, distribution, and energy storage. A HIV-associated lipodystrophic condition was recognized early in the epidemic, characterized by clinically apparent changes in subcutaneous, visceral, and dorsocervical adipose depots. Underlying these changes is altered adipose tissue morphology and expression of genes central to adipocyte maturation, regulation, metabolism, and cytokine signaling. HIV viral proteins persist in circulation and locally within adipose tissue despite suppression of plasma viremia on ART, and exposure to these proteins impairs preadipocyte maturation and reduces adipocyte expression of peroxisome proliferator-activated receptor gamma (PPAR-γ) and other genes involved in cell regulation. Several early nucleoside reverse transcriptase inhibitor and protease inhibitor antiretroviral drugs demonstrated substantial adipocyte toxicity, including reduced mitochondrial DNA content and respiratory chain enzymes, reduced PPAR-γ and other regulatory gene expression, and increased proinflammatory cytokine production. Newer-generation agents, such as integrase inhibitors, appear to have fewer adverse effects. HIV infection also alters the balance of CD4+ and CD8+ T cells in adipose tissue, with effects on macrophage activation and local inflammation, while the presence of latently infected CD4+ T cells in adipose tissue may constitute a protected viral reservoir. This review provides a synthesis of the literature on how HIV virus, ART treatment, and host characteristics interact to affect adipose tissue distribution, immunology, and contribution to metabolic health, and adipocyte maturation, cellular regulation, and energy storage. © 2017 American Physiological Society. Compr Physiol 7:1339-1357, 2017. Copyright © 2017 John Wiley & Sons, Inc.

  18. Flow cytometry on the stromal-vascular fraction of white adipose tissue.

    PubMed

    Brake, Danett K; Smith, C Wayne

    2008-01-01

    Adipose tissue contains cell types other than adipocytes that may contribute to complications linked to obesity. For example, macrophages have been shown to infiltrate adipose tissue in response to a high-fat diet. Isolation of the stromal-vascular fraction of adipose tissue allows one to use flow cytometry to analyze cell surface markers on leukocytes. Here, we present a technical approach to identify subsets of leukocytes that differentially express cell surface markers.

  19. [Role of chronic inflammation in adipose tissue in the pathophysiology of obesity].

    PubMed

    Suganami, Takayoshi; Ogawa, Yoshihiro

    2013-02-01

    Obesity may be viewed as a chronic low-grade inflammatory disease as well as a metabolic disease. Evidence has accumulated suggesting that chronic inflammation in adipose tissue leads to dramatic changes in number and cell type of stromal cells during the course of obesity, which is referred to as"adipose tissue remodeling". Among stromal cells, macrophages in obese adipose tissue are considered to be crucial for adipose tissue inflammation, which results in dysregulated adipocytokine production and ectopic fat accumulation. Understanding the molecular mechanism underlying adipose tissue inflammation would contribute to the identification of novel therapeutic strategies to prevent or treat obesity-induced metabolic derangements.

  20. Obesity-induced DNA released from adipocytes stimulates chronic adipose tissue inflammation and insulin resistance.

    PubMed

    Nishimoto, Sachiko; Fukuda, Daiju; Higashikuni, Yasutomi; Tanaka, Kimie; Hirata, Yoichiro; Murata, Chie; Kim-Kaneyama, Joo-Ri; Sato, Fukiko; Bando, Masahiro; Yagi, Shusuke; Soeki, Takeshi; Hayashi, Tetsuya; Imoto, Issei; Sakaue, Hiroshi; Shimabukuro, Michio; Sata, Masataka

    2016-03-01

    Obesity stimulates chronic inflammation in adipose tissue, which is associated with insulin resistance, although the underlying mechanism remains largely unknown. Here we showed that obesity-related adipocyte degeneration causes release of cell-free DNA (cfDNA), which promotes macrophage accumulation in adipose tissue via Toll-like receptor 9 (TLR9), originally known as a sensor of exogenous DNA fragments. Fat-fed obese wild-type mice showed increased release of cfDNA, as determined by the concentrations of single-stranded DNA (ssDNA) and double-stranded DNA (dsDNA) in plasma. cfDNA released from degenerated adipocytes promoted monocyte chemoattractant protein-1 (MCP-1) expression in wild-type macrophages, but not in TLR9-deficient (Tlr9 (-/-) ) macrophages. Fat-fed Tlr9 (-/-) mice demonstrated reduced macrophage accumulation and inflammation in adipose tissue and better insulin sensitivity compared with wild-type mice, whereas bone marrow reconstitution with wild-type bone marrow restored the attenuation of insulin resistance observed in fat-fed Tlr9 (-/-) mice. Administration of a TLR9 inhibitory oligonucleotide to fat-fed wild-type mice reduced the accumulation of macrophages in adipose tissue and improved insulin resistance. Furthermore, in humans, plasma ssDNA level was significantly higher in patients with computed tomography-determined visceral obesity and was associated with homeostasis model assessment of insulin resistance (HOMA-IR), which is the index of insulin resistance. Our study may provide a novel mechanism for the development of sterile inflammation in adipose tissue and a potential therapeutic target for insulin resistance.

  1. Adipose tissue macrophages in the Development of Obesity-induced Inflammation, Insulin Resistance and Type 2 Diabetes

    PubMed Central

    Lee, Jongsoon

    2014-01-01

    It has been increasingly accepted that chronic subacute inflammation plays an important role in the development of insulin resistance and Type 2 Diabetes in animals and humans. Particularly supporting this is that suppression of systemic inflammation in Type 2 Diabetes improves glycemic control; this also points to a new potential therapeutic target for the treatment of Type 2 Diabetes. Recent studies strongly suggest that obesity-induced inflammation is mainly mediated by tissue resident immune cells, with particular attention being focused on adipose tissue macrophages (ATMs). This review delineates the current progress made in understanding obesity-induced inflammation and the roles ATMs play in this process. PMID:23397293

  2. Noncanonical Wnt signaling promotes obesity-induced adipose tissue inflammation and metabolic dysfunction independent of adipose tissue expansion.

    PubMed

    Fuster, José J; Zuriaga, María A; Ngo, Doan Thi-Minh; Farb, Melissa G; Aprahamian, Tamar; Yamaguchi, Terry P; Gokce, Noyan; Walsh, Kenneth

    2015-04-01

    Adipose tissue dysfunction plays a pivotal role in the development of insulin resistance in obese individuals. Cell culture studies and gain-of-function mouse models suggest that canonical Wnt proteins modulate adipose tissue expansion. However, no genetic evidence supports a role for endogenous Wnt proteins in adipose tissue dysfunction, and the role of noncanonical Wnt signaling remains largely unexplored. Here we provide evidence from human, mouse, and cell culture studies showing that Wnt5a-mediated, noncanonical Wnt signaling contributes to obesity-associated metabolic dysfunction by increasing adipose tissue inflammation. Wnt5a expression is significantly upregulated in human visceral fat compared with subcutaneous fat in obese individuals. In obese mice, Wnt5a ablation ameliorates insulin resistance, in parallel with reductions in adipose tissue inflammation. Conversely, Wnt5a overexpression in myeloid cells augments adipose tissue inflammation and leads to greater impairments in glucose homeostasis. Wnt5a ablation or overexpression did not affect fat mass or adipocyte size. Mechanistically, Wnt5a promotes the expression of proinflammatory cytokines by macrophages in a Jun NH2-terminal kinase-dependent manner, leading to defective insulin signaling in adipocytes. Exogenous interleukin-6 administration restores insulin resistance in obese Wnt5a-deficient mice, suggesting a central role for this cytokine in Wnt5a-mediated metabolic dysfunction. Taken together, these results demonstrate that noncanonical Wnt signaling contributes to obesity-induced insulin resistance independent of adipose tissue expansion. © 2015 by the American Diabetes Association. Readers may use this article as long as the work is properly cited, the use is educational and not for profit, and the work is not altered.

  3. Eosinophils Reduce Chronic Inflammation in Adipose Tissue by Secreting Th2 Cytokines and Promoting M2 Macrophages Polarization.

    PubMed

    Zhang, Yi; Yang, Peng; Cui, Ran; Zhang, Manna; Li, Hong; Qian, Chunhua; Sheng, Chunjun; Qu, Shen; Bu, Le

    2015-01-01

    Obesity is now recognized as a low-grade, chronic inflammatory disease that is linked to a myriad of disorders including cardiovascular diseases, type 2 diabetes, and liver diseases. Recently it is found that eosinophils accelerate alternative activation macrophage (AAM) polarization by secreting Th2 type cytokines such as interleukin-4 and interleukin-13, thereby reducing metainflammation in adipose tissue. In this review, we focused on the role of eosinophils in regulating metabolic homeostasis and obesity.

  4. Adipocyte-Macrophage Cross-Talk in Obesity.

    PubMed

    Engin, Ayse Basak

    2017-01-01

    Obesity is characterized by the chronic low-grade activation of the innate immune system. In this respect, macrophage-elicited metabolic inflammation and adipocyte-macrophage interaction has a primary importance in obesity. Large amounts of macrophages are accumulated by different mechanisms in obese adipose tissue. Hypertrophic adipocyte-derived chemotactic monocyte chemoattractant protein-1 (MCP-1)/C-C chemokine receptor 2 (CCR2) pathway also promotes more macrophage accumulation into the obese adipose tissue. However, increased local extracellular lipid concentrations is a final mechanism for adipose tissue macrophage accumulation. A paracrine loop involving free fatty acids and tumor necrosis factor-alpha (TNF-alpha) between adipocytes and macrophages establishes a vicious cycle that aggravates inflammatory changes in the adipose tissue. Adipocyte-specific caspase-1 and production of interleukin-1beta (IL-1beta) by macrophages; both adipocyte and macrophage induction by toll like receptor-4 (TLR4) through nuclear factor-kappaB (NF-kappaB) activation; free fatty acid-induced and TLR-mediated activation of c-Jun N-terminal kinase (JNK)-related pro-inflammatory pathways in CD11c+ immune cells; are effective in macrophage accumulation and in the development of adipose tissue inflammation. Old adipocytes are removed by macrophages through trogocytosis or sending an "eat me" signal. The obesity-induced changes in adipose tissue macrophage numbers are mainly due to increases in the triple-positive CD11b+ F4/80+ CD11c+ adipose tissue macrophage subpopulation. The ratio of M1-to-M2 macrophages is increased in obesity. Furthermore, hypoxia along with higher concentrations of free fatty acids exacerbates macrophage-mediated inflammation in obesity. The metabolic status of adipocytes is a major determinant of macrophage inflammatory output. Macrophage/adipocyte fatty-acid-binding proteins act at the interface of metabolic and inflammatory pathways. Both macrophages and

  5. Depot-dependent effects of adipose tissue explants on co-cultured hepatocytes.

    PubMed

    Du, Zhen-Yu; Ma, Tao; Lock, Erik-Jan; Hao, Qin; Kristiansen, Karsten; Frøyland, Livar; Madsen, Lise

    2011-01-01

    We have developed an in vitro hepatocyte-adipose tissue explant (ATE) co-culture model enabling examination of the effect of visceral and subcutaneous adipose tissues on primary rat hepatocytes. Initial analyses of inflammatory marker genes were performed in fractionated epididymal or inguinal adipose tissues. Expressions of inflammation related genes (IL-6, TNF-α, COX-2) were higher in the inguinal than the epididymal ATE. Similarly, expressions of marker genes of macrophage and monocyte (MPEG-1, CD68, F4/80, CD64) were higher in the stromal vascular fraction (SVF) isolated from inguinal ATE than that from epididymal ATE. However, expressions of lipolysis related genes (ATGL, HSL, perilipin-1) were higher in the epididymal adipocytes than inguinal adipocytes. Moreover, secretion of IL-6 and PGE(2) was higher from inguinal ATEs than from epididymal ATEs. There was a trend that the total levels of IL-6, TNF-α and PGE(2) in the media from inguinal ATEs co-cultured with primary rat hepatocytes were higher than that in the media from epididymal ATEs co-cultured with hepatocytes, although the significant difference was only seen in PGE(2). Lipolysis, measured as glycerol release, was similar in the ATEs isolated from inguinal and epididymal adipose tissues when cultured alone, but the glycerol release was higher in the ATEs isolated from epididymal than from inguinal adipose tissue when co-cultured with hepatocytes. Compared to epididymal ATEs, the ATEs from inguinal adipose tissue elicited a stronger cytotoxic response and higher level of insulin resistance in the co-cultured hepatocytes. In conclusion, our results reveal depot-dependent effects of ATEs on co-cultured primary hepatocytes, which in part may be related to a more pronounced infiltration of stromal vascular cells (SVCs), particularly macrophages, in inguinal adipose tissue resulting in stronger responses in terms of hepatotoxicity and insulin-resistance.

  6. Intermittent fasting promotes adipose thermogenesis and metabolic homeostasis via VEGF-mediated alternative activation of macrophage.

    PubMed

    Kim, Kyoung-Han; Kim, Yun Hye; Son, Joe Eun; Lee, Ju Hee; Kim, Sarah; Choe, Min Seon; Moon, Joon Ho; Zhong, Jian; Fu, Kiya; Lenglin, Florine; Yoo, Jeong-Ah; Bilan, Philip J; Klip, Amira; Nagy, Andras; Kim, Jae-Ryong; Park, Jin Gyoon; Hussein, Samer Mi; Doh, Kyung-Oh; Hui, Chi-Chung; Sung, Hoon-Ki

    2017-11-01

    Intermittent fasting (IF), a periodic energy restriction, has been shown to provide health benefits equivalent to prolonged fasting or caloric restriction. However, our understanding of the underlying mechanisms of IF-mediated metabolic benefits is limited. Here we show that isocaloric IF improves metabolic homeostasis against diet-induced obesity and metabolic dysfunction primarily through adipose thermogenesis in mice. IF-induced metabolic benefits require fasting-mediated increases of vascular endothelial growth factor (VEGF) expression in white adipose tissue (WAT). Furthermore, periodic adipose-VEGF overexpression could recapitulate the metabolic improvement of IF in non-fasted animals. Importantly, fasting and adipose-VEGF induce alternative activation of adipose macrophage, which is critical for thermogenesis. Human adipose gene analysis further revealed a positive correlation of adipose VEGF-M2 macrophage-WAT browning axis. The present study uncovers the molecular mechanism of IF-mediated metabolic benefit and suggests that isocaloric IF can be a preventive and therapeutic approach against obesity and metabolic disorders.

  7. Intermittent fasting promotes adipose thermogenesis and metabolic homeostasis via VEGF-mediated alternative activation of macrophage

    PubMed Central

    Kim, Kyoung-Han; Kim, Yun Hye; Son, Joe Eun; Lee, Ju Hee; Kim, Sarah; Choe, Min Seon; Moon, Joon Ho; Zhong, Jian; Fu, Kiya; Lenglin, Florine; Yoo, Jeong-Ah; Bilan, Philip J; Klip, Amira; Nagy, Andras; Kim, Jae-Ryong; Park, Jin Gyoon; Hussein, Samer MI; Doh, Kyung-Oh; Hui, Chi-chung; Sung, Hoon-Ki

    2017-01-01

    Intermittent fasting (IF), a periodic energy restriction, has been shown to provide health benefits equivalent to prolonged fasting or caloric restriction. However, our understanding of the underlying mechanisms of IF-mediated metabolic benefits is limited. Here we show that isocaloric IF improves metabolic homeostasis against diet-induced obesity and metabolic dysfunction primarily through adipose thermogenesis in mice. IF-induced metabolic benefits require fasting-mediated increases of vascular endothelial growth factor (VEGF) expression in white adipose tissue (WAT). Furthermore, periodic adipose-VEGF overexpression could recapitulate the metabolic improvement of IF in non-fasted animals. Importantly, fasting and adipose-VEGF induce alternative activation of adipose macrophage, which is critical for thermogenesis. Human adipose gene analysis further revealed a positive correlation of adipose VEGF-M2 macrophage-WAT browning axis. The present study uncovers the molecular mechanism of IF-mediated metabolic benefit and suggests that isocaloric IF can be a preventive and therapeutic approach against obesity and metabolic disorders. PMID:29039412

  8. Mycobacterium tuberculosis infection modulates adipose tissue biology

    PubMed Central

    Kühl, Anja A.; Kupz, Andreas; Vogelzang, Alexis; Mollenkopf, Hans-Joachim; Löwe, Delia; Bandermann, Silke; Dorhoi, Anca; Brinkmann, Volker

    2017-01-01

    Mycobacterium tuberculosis (Mtb) primarily resides in the lung but can also persist in extrapulmonary sites. Macrophages are considered the prime cellular habitat in all tissues. Here we demonstrate that Mtb resides inside adipocytes of fat tissue where it expresses stress-related genes. Moreover, perigonadal fat of Mtb-infected mice disseminated the infection when transferred to uninfected animals. Adipose tissue harbors leukocytes in addition to adipocytes and other cell types and we observed that Mtb infection induces changes in adipose tissue biology depending on stage of infection. Mice infected via aerosol showed infiltration of inducible nitric oxide synthase (iNOS) or arginase 1 (Arg1)-negative F4/80+ cells, despite recruitment of CD3+, CD4+ and CD8+ T cells. Gene expression analysis of adipose tissue of aerosol Mtb-infected mice provided evidence for upregulated expression of genes associated with T cells and NK cells at 28 days post-infection. Strikingly, IFN-γ-producing NK cells and Mtb-specific CD8+ T cells were identified in perigonadal fat, specifically CD8+CD44-CD69+ and CD8+CD44-CD103+ subpopulations. Gene expression analysis of these cells revealed that they expressed IFN-γ and the lectin-like receptor Klrg1 and down-regulated CD27 and CD62L, consistent with an effector phenotype of Mtb-specific CD8+ T cells. Sorted NK cells expressed higher abundance of Klrg1 upon infection, as well. Our results reveal the ability of Mtb to persist in adipose tissue in a stressed state, and that NK cells and Mtb-specific CD8+ T cells infiltrate infected adipose tissue where they produce IFN-γ and assume an effector phenotype. We conclude that adipose tissue is a potential niche for Mtb and that due to infection CD8+ T cells and NK cells are attracted to this tissue. PMID:29040326

  9. Impact of Perturbed Pancreatic β-Cell Cholesterol Homeostasis on Adipose Tissue and Skeletal Muscle Metabolism

    PubMed Central

    Cochran, Blake J.; Hou, Liming; Manavalan, Anil Paul Chirackal; Moore, Benjamin M.; Tabet, Fatiha; Sultana, Afroza; Cuesta Torres, Luisa; Tang, Shudi; Shrestha, Sudichhya; Senanayake, Praween; Patel, Mili; Ryder, William J.; Bongers, Andre; Maraninchi, Marie; Wasinger, Valerie C.; Westerterp, Marit; Tall, Alan R.; Barter, Philip J.

    2016-01-01

    Elevated pancreatic β-cell cholesterol levels impair insulin secretion and reduce plasma insulin levels. This study establishes that low plasma insulin levels have a detrimental effect on two major insulin target tissues: adipose tissue and skeletal muscle. Mice with increased β-cell cholesterol levels were generated by conditional deletion of the ATP-binding cassette transporters, ABCA1 and ABCG1, in β-cells (β-DKO mice). Insulin secretion was impaired in these mice under basal and high-glucose conditions, and glucose disposal was shifted from skeletal muscle to adipose tissue. The β-DKO mice also had increased body fat and adipose tissue macrophage content, elevated plasma interleukin-6 and MCP-1 levels, and decreased skeletal muscle mass. They were not, however, insulin resistant. The adipose tissue expansion and reduced skeletal muscle mass, but not the systemic inflammation or increased adipose tissue macrophage content, were reversed when plasma insulin levels were normalized by insulin supplementation. These studies identify a mechanism by which perturbation of β-cell cholesterol homeostasis and impaired insulin secretion increase adiposity, reduce skeletal muscle mass, and cause systemic inflammation. They further identify β-cell dysfunction as a potential therapeutic target in people at increased risk of developing type 2 diabetes. PMID:27702832

  10. Breast Tissue Stromal Cells Preferentially Promote Generation of M2 Macrophages: A Novel Mechanism for Tumor Supportive Properties of Breast Microenvironment

    DTIC Science & Technology

    2011-08-01

    macrophages (MQs), on growth of breast tumor cells, and (2) to test the hypothesis that MSCs of non -breast adipose tissues, in contrast to MSCs of...macrophages in normal and malignant tissues. In contrast to all studies focused on the role of breast tissue microenvironment in growth of primary breast...the phenotype of macrophages, provide an immune environment suitable for growth of breast cancer cells, but MSCs present in non -breast adipose

  11. Similarity of mouse perivascular and brown adipose tissues and their resistance to diet-induced inflammation

    PubMed Central

    Fitzgibbons, Timothy P.; Kogan, Sophia; Aouadi, Myriam; Hendricks, Greg M.; Straubhaar, Juerg

    2011-01-01

    Thoracic perivascular adipose tissue (PVAT) is a unique adipose depot that likely influences vascular function and susceptibility to pathogenesis in obesity and the metabolic syndrome. Surprisingly, PVAT has been reported to share characteristics of both brown and white adipose, but a detailed direct comparison to interscapular brown adipose tissue (BAT) has not been performed. Here we show by full genome DNA microarray analysis that global gene expression profiles of PVAT are virtually identical to BAT, with equally high expression of Ucp-1, Cidea, and other genes known to be uniquely or very highly expressed in BAT. PVAT and BAT also displayed nearly identical phenotypes upon immunohistochemical analysis, and electron microscopy confirmed that PVAT contained multilocular lipid droplets and abundant mitochondria. Compared with white adipose tissue (WAT), PVAT and BAT from C57BL6/J mice fed a high-fat diet for 13 wk had markedly lower expression of immune cell-enriched mRNAs, suggesting resistance to obesity-induced inflammation. Indeed, staining of BAT and PVAT for macrophage markers (F4/80 and CD68) in obese mice showed virtually no macrophage infiltration, and FACS analysis of BAT confirmed the presence of very few CD11b+/CD11c+ macrophages in BAT (1.0%) compared with WAT (31%). In summary, murine PVAT from the thoracic aorta is virtually identical to interscapular BAT, is resistant to diet-induced macrophage infiltration, and thus may play an important role in protecting the vascular bed from inflammatory stress. PMID:21765057

  12. The physiological and pathophysiological roles of taurine in adipose tissue in relation to obesity.

    PubMed

    Murakami, Shigeru

    2017-10-01

    Obesity is caused by an imbalance between energy intake and energy expenditure. It is established that obesity is a state of low-grade chronic inflammation, which is characterized by enlarged hypertrophied adipocytes, increased infiltration by macrophages and marked changes in the secretion of adipokines and free fatty acids. The effects of taurine on the pathogenesis of obesity have been reported in animals and humans. Although the mechanisms underlying the anti-obesity action of taurine remain to be defined, taurine seems to ameliorate obesity through stimulation of energy expenditure, modulation of lipid metabolism, anorexic effect, anti-inflammatory and anti-oxidative effects. Recent studies revealed that taurine supplementation reduces the infiltration of macrophages and modulates the polarization of adipose tissue macrophages in high-fat diet-induced obese mice. In addition, taurine downregulates the production of pro-inflammatory cytokines by adipocytes, suggesting that taurine plays an anti-inflammatory role in adipose tissue. This article reviews the effects and mechanisms of taurine on the development of obesity, focusing on the role of taurine in white adipose tissue. Copyright © 2017 Elsevier Inc. All rights reserved.

  13. IL-33 induces protective effects in adipose tissue inflammation during obesity in mice

    PubMed Central

    Miller, Ashley M.; Asquith, Darren L.; Hueber, Axel J.; Anderson, Lesley A.; Holmes, William M.; McKenzie, Andrew N.; Xu, Damo; Sattar, Naveed; McInnes, Iain B.; Liew, Foo Y.

    2014-01-01

    Rationale Chronic low-grade inflammation involving adipose tissue likely contributes to the metabolic consequences of obesity. The cytokine IL-33 and its receptor ST2 are expressed in adipose tissue but their role in adipose tissue inflammation during obesity is unclear. Objective To examine the functional role of IL-33 in adipose tissues, and investigate the effects on adipose tissue inflammation and obesity in vivo. Methods and Results We demonstrate that treatment of adipose tissue cultures in vitro with IL-33 induced production of Th2 cytokines (IL-5, IL-13, IL-10), and reduced expression of adipogenic and metabolic genes. Administration of recombinant IL-33 to genetically obese diabetic (ob/ob) mice led to reduced adiposity, reduced fasting glucose and improved glucose and insulin tolerance. IL-33 also induced accumulation of Th2 cells in adipose tissue and polarization of adipose tissue macrophages towards an M2 alternatively activated phenotype (CD206+), a lineage associated with protection against obesity-related metabolic events. Furthermore, mice lacking endogenous ST2 fed HFD had increased body weight and fat mass, impaired insulin secretion and glucose regulation compared to WT controls fed HFD. Conclusions In conclusion, IL-33 may play a protective role in the development of adipose tissue inflammation during obesity. PMID:20634488

  14. Haematopoietic leptin receptor deficiency does not affect macrophage accumulation in adipose tissue or systemic insulin sensitivity.

    PubMed

    Gutierrez, Dario A; Hasty, Alyssa H

    2012-03-01

    The adipokine leptin is primarily produced by white adipose tissue (AT) and is a potent monocyte/macrophage chemoattractant in vitro. The long form of the leptin receptor (LepR) is required for monocyte/macrophage chemotaxis towards leptin. In this study, we examined the effects of haematopoietic LepR as well as LepR with C-C chemokine receptor 2 (CCR2) deficiency (double knockout (DKO)) on macrophage recruitment to AT after two different periods of high fat diet (HFD) feeding. Briefly, 8-week-old C57BL/6 mice were transplanted with bone marrow (BM) from Lepr(+/+), Lepr(-/-) or DKO donors (groups named BM-Lepr(+/+), BM-Lepr(-/-) and BM-DKO respectively), and were placed on an HFD for 6 or 12 weeks. At the end of the study, macrophage infiltration and the inflammatory state of AT were evaluated by real-time RT-PCR, histology and flow cytometry. In addition, glucose and insulin tolerance were assessed at both time points. Our results showed no differences in macrophage accumulation or AT inflammatory state between the BM-Lepr(+/+) and BM-Lepr(-/-) mice after 6 or 12 weeks of HFD feeding; any effects observed in the BM-DKO were attributed to the haematopoietic deficiency of CCR2. In addition, no changes in glucose or insulin tolerance were observed between groups after either period of HFD feeding. Our findings suggest that although leptin is a potent chemoattractant in vitro, haematopoietic LepR deficiency does not affect macrophage accumulation in AT in early to moderate stages of diet-induced obesity.

  15. Glucose-6-Phosphate Dehydrogenase Deficiency Improves Insulin Resistance With Reduced Adipose Tissue Inflammation in Obesity.

    PubMed

    Ham, Mira; Choe, Sung Sik; Shin, Kyung Cheul; Choi, Goun; Kim, Ji-Won; Noh, Jung-Ran; Kim, Yong-Hoon; Ryu, Je-Won; Yoon, Kun-Ho; Lee, Chul-Ho; Kim, Jae Bum

    2016-09-01

    Glucose-6-phosphate dehydrogenase (G6PD), a rate-limiting enzyme of the pentose phosphate pathway, plays important roles in redox regulation and de novo lipogenesis. It was recently demonstrated that aberrant upregulation of G6PD in obese adipose tissue mediates insulin resistance as a result of imbalanced energy metabolism and oxidative stress. It remains elusive, however, whether inhibition of G6PD in vivo may relieve obesity-induced insulin resistance. In this study we showed that a hematopoietic G6PD defect alleviates insulin resistance in obesity, accompanied by reduced adipose tissue inflammation. Compared with wild-type littermates, G6PD-deficient mutant (G6PD(mut)) mice were glucose tolerant upon high-fat-diet (HFD) feeding. Intriguingly, the expression of NADPH oxidase genes to produce reactive oxygen species was alleviated, whereas that of antioxidant genes was enhanced in the adipose tissue of HFD-fed G6PD(mut) mice. In diet-induced obesity (DIO), the adipose tissue of G6PD(mut) mice decreased the expression of inflammatory cytokines, accompanied by downregulated proinflammatory macrophages. Accordingly, macrophages from G6PD(mut) mice greatly suppressed lipopolysaccharide-induced proinflammatory signaling cascades, leading to enhanced insulin sensitivity in adipocytes and hepatocytes. Furthermore, adoptive transfer of G6PD(mut) bone marrow to wild-type mice attenuated adipose tissue inflammation and improved glucose tolerance in DIO. Collectively, these data suggest that inhibition of macrophage G6PD would ameliorate insulin resistance in obesity through suppression of proinflammatory responses. © 2016 by the American Diabetes Association.

  16. Des-acyl ghrelin inhibits the capacity of macrophages to stimulate the expression of aromatase in breast adipose stromal cells.

    PubMed

    Au, CheukMan C; Docanto, Maria M; Zahid, Heba; Raffaelli, Francesca-Maria; Ferrero, Richard L; Furness, John B; Brown, Kristy A

    2017-06-01

    Des-acyl ghrelin is the unacylated form of the well-characterized appetite-stimulating hormone ghrelin. It affects a number of physiological processes, including increasing adipose lipid accumulation and inhibiting adipose tissue inflammation. Breast adipose tissue inflammation in obesity is associated with an increase in the expression of the estrogen biosynthetic enzyme, aromatase, and is hypothesized to create a hormonal milieu conducive to tumor growth. We previously reported that des-acyl ghrelin inhibits the expression and activity of aromatase in isolated human adipose stromal cells (ASCs), the main site of aromatase expression in the adipose tissue. The current study aimed to examine the effect of des-acyl ghrelin on the capacity of mouse macrophages (RAW264.7 cells) and human adipose tissue macrophages (ATMs) to stimulate aromatase expression in primary human breast ASCs. RAW264.7 cells were treated with 0, 10 and 100pM des-acyl ghrelin following activation with phorbol 12-myristate 13-acetate, and cells and conditioned media were collected after 6 and 24h. The effect of des-acyl ghrelin on macrophage polarization was examined by assessing mRNA expression of pro-inflammatory M1-specific marker Cd11c and anti-inflammatory M2-specific marker Cd206, as well as expression of Tnf and Ptgs2, known mediators of the macrophage-dependent stimulation of aromatase. TNF protein in conditioned media was assessed by ELISA. The effect of RAW264.7 and ATM-conditioned media on aromatase expression in ASCs was assessed after 6h. Results demonstrate des-acyl ghrelin significantly increases the expression of Cd206 and suppresses the expression of Cd11c, Tnf and Ptgs2 in activated RAW264.7 cells. Treatment of RAW264.7 and ATMs with des-acyl ghrelin also significantly reduces the capacity of these cells to stimulate aromatase transcript expression in human breast ASCs. Overall, these findings suggest that in addition to direct effects on aromatase in ASCs, des-acyl ghrelin also

  17. Vitamin D and adipose tissue-more than storage.

    PubMed

    Mutt, Shivaprakash J; Hyppönen, Elina; Saarnio, Juha; Järvelin, Marjo-Riitta; Herzig, Karl-Heinz

    2014-01-01

    The pandemic increase in obesity is inversely associated with vitamin D levels. While a higher BMI was causally related to lower 25-hydroxyvitamin D (25(OH)D), no evidence was obtained for a BMI lowering effect by higher 25(OH)D. Some of the physiological functions of 1,25(OH)2D3 (1,25-dihydroxycholecalciferol or calcitriol) via its receptor within the adipose tissue have been investigated such as its effect on energy balance, adipogenesis, adipokine, and cytokine secretion. Adipose tissue inflammation has been recognized as the key component of metabolic disorders, e.g., in the metabolic syndrome. The adipose organ secretes more than 260 different proteins/peptides. However, the molecular basis of the interactions of 1,25(OH)2D3, vitamin D binding proteins (VDBPs) and nuclear vitamin D receptor (VDR) after sequestration in adipose tissue and their regulations are still unclear. 1,25(OH)2D3 and its inactive metabolites are known to inhibit the formation of adipocytes in mouse 3T3-L1 cell line. In humans, 1,25(OH)2D3 promotes preadipocyte differentiation under cell culture conditions. Further evidence of its important functions is given by VDR knock out (VDR(-/-)) and CYP27B1 knock out (CYP27B1 (-/-)) mouse models: Both VDR(-/-) and CYP27B1(-/-) models are highly resistant to the diet induced weight gain, while the specific overexpression of human VDR in adipose tissue leads to increased adipose tissue mass. The analysis of microarray datasets from human adipocytes treated with macrophage-secreted products up-regulated VDR and CYP27B1 genes indicating the capacity of adipocytes to even produce active 1,25(OH)2D3. Experimental studies demonstrate that 1,25(OH)2D3 has an active role in adipose tissue by modulating inflammation, adipogenesis and adipocyte secretion. Yet, further in vivo studies are needed to address the effects and the effective dosages of vitamin D in human adipose tissue and its relevance in the associated diseases.

  18. Retinoic acid receptor-related orphan receptor α stimulates adipose tissue inflammation by modulating endoplasmic reticulum stress.

    PubMed

    Liu, Yin; Chen, Yulong; Zhang, Jinlong; Liu, Yulan; Zhang, Yanjie; Su, Zhiguang

    2017-08-25

    Adipose tissue inflammation has been linked to metabolic diseases such as obesity and type 2 diabetes. However, the molecules that mediate inflammation in adipose tissue have not been addressed. Although retinoic acid receptor-related orphan receptor α (RORα) is known to be involved in the regulation of inflammatory response in some tissues, its role is largely unknown in adipose tissue. Conversely, it is known that endoplasmic reticulum (ER) stress and unfolding protein response (UPR) signaling affect the inflammatory response in obese adipose tissue, but whether RORα regulates these processes remains unknown. In this study, we investigate the link between RORα and adipose tissue inflammation. We showed that the inflammatory response in macrophages or 3T3-L1 adipocytes stimulated by lipopolysaccharide, as well as adipose tissue in obese mice, markedly increased the expression of RORα. Adenovirus-mediated overexpression of RORα or treatment with the RORα-specific agonist SR1078 enhanced the expression of inflammatory cytokines and increased the number of infiltrated macrophages into adipose tissue. Furthermore, SR1078 up-regulated the mRNA expression of ER stress response genes and enhanced phosphorylations of two of the three mediators of major UPR signaling pathways, PERK and IRE1α. Finally, we found that alleviation of ER stress using a chemical chaperone followed by the suppression of RORα induced inflammation in adipose tissue. Our data suggest that RORα-induced ER stress response potentially contributes to the adipose tissue inflammation that can be mitigated by treatment with chemical chaperones. The relationships established here between RORα expression, inflammation, and UPR signaling may have implications for therapeutic targeting of obesity-related metabolic diseases. © 2017 by The American Society for Biochemistry and Molecular Biology, Inc.

  19. Adipose tissue inflammation and reduced insulin sensitivity in ovariectomized mice occurs in the absence of increased adiposity

    USDA-ARS?s Scientific Manuscript database

    Menopause promotes central obesity, adipose tissue (AT) inflammation and insulin resistance (IR). Both obesity and the loss of estrogen can activate innate and adaptive immune cells (macrophages (M's), T-cells). The respective impacts of weight gain and loss of ovarian hormones on AT inflammation an...

  20. Expression of ceramide-metabolising enzymes in subcutaneous and intra-abdominal human adipose tissue

    PubMed Central

    2012-01-01

    Background Inflammation and increased ceramide concentrations characterise adipose tissue of obese women with high liver fat content compared to equally obese women with normal liver fat content. The present study characterises enzymes involved in ceramide metabolism in subcutaneous and intra-abdominal adipose tissue. Methods Pathways leading to increased ceramide concentrations in inflamed versus non-inflamed adipose tissue were investigated by quantifying expression levels of key enzymes involved in ceramide metabolism. Sphingomyelinases (sphingomyelin phosphodiesterases SMPD1-3) were investigated further using immunohistochemistry to establish their location within adipose tissue, and their mRNA expression levels were determined in subcutaneous and intra-abdominal adipose tissue from both non-obese and obese subject. Results Gene expression levels of sphingomyelinases, enzymes that hydrolyse sphingomyelin to ceramide, rather than enzymes involved in de novo ceramide synthesis, were higher in inflamed compared to non-inflamed adipose tissue of obese women (with high and normal liver fat contents respectively). Sphingomyelinases were localised to both macrophages and adipocytes, but also to blood vessels and to extracellular regions surrounding vessels within adipose tissue. Expression levels of SMPD3 mRNA correlated significantly with concentrations of different ceramides and sphingomyelins. In both non-obese and obese subjects SMPD3 mRNA levels were higher in the more inflamed intra-abdominal compared to the subcutaneous adipose tissue depot. Conclusions Generation of ceramides within adipose tissue as a result of sphingomyelinase action may contribute to inflammation in human adipose tissue. PMID:22974251

  1. Dendritic Cells Promote Macrophage Infiltration and Comprise a Substantial Proportion of Obesity-Associated Increases in CD11c+ Cells in Adipose Tissue and Liver

    PubMed Central

    Stefanovic-Racic, Maja; Yang, Xiao; Turner, Michael S.; Mantell, Benjamin S.; Stolz, Donna B.; Sumpter, Tina L.; Sipula, Ian J.; Dedousis, Nikolaos; Scott, Donald K.; Morel, Penelope A.; Thomson, Angus W.; O’Doherty, Robert M.

    2012-01-01

    Obesity-associated increases in adipose tissue (AT) CD11c+ cells suggest that dendritic cells (DC), which are involved in the tissue recruitment and activation of macrophages, may play a role in determining AT and liver immunophenotype in obesity. This study addressed this hypothesis. With the use of flow cytometry, electron microscopy, and loss-and-gain of function approaches, the contribution of DC to the pattern of immune cell alterations and recruitment in obesity was assessed. In AT and liver there was a substantial, high-fat diet (HFD)–induced increase in DC. In AT, these increases were associated with crown-like structures, whereas in liver the increase in DC constituted an early and reversible response to diet. Notably, mice lacking DC had reduced AT and liver macrophages, whereas DC replacement in DC-null mice increased liver and AT macrophage populations. Furthermore, delivery of bone marrow–derived DC to lean wild-type mice increased AT and liver macrophage infiltration. Finally, mice lacking DC were resistant to the weight gain and metabolic abnormalities of an HFD. Together, these data demonstrate that DC are elevated in obesity, promote macrophage infiltration of AT and liver, contribute to the determination of tissue immunophenotype, and play a role in systemic metabolic responses to an HFD. PMID:22851575

  2. Stevioside ameliorates high-fat diet-induced insulin resistance and adipose tissue inflammation by downregulating the NF-{kappa}B pathway

    DOE Office of Scientific and Technical Information (OSTI.GOV)

    Wang, Zhiquan; Xue, Liqiong; Guo, Cuicui

    Highlights: Black-Right-Pointing-Pointer Stevioside ameliorates high-fat diet-induced insulin resistance. Black-Right-Pointing-Pointer Stevioside alleviates the adipose tissue inflammation. Black-Right-Pointing-Pointer Stevioside reduces macrophages infiltration into the adipose tissue. Black-Right-Pointing-Pointer Stevioside suppresses the activation of NF-{kappa}B in the adipose tissue. -- Abstract: Accumulating evidence suggests that adipose tissue is the main source of pro-inflammatory molecules that predispose individuals to insulin resistance. Stevioside (SVS) is a widely used sweetener with multiple beneficial effects for diabetic patients. In this study, we investigated the effect of SVS on insulin resistance and the pro-inflammatory state of adipose tissue in mice fed with a high-fat diet (HFD). Oral administration ofmore » SVS for 1 month had no effect on body weight, but it significantly improved fasting glucose, basal insulin levels, glucose tolerance and whole body insulin sensitivity. Interestingly, these changes were accompanied with decreased expression levels of several inflammatory cytokines in adipose tissue, including TNF-{alpha}, IL6, IL10, IL1{beta}, KC, MIP-1{alpha}, CD11b and CD14. Moreover, macrophage infiltration in adipose tissue was remarkably reduced by SVS. Finally, SVS significantly suppressed the nuclear factor-kappa b (NF-{kappa}B) signaling pathway in adipose tissue. Collectively, these results suggested that SVS may ameliorate insulin resistance in HFD-fed mice by attenuating adipose tissue inflammation and inhibiting the NF-{kappa}B pathway.« less

  3. Mechanisms of Chronic State of Inflammation as Mediators That Link Obese Adipose Tissue and Metabolic Syndrome

    PubMed Central

    Fuentes, Eduardo; Fuentes, Francisco; Badimon, Lina; Palomo, Iván

    2013-01-01

    The metabolic syndrome is a cluster of cardiometabolic alterations that include the presence of arterial hypertension, insulin resistance, dyslipidemia, and abdominal obesity. Obesity is associated with a chronic inflammatory response, characterized by abnormal adipokine production, and the activation of proinflammatory signalling pathways resulting in the induction of several biological markers of inflammation. Macrophage and lymphocyte infiltration in adipose tissue may contribute to the pathogenesis of obesity-mediated metabolic disorders. Adiponectin can either act directly on macrophages to shift polarization and/or prime human monocytes into alternative M2-macrophages with anti-inflammatory properties. Meanwhile, the chronic inflammation in adipose tissue is regulated by a series of transcription factors, mainly PPARs and C/EBPs, that in conjunction regulate the expression of hundreds of proteins that participate in the metabolism and storage of lipids and, as such, the secretion by adipocytes. Therefore, the management of the metabolic syndrome requires the development of new therapeutic strategies aimed to alter the main genetic pathways involved in the regulation of adipose tissue metabolism. PMID:23843680

  4. Adipose tissue conditioned media support macrophage lipid-droplet biogenesis by interfering with autophagic flux.

    PubMed

    Bechor, Sapir; Nachmias, Dikla; Elia, Natalie; Haim, Yulia; Vatarescu, Maayan; Leikin-Frenkel, Alicia; Gericke, Martin; Tarnovscki, Tanya; Las, Guy; Rudich, Assaf

    2017-09-01

    Obesity promotes the biogenesis of adipose tissue (AT) foam cells (FC), which contribute to AT insulin resistance. Autophagy, an evolutionarily-conserved house-keeping process, was implicated in cellular lipid handling by either feeding and/or degrading lipid-droplets (LDs). We hypothesized that beyond phagocytosis of dead adipocytes, AT-FC biogenesis is supported by the AT microenvironment by regulating autophagy. Non-polarized ("M0") RAW264.7 macrophages exposed to AT conditioned media (AT-CM) exhibited a markedly enhanced LDs biogenesis rate compared to control cells (8.3 Vs 0.3 LDs/cells/h, p<0.005). Autophagic flux was decreased by AT-CM, and fluorescently following autophagosomes over time revealed ~20% decline in new autophagic vesicles' formation rate, and 60-70% decrease in autophagosomal growth rate, without marked alternations in the acidic lysosomal compartment. Suppressing autophagy by either targeting autophagosome formation (pharmacologically, with 3-methyladenine or genetically, with Atg12±Atg7-siRNA), decreased the rate of LD formation induced by oleic acid. Conversely, interfering with late autophago-lysosomal function, either pharmacologically with bafilomycin-A1, chloroquine or leupeptin, enhanced LD formation in macrophages without affecting LD degradation rate. Similarly enhanced LD biogenesis rate was induced by siRNA targeting Lamp-1 or the V-ATPase. Collectively, we propose that secreted products from AT interrupt late autophagosome maturation in macrophages, supporting enhanced LDs biogenesis and AT-FC formation, thereby contributing to AT dysfunction in obesity. Copyright © 2017 The Author(s). Published by Elsevier B.V. All rights reserved.

  5. C1q/TNF-related protein 6 (CTRP6) links obesity to adipose tissue inflammation and insulin resistance.

    PubMed

    Lei, Xia; Seldin, Marcus M; Little, Hannah C; Choy, Nicholas; Klonisch, Thomas; Wong, G William

    2017-09-08

    Obesity is associated with chronic low-grade inflammation, and metabolic regulators linking obesity to inflammation have therefore received much attention. Secreted C1q/TNF-related proteins (CTRPs) are one such group of regulators that regulate glucose and fat metabolism in peripheral tissues and modulate inflammation in adipose tissue. We have previously shown that expression of CTRP6 is up-regulated in leptin-deficient mice and, conversely, down-regulated by the anti-diabetic drug rosiglitazone. Here, we provide evidence for a novel role of CTRP6 in modulating both inflammation and insulin sensitivity. We found that in obese and diabetic humans and mouse models, CTRP6 expression was markedly up-regulated in adipose tissue and that stromal vascular cells, such as macrophages, are a major CTRP6 source. Overexpressing mouse or human CTRP6 impaired glucose disposal in peripheral tissues in response to glucose and insulin challenge in wild-type mice. Conversely, Ctrp6 gene deletion improved insulin action and increased metabolic rate and energy expenditure in diet-induced obese mice. Mechanistically, CTRP6 regulates local inflammation and glucose metabolism by targeting macrophages and adipocytes, respectively. In cultured macrophages, recombinant CTRP6 dose-dependently up-regulated the expression and production of TNF-α. Conversely, CTRP6 deficiency reduced circulating inflammatory cytokines and pro-inflammatory macrophages in adipose tissue. CTRP6-overexpressing mice or CTRP6-treated adipocytes had reduced insulin-stimulated Akt phosphorylation and glucose uptake. In contrast, loss of CTRP6 enhanced insulin-stimulated Akt activation in adipose tissue. Together, these results establish CTRP6 as a novel metabolic/immune regulator linking obesity to adipose tissue inflammation and insulin resistance. © 2017 by The American Society for Biochemistry and Molecular Biology, Inc.

  6. Metabolic inflammation in inflammatory bowel disease: crosstalk between adipose tissue and bowel.

    PubMed

    Gonçalves, Pedro; Magro, Fernando; Martel, Fátima

    2015-02-01

    Epidemiological studies show that both the incidence of inflammatory bowel disease (IBD) and the proportion of people with obesity and/or obesity-associated metabolic syndrome increased markedly in developed countries during the past half century. Obesity is also associated with the development of more active IBD and requirement for hospitalization and with a decrease in the time span between diagnosis and surgery. Patients with IBD, especially Crohn's disease, present fat-wrapping or "creeping fat," which corresponds to ectopic adipose tissue extending from the mesenteric attachment and covering the majority of the small and large intestinal surface. Mesenteric adipose tissue in patients with IBD presents several morphological and functional alterations, e.g., it is more infiltrated with immune cells such as macrophages and T cells. All these lines of evidence clearly show an association between obesity, adipose tissue, and functional bowel disorders. In this review, we will show that the mesenteric adipose tissue and creeping fat are not innocent by standers but actively contribute to the intestinal and systemic inflammatory responses in patients with IBD. More specifically, we will review evidence showing that adipose tissue in IBD is associated with major alterations in the secretion of cytokines and adipokines involved in inflammatory process, in adipose tissue mesenchymal stem cells and adipogenesis, and in the interaction between adipose tissue and other intestinal components (immune, lymphatic, neuroendocrine, and intestinal epithelial systems). Collectively, these studies underline the importance of adipose tissue for the identification of novel therapeutic approaches for IBD.

  7. Elevated Expression of Osteopontin May Be Related to Adipose Tissue Macrophage Accumulation and Liver Steatosis in Morbid Obesity

    PubMed Central

    Bertola, Adeline; Deveaux, Vanessa; Bonnafous, Stéphanie; Rousseau, Déborah; Anty, Rodolphe; Wakkach, Abdelilah; Dahman, Moncef; Tordjman, Joan; Clément, Karine; McQuaid, Siobhán E.; Frayn, Keith N.; Huet, Pierre-Michel; Gugenheim, Jean; Lotersztajn, Sophie; Le Marchand-Brustel, Yannick; Tran, Albert; Gual, Philippe

    2009-01-01

    OBJECTIVE—Osteopontin (OPN) plays an important role in the development of insulin resistance and liver complications in dietary murine models. We aimed to determine the expression pattern of OPN and its receptor CD44 in obese patients and mice according to insulin resistance and liver steatosis. RESEARCH DESIGN AND METHODS—OPN and CD44 expressions were studied in 52 morbidly obese patients and in mice. Cellular studies were performed in HepG2 cells. RESULTS—Hepatic OPN and CD44 expressions were strongly correlated with liver steatosis and insulin resistance in obese patients and mice. This increased OPN expression could be due to the accumulation of triglycerides, since fat loading in HepG2 promotes OPN expression. In contrast, OPN expression in adipose tissue (AT) was enhanced independently of insulin resistance and hepatic steatosis in obese patients. The elevated OPN expression in AT was paralleled with the AT macrophage infiltration, and both phenomena were reversed after weight loss. The circulating OPN level was slightly elevated in obese patients and was not related to liver steatosis. Further, AT did not appear to secrete OPN. In contrast, bariatric surgery–induced weight loss induced a strong increase in circulating OPN. CONCLUSIONS—The modestly elevated circulating OPN levels in morbidly obese patients were not related to liver steatosis and did not appear to result from adipose tissue secretion. In subcutaneous AT, expression of OPN was directly related to macrophage accumulation independently from liver complications. In contrast, hepatic OPN and CD44 expressions were related to insulin resistance and steatosis, suggesting their local implication in the progression of liver injury. PMID:18952835

  8. Vegetable oil induced inflammatory response by altering TLR-NF-κB signalling, macrophages infiltration and polarization in adipose tissue of large yellow croaker (Larimichthys crocea).

    PubMed

    Tan, Peng; Dong, Xiaojing; Mai, Kangsen; Xu, Wei; Ai, Qinghui

    2016-12-01

    High level of vegetable oil (VO) in diets could induce strong inflammatory response, and thus decrease nonspecific immunity and disease resistance in most marine fish species. The present study was conducted to investigate whether dietary VO could exert these anti-immunological effects by altering TLR-NF-κB signalling, macrophages infiltration and polarization in adipose tissue of large yellow croaker (Larimichthys crocea). Three iso-nitrogenous and iso-lipid diets with 0% (FO, fish oil, the control), 50% (FV, fish oil and vegetable oil mixed) and 100% (VO, vegetable oil) vegetable oil were fed to fish with three replicates for ten weeks. The results showed that activities of respiratory burst (RB) and alternative complement pathway (ACP), as well as disease resistance after immune challenge were significantly decreased in large yellow croaker fed VO diets compared to FO diets. Inflammatory response of experimental fish was markedly elevated by VO reflected by increase of pro-inflammatory cytokines (IL1β and TNFα) and decrease of anti-inflammatory cytokine (arginase I and IL10) genes expression. TLR-related genes expression, nucleus p65 protein, IKKα/β and IκBα phosphorylation were all significantly increased in the AT of large yellow croaker fed VO diets. Moreover, the expression of macrophage infiltration marker proteins (cluster of differentiation 68 [CD68] and colony-stimulating factor 1 receptor [CSF1R]) was significantly increased while the expression of anti-inflammatory M2 macrophage polarization marker proteins (macrophage mannose receptor 1 [MRC1] and cluster of differentiation 209 [CD209]) was significantly decreased in the AT of large yellow croaker fed VO diets. In conclusion, VO could induce inflammatory responses by activating TLR-NF-κB signalling, increasing macrophage infiltration into adipose tissue and polarization of macrophage in large yellow croaker. Copyright © 2016. Published by Elsevier Ltd.

  9. Adipose Tissue Is a Neglected Viral Reservoir and an Inflammatory Site during Chronic HIV and SIV Infection

    PubMed Central

    Damouche, Abderaouf; Huot, Nicolas; Dejucq-Rainsford, Nathalie; Satie, Anne-Pascale; Mélard, Adeline; David, Ludivine; Gommet, Céline; Ghosn, Jade; Noel, Nicolas; Pourcher, Guillaume; Martinez, Valérie; Benoist, Stéphane; Béréziat, Véronique; Cosma, Antonio; Favier, Benoit; Vaslin, Bruno; Rouzioux, Christine; Capeau, Jacqueline; Müller-Trutwin, Michaela; Dereuddre-Bosquet, Nathalie; Le Grand, Roger; Lambotte, Olivier; Bourgeois, Christine

    2015-01-01

    Two of the crucial aspects of human immunodeficiency virus (HIV) infection are (i) viral persistence in reservoirs (precluding viral eradication) and (ii) chronic inflammation (directly associated with all-cause morbidities in antiretroviral therapy (ART)-controlled HIV-infected patients). The objective of the present study was to assess the potential involvement of adipose tissue in these two aspects. Adipose tissue is composed of adipocytes and the stromal vascular fraction (SVF); the latter comprises immune cells such as CD4+ T cells and macrophages (both of which are important target cells for HIV). The inflammatory potential of adipose tissue has been extensively described in the context of obesity. During HIV infection, the inflammatory profile of adipose tissue has been revealed by the occurrence of lipodystrophies (primarily related to ART). Data on the impact of HIV on the SVF (especially in individuals not receiving ART) are scarce. We first analyzed the impact of simian immunodeficiency virus (SIV) infection on abdominal subcutaneous and visceral adipose tissues in SIVmac251 infected macaques and found that both adipocytes and adipose tissue immune cells were affected. The adipocyte density was elevated, and adipose tissue immune cells presented enhanced immune activation and/or inflammatory profiles. We detected cell-associated SIV DNA and RNA in the SVF and in sorted CD4+ T cells and macrophages from adipose tissue. We demonstrated that SVF cells (including CD4+ T cells) are infected in ART-controlled HIV-infected patients. Importantly, the production of HIV RNA was detected by in situ hybridization, and after the in vitro reactivation of sorted CD4+ T cells from adipose tissue. We thus identified adipose tissue as a crucial cofactor in both viral persistence and chronic immune activation/inflammation during HIV infection. These observations open up new therapeutic strategies for limiting the size of the viral reservoir and decreasing low-grade chronic

  10. Liver fat content is linked to inflammatory changes in subcutaneous adipose tissue in type 2 diabetes patients.

    PubMed

    Jansen, Henry J; Vervoort, Gerald M; van der Graaf, Marinette; Stienstra, Rinke; Tack, Cees J

    2013-11-01

    Patients with type 2 diabetes mellitus (T2DM) are typically overweight and have an increased liver fat content (LFAT). High LFAT may be explained by an increased efflux of free fatty acids from the adipose tissue, which is partly instigated by inflammatory changes. This would imply an association between inflammatory features of the adipose tissue and liver fat content. To analyse associations between inflammatory features of the adipose tissue and liver fat content. A cross-sectional study. Twenty-seven obese patients with insulin-treated T2DM were studied. LFAT content was measured by proton magnetic resonance spectroscopy. A subcutaneous (sc) fat biopsy was obtained to determine morphology and protein levels within adipose tissue. In addition to fat cell size, the percentage of macrophages and the presence of crown-like structures (CLSs) within sc fat were assessed by CD68-immunohistochemical staining. Mean LFAT percentage was 11·1 ± 1·7% (range: 0·75-32·9%); 63% of the patients were diagnosed with an elevated LFAT (upper range of normal ≤5·5%). Whereas adipocyte size did not correlate with LFAT, 3 of 4 subjects with CLSs in sc fat had elevated LFAT and the percentage of macrophages present in sc adipose tissue was positively associated with LFAT. Protein concentrations of adiponectin within adipose tissue negatively correlated with LFAT. Adipose tissue protein levels of the key inflammatory adipokine plasminogen activator inhibitor-1 (PAI-1) were positively associated with LFAT. Several pro-inflammatory changes in sc adipose tissue associate with increased LFAT content in obese insulin-treated patients with T2DM. These findings suggest that inflammatory changes at the level of the adipose tissue may drive liver fat accumulation. © 2012 John Wiley & Sons Ltd.

  11. Brown adipose tissue

    PubMed Central

    Townsend, Kristy; Tseng, Yu-Hua

    2012-01-01

    Obesity is currently a global pandemic, and is associated with increased mortality and co-morbidities including many metabolic diseases. Obesity is characterized by an increase in adipose mass due to increased energy intake, decreased energy expenditure, or both. While white adipose tissue is specialized for energy storage, brown adipose tissue has a high concentration of mitochondria and uniquely expresses uncoupling protein 1, enabling it to be specialized for energy expenditure and thermogenesis. Although brown fat was once considered only necessary in babies, recent morphological and imaging studies have provided evidence that, contrary to prior belief, this tissue is present and active in adult humans. In recent years, the topic of brown adipose tissue has been reinvigorated with many new studies regarding brown adipose tissue differentiation, function and therapeutic promise. This review summarizes the recent advances, discusses the emerging questions and offers perspective on the potential therapeutic applications targeting this tissue. PMID:23700507

  12. Adipose tissue deficiency of hormone-sensitive lipase causes fatty liver in mice

    PubMed Central

    Yang, Hao; Wang, Shu Pei; Mitchell, Grant A.

    2017-01-01

    Fatty liver is a major health problem worldwide. People with hereditary deficiency of hormone-sensitive lipase (HSL) are reported to develop fatty liver. In this study, systemic and tissue-specific HSL-deficient mice were used as models to explore the underlying mechanism of this association. We found that systemic HSL deficient mice developed fatty liver in an age-dependent fashion between 3 and 8 months of age. To further explore the mechanism of fatty liver in HSL deficiency, liver-specific HSL knockout mice were created. Surprisingly, liver HSL deficiency did not influence liver fat content, suggesting that fatty liver in HSL deficiency is not liver autonomous. Given the importance of adipose tissue in systemic triglyceride metabolism, we created adipose-specific HSL knockout mice and found that adipose HSL deficiency, to a similar extent as systemic HSL deficiency, causes age-dependent fatty liver in mice. Mechanistic study revealed that deficiency of HSL in adipose tissue caused inflammatory macrophage infiltrates, progressive lipodystrophy, abnormal adipokine secretion and systemic insulin resistance. These changes in adipose tissue were associated with a constellation of changes in liver: low levels of fatty acid oxidation, of very low density lipoprotein secretion and of triglyceride hydrolase activity, each favoring the development of hepatic steatosis. In conclusion, HSL-deficient mice revealed a complex interorgan interaction between adipose tissue and liver: the role of HSL in the liver is minimal but adipose tissue deficiency of HSL can cause age-dependent hepatic steatosis. Adipose tissue is a potential target for treating the hepatic steatosis of HSL deficiency. PMID:29232702

  13. Adipose tissue deficiency of hormone-sensitive lipase causes fatty liver in mice.

    PubMed

    Xia, Bo; Cai, Guo He; Yang, Hao; Wang, Shu Pei; Mitchell, Grant A; Wu, Jiang Wei

    2017-12-01

    Fatty liver is a major health problem worldwide. People with hereditary deficiency of hormone-sensitive lipase (HSL) are reported to develop fatty liver. In this study, systemic and tissue-specific HSL-deficient mice were used as models to explore the underlying mechanism of this association. We found that systemic HSL deficient mice developed fatty liver in an age-dependent fashion between 3 and 8 months of age. To further explore the mechanism of fatty liver in HSL deficiency, liver-specific HSL knockout mice were created. Surprisingly, liver HSL deficiency did not influence liver fat content, suggesting that fatty liver in HSL deficiency is not liver autonomous. Given the importance of adipose tissue in systemic triglyceride metabolism, we created adipose-specific HSL knockout mice and found that adipose HSL deficiency, to a similar extent as systemic HSL deficiency, causes age-dependent fatty liver in mice. Mechanistic study revealed that deficiency of HSL in adipose tissue caused inflammatory macrophage infiltrates, progressive lipodystrophy, abnormal adipokine secretion and systemic insulin resistance. These changes in adipose tissue were associated with a constellation of changes in liver: low levels of fatty acid oxidation, of very low density lipoprotein secretion and of triglyceride hydrolase activity, each favoring the development of hepatic steatosis. In conclusion, HSL-deficient mice revealed a complex interorgan interaction between adipose tissue and liver: the role of HSL in the liver is minimal but adipose tissue deficiency of HSL can cause age-dependent hepatic steatosis. Adipose tissue is a potential target for treating the hepatic steatosis of HSL deficiency.

  14. Overall Adiposity, Adipose Tissue Distribution, and Endometriosis: A Systematic Review.

    PubMed

    Backonja, Uba; Buck Louis, Germaine M; Lauver, Diane R

    2016-01-01

    Endometriosis has been associated with a lean body habitus. However, we do not understand whether endometriosis is also associated with other characteristics of adiposity, including adipose tissue distribution and amount of visceral adipose tissue (VAT; adipose tissue lining inner organs). Having these understandings may provide insights on how endometriosis develops-some of the physiological actions of adipose tissue differ depending on tissue amount and location and are related to proposed mechanisms of endometriosis development. The aim of this study was to review the literature regarding overall adiposity, adipose tissue distribution and/or VAT, and endometriosis. We reviewed and synthesized studies indexed in PubMed and/or Web of Science. We included studies that had one or more measures of overall adiposity, adipose tissue distribution, and/or VAT and women with and without endometriosis for comparison. We summarized the findings and commented on the methods used and potential sources of bias. Of 366 identified publications, 19 (5.2%) were eligible. Two additional publications were identified from reference lists. Current research included measures of overall adiposity (e.g., body figure drawings) or adipose tissue distribution (e.g., waist-to-hip ratio), but not VAT. The weight of evidence indicated that endometriosis was associated with low overall adiposity and with a preponderance of adipose tissue distributed below the waist (peripheral). Endometriosis may be associated with being lean or having peripherally distributed adipose tissue. Well-designed studies with various sampling frameworks and precise measures of adiposity and endometriosis are needed to confirm associations between adiposity measures and endometriosis and delineate potential etiological mechanisms underlying endometriosis.

  15. Overall Adiposity, Adipose Tissue Distribution, and Endometriosis: A Systematic Review

    PubMed Central

    Backonja, Uba; Buck Louis, Germaine M.; Lauver, Diane R.

    2015-01-01

    Background Endometriosis has been associated with a lean body habitus. However, we do not understand whether endometriosis is also associated with other characteristics of adiposity, including adipose tissue distribution and amount of visceral adipose tissue (VAT; adipose tissue lining inner organs). Having these understandings may provide insights on how endometriosis develops—some of the physiologic actions of adipose tissue differ depending on tissue amount and location, and are related to proposed mechanisms of endometriosis development. Objectives To review the literature regarding overall adiposity, adipose tissue distribution and/or VAT, and endometriosis. Methods We reviewed and synthesized studies indexed in PubMed and/or Web of Science. We included studies that had one or more measures of overall adiposity, adipose tissue distribution, and/or VAT, and women with and without endometriosis for comparison. We summarized the findings and commented on the methods used and potential sources of bias. Results Out of 366 identified publications, 19 (5.2%) were eligible. Two additional publications were identified from reference lists. Current research included measures of overall adiposity (e.g., body figure drawings) or adipose tissue distribution (e.g., waist-to-hip ratio), but not VAT. The weight of evidence indicated that endometriosis was associated with low overall adiposity and with a preponderance of adipose tissue distributed below the waist (peripheral). Discussion Endometriosis may be associated with being lean or having peripherally distributed adipose tissue. Well-designed studies with various sampling frameworks and precise measures of adiposity and endometriosis are needed to confirm associations between adiposity measures and endometriosis, and delineate potential etiologic mechanisms underlying endometriosis. PMID:26938364

  16. Regulation of Small Ubiquitin-Like Modifier-1, Nuclear Receptor Coreceptor, Histone Deacetylase 3, and Peroxisome Proliferator-Activated Receptor-γ in Human Adipose Tissue

    PubMed Central

    Bodles-Brakhop, Angela M.; Yao-Borengasser, Aiwei; Zhu, Beibei; Starnes, Catherine P.; McGehee, Robert E.; Peterson, Charlotte A.; Kern, Philip A.

    2012-01-01

    Abstract Background This study investigated the regulation of peroxisome proliferator-activated receptor-γ (PPARγ), the histone deacetylase 3 (HDAC3)–nuclear receptor coreceptor (NCoR) complex (a corepressor of transcription used by PPARγ), and small ubiquitin-like modifier-1 (SUMO-1) (a posttranslational modifier of PPARγ) in human adipose tissue and both adipocyte and macrophage cell lines. The objective was to determine whether there were alterations in the human adipose tissue gene expression levels of PPARγ, HDAC3, NCoR, and SUMO-1 associated either with obesity or with treatment of impaired glucose tolerance (IGT) subjects with insulin-sensitizing medications. Methods We obtained subcutaneous adipose tissue biopsies from 86 subjects with a wide range of body mass index (BMI) and insulin sensitivity (SI). Additionally, adipose tissue biopsies were obtained from a randomized subgroup of IGT subjects before and after 10 weeks of treatment with either pioglitazone or metformin. Results The adipose mRNA levels of PPARγ, NCoR, HDAC3, and SUMO-1 correlated strongly with each other (P<0.0001); however, SUMO-1, NCoR, and HDAC3 gene expression were not significantly associated with BMI or SI. Pioglitazone increased SUMO-1 expression by 23% (P<0.002) in adipose tissue and an adipocyte cell line (P<0.05), but not in macrophages. Small interfering RNA (siRNA)-mediated knockdown of SUMO-1 decreased PPARγ, HDAC3, and NCoR in THP-1 cells and increased tumor necrosis factor-α (TNF-α) induction in response to lipopolysaccharide (LPS). Conclusions These results suggest that the coordinate regulation of SUMO-1, PPARγ1/2, HDAC3, and NCoR may be more tightly controlled in macrophages than in adipocytes in human adipose and that these modulators of PPARγ activity may be particularly important in the negative regulation of macrophage-mediated adipose inflammation by pioglitazone. PMID:22651256

  17. Improvement of adipose tissue-derived cells by low-energy extracorporeal shock wave therapy.

    PubMed

    Priglinger, Eleni; Schuh, Christina M A P; Steffenhagen, Carolin; Wurzer, Christoph; Maier, Julia; Nuernberger, Sylvia; Holnthoner, Wolfgang; Fuchs, Christiane; Suessner, Susanne; Rünzler, Dominik; Redl, Heinz; Wolbank, Susanne

    2017-09-01

    Cell-based therapies with autologous adipose tissue-derived cells have shown great potential in several clinical studies in the last decades. The majority of these studies have been using the stromal vascular fraction (SVF), a heterogeneous mixture of fibroblasts, lymphocytes, monocytes/macrophages, endothelial cells, endothelial progenitor cells, pericytes and adipose-derived stromal/stem cells (ASC) among others. Although possible clinical applications of autologous adipose tissue-derived cells are manifold, they are limited by insufficient uniformity in cell identity and regenerative potency. In our experimental set-up, low-energy extracorporeal shock wave therapy (ESWT) was performed on freshly obtained human adipose tissue and isolated adipose tissue SVF cells aiming to equalize and enhance stem cell properties and functionality. After ESWT on adipose tissue we could achieve higher cellular adenosine triphosphate (ATP) levels compared with ESWT on the isolated SVF as well as the control. ESWT on adipose tissue resulted in a significantly higher expression of single mesenchymal and vascular marker compared with untreated control. Analysis of SVF protein secretome revealed a significant enhancement in insulin-like growth factor (IGF)-1 and placental growth factor (PLGF) after ESWT on adipose tissue. Summarizing we could show that ESWT on adipose tissue enhanced the cellular ATP content and modified the expression of single mesenchymal and vascular marker, and thus potentially provides a more regenerative cell population. Because the effectiveness of autologous cell therapy is dependent on the therapeutic potency of the patient's cells, this technology might raise the number of patients eligible for autologous cell transplantation. Copyright © 2017 International Society for Cellular Therapy. Published by Elsevier Inc. All rights reserved.

  18. Role of A1 and A2A adenosine receptor agonists in adipose tissue inflammation induced by obesity in mice.

    PubMed

    DeOliveira, Caroline Candida; Paiva Caria, Cintia Rabelo E; Ferreira Gotardo, Erica Martins; Ribeiro, Marcelo Lima; Gambero, Alessandra

    2017-03-15

    Adenosine receptors are expressed in adipose tissue and control physiological and pathological events such as lipolysis and inflammation. The aim of this study was to evaluate the activity of N 6 -cyclopentyladenosine (CPA), a potent and selective A 1 adenosine receptor agonist; 2-p-(2-carboxyethyl)phenethylamino-5'-N-ethylcarboxyamidoadenosine hydrochloride (CGS-21680), an A 2A adenosine receptor agonist; and 5'-N-ethylcarboxamidoadenosine (NECA), a potent non-selective adenosine receptor agonist on adipose tissue inflammatory alterations induced by obesity in mice. Swiss mice were fed with a high-fat diet for 12 weeks and agonists were administered in the last two weeks. Body weight, adiposity and glucose homeostasis were evaluated. Inflammation in adipose tissue was assessed by evaluation of adipokine production and macrophage infiltration. Adenosine receptor signaling in adipose tissue was also evaluated. Mice that received CGS21680 presented an improvement in glucose homeostasis in association with systemically reduced inflammatory markers (TNF-α, PAI-1) and in the visceral adipose tissue (TNF-α, MCP-1, macrophage infiltration). Activation of p38 signaling was found in adipose tissue of this group of mice. NECA-treated mice presented some improvements in glucose homeostasis associated with an observed weight loss. Mice that received CPA presented only a reduction in the ex vivo basal lipolysis rate measured within visceral adipose tissue. In conclusion, administration of the A 2A receptor agonist to obese mice resulted in improvements in glucose homeostasis and adipose tissue inflammation, corroborating the idea that new therapeutics to treat obesity could emerge from these compounds. Copyright © 2017 Elsevier B.V. All rights reserved.

  19. Supercritical carbon dioxide extracted extracellular matrix material from adipose tissue.

    PubMed

    Wang, Jun Kit; Luo, Baiwen; Guneta, Vipra; Li, Liang; Foo, Selin Ee Min; Dai, Yun; Tan, Timothy Thatt Yang; Tan, Nguan Soon; Choong, Cleo; Wong, Marcus Thien Chong

    2017-06-01

    Adipose tissue is a rich source of extracellular matrix (ECM) material that can be isolated by delipidating and decellularizing the tissue. However, the current delipidation and decellularization methods either involve tedious and lengthy processes or require toxic chemicals, which may result in the elimination of vital proteins and growth factors found in the ECM. Hence, an alternative delipidation and decellularization method for adipose tissue was developed using supercritical carbon dioxide (SC-CO 2 ) that eliminates the need of any harsh chemicals and also reduces the amount of processing time required. The resultant SC-CO 2 -treated ECM material showed an absence of nuclear content but the preservation of key proteins such as collagen Type I, collagen Type III, collagen Type IV, elastin, fibronectin and laminin. In addition, other biological factors such as glycosaminoglycans (GAGs) and growth factors such as basic fibroblast growth factor (bFGF) and vascular endothelial growth factor (VEGF) were also retained. Subsequently, the resulting SC-CO 2 -treated ECM material was used as a bioactive coating on tissue culture plastic (TCP). Four different cell types including adipose tissue-derived mesenchymal stem cells (ASCs), human umbilical vein endothelial cells (HUVECs), immortalized human keratinocyte (HaCaT) cells and human monocytic leukemia cells (THP-1) were used in this study to show that the SC-CO 2 -treated ECM coating can be potentially used for various biomedical applications. The SC-CO 2 -treated ECM material showed improved cell-material interactions for all cell types tested. In addition, in vitro scratch wound assay using HaCaT cells showed that the presence of SC-CO 2 -treated ECM material enhanced keratinocyte migration whilst the in vitro cellular studies using THP-1-derived macrophages showed that the SC-CO 2 -treated ECM material did not evoke pro-inflammatory responses from the THP-1-derived macrophages. Overall, this study shows the efficacy

  20. Collecting lymphatic vessel permeability facilitates adipose tissue inflammation and distribution of antigen to lymph node-homing adipose tissue dendritic cells.

    PubMed

    Kuan, Emma L; Ivanov, Stoyan; Bridenbaugh, Eric A; Victora, Gabriel; Wang, Wei; Childs, Ed W; Platt, Andrew M; Jakubzick, Claudia V; Mason, Robert J; Gashev, Anatoliy A; Nussenzweig, Michel; Swartz, Melody A; Dustin, Michael L; Zawieja, David C; Randolph, Gwendalyn J

    2015-06-01

    Collecting lymphatic vessels (CLVs), surrounded by fat and endowed with contractile muscle and valves, transport lymph from tissues after it is absorbed into lymphatic capillaries. CLVs are not known to participate in immune responses. In this study, we observed that the inherent permeability of CLVs allowed broad distribution of lymph components within surrounding fat for uptake by adjacent macrophages and dendritic cells (DCs) that actively interacted with CLVs. Endocytosis of lymph-derived Ags by these cells supported recall T cell responses in the fat and also generated Ag-bearing DCs for emigration into adjacent lymph nodes (LNs). Enhanced recruitment of DCs to inflammation-reactive LNs significantly relied on adipose tissue DCs to maintain sufficient numbers of Ag-bearing DCs as the LN expanded. Thus, CLVs coordinate inflammation and immunity within adipose depots and foster the generation of an unexpected pool of APCs for Ag transport into the adjacent LN. Copyright © 2015 by The American Association of Immunologists, Inc.

  1. Amyloid Precursor Protein and Proinflammatory Changes Are Regulated in Brain and Adipose Tissue in a Murine Model of High Fat Diet-Induced Obesity

    PubMed Central

    Puig, Kendra L.; Floden, Angela M.; Adhikari, Ramchandra; Golovko, Mikhail Y.; Combs, Colin K.

    2012-01-01

    Background Middle age obesity is recognized as a risk factor for Alzheimer's disease (AD) although a mechanistic linkage remains unclear. Based upon the fact that obese adipose tissue and AD brains are both areas of proinflammatory change, a possible common event is chronic inflammation. Since an autosomal dominant form of AD is associated with mutations in the gene coding for the ubiquitously expressed transmembrane protein, amyloid precursor protein (APP) and recent evidence demonstrates increased APP levels in adipose tissue during obesity it is feasible that APP serves some function in both disease conditions. Methodology/Principal Findings To determine whether diet-induced obesity produced proinflammatory changes and altered APP expression in brain versus adipose tissue, 6 week old C57BL6/J mice were maintained on a control or high fat diet for 22 weeks. Protein levels and cell-specific APP expression along with markers of inflammation and immune cell activation were compared between hippocampus, abdominal subcutaneous fat and visceral pericardial fat. APP stimulation-dependent changes in macrophage and adipocyte culture phenotype were examined for comparison to the in vivo changes. Conclusions/Significance Adipose tissue and brain from high fat diet fed animals demonstrated increased TNF-α and microglial and macrophage activation. Both brains and adipose tissue also had elevated APP levels localizing to neurons and macrophage/adipocytes, respectively. APP agonist antibody stimulation of macrophage cultures increased specific cytokine secretion with no obvious effects on adipocyte culture phenotype. These data support the hypothesis that high fat diet-dependent obesity results in concomitant pro-inflammatory changes in brain and adipose tissue that is characterized, in part, by increased levels of APP that may be contributing specifically to inflammatory changes that occur. PMID:22276186

  2. Catalpol ameliorates high-fat diet-induced insulin resistance and adipose tissue inflammation by suppressing the JNK and NF-κB pathways

    DOE Office of Scientific and Technical Information (OSTI.GOV)

    Zhou, Jun, E-mail: hustzhj@hust.edu.cn; Xu, Gang; Ma, Shuai

    Catalpol, a bioactive component from the root of Rehmannia glutinosa, has been shown to possess hypoglycemic effects in type 2 diabetic animal models, however, the underlying mechanisms remain poorly understood. Here we investigated the effect of catalpol on high-fat diet (HFD)-induced insulin resistance and adipose tissue inflammation in mice. Oral administration of catalpol at 100 mg/kg for 4 weeks had no effect on body weight of HFD-induced obese mice, but it significantly improved fasting glucose and insulin levels, glucose tolerance and insulin tolerance. Moreover, macrophage infiltration into adipose tissue was markedly reduced by catalpol. Intriguingly, catalpol also significantly reduced mRNA expressionsmore » of M1 pro-inflammatory cytokines, but increased M2 anti-inflammatory gene expressions in adipose tissue. Concurrently, catalpol significantly suppressed the c-Jun NH2-terminal kinase (JNK) and nuclear factor-kappa B (NF-κB) signaling pathways in adipose tissue. Collectively, these results suggest that catalpol may ameliorate HFD-induced insulin resistance in mice by attenuating adipose tissue inflammation and suppressing the JNK and NF-κB pathways, and thus provide important new insights into the underlying mechanisms of the antidiabetic effect of catalpol. - Highlights: • Catalpol ameliorates high-fat diet (HFD)-induced insulin resistance in mice. • Catalpol reduces adipose tissue macrophage infiltration in HFD-fed mice. • Catalpol regulates M1 and M2 inflammatory gene expression in obese adipose tissue. • Catalpol suppresses the JNK and NF-κB signaling pathways in obese adipose tissue.« less

  3. (n-3) Fatty Acids Alleviate Adipose Tissue Inflammation and Insulin Resistance: Mechanistic Insights12

    PubMed Central

    Kalupahana, Nishan S.; Claycombe, Kate J.; Moustaid-Moussa, Naima

    2011-01-01

    Obesity is associated with the metabolic syndrome, a significant risk factor for developing type 2 diabetes and cardiovascular diseases. Chronic low-grade inflammation occurring in the adipose tissue of obese individuals is causally linked to the pathogenesis of insulin resistance and the metabolic syndrome. Although the exact trigger of this inflammatory process is unknown, adipose tissue hypoxia, endoplasmic reticular stress, and saturated fatty acid–mediated activation of innate immune processes have been identified as important processes in these disorders. Furthermore, macrophages and T lymphocytes have important roles in orchestrating this immune process. Although energy restriction leading to weight loss is the primary dietary intervention to reverse these obesity-associated metabolic disorders, other interventions targeted at alleviating adipose tissue inflammation have not been explored in detail. In this regard, (n-3) PUFA of marine origin both prevent and reverse high-fat-diet–induced adipose tissue inflammation and insulin resistance in rodents. We provide an update on the pathogenesis of adipose tissue inflammation and insulin resistance in obesity and discuss potential mechanisms by which (n-3) PUFA prevent and reverse these changes and the implications in human health. PMID:22332072

  4. Exosome-Like Vesicles Derived from Adipose Tissue Provide Biochemical Cues for Adipose Tissue Regeneration.

    PubMed

    Dai, Minjia; Yu, Mei; Zhang, Yan; Tian, Weidong

    2017-11-01

    There is an emerging need for soft tissue replacements in the field of reconstructive surgery for the treatment of congenital deformities, posttraumatic repair, and cancer rehabilitation. Previous studies have shown that the bioactive adipose tissue extract can induce adipogenesis without additional stem cells or growth factors. In this study, we innovatively investigated whether exosome-like vesicles derived from adipose tissue (ELV-AT) could direct stem cell differentiation and trigger adipose tissue regeneration. In vitro, ELV-AT can induce adipogenesis of adipose-derived stem cells and promote proliferation, migration, and angiogenic potential of the aorta endothelial cells. In vivo, ELV-AT were transplanted to a chamber on the back of nude mice and neoadipose tissues were formed. Our findings indicated that ELV-AT could be used as a cell-free therapeutic approach for adipose tissue regeneration.

  5. Regulation of metabolic health and adipose tissue function by group 2 innate lymphoid cells

    PubMed Central

    Cautivo, Kelly M.; Molofsky, Ari B.

    2016-01-01

    Adipose tissue (AT) is home to an abundance of immune cells. With chronic obesity, inflammatory immune cells accumulate and promote insulin resistance and the progression to type 2 diabetes mellitus (T2DM). In contrast, recent studies have highlighted the regulation and function of immune cells in lean, healthy adipose tissue, including those associated with type 2 or “allergic” immunity. Although traditionally activated by infection with multicellular helminthes, AT type 2 immunity is active independently of infection, and promotes tissue homeostasis, adipose tissue “browning”, and systemic insulin sensitivity, protecting against obesity-induced metabolic dysfunction and T2DM. In particular, group 2 innate lymphoid cells (ILC2s) are integral regulators of AT type 2 immunity, producing the cytokines IL-5 and IL-13, promoting eosinophils and alternatively activated macrophages, and cooperating with and promoting AT regulatory T (Treg) cells. In this review, we focus on the recent developments in our understanding of ILC2 cells and type 2 immunity in adipose tissue metabolism and homeostasis. PMID:27120716

  6. Isolation, Characterization, and Purification of Macrophages from Tissues Affected by Obesity-related Inflammation.

    PubMed

    Allen, Joselyn N; Dey, Adwitia; Nissly, Ruth; Fraser, James; Yu, Shan; Balandaram, Gayathri; Peters, Jeffrey M; Hankey-Giblin, Pamela A

    2017-04-03

    Obesity promotes a chronic inflammatory state that is largely mediated by tissue-resident macrophages as well as monocyte-derived macrophages. Diet-induced obesity (DIO) is a valuable model in studying the role of macrophage heterogeneity; however, adequate macrophage isolations are difficult to acquire from inflamed tissues. In this protocol, we outline the isolation steps and necessary troubleshooting guidelines derived from our studies for obtaining a suitable population of tissue-resident macrophages from mice following 18 weeks of high-fat (HFD) or high-fat/high-cholesterol (HFHCD) diet intervention. This protocol focuses on three hallmark tissues studied in obesity and atherosclerosis including the liver, white adipose tissues (WAT), and the aorta. We highlight how dualistic usage of flow cytometry can achieve a new dimension of isolation and characterization of tissue-resident macrophages. A fundamental section of this protocol addresses the intricacies underlying tissue-specific enzymatic digestions and macrophage isolation, and subsequent cell-surface antibody staining for flow cytometric analysis. This protocol addresses existing complexities underlying fluorescent-activated cell sorting (FACS) and presents clarifications to these complexities so as to obtain broad range characterization from adequately sorted cell populations. Alternate enrichment methods are included for sorting cells, such as the dense liver, allowing for flexibility and time management when working with FACS. In brief, this protocol aids the researcher to evaluate macrophage heterogeneity from a multitude of inflamed tissues in a given study and provides insightful troubleshooting tips that have been successful for favorable cellular isolation and characterization of immune cells in DIO-mediated inflammation.

  7. An adipoinductive role of inflammation in adipose tissue engineering: key factors in the early development of engineered soft tissues.

    PubMed

    Lilja, Heidi E; Morrison, Wayne A; Han, Xiao-Lian; Palmer, Jason; Taylor, Caroline; Tee, Richard; Möller, Andreas; Thompson, Erik W; Abberton, Keren M

    2013-05-15

    Tissue engineering and cell implantation therapies are gaining popularity because of their potential to repair and regenerate tissues and organs. To investigate the role of inflammatory cytokines in new tissue development in engineered tissues, we have characterized the nature and timing of cell populations forming new adipose tissue in a mouse tissue engineering chamber (TEC) and characterized the gene and protein expression of cytokines in the newly developing tissues. EGFP-labeled bone marrow transplant mice and MacGreen mice were implanted with TEC for periods ranging from 0.5 days to 6 weeks. Tissues were collected at various time points and assessed for cytokine expression through ELISA and mRNA analysis or labeled for specific cell populations in the TEC. Macrophage-derived factors, such as monocyte chemotactic protein-1 (MCP-1), appear to induce adipogenesis by recruiting macrophages and bone marrow-derived precursor cells to the TEC at early time points, with a second wave of nonbone marrow-derived progenitors. Gene expression analysis suggests that TNFα, LCN-2, and Interleukin 1β are important in early stages of neo-adipogenesis. Increasing platelet-derived growth factor and vascular endothelial cell growth factor expression at early time points correlates with preadipocyte proliferation and induction of angiogenesis. This study provides new information about key elements that are involved in early development of new adipose tissue.

  8. The "Big Bang" in obese fat: Events initiating obesity-induced adipose tissue inflammation.

    PubMed

    Wensveen, Felix M; Valentić, Sonja; Šestan, Marko; Turk Wensveen, Tamara; Polić, Bojan

    2015-09-01

    Obesity is associated with the accumulation of pro-inflammatory cells in visceral adipose tissue (VAT), which is an important underlying cause of insulin resistance and progression to diabetes mellitus type 2 (DM2). Although the role of pro-inflammatory cytokines in disease development is established, the initiating events leading to immune cell activation remain elusive. Lean adipose tissue is predominantly populated with regulatory cells, such as eosinophils and type 2 innate lymphocytes. These cells maintain tissue homeostasis through the excretion of type 2 cytokines, such as IL-4, IL-5, and IL-13, which keep adipose tissue macrophages (ATMs) in an anti-inflammatory, M2-like state. Diet-induced obesity is associated with the loss of tissue homeostasis and development of type 1 inflammatory responses in VAT, characterized by IFN-γ. A key event is a shift of ATMs toward an M1 phenotype. Recent studies show that obesity-induced adipocyte hypertrophy results in upregulated surface expression of stress markers. Adipose stress is detected by local sentinels, such as NK cells and CD8(+) T cells, which produce IFN-γ, driving M1 ATM polarization. A rapid accumulation of pro-inflammatory cells in VAT follows, leading to inflammation. In this review, we provide an overview of events leading to adipose tissue inflammation, with a special focus on adipose homeostasis and the obesity-induced loss of homeostasis which marks the initiation of VAT inflammation. © 2015 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

  9. Adipose tissue in myocardial infarction.

    PubMed

    Su, Leon; Siegel, John E; Fishbein, Michael C

    2004-01-01

    The histologic evolution of myocardial infarction (MI) has been studied in some detail. However, there is little mention of the presence of adipose tissue in healed MI(HMI). Ninety-one hearts explanted during 1997-2001 were examined to determine the extent of adipose tissue within HMI. The medical records, surgical pathology reports, and all histologic sections of the explanted heart, from patients undergoing heart transplantation for ischemic heart disease, were reviewed. Adipose tissue within the areas of HMI was quantified. The location of the HMI, the age and gender of the patient, age of HMI, and whether the patient was treated with coronary artery bypass surgery (CABG) were noted. Of the 91 hearts examined, 168 HMIs were identified; 141 (84%) contained some mature fat within the HMI. Adipose tissue increased with increasing age, in males, and in those patients who had CABG surgery. The amount of adipose tissue was not related to the location or age of the HMI. Adipose tissue is a prevalent histological finding in HMIs. The pathogenesis of adipose tissue is unknown, but may be influenced by current medical therapy for ischemic heart disease, thus explaining why adipose tissue in HMIs was not reported until 1997. The presence of fat supports the speculation that a regenerative cell, or multipotent stem cell, exists within the heart, and under the influence of microenvironmental or therapeutic factors can differentiate into fat, other mesenchymal tissues, and potentially even myocardium.

  10. Decellularized skin/adipose tissue flap matrix for engineering vascularized composite soft tissue flaps.

    PubMed

    Zhang, Qixu; Johnson, Joshua A; Dunne, Lina W; Chen, Youbai; Iyyanki, Tejaswi; Wu, Yewen; Chang, Edward I; Branch-Brooks, Cynthia D; Robb, Geoffrey L; Butler, Charles E

    2016-04-15

    Using a perfusion decellularization protocol, we developed a decellularized skin/adipose tissue flap (DSAF) comprising extracellular matrix (ECM) and intact vasculature. Our DSAF had a dominant vascular pedicle, microcirculatory vascularity, and a sensory nerve network and retained three-dimensional (3D) nanofibrous structures well. DSAF, which was composed of collagen and laminin with well-preserved growth factors (e.g., vascular endothelial growth factor, basic fibroblast growth factor), was successfully repopulated with human adipose-derived stem cells (hASCs) and human umbilical vein endothelial cells (HUVECs), which integrated with DSAF and formed 3D aggregates and vessel-like structures in vitro. We used microsurgery techniques to re-anastomose the recellularized DSAF into nude rats. In vivo, the engineered flap construct underwent neovascularization and constructive remodeling, which was characterized by the predominant infiltration of M2 macrophages and significant adipose tissue formation at 3months postoperatively. Our results indicate that DSAF co-cultured with hASCs and HUVECs is a promising platform for vascularized soft tissue flap engineering. This platform is not limited by the flap size, as the entire construct can be immediately perfused by the recellularized vascular network following simple re-integration into the host using conventional microsurgical techniques. Significant soft tissue loss resulting from traumatic injury or tumor resection often requires surgical reconstruction using autologous soft tissue flaps. However, the limited availability of qualitative autologous flaps as well as the donor site morbidity significantly limits this approach. Engineered soft tissue flap grafts may offer a clinically relevant alternative to the autologous flap tissue. In this study, we engineered vascularized soft tissue free flap by using skin/adipose flap extracellular matrix scaffold (DSAF) in combination with multiple types of human cells. Following

  11. Flaxseed Oil Alleviates Chronic HFD-Induced Insulin Resistance through Remodeling Lipid Homeostasis in Obese Adipose Tissue.

    PubMed

    Yu, Xiao; Tang, Yuhan; Liu, Peiyi; Xiao, Lin; Liu, Liegang; Shen, Ruiling; Deng, Qianchun; Yao, Ping

    2017-11-08

    Emerging evidence suggests that higher circulating long-chain n-3 polyunsaturated fatty acids (n-3PUFA) levels were intimately associated with lower prevalence of obesity and insulin resistance. However, the understanding of bioactivity and potential mechanism of α-linolenic acid-rich flaxseed oil (ALA-FO) against insulin resistance was still limited. This study evaluated the effect of FO on high-fat diet (HFD)-induced insulin resistance in C57BL/6J mice focused on adipose tissue lipolysis. Mice after HFD feeding for 16 weeks (60% fat-derived calories) exhibited systemic insulin resistance, which was greatly attenuated by medium dose of FO (M-FO), paralleling with differential accumulation of ALA and its n-3 derivatives across serum lipid fractions. Moreover, M-FO was sufficient to effectively block the metabolic activation of adipose tissue macrophages (ATMs), thereby improving adipose tissue insulin signaling. Importantly, suppression of hypoxia-inducible factors HIF-1α and HIF-2α were involved in FO-mediated modulation of adipose tissue lipolysis, accompanied by specific reconstitution of n-3PUFA within adipose tissue lipid fractions.

  12. Chronic hyperinsulinemia promotes meta-inflammation and extracellular matrix deposition in adipose tissue: Implications of nitric oxide.

    PubMed

    Kumar, Durgesh; Shankar, Kripa; Patel, Saraswati; Gupta, Abhishek; Varshney, Salil; Gupta, Sanchita; Rajan, Sujith; Srivastava, Ankita; Vishwakarma, Achchhe Lal; Gaikwad, Anil N

    2018-05-10

    Various imperative studies support the notion that hyperinsulinemia (HI) itself serves as the common link between adipose tissue inflammation (ATI) and metabolic syndrome. However, the contribution of HI mediated ATI and its metabolic consequences are yet to be explored. We induced chronic HI per se in mice by administration of exogenous insulin for 8 weeks through mini-osmotic pumps. For the reduction of circulating insulin in response to excess calorie intake, we have partially ablated β-cells by using streptozotocin (STZ) in the diet-induced obesity (DIO) and genetic mice models (db/db). Flow cytometry analysis was performed for the quantification of immune cells in stromal vascular fraction (SVF) isolated from epididymal white adipose tissue (eWAT). Our studies demonstrated that chronic HI augmented ATI in terms of elevated pro-inflammatory cells (M1 macrophages and NK-cells) and suppressed anti-inflammatory cells (M2 macrophages, eosinophils and regulatory T-cells). These results were correlated with altered obesity-associated metabolic phenotype. Partial reduction of circulating insulin level attenuated excess calorie-induced ATI and improved insulin sensitivity. Mechanistically, an imbalance in M1 and M2 macrophage proportions in eWAT promoted iNOS (inducible nitric oxide synthase): arginase-1 imbalance that resulted into extracellular matrix (ECM) deposition and insulin resistance (IR) development. However, iNOS -/- mice were protected from HI-induced M1:M2 macrophage imbalance, ECM deposition and IR in adipose tissue. Overall, we conclude that chronic HI per se contributed in ATI and iNOS corroborated ECM deposition. Copyright © 2018. Published by Elsevier B.V.

  13. Increased Adipocyte Size, Macrophage Infiltration, and Adverse Local Adipokine Profile in Perirenal Fat in Cushing's Syndrome.

    PubMed

    Roerink, Sean H P P; Wagenmakers, Margreet A E M; Langenhuijsen, Johan F; Ballak, Dov B; Rooijackers, Hanne M M; d'Ancona, Frank C; van Dielen, François M; Smit, Jan W A; Plantinga, Theo S; Netea-Maier, Romana T; Hermus, Ad R M M

    2017-08-01

    To analyze changes in fat cell size, macrophage infiltration, and local adipose tissue adipokine profiles in different fat depots in patients with active Cushing's syndrome. Subcutaneous (SC) and perirenal (PR) adipose tissue of 10 patients with Cushing's syndrome was compared to adipose tissue of 10 gender-, age-, and BMI-matched controls with regard to adipocyte size determined by digital image analysis on hematoxylin and eosin stainings, macrophage infiltration determined by digital image analysis on CD68 stainings, and adipose tissue leptin and adiponectin levels using fluorescent bead immunoassays and ELISA techniques. Compared to the controls, mean adipocyte size was larger in PR adipose tissue in patients. The percentage of macrophage infiltration of the PR adipose tissue and PR adipose tissue lysate leptin levels were higher and adiponectin levels were lower in SC and PR adipose tissue lysates in patients. The adiponectin levels were also lower in the SC adipose tissue supernatants of patients. Associations were found between the severity of hypercortisolism and PR adipocyte size. Cushing's syndrome is associated with hypertrophy of PR adipocytes and a higher percentage of macrophage infiltration in PR adipose tissue. These changes are associated with an adverse local adipokine profile. © 2017 The Obesity Society.

  14. Compound C inhibits macrophage chemotaxis through an AMPK-independent mechanism

    DOE Office of Scientific and Technical Information (OSTI.GOV)

    Lee, Youngyi; Department of Biochemistry, Chonbuk National University Medical School, Jeonju, Jeonbuk 54896; Park, Byung-Hyun, E-mail: bhpark@jbnu.ac.kr

    Macrophage infiltration in adipose tissue is a well-established cause of obesity-linked insulin resistance. AMP-activated protein kinase (AMPK) activation in peripheral tissues such as adipose tissue has beneficial effects on the protection against obesity-induced insulin resistance, which is mainly mediated by prevention of adipose tissue macrophage infiltration and inflammation. In examining the role of AMPK on adipose tissue inflammation, we unexpectedly found that compound C (CC), despite its inhibition of AMPK, robustly inhibited macrophage chemotaxis in RAW 264.7 cells when adipocyte conditioned medium (CM) was used as a chemoattractant. Here, we report that CC inhibition of macrophage migration occurred independently ofmore » AMPK. Mechanistically, this inhibitory effect of cell migration by CC was mediated by inhibition of the focal adhesion kinase, AKT, nuclear factor κB pathways. Moreover, the expression of chemokine monocyte chemoattractant protein-1 and pro-inflammatory genes such as tumor necrosis factor α and inducible nitric oxide synthase were prevented by CC treatment in RAW 264.7 cells stimulated with either adipocyte CM or lipopolysaccharide. Lastly, in accord with the findings of the anti-inflammatory effect of CC, we demonstrated that CC functioned as a repressor of macrophage CM-mediated insulin resistance in adipocytes. Taken together, our results suggest that CC serves as a useful inhibitory molecule against macrophage chemotaxis into adipose tissue and thus might have therapeutic potential for the treatment of obesity-linked adipose inflammation. - Highlights: • Compound C (CC) inhibits macrophage chemotaxis regardless of AMPK suppression. • CC enhances insulin sensitivity in adipocytes. • CC inhibits focal adhesion kinase, AKT, and NF-κB signaling in RAW 264.7 cells.« less

  15. Immune response in the adipose tissue of lean mice infected with the protozoan parasite Neospora caninum

    PubMed Central

    Teixeira, Luzia; Moreira, João; Melo, Joana; Bezerra, Filipa; Marques, Raquel M; Ferreirinha, Pedro; Correia, Alexandra; Monteiro, Mariana P; Ferreira, Paula G; Vilanova, Manuel

    2015-01-01

    The adipose tissue can make important contributions to immune function. Nevertheless, only a limited number of reports have investigated in lean hosts the immune response elicited in this tissue upon infection. Previous studies suggested that the intracellular protozoan Neospora caninum might affect adipose tissue physiology. Therefore, we investigated in mice challenged with this protozoan if immune cell populations within adipose tissue of different anatomical locations could be differently affected. Early in infection, parasites were detected in the adipose tissue and by 7 days of infection increased numbers of macrophages, regulatory T (Treg) cells and T-bet+ cells were observed in gonadal, mesenteric, omental and subcutaneous adipose tissue. Increased expression of interferon-γ was also detected in gonadal adipose tissue of infected mice. Two months after infection, parasite DNA was no longer detected in these tissues, but T helper type 1 (Th1) cell numbers remained above control levels in the infected mice. Moreover, the Th1/Treg cell ratio was higher than that of controls in the mesenteric and subcutaneous adipose tissue. Interestingly, chronically infected mice presented a marked increase of serum leptin, a molecule that plays a role in energy balance regulation as well as in promoting Th1-type immune responses. Altogether, we show that an apicomplexa parasitic infection influences immune cellular composition of adipose tissue throughout the body as well as adipokine production, still noticed at a chronic phase of infection when parasites were already cleared from that particular tissue. This strengthens the emerging view that infections can have long-term consequences for the physiology of adipose tissue. PMID:25581844

  16. Reduced Adipose Tissue Oxygenation in Human Obesity

    PubMed Central

    Pasarica, Magdalena; Sereda, Olga R.; Redman, Leanne M.; Albarado, Diana C.; Hymel, David T.; Roan, Laura E.; Rood, Jennifer C.; Burk, David H.; Smith, Steven R.

    2009-01-01

    OBJECTIVE— Based on rodent studies, we examined the hypothesis that increased adipose tissue (AT) mass in obesity without an adequate support of vascularization might lead to hypoxia, macrophage infiltration, and inflammation. RESEARCH DESIGN AND METHODS— Oxygen partial pressure (AT pO2) and AT temperature in abdominal AT (9 lean and 12 overweight/obese men and women) was measured by direct insertion of a polarographic Clark electrode. Body composition was measured by dual-energy X-ray absorptiometry, and insulin sensitivity was measured by hyperinsulinemic-euglycemic clamp. Abdominal subcutaneous tissue was used for staining, quantitative RT-PCR, and chemokine secretion assay. RESULTS— AT pO2 was lower in overweight/obese subjects than lean subjects (47 ± 10.6 vs. 55 ± 9.1 mmHg); however, this level of pO2 did not activate the classic hypoxia targets (pyruvate dehydrogenase kinase and vascular endothelial growth factor [VEGF]). AT pO2 was negatively correlated with percent body fat (R = −0.50, P < 0.05). Compared with lean subjects, overweight/obese subjects had 44% lower capillary density and 58% lower VEGF, suggesting AT rarefaction (capillary drop out). This might be due to lower peroxisome proliferator–activated receptor γ1 and higher collagen VI mRNA expression, which correlated with AT pO2 (P < 0.05). Of clinical importance, AT pO2 negatively correlated with CD68 mRNA and macrophage inflammatory protein 1α secretion (R = −0.58, R = −0.79, P < 0.05), suggesting that lower AT pO2 could drive AT inflammation in obesity. CONCLUSIONS— Adipose tissue rarefaction might lie upstream of both low AT pO2 and inflammation in obesity. These results suggest novel approaches to treat the dysfunctional AT found in obesity. PMID:19074987

  17. Mesenchymal Stem Cells From Bone Marrow, Adipose Tissue, and Lung Tissue Differentially Mitigate Lung and Distal Organ Damage in Experimental Acute Respiratory Distress Syndrome.

    PubMed

    Silva, Johnatas D; Lopes-Pacheco, Miquéias; Paz, Ana H R; Cruz, Fernanda F; Melo, Elga B; de Oliveira, Milena V; Xisto, Débora G; Capelozzi, Vera L; Morales, Marcelo M; Pelosi, Paolo; Cirne-Lima, Elizabeth; Rocco, Patricia R M

    2018-02-01

    Mesenchymal stem cells-based therapies have shown promising effects in experimental acute respiratory distress syndrome. Different mesenchymal stem cells sources may result in diverse effects in respiratory diseases; however, there is no information regarding the best source of mesenchymal stem cells to treat pulmonary acute respiratory distress syndrome. We tested the hypothesis that mesenchymal stem cells derived from bone marrow, adipose tissue, and lung tissue would lead to different beneficial effects on lung and distal organ damage in experimental pulmonary acute respiratory distress syndrome. Animal study and primary cell culture. Laboratory investigation. Seventy-five Wistar rats. Wistar rats received saline (control) or Escherichia coli lipopolysaccharide (acute respiratory distress syndrome) intratracheally. On day 2, acute respiratory distress syndrome animals were further randomized to receive saline or bone marrow, adipose tissue, or lung tissue mesenchymal stem cells (1 × 10 cells) IV. Lung mechanics, histology, and protein levels of inflammatory mediators and growth factors were analyzed 5 days after mesenchymal stem cells administration. RAW 264.7 cells (a macrophage cell line) were incubated with lipopolysaccharide followed by coculture or not with bone marrow, adipose tissue, and lung tissue mesenchymal stem cells (10 cells/mL medium). Regardless of mesenchymal stem cells source, cells administration improved lung function and reduced alveolar collapse, tissue cellularity, collagen, and elastic fiber content in lung tissue, as well as decreased apoptotic cell counts in liver. Bone marrow and adipose tissue mesenchymal stem cells administration also reduced levels of tumor necrosis factor-α, interleukin-1β, keratinocyte-derived chemokine, transforming growth factor-β, and vascular endothelial growth factor, as well as apoptotic cell counts in lung and kidney, while increasing expression of keratinocyte growth factor in lung tissue

  18. Macrophages: development and tissue specialization.

    PubMed

    Varol, Chen; Mildner, Alexander; Jung, Steffen

    2015-01-01

    Macrophages are myeloid immune cells that are strategically positioned throughout the body tissues, where they ingest and degrade dead cells, debris, and foreign material and orchestrate inflammatory processes. Here we review two major recent paradigm shifts in our understanding of tissue macrophage biology. The first is the realization that most tissue-resident macrophages are established prenatally and maintained through adulthood by longevity and self-renewal. Their generation and maintenance are thus independent from ongoing hematopoiesis, although the cells can be complemented by adult monocyte-derived macrophages. Second, aside from being immune sentinels, tissue macrophages form integral components of their host tissue. This entails their specialization in response to local environmental cues to contribute to the development and specific function of their tissue of residence. Factors that govern tissue macrophage specialization are emerging. Moreover, tissue specialization is reflected in discrete gene expression profiles of macrophages, as well as epigenetic signatures reporting actual and potential enhancer usage.

  19. Comparison of Dorsocervical With Abdominal Subcutaneous Adipose Tissue in Patients With and Without Antiretroviral Therapy–Associated Lipodystrophy

    PubMed Central

    Sevastianova, Ksenia; Sutinen, Jussi; Greco, Dario; Sievers, Meline; Salmenkivi, Kaisa; Perttilä, Julia; Olkkonen, Vesa M.; Wågsäter, Dick; Lidell, Martin E.; Enerbäck, Sven; Eriksson, Per; Walker, Ulrich A.; Auvinen, Petri; Ristola, Matti; Yki-Järvinen, Hannele

    2011-01-01

    OBJECTIVE Combination antiretroviral therapy (cART) is associated with lipodystrophy, i.e., loss of subcutaneous adipose tissue in the abdomen, limbs, and face and its accumulation intra-abdominally. No fat is lost dorsocervically and it can even accumulate in this region (buffalo hump). It is unknown how preserved dorsocervical fat differs from abdominal subcutaneous fat in HIV-1–infected cART-treated patients with (cART+LD+) and without (cART+LD−) lipodystrophy. RESEARCH DESIGN AND METHODS We used histology, microarray, PCR, and magnetic resonance imaging to compare dorsocervical and abdominal subcutaneous adipose tissue in cART+LD+ (n = 21) and cART+LD− (n = 11). RESULTS Albeit dorsocervical adipose tissue in cART+LD+ seems spared from lipoatrophy, its mitochondrial DNA (mtDNA; copies/cell) content was significantly lower (by 62%) than that of the corresponding tissue in cART+LD−. Expression of CD68 mRNA, a marker of macrophages, and numerous inflammatory genes in microarray were significantly lower in dorsocervical versus abdominal subcutaneous adipose tissue. Genes with the greatest difference in expression between the two depots were those involved in regulation of transcription and regionalization (homeobox genes), irrespective of lipodystrophy status. There was negligible mRNA expression of uncoupling protein 1, a gene characteristic of brown adipose tissue, in either depot. CONCLUSIONS Because mtDNA is depleted even in the nonatrophic dorsocervical adipose tissue, it is unlikely that the cause of lipoatrophy is loss of mtDNA. Dorsocervical adipose tissue is less inflamed than lipoatrophic adipose tissue. It does not resemble brown adipose tissue. The greatest difference in gene expression between dorsocervical and abdominal subcutaneous adipose tissue is in expression of homeobox genes. PMID:21602514

  20. Adipose tissue-organotypic culture system as a promising model for studying adipose tissue biology and regeneration

    PubMed Central

    Uchihashi, Kazuyoshi; Aoki, Shigehisa; Sonoda, Emiko; Yamasaki, Fumio; Piao, Meihua; Ootani, Akifumi; Yonemitsu, Nobuhisa; Sugihara, Hajime

    2009-01-01

    Adipose tissue consists of mature adipocytes, preadipocytes and mesenchymal stem cells (MSCs), but a culture system for analyzing their cell types within the tissue has not been established. We have recently developed “adipose tissue-organotypic culture system” that maintains unilocular structure, proliferative ability and functions of mature adipocytes for a long term, using three-dimensional collagen gel culture of the tissue fragments. In this system, both preadipocytes and MSCs regenerate actively at the peripheral zone of the fragments. Our method will open up a new way for studying both multiple cell types within adipose tissue and the cell-based mechanisms of obesity and metabolic syndrome. Thus, it seems to be a promising model for investigating adipose tissue biology and regeneration. In this article, we introduce adipose tissue-organotypic culture, and propose two theories regarding the mechanism of tissue regeneration that occurs specifically at peripheral zone of tissue fragments in vitro. PMID:19794899

  1. The Pathogenesis of Obesity-Associated Adipose Tissue Inflammation.

    PubMed

    Engin, Atilla

    2017-01-01

    Obesity is characterized by a state of chronic, low-grade inflammation. However, excessive fatty acid release may worsen adipose tissue inflammation and contributes to insulin resistance. In this case, several novel and highly active molecules are released abundantly by adipocytes like leptin, resistin, adiponectin or visfatin, as well as some more classical cytokines. Most likely cytokines that are released by inflammatory cells infiltrating obese adipose tissue are such as tumor necrosis factor-alpha (TNF-alpha), interleukin 6 (IL-6), monocyte chemoattractant protein 1 (MCP-1) (CCL-2) and IL-1. All of those molecules may act on immune cells leading to local and generalized inflammation. In this process, toll-like receptor 4 (TLR4)/phosphatidylinositol-3'-kinase (PI3K)/Protein kinase B (Akt) signaling pathway, the unfolded protein response (UPR) due to endoplasmic reticulum (ER) stress through hyperactivation of c-Jun N-terminal Kinase (JNK) -Activator Protein 1 (AP1) and inhibitor of nuclear factor kappa-B kinase beta (IKKbeta)-nuclear factor kappa B (NF-kappaB) pathways play an important role, and may also affect vascular endothelial function by modulating vascular nitric oxide and superoxide release. Additionally, systemic oxidative stress, macrophage recruitment, increase in the expression of NOD-like receptor (NLR) family protein (NLRP3) inflammasone and adipocyte death are predominant determinants in the pathogenesis of obesity-associated adipose tissue inflammation. In this chapter potential involvement of these factors that contribute to the adverse effects of obesity are reviewed.

  2. Microbiota depletion promotes browning of white adipose tissue and reduces obesity

    PubMed Central

    Chevalier, Claire; Stojanović, Ozren; Colin, Didier J.; Stevanović, Ana; Veyrat-Durebex, Christelle; Tarallo, Valentina; Rigo, Dorothée; Germain, Stéphane; Ilievska, Miroslava; Montet, Xavier; Seimbille, Yann; Hapfelmeier, Siegfried; Trajkovski, Mirko

    2015-01-01

    Brown adipose tissue (BAT) promotes a lean and healthy phenotype and improves insulin sensitivity1. In response to cold or exercise brown fat cells also emerge in the white adipose tissue (named beige cells), a process known as browning2,3,4. Here, we show that the development of functional beige fat is promoted by microbiota depletion either by antibiotic treatment or in germ-free mice within the inguinal subcutaneous and perigonadal visceral adipose tissues (ingSAT and pgVAT, respectively). This leads to improved glucose tolerance, insulin sensitivity and decreased white fat and adipocyte size in lean mice and obese leptin-deficient (ob/ob) and high fat diet (HFD)-fed mice. These metabolic improvements are mediated by eosinophil infiltration and enhanced type 2 cytokine signaling and M2 macrophage polarization in the subcutaneous white fat depots of microbiota-depleted animals. The metabolic phenotype and the browning of the subcutaneous fat are impaired by suppression of the type 2 signaling and are reversed by recolonization of the antibiotic-treated, or the germ-free mice with microbes. These results provide insight into microbiota-fat signaling axis and beige fat development in health and metabolic disease. PMID:26569380

  3. Increased asthma and adipose tissue inflammatory gene expression with obesity and Inuit migration to a western country.

    PubMed

    Backer, Vibeke; Baines, Katherine J; Powell, Heather; Porsbjerg, Celeste; Gibson, Peter G

    2016-02-01

    An overlap between obesity and asthma exists, and inflammatory cells in adipose tissue could drive the development of asthma. Comparison of adipose tissue gene expression among Inuit living in Greenland to those in Denmark provides an opportunity to assess how changes in adipose tissue inflammation can be modified by migration and diet. To examine mast cell and inflammatory markers in adipose tissue and the association with asthma. Two Inuit populations were recruited, one living in Greenland and another in Denmark. All underwent adipose subcutaneous biopsy, followed by clinical assessment of asthma, and measurement of AHR. Adipose tissue biopsies were homogenised, RNA extracted, and PCR was performed to determine the relative gene expression of mast cell (tryptase, chymase, CPA3) and inflammatory markers (IL-6, IL-1β, and CD163). Of the 1059 Greenlandic Inuit participants, 556 were living in Greenland and 6.4% had asthma. Asthma was increased in Denmark (9%) compared to Greenland (3.6%, p < 0.0001) and associated with increased adipose tissue IL-6 gene expression and increased BMI. There was no association between asthma and adipose tissue mast cell gene expression. Pro-inflammatory gene expression (IL-6, IL-1β) was higher in those living in Denmark, and with increasing BMI and dietary changes. The anti-inflammatory (M2) macrophage marker, CD163, was higher in Greenland-dwelling Inuit (p < 0.01). No association was found between gene expression of mast cell markers in adipose tissue and asthma. Among Greenlandic Inuit, adipose tissue inflammation is also increased in those who migrate to Denmark, possibly as a result of dietary changes. Copyright © 2015 Elsevier Ltd. All rights reserved.

  4. Very-long-chain ω-3 fatty acid supplements and adipose tissue functions: a randomized controlled trial.

    PubMed

    Hames, Kazanna C; Morgan-Bathke, Maria; Harteneck, Debra A; Zhou, Lendia; Port, John D; Lanza, Ian R; Jensen, Michael D

    2017-06-01

    Background: Increased omega-3 (n-3) fatty acid consumption is reported to benefit patients with metabolic syndrome, possibly due to improved adipose tissue function. Objective: We tested the effects of high-dose, very-long-chain ω-3 fatty acids on adipose tissue inflammation and insulin regulation of lipolysis. Design: A double-blind, placebo-controlled study compared 6 mo of 3.9 g eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA)/d (4.2 g total ω-3/d; n = 12) with a placebo (4.2 g oleate/d; n = 9) in insulin-resistant adults. Before and after treatment, the volunteers underwent adipose tissue biopsies to measure the total (CD68 + ), pro- (CD14 + = M1), and anti- (CD206 + = M2) inflammatory macrophages, crown-like structures, and senescent cells, as well as a 2-step pancreatic clamping with a [U- 13 C]palmitate infusion to determine the insulin concentration needed to suppress palmitate flux by 50% (IC 50(palmitate) f). Results: In the ω-3 group, the EPA and DHA contributions to plasma free fatty acids increased ( P = 0.0003 and P = 0.003, respectively), as did the EPA and DHA content in adipose tissue ( P < 0.0001 and P < 0.0001, respectively). Despite increases in adipose and plasma EPA and DHA in the ω-3 group, there were no significant changes in the IC 50(palmitate) f (19 ± 2 compared with 24 ± 3 μIU/mL), adipose macrophages (total: 31 ± 2/100 adipocytes compared with 33 ± 2/100 adipocytes; CD14 + : 13 ± 2/100 adipocytes compared with 14 ± 2/100 adipocytes; CD206 + : 28 ± 2/100 adipocytes compared with 29 ± 3/100 adipocytes), crown-like structures (1 ± 0/10 images compared with 1 ± 0/10 images), or senescent cells (4% ± 1% compared with 4% ± 1%). There were no changes in these outcomes in the placebo group. Conclusions: Six months of high-dose ω-3 supplementation raised plasma and adipose ω-3 fatty acid concentrations but had no beneficial effects on adipose tissue lipolysis or inflammation in insulin-resistant adults. This trial

  5. Loss of PPAR gamma in immune cells impairs the ability of abscisic acid to improve insulin sensitivity by suppressing monocyte chemoattractant protein-1 expression and macrophage infiltration into white adipose tissue.

    PubMed

    Guri, Amir J; Hontecillas, Raquel; Ferrer, Gerardo; Casagran, Oriol; Wankhade, Umesh; Noble, Alexis M; Eizirik, Decio L; Ortis, Fernanda; Cnop, Miriam; Liu, Dongmin; Si, Hongwei; Bassaganya-Riera, Josep

    2008-04-01

    Abscisic acid (ABA) is a natural phytohormone and peroxisome proliferator-activated receptor gamma (PPARgamma) agonist that significantly improves insulin sensitivity in db/db mice. Although it has become clear that obesity is associated with macrophage infiltration into white adipose tissue (WAT), the phenotype of adipose tissue macrophages (ATMs) and the mechanisms by which insulin-sensitizing compounds modulate their infiltration remain unknown. We used a loss-of-function approach to investigate whether ABA ameliorates insulin resistance through a mechanism dependent on immune cell PPARgamma. We characterized two phenotypically distinct ATM subsets in db/db mice based on their surface expression of F4/80. F4/80(hi) ATMs were more abundant and expressed greater concentrations of chemokine receptor (CCR) 2 and CCR5 when compared to F4/80(lo) ATMs. ABA significantly decreased CCR2(+) F4/80(hi) infiltration into WAT and suppressed monocyte chemoattractant protein-1 (MCP-1) expression in WAT and plasma. Furthermore, the deficiency of PPARgamma in immune cells, including macrophages, impaired the ability of ABA to suppress the infiltration of F4/80(hi) ATMs into WAT, to repress WAT MCP-1 expression and to improve glucose tolerance. We provide molecular evidence in vivo demonstrating that ABA improves insulin sensitivity and obesity-related inflammation by inhibiting MCP-1 expression and F4/80(hi) ATM infiltration through a PPARgamma-dependent mechanism.

  6. Berberine alleviates adipose tissue fibrosis by inducing AMP-activated kinase signaling in high-fat diet-induced obese mice.

    PubMed

    Wang, Lijun; Ye, Xiao; Hua, Yanyin; Song, Yingxiang

    2018-05-28

    Adipose tissue fibrosis is a novel mechanism for the development of obesity related insulin resistance. Berberine (BBR) has been shown to relieve several metabolic disorders, including obesity and type 2 diabetes. However, the effects of BBR on obesity related adipose fibrosis remain poorly understood. The objective of this study was to assess the effects of BBR on adipose tissue fibrosis in high fat diet (HFD)-induced obese mice. The results showed that BBR reduced animal body weight and significantly improved glucose tolerance in HFD mice. In addition, BBR treatment markedly attenuated collagen deposition and reversed the up-regulation of fibrosis associated genes in the adipose tissue of HFD mice. Moreover, BBR treatment activated AMP-activated kinase signaling and reduced TGF-β1 and Smad3 phosphorylation. Of note, the inhibitory effects of BBR on adipose tissue fibrosis were significantly blocked by AMPK inhibition with compound C, an AMPK inhibitor. Macrophage infiltration and polarization induced by HFD were also reversed after BBR administration. These findings suggest that BBR displays beneficial effects in the treatment of obesity, in part via improvement of adipose tissue fibrosis. Copyright © 2018 Elsevier Masson SAS. All rights reserved.

  7. Adipose and mammary epithelial tissue engineering.

    PubMed

    Zhu, Wenting; Nelson, Celeste M

    2013-01-01

    Breast reconstruction is a type of surgery for women who have had a mastectomy, and involves using autologous tissue or prosthetic material to construct a natural-looking breast. Adipose tissue is the major contributor to the volume of the breast, whereas epithelial cells comprise the functional unit of the mammary gland. Adipose-derived stem cells (ASCs) can differentiate into both adipocytes and epithelial cells and can be acquired from autologous sources. ASCs are therefore an attractive candidate for clinical applications to repair or regenerate the breast. Here we review the current state of adipose tissue engineering methods, including the biomaterials used for adipose tissue engineering and the application of these techniques for mammary epithelial tissue engineering. Adipose tissue engineering combined with microfabrication approaches to engineer the epithelium represents a promising avenue to replicate the native structure of the breast.

  8. Adipose and mammary epithelial tissue engineering

    PubMed Central

    Zhu, Wenting; Nelson, Celeste M.

    2013-01-01

    Breast reconstruction is a type of surgery for women who have had a mastectomy, and involves using autologous tissue or prosthetic material to construct a natural-looking breast. Adipose tissue is the major contributor to the volume of the breast, whereas epithelial cells comprise the functional unit of the mammary gland. Adipose-derived stem cells (ASCs) can differentiate into both adipocytes and epithelial cells and can be acquired from autologous sources. ASCs are therefore an attractive candidate for clinical applications to repair or regenerate the breast. Here we review the current state of adipose tissue engineering methods, including the biomaterials used for adipose tissue engineering and the application of these techniques for mammary epithelial tissue engineering. Adipose tissue engineering combined with microfabrication approaches to engineer the epithelium represents a promising avenue to replicate the native structure of the breast. PMID:23628872

  9. IGF1 Shapes Macrophage Activation in Response to Immunometabolic Challenge.

    PubMed

    Spadaro, Olga; Camell, Christina D; Bosurgi, Lidia; Nguyen, Kim Y; Youm, Yun-Hee; Rothlin, Carla V; Dixit, Vishwa Deep

    2017-04-11

    In concert with their phagocytic activity, macrophages are thought to regulate the host immunometabolic responses primarily via their ability to produce specific cytokines and metabolites. Here, we show that IL-4-differentiated, M2-like macrophages secrete IGF1, a hormone previously thought to be exclusively produced from liver. Ablation of IGF1 receptors from myeloid cells reduced phagocytosis, increased macrophages in adipose tissue, elevated adiposity, lowered energy expenditure, and led to insulin resistance in mice fed a high-fat diet. The investigation of adipose macrophage phenotype in obese myeloid IGF1R knockout (MIKO) mice revealed a reduction in transcripts associated with M2-like macrophage activation. Furthermore, the MIKO mice infected with helminth Nippostrongylus brasiliensis displayed delayed resolution from infection with normal insulin sensitivity. Surprisingly, cold challenge did not trigger an overt M2-like state and failed to induce tyrosine hydroxylase expression in adipose tissue macrophages of control or MIKO mice. These results show that IGF1 signaling shapes the macrophage-activation phenotype. Copyright © 2017 The Author(s). Published by Elsevier Inc. All rights reserved.

  10. Irbesartan increased PPAR{gamma} activity in vivo in white adipose tissue of atherosclerotic mice and improved adipose tissue dysfunction

    DOE Office of Scientific and Technical Information (OSTI.GOV)

    Iwai, Masaru; Kanno, Harumi; Senba, Izumi

    2011-03-04

    Research highlights: {yields} Atherosclerotic apolipoprotein E-deficient (ApoEKO) mice were treated with irbesartan. {yields} Irbesartan decreased white adipose tissue weight without affecting body weight. {yields} DNA-binding for PPAR{gamma} was increased in white adipose tissue in vivo by irbesartan. {yields} Irbesartan increased adipocyte number in white adipose tissue. {yields} Irbesatan increased the expression of adiponectin and leptin in white adipose tissue. -- Abstract: The effect of the PPAR{gamma} agonistic action of an AT{sub 1} receptor blocker, irbesartan, on adipose tissue dysfunction was explored using atherosclerotic model mice. Adult male apolipoprotein E-deficient (ApoEKO) mice at 9 weeks of age were treated with amore » high-cholesterol diet (HCD) with or without irbesartan at a dose of 50 mg/kg/day for 4 weeks. The weight of epididymal and retroperitoneal adipose tissue was decreased by irbesartan without changing food intake or body weight. Treatment with irbesartan increased the expression of PPAR{gamma} in white adipose tissue and the DNA-binding activity of PPAR{gamma} in nuclear extract prepared from adipose tissue. The expression of adiponectin, leptin and insulin receptor was also increased by irbesartan. These results suggest that irbesartan induced activation of PPAR{gamma} and improved adipose tissue dysfunction including insulin resistance.« less

  11. Is epicardial adipose tissue, assessed by echocardiography, a reliable method for visceral adipose tissue prediction?

    PubMed

    Silaghi, Alina Cristina; Poantă, Laura; Valea, Ana; Pais, Raluca; Silaghi, Horatiu

    2011-03-01

    Epicardial adipose tissue is an ectopic fat storage at the heart surface in direct contact with the coronary arteries. It is considered a metabolically active tissue, being a local source of pro-inflammatory factors that contribute to the pathogenesis of coronary artery disease. The AIM of our study was to establish correlations between echocardiographic assessment of epicardial adipose tissue and anthropometric and ultrasound measurements of the central and peripheral fat depots. The study was conducted on 22 patients with or without coronaropathy. Epicardial adipose tissue was measured using Aloka Prosound α 10 machine with a 3.5-7.5 MHz variable-frequency transducer and subcutaneous and visceral fat with Esaote Megas GPX machine and 3.5-7.5 MHz variable frequency transducer. Epicardial adipose tissue measured by echocardiography is correlated with waist circumference (p < 0.05), visceral adipose tissue thickness measured by ultrasonography (US) and is not correlated with body mass index (p = 0.315), hip and thigh circumference or subcutaneous fat thickness measured by US. Our study confirms that US assessment of epicardial fat correlates with anthropometric and US measurements of the central fat, representing an indirect but reliable marker of the visceral fat.

  12. Quantification of Adipose Tissue Leukocytosis in Obesity

    PubMed Central

    Grant, Ryan; Youm, Yun-Hee; Ravussin, Anthony; Dixit, Vishwa Deep

    2014-01-01

    Summary The infiltration of immune cell subsets in adipose tissue termed ‘adipose tissue leukocytosis’ is a critical event in the development of chronic inflammation and obesity-associated comorbidities. Given that a significant proportion of cells in adipose tissue of obese patients are of hematopoietic lineage, the distinct adipose depots represent an uncharacterized immunological organ that can impact metabolic functions. Here, we describe approaches to characterize and isolate leukocytes from the complex adipose tissue microenvironment to aid mechanistic studies to understand the role of specific pattern recognition receptors (PRRs) such as inflammasomes in adipose-immune crosstalk. PMID:23852606

  13. CCR2 deficiency leads to increased eosinophils, alternative macrophage activation, and type 2 cytokine expression in adipose tissue.

    PubMed

    Bolus, W Reid; Gutierrez, Dario A; Kennedy, Arion J; Anderson-Baucum, Emily K; Hasty, Alyssa H

    2015-10-01

    Adipose tissue (AT) inflammation during obesity is mediated by immune cells and closely correlates with systemic insulin resistance. In lean AT, eosinophils are present in low but significant numbers and capable of promoting alternative macrophage activation in an IL-4/IL-13-dependent manner. In WT mice, obesity causes the proportion of AT eosinophils to decline, concomitant with inflammation and classical activation of AT macrophages. In this study, we show that CCR2 deficiency leads to increased eosinophil accumulation in AT. Furthermore, in contrast to WT mice, the increase in eosinophils in CCR2(-/-) AT is sustained and even amplified during obesity. Interestingly, a significant portion of eosinophils is found in CLSs in AT of obese CCR2(-/-) mice, which is the first time eosinophils have been shown to localize to these inflammatory hot spots. CCR2(-/-) bone marrow precursors displayed increased expression of various key eosinophil genes during in vitro differentiation to eosinophils, suggesting a potentially altered eosinophil phenotype in the absence of CCR2. In addition, the proportion of eosinophils in AT positively correlated with local expression of Il5, a potent eosinophil stimulator. The increase in eosinophils in CCR2(-/-) mice was detected in all white fat pads analyzed and in the peritoneal cavity but not in bone marrow, blood, spleen, or liver. In AT of CCR2(-/-) mice, an increased eosinophil number positively correlated with M2-like macrophages, expression of the Treg marker Foxp3, and type 2 cytokines, Il4, Il5, and Il13. This is the first study to link CCR2 function with regulation of AT eosinophil accumulation. © Society for Leukocyte Biology.

  14. CCR2 deficiency leads to increased eosinophils, alternative macrophage activation, and type 2 cytokine expression in adipose tissue

    PubMed Central

    Bolus, W. Reid; Gutierrez, Dario A.; Kennedy, Arion J.; Anderson-Baucum, Emily K.; Hasty, Alyssa H.

    2015-01-01

    Adipose tissue (AT) inflammation during obesity is mediated by immune cells and closely correlates with systemic insulin resistance. In lean AT, eosinophils are present in low but significant numbers and capable of promoting alternative macrophage activation in an IL-4/IL-13-dependent manner. In WT mice, obesity causes the proportion of AT eosinophils to decline, concomitant with inflammation and classical activation of AT macrophages. In this study, we show that CCR2 deficiency leads to increased eosinophil accumulation in AT. Furthermore, in contrast to WT mice, the increase in eosinophils in CCR2−/− AT is sustained and even amplified during obesity. Interestingly, a significant portion of eosinophils is found in CLSs in AT of obese CCR2−/− mice, which is the first time eosinophils have been shown to localize to these inflammatory hot spots. CCR2−/− bone marrow precursors displayed increased expression of various key eosinophil genes during in vitro differentiation to eosinophils, suggesting a potentially altered eosinophil phenotype in the absence of CCR2. In addition, the proportion of eosinophils in AT positively correlated with local expression of Il5, a potent eosinophil stimulator. The increase in eosinophils in CCR2−/− mice was detected in all white fat pads analyzed and in the peritoneal cavity but not in bone marrow, blood, spleen, or liver. In AT of CCR2−/− mice, an increased eosinophil number positively correlated with M2-like macrophages, expression of the Treg marker Foxp3, and type 2 cytokines, Il4, Il5, and Il13. This is the first study to link CCR2 function with regulation of AT eosinophil accumulation. PMID:25934927

  15. Depletion of H2S during obesity enhances store-operated Ca2+ entry in adipose tissue macrophages to increase cytokine production.

    PubMed

    Velmurugan, Gopal V; Huang, Huiya; Sun, Hongbin; Candela, Joseph; Jaiswal, Mukesh K; Beaman, Kenneth D; Yamashita, Megumi; Prakriya, Murali; White, Carl

    2015-12-15

    The increased production of proinflammatory cytokines by adipose tissue macrophages (ATMs) contributes to chronic, low-level inflammation during obesity. We found that obesity in mice reduced the bioavailability of the gaseous signaling molecule hydrogen sulfide (H2S). Steady-state, intracellular concentrations of H2S were lower in ATMs isolated from mice with diet-induced obesity than in ATMs from lean mice. In addition, the intracellular concentration of H2S in the macrophage cell line RAW264.7 was reduced during an acute inflammatory response evoked by the microbial product lipopolysaccharide (LPS). Reduced intracellular concentrations of H2S led to increased Ca(2+) influx through the store-operated Ca(2+) entry (SOCE) pathway, which was prevented by the exogenous H2S donor GYY4137. Furthermore, GYY4137 inhibited the Orai3 channel, a key component of the SOCE machinery. The enhanced production of proinflammatory cytokines by RAW264.7 cells and ATMs from obese mice was reduced by exogenous H2S or by inhibition of SOCE. Together, these data suggest that the depletion of macrophage H2S that occurs during acute (LPS-induced) or chronic (obesity) inflammation increases SOCE through disinhibition of Orai3 and promotes the production of proinflammatory cytokines. Copyright © 2015, American Association for the Advancement of Science.

  16. Adipose Tissue Quantification by Imaging Methods: A Proposed Classification

    PubMed Central

    Shen, Wei; Wang, ZiMian; Punyanita, Mark; Lei, Jianbo; Sinav, Ahmet; Kral, John G.; Imielinska, Celina; Ross, Robert; Heymsfield, Steven B.

    2007-01-01

    Recent advances in imaging techniques and understanding of differences in the molecular biology of adipose tissue has rendered classical anatomy obsolete, requiring a new classification of the topography of adipose tissue. Adipose tissue is one of the largest body compartments, yet a classification that defines specific adipose tissue depots based on their anatomic location and related functions is lacking. The absence of an accepted taxonomy poses problems for investigators studying adipose tissue topography and its functional correlates. The aim of this review was to critically examine the literature on imaging of whole body and regional adipose tissue and to create the first systematic classification of adipose tissue topography. Adipose tissue terminology was examined in over 100 original publications. Our analysis revealed inconsistencies in the use of specific definitions, especially for the compartment termed “visceral” adipose tissue. This analysis leads us to propose an updated classification of total body and regional adipose tissue, providing a well-defined basis for correlating imaging studies of specific adipose tissue depots with molecular processes. PMID:12529479

  17. Isolation and Differentiation of Murine Macrophages.

    PubMed

    Rios, Francisco J; Touyz, Rhian M; Montezano, Augusto C

    2017-01-01

    Macrophages play a major role in inflammation, wound healing, and tissue repair. Infiltrated monocytes differentiate into different macrophage subtypes with protective or pathogenic activities in vascular lesions. In the heart and vascular tissues, pathological activation promotes cardiovascular inflammation and remodeling and there is increasing evidence that macrophages play important mechanisms in this environment. Primary murine macrophages can be obtained from: bone marrow by different treatments (granulocyte-macrophage colony-stimulating factor-GM-CSF, macrophage colony-stimulating factor-M-CSF or supernatant of murine fibroblast L929), peritoneal cavity (resident or thioglycolate elicit macrophages), from the lung (alveolar macrophages) or from adipose tissue. In this chapter we describe some protocols to obtain primary murine macrophages and how to identify a pure macrophage population or activation phenotypes using different markers.

  18. Enhanced Inflammation without Impairment of Insulin Signaling in the Visceral Adipose Tissue of 5α-Dihydrotestosterone-Induced Animal Model of Polycystic Ovary Syndrome.

    PubMed

    Milutinović, Danijela Vojnović; Nikolić, Marina; Veličković, Nataša; Djordjevic, Ana; Bursać, Biljana; Nestorov, Jelena; Teofilović, Ana; Antić, Ivana Božić; Macut, Jelica Bjekić; Zidane, Abdulbaset Shirif; Matić, Gordana; Macut, Djuro

    2017-09-01

    Polycystic ovary syndrome is a heterogeneous endocrine and metabolic disorder associated with abdominal obesity, dyslipidemia and insulin resistance. Since abdominal obesity is characterized by low-grade inflammation, the aim of the study was to investigate whether visceral adipose tissue inflammation linked to abdominal obesity and dyslipidemia could lead to impaired insulin sensitivity in the animal model of polycystic ovary syndrome.Female Wistar rats were treated with nonaromatizable 5α-dihydrotestosterone pellets in order to induce reproductive and metabolic characteristics of polycystic ovary syndrome. Glucose, triglycerides, non-esterified fatty acids and insulin were determined in blood plasma. Visceral adipose tissue inflammation was evaluated by the nuclear factor kappa B intracellular distribution, macrophage migration inhibitory factor protein level, as well as TNFα, IL6 and IL1β mRNA levels. Insulin sensitivity was assessed by intraperitoneal glucose tolerance test and homeostasis model assessment index, and through analysis of insulin signaling pathway in the visceral adipose tissue.Dihydrotestosterone treatment led to increased body weight, abdominal obesity and elevated triglycerides and non-esterified fatty acids, which were accompanied by the activation of nuclear factor kappa B and increase in macrophage migration inhibitory factor, IL6 and IL1β levels in the visceral adipose tissue. In parallel, insulin sensitivity was affected in 5α-dihydrotestosterone-treated animals only at the systemic and not at the level of visceral adipose tissue.The results showed that abdominal obesity and dyslipidemia in the animal model of polycystic ovary syndrome were accompanied with low-grade inflammation in the visceral adipose tissue. However, these metabolic disturbances did not result in decreased tissue insulin sensitivity. © Georg Thieme Verlag KG Stuttgart · New York.

  19. Origin and Functions of Tissue Macrophages

    PubMed Central

    Epelman, Slava; Lavine, Kory J.; Randolph, Gwendalyn J.

    2015-01-01

    Macrophages are distributed in tissues throughout the body and contribute to both homeostasis and disease. Recently, it has become evident that most adult tissue macrophages originate during embryonic development and not from circulating monocytes. Each tissue has its own composition of embryonically derived and adult-derived macrophages, but it is unclear whether macrophages of distinct origins are functionally interchangeable or have unique roles at steady state. This new understanding also prompts reconsideration of the function of circulating monocytes. Classical Ly6chi monocytes patrol the extravascular space in resting organs, and Ly6clo nonclassical monocytes patrol the vasculature. Inflammation triggers monocytes to differentiate into macrophages, but whether resident and newly recruited macrophages possess similar functions during inflammation is unclear. Here, we define the tools used for identifying the complex origin of tissue macrophages and discuss the relative contributions of tissue niche versus ontological origin to the regulation of macrophage functions during steady state and inflammation. PMID:25035951

  20. Effects of chronic antipsychotic drug exposure on the expression of Translocator Protein and inflammatory markers in rat adipose tissue.

    PubMed

    Calevro, Anita; Cotel, Marie-Caroline; Natesan, Sridhar; Modo, Michel; Vernon, Anthony C; Mondelli, Valeria

    2018-05-16

    The precise effect of antipsychotic drugs on either central or peripheral inflammation remains unclear. An important issue in this debate is to what extent the known peripheral metabolic effects of antipsychotics, including increased adiposity, may contribute to increased inflammation. Adipose tissue is known to contribute to the development of systemic inflammation, which can eventually lead to insulin resistance and metabolic dysregulation. As a first step to address this question, we evaluated whether chronic exposure to clinically comparable doses of haloperidol or olanzapine resulted in the immune activation of rat adipose tissue. Samples of visceral adipose tissue were sampled from male Sprague-Dawley rats exposed to, haloperidol, olanzapine or vehicle (all n = 8), for 8 weeks. From these we measured a cytokine profile, protein expression of F4/80 (a phenotypic macrophage marker) and translocator protein (TSPO), a target for radiotracers putatively indicating microgliosis in clinical neuroimaging studies. Chronic olanzapine exposure resulted in significantly higher adipose IL-6 levels compared with vehicle-controls (ANOVA p = 0.008, Bonferroni post-hoc test p = 0.006); in parallel, animals exposed to olanzapine had significantly higher F4/80 expression when compared with vehicle-controls (Mann Whitney Test, p = 0.014), whereas there was no difference between haloperidol and vehicle groups (Mann Whitney test, p = 0.1). There were no significant effects of either drug on adipose TSPO protein levels. Nevertheless, we found a positive correlation between F4/80 and TSPO adipose protein levels in the olanzapine-exposed rats (Spearman's rho = 0.76, p = 0.037). Our data suggest that chronic exposure to olanzapine, but not haloperidol, increases production of the pro-inflammatory cytokine IL-6 in adipose tissue and increased macrophages expression (F4/80), in the absence of measurable changes in TSPO with respect to vehicle. This may have

  1. Abscisic acid synergizes with rosiglitazone to improve glucose tolerance, down-modulate macrophage accumulation in adipose tissue: possible action of the cAMP/PKA/PPAR γ axis

    PubMed Central

    Guri, Amir J; Hontecillas, Raquel; Bassaganya-Riera, Josep

    2010-01-01

    Background & Aims Abscisic acid (ABA) is effective in preventing insulin resistance and obesity-related inflammation through a PPAR γ-dependent mechanism. The objective of this study was to assess the efficacy ABA in improving glucose homeostasis and suppress inflammation when administered in combination with rosiglitazone (Ros) and to determine whether PPAR γ activation by ABA is initiated via cAMP/protein kinase A (PKA) signaling. Methods Obese db/db mice were fed high-fat diets containing 0, 10, or 70 mg/kg Ros with and without racemic ABA (100 mg/kg) for 60 days. Glucose tolerance and fasting insulin levels were assessed at 6 and 8 weeks, respectively, and adipose tissue macrophage (ATM) infiltration was examined by flow cytometry. Gene expression was examined on white adipose tissue (WAT) and stromal vascular cells (SVCs) cultured with ABA, Ros, or an ABA/Ros combination. Results Both Ros and ABA improved glucose tolerance, and ABA decreased plasma insulin levels while having no effect on Ros-induced weight gain. ABA in combination with low-dose Ros (10 mg/kg; Roslo) synergistically inhibited ATM infiltration. Treatment of SVCs with Ros, ABA or ABA/Ros suppressed expression of the M1 marker CCL17. ABA and Ros synergistically increased PPAR γ activity and pretreatment with a cAMP-inhibitor or a PKA-inhibitor abrogated ABA-induced PPAR γ activation. Conclusions ABA and Ros act synergistically to modulate PPAR γ activity and macrophage accumulation in WAT and ABA enhances PPAR γ activity through a membrane-initiated mechanism dependent on cAMP/PKA signaling. PMID:20207056

  2. Adipose Tissue-Derived Pericytes for Cartilage Tissue Engineering.

    PubMed

    Zhang, Jinxin; Du, Chunyan; Guo, Weimin; Li, Pan; Liu, Shuyun; Yuan, Zhiguo; Yang, Jianhua; Sun, Xun; Yin, Heyong; Guo, Quanyi; Zhou, Chenfu

    2017-01-01

    Mesenchymal stem cells (MSCs) represent a promising alternative source for cartilage tissue engineering. However, MSC culture is labor-intensive, so these cells cannot be applied immediately to regenerate cartilage for clinical purposes. Risks during the ex vivo expansion of MSCs, such as infection and immunogenicity, can be a bottleneck in their use in clinical tissue engineering. As a novel stem cell source, pericytes are generally considered to be the origin of MSCs. Pericytes do not have to undergo time-consuming ex vivo expansion because they are uncultured cells. Adipose tissue is another optimal stem cell reservoir. Because adipose tissue is well vascularized, a considerable number of pericytes are located around blood vessels in this accessible and dispensable tissue, and autologous pericytes can be applied immediately for cartilage regeneration. Thus, we suggest that adipose tissue-derived pericytes are promising seed cells for cartilage regeneration. Many studies have been performed to develop isolation methods for the adipose tissuederived stromal vascular fraction (AT-SVF) using lipoaspiration and sorting pericytes from AT-SVF. These methods are useful for sorting a large number of viable pericytes for clinical therapy after being combined with automatic isolation using an SVF device and automatic magnetic-activated cell sorting. These tools should help to develop one-step surgery for repairing cartilage damage. However, the use of adipose tissue-derived pericytes as a cell source for cartilage tissue engineering has not drawn sufficient attention and preclinical studies are needed to improve cell purity, to increase sorting efficiency, and to assess safety issues of clinical applications. Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.org.

  3. NK cells link obesity-induced adipose stress to inflammation and insulin resistance.

    PubMed

    Wensveen, Felix M; Jelenčić, Vedrana; Valentić, Sonja; Šestan, Marko; Wensveen, Tamara Turk; Theurich, Sebastian; Glasner, Ariella; Mendrila, Davor; Štimac, Davor; Wunderlich, F Thomas; Brüning, Jens C; Mandelboim, Ofer; Polić, Bojan

    2015-04-01

    An important cause of obesity-induced insulin resistance is chronic systemic inflammation originating in visceral adipose tissue (VAT). VAT inflammation is associated with the accumulation of proinflammatory macrophages in adipose tissue, but the immunological signals that trigger their accumulation remain unknown. We found that a phenotypically distinct population of tissue-resident natural killer (NK) cells represented a crucial link between obesity-induced adipose stress and VAT inflammation. Obesity drove the upregulation of ligands of the NK cell-activating receptor NCR1 on adipocytes; this stimulated NK cell proliferation and interferon-γ (IFN-γ) production, which in turn triggered the differentiation of proinflammatory macrophages and promoted insulin resistance. Deficiency of NK cells, NCR1 or IFN-γ prevented the accumulation of proinflammatory macrophages in VAT and greatly ameliorated insulin sensitivity. Thus NK cells are key regulators of macrophage polarization and insulin resistance in response to obesity-induced adipocyte stress.

  4. Relationship between energy dense diets and white adipose tissue inflammation in metabolic syndrome.

    PubMed

    Alemany, Marià

    2013-01-01

    Metabolic syndrome (MS) is a widespread pathologic state that manifests as multiple intertwined diseases affecting the entire body. This review analyzes the contribution of adipose tissue inflammation to its development. The main factor in the appearance of MS is an excess of dietary energy (largely fats), eliciting insulin resistance and creating the problem of excess energy disposal. Under these conditions, amino acid catabolism is diminished, which indirectly alters the production of nitric oxide and affects blood flow regulation. The oxidation of nitric oxide to nitrite and nitrate affects microbiota composition and functions. Adipose tissue cannot incorporate excessive nutrients after cell enlargement and loss of function. Tissue damage is a form of aggression, and the response is proinflammatory cytokine release. Cytokines favor the massive penetration of immune system cells, such as macrophages, which unsuccessfully try to fight an elusive danger for which they are not prepared. The consequence is low-level maintenance of the inflammatory state, which affects endoplasmic reticulum function and the endothelial response to excess regulatory mechanisms affecting blood flow and substrate/oxygen supply. When inflammation becomes chronic, the pathologic consequences are disseminated throughout the body because unused substrates and signals from adipose tissue affect energy partitioning and organ function. This maintenance of an unbalanced state ultimately results in the establishment of MS and associated pathologies. New research should focus on identifying ways to disarm the inflammatory response of adipose tissue when the dangers of dietary excess have already been controlled. Copyright © 2013. Published by Elsevier Inc.

  5. Arteriogenesis in murine adipose tissue is contingent on CD68+/CD206+ macrophages

    PubMed Central

    Seaman, Scott A.; Cao, Yiqi; Campbell, Chris A.; Peirce, Shayn M.

    2016-01-01

    Objective The surgical transfer of skin, fat, and/or muscle from a donor site to a recipient site within the same patient, is a widely performed procedure in reconstructive surgeries. A surgical pre-treatment strategy that is intended to increase perfusion in the flap, termed “flap delay”, is a commonly employed technique by plastic surgeons prior to flap transplantation. Here, we explored whether CD68+/CD206+ macrophages are required for arteriogenesis within the flap by performing gain-of-function and loss-of-function studies in a previously published flap delay murine model. Methods and Results Local injection of M2-polarized macrophages into the flap resulted in an increase in collateral vessel diameter. Application of a thin biomaterial film loaded with a pharmacological agent (FTY720), which has been previously shown to recruit CD68+/CD206+ macrophages to remodeling tissue, increased CD68+/CD206+ cell recruitment and collateral vessel enlargement. Conversely, when local macrophage populations were depleted within the inguinal fat pad via clodronate liposome delivery, we observed fewer CD68+ cells accompanied by diminished collateral vessel enlargement. Conclusions Our study underscores the importance of macrophages during microvascular adaptations that are induced by flap delay. These studies suggest a mechanism for a translatable therapeutic target that may be used to enhance the clinical flap delay procedure. PMID:27976451

  6. Effect of energy restriction and physical exercise intervention on phenotypic flexibility as examined by transcriptomics analyses of mRNA from adipose tissue and whole body magnetic resonance imaging.

    PubMed

    Lee, Sindre; Norheim, Frode; Langleite, Torgrim M; Noreng, Hans J; Storås, Trygve H; Afman, Lydia A; Frost, Gary; Bell, Jimmy D; Thomas, E Louise; Kolnes, Kristoffer J; Tangen, Daniel S; Stadheim, Hans K; Gilfillan, Gregor D; Gulseth, Hanne L; Birkeland, Kåre I; Jensen, Jørgen; Drevon, Christian A; Holen, Torgeir

    2016-11-01

    Overweight and obesity lead to changes in adipose tissue such as inflammation and reduced insulin sensitivity. The aim of this study was to assess how altered energy balance by reduced food intake or enhanced physical activity affect these processes. We studied sedentary subjects with overweight/obesity in two intervention studies, each lasting 12 weeks affecting energy balance either by energy restriction (~20% reduced intake of energy from food) in one group, or by enhanced energy expenditure due to physical exercise (combined endurance- and strength-training) in the other group. We monitored mRNA expression by microarray and mRNA sequencing from adipose tissue biopsies. We also measured several plasma parameters as well as fat distribution with magnetic resonance imaging and spectroscopy. Comparison of microarray and mRNA sequencing showed strong correlations, which were also confirmed using RT-PCR In the energy restricted subjects (body weight reduced by 5% during a 12 weeks intervention), there were clear signs of enhanced lipolysis as monitored by mRNA in adipose tissue as well as plasma concentration of free-fatty acids. This increase was strongly related to increased expression of markers for M1-like macrophages in adipose tissue. In the exercising subjects (glucose infusion rate increased by 29% during a 12-week intervention), there was a marked reduction in the expression of markers of M2-like macrophages and T cells, suggesting that physical exercise was especially important for reducing inflammation in adipose tissue with insignificant reduction in total body weight. Our data indicate that energy restriction and physical exercise affect energy-related pathways as well as inflammatory processes in different ways, probably related to macrophages in adipose tissue. © 2016 The Authors. Physiological Reports published by Wiley Periodicals, Inc. on behalf of the American Physiological Society and The Physiological Society.

  7. Contribution of Adipose Tissue to Development of Cancer

    PubMed Central

    Cozzo, Alyssa J.; Fuller, Ashley M.; Makowski, Liza

    2018-01-01

    Solid tumor growth and metastasis require the interaction of tumor cells with the surrounding tissue, leading to a view of tumors as tissue-level phenomena rather than exclusively cell-intrinsic anomalies. Due to the ubiquitous nature of adipose tissue, many types of solid tumors grow in proximate or direct contact with adipocytes and adipose-associated stromal and vascular components, such as fibroblasts and other connective tissue cells, stem and progenitor cells, endothelial cells, innate and adaptive immune cells, and extracellular signaling and matrix components. Excess adiposity in obesity both increases risk of cancer development and negatively influences prognosis in several cancer types, in part due to interaction with adipose tissue cell populations. Herein, we review the cellular and noncellular constituents of the adipose “organ,” and discuss the mechanisms by which these varied microenvironmental components contribute to tumor development, with special emphasis on obesity. Due to the prevalence of breast and prostate cancers in the United States, their close anatomical proximity to adipose tissue depots, and their complex epidemiologic associations with obesity, we particularly highlight research addressing the contribution of adipose tissue to the initiation and progression of these cancer types. Obesity dramatically modifies the adipose tissue microenvironment in numerous ways, including induction of fibrosis and angiogenesis, increased stem cell abundance, and expansion of proinflammatory immune cells. As many of these changes also resemble shifts observed within the tumor microenvironment, proximity to adipose tissue may present a hospitable environment to developing tumors, providing a critical link between adiposity and tumorigenesis. PMID:29357128

  8. The development and endocrine functions of adipose tissue

    USDA-ARS?s Scientific Manuscript database

    White adipose tissue is a mesenchymal tissue that begins developing in the fetus. Classically known for storing the body’s fuel reserves, adipose tissue is now recognized as an endocrine organ. As such, the secretions from adipose tissue are known to affect several systems such as the vascular and...

  9. Phagocytosis imprints heterogeneity in tissue-resident macrophages

    PubMed Central

    A-Gonzalez, Noelia; Quintana, Juan A.; Mazariegos, Marina; González de la Aleja, Arturo; Nicolás-Ávila, José A.; Crainiciuc, Georgiana; Rothlin, Carla V.; Peinado, Héctor; Castrillo, Antonio

    2017-01-01

    Tissue-resident macrophages display varying phenotypic and functional properties that are largely specified by their local environment. One of these functions, phagocytosis, mediates the natural disposal of billions of cells, but its mechanisms and consequences within living tissues are poorly defined. Using a parabiosis-based strategy, we identified and isolated macrophages from multiple tissues as they phagocytosed blood-borne cellular material. Phagocytosis was circadianally regulated and mediated by distinct repertoires of receptors, opsonins, and transcription factors in macrophages from each tissue. Although the tissue of residence defined the core signature of macrophages, phagocytosis imprinted a distinct antiinflammatory profile. Phagocytic macrophages expressed CD206, displayed blunted expression of Il1b, and supported tissue homeostasis. Thus, phagocytosis is a source of macrophage heterogeneity that acts together with tissue-derived factors to preserve homeostasis. PMID:28432199

  10. [Human brown adipose tissue].

    PubMed

    Virtanen, Kirsi A; Nuutila, Pirjo

    2015-01-01

    Adult humans have heat-producing and energy-consuming brown adipose tissue in the clavicular region of the neck. There are two types of brown adipose cells, the so-called classic and beige adipose cells. Brown adipose cells produce heat by means of uncoupler protein 1 (UCP1) from fatty acids and sugar. By applying positron emission tomography (PET) measuring the utilization of sugar, the metabolism of brown fat has been shown to multiply in the cold, presumably influencing energy consumption. Active brown fat is most likely present in young adults, persons of normal weight and women, least likely in obese persons.

  11. Spontaneous hypertension occurs with adipose tissue dysfunction in perilipin-1 null mice.

    PubMed

    Zou, Liangqiang; Wang, Weiyi; Liu, Shangxin; Zhao, Xiaojing; Lyv, Ying; Du, Congkuo; Su, Xueying; Geng, Bin; Xu, Guoheng

    2016-02-01

    Perilipin-1 (Plin1) coats lipid droplets exclusively in adipocytes and regulates two principle functions of adipose tissue, triglyceride storage and hydrolysis, which are disrupted upon Plin1 deficiency. In the present study, we investigated the alterations in systemic metabolites and hormones, vascular function and adipose function in spontaneous hypertensive mice lacking perilipin-1 (Plin1-/-). Plin1-/- mice developed spontaneous hypertension without obvious alterations in systemic metabolites and hormones. Plin1 expressed only in adipose cells but not in vascular cells, so its ablation would have no direct effect in situ on blood vessels. Instead, Plin1-/- mice showed dysfunctions of perivascular adipose tissue (PVAT), a fat depot that anatomically surrounds systemic arteries and has an anticontractile effect. In Plin1-/- mice, aortic and mesenteric PVAT were reduced in mass and adipocyte derived relaxing factor secretion, but increased in basal lipolysis, angiotensin II secretion, macrophage infiltration and oxidative stress. Such multiple culprits impaired the anticontractile effect of PVAT to promote vasoconstriction of aortic and mesenteric arteries of Plin1-/- mice. Furthermore, arterial vessels of Plin1-/- mice showed increasing angiotensin II receptor type 1, monocyte chemotactic protein-1 and interlukin-6 expression, structural damage of endothelial and smooth muscle cells, along with impaired endothelium-dependent relaxation. Hypertension in Plin1-/- mice might occur as a deleterious consequence of PVAT dysfunction. This finding provides the direct evidence that links dysfunctional PVAT to vascular dysfunction and hypertension, particularly in pathophysiological states. This hypertensive mouse model might mimic and explain the hypertension occurring in patients with adipose tissue dysfunction, particularly with Plin1 mutations. Copyright © 2015 Elsevier B.V. All rights reserved.

  12. Cross Talk between Adipose Tissue and Placenta in Obese and Gestational Diabetes Mellitus Pregnancies via Exosomes.

    PubMed

    Jayabalan, Nanthini; Nair, Soumyalekshmi; Nuzhat, Zarin; Rice, Gregory E; Zuñiga, Felipe A; Sobrevia, Luis; Leiva, Andrea; Sanhueza, Carlos; Gutiérrez, Jaime Agustín; Lappas, Martha; Freeman, Dilys Jane; Salomon, Carlos

    2017-01-01

    Obesity is an important public health issue worldwide, where it is commonly associated with the development of metabolic disorders, especially insulin resistance (IR). Maternal obesity is associated with an increased risk of pregnancy complications, especially gestational diabetes mellitus (GDM). Metabolism is a vital process for energy production and the maintenance of essential cellular functions. Excess energy storage is predominantly regulated by the adipose tissue. Primarily made up of adipocytes, adipose tissue acts as the body's major energy reservoir. The role of adipose tissue, however, is not restricted to a "bag of fat." The adipose tissue is an endocrine organ, secreting various adipokines, enzymes, growth factors, and hormones that take part in glucose and lipid metabolism. In obesity, the greater portion of the adipose tissue comprises fat, and there is increased pro-inflammatory cytokine secretion, macrophage infiltration, and reduced insulin sensitivity. Obesity contributes to systemic IR and its associated metabolic complications. Similar to adipose tissue, the placenta is also an endocrine organ. During pregnancy, the placenta secretes various molecules to maintain pregnancy physiology. In addition, the placenta plays an important role in metabolism and exchange of nutrients between mother and fetus. Inflammation at the placenta may contribute to the severity of maternal IR and her likelihood of developing GDM and may also mediate the adverse consequences of obesity and GDM on the fetus. Interestingly, studies on maternal insulin sensitivity and secretion of placental hormones have not shown a positive correlation between these phenomena. Recently, a great interest in the field of extracellular vesicles (EVs) has been observed in the literature. EVs are produced by a wide range of cells and are present in all biological fluids. EVs are involved in cell-to-cell communication. Recent evidence points to an association between adipose tissue

  13. Cross Talk between Adipose Tissue and Placenta in Obese and Gestational Diabetes Mellitus Pregnancies via Exosomes

    PubMed Central

    Jayabalan, Nanthini; Nair, Soumyalekshmi; Nuzhat, Zarin; Rice, Gregory E.; Zuñiga, Felipe A.; Sobrevia, Luis; Leiva, Andrea; Sanhueza, Carlos; Gutiérrez, Jaime Agustín; Lappas, Martha; Freeman, Dilys Jane; Salomon, Carlos

    2017-01-01

    Obesity is an important public health issue worldwide, where it is commonly associated with the development of metabolic disorders, especially insulin resistance (IR). Maternal obesity is associated with an increased risk of pregnancy complications, especially gestational diabetes mellitus (GDM). Metabolism is a vital process for energy production and the maintenance of essential cellular functions. Excess energy storage is predominantly regulated by the adipose tissue. Primarily made up of adipocytes, adipose tissue acts as the body’s major energy reservoir. The role of adipose tissue, however, is not restricted to a “bag of fat.” The adipose tissue is an endocrine organ, secreting various adipokines, enzymes, growth factors, and hormones that take part in glucose and lipid metabolism. In obesity, the greater portion of the adipose tissue comprises fat, and there is increased pro-inflammatory cytokine secretion, macrophage infiltration, and reduced insulin sensitivity. Obesity contributes to systemic IR and its associated metabolic complications. Similar to adipose tissue, the placenta is also an endocrine organ. During pregnancy, the placenta secretes various molecules to maintain pregnancy physiology. In addition, the placenta plays an important role in metabolism and exchange of nutrients between mother and fetus. Inflammation at the placenta may contribute to the severity of maternal IR and her likelihood of developing GDM and may also mediate the adverse consequences of obesity and GDM on the fetus. Interestingly, studies on maternal insulin sensitivity and secretion of placental hormones have not shown a positive correlation between these phenomena. Recently, a great interest in the field of extracellular vesicles (EVs) has been observed in the literature. EVs are produced by a wide range of cells and are present in all biological fluids. EVs are involved in cell-to-cell communication. Recent evidence points to an association between adipose tissue

  14. Macrophages in tissue repair, regeneration, and fibrosis

    PubMed Central

    Wynn, Thomas A.; Vannella, Kevin M.

    2016-01-01

    Inflammatory monocytes and resident tissue macrophages are key regulators of tissue repair, regeneration, and fibrosis. Following tissue injury, monocytes and macrophages undergo marked phenotypic and functional changes to play critical roles during the initiation, maintenance, and resolution phases of tissue repair. Disturbances in macrophage function can lead to aberrant repair, with uncontrolled inflammatory mediator and growth factor production, deficient generation of anti-inflammatory macrophages, or failed communication between macrophages and epithelial cells, endothelial cells, fibroblasts, and stem or tissue progenitor cells all contributing to a state of persistent injury, which may lead to the development of pathological fibrosis. In this review, we discuss the mechanisms that instruct macrophages to adopt pro-inflammatory, pro-wound healing, pro-fibrotic, anti-inflammatory, anti-fibrotic, pro-resolving, and tissue regenerating phenotypes following injury, and highlight how some of these mechanisms and macrophage activation states could be exploited therapeutically. PMID:26982353

  15. The role of glucose-6-phosphate dehydrogenase in adipose tissue inflammation in obesity.

    PubMed

    Park, Yoon Jeong; Choe, Sung Sik; Sohn, Jee Hyung; Kim, Jae Bum

    2017-04-03

    Obesity is closely associated with metabolic diseases including type 2 diabetes. One hallmark characteristics of obesity is chronic inflammation that is coordinately controlled by complex signaling networks in adipose tissues. Compelling evidence indicates that reactive oxygen species (ROS) and its related signaling pathways play crucial roles in the progression of chronic inflammation in obesity. The pentose phosphate pathway (PPP) is an anabolic pathway that utilizes the glucoses to generate molecular building blocks and reducing equivalents in the form of NADPH. In particular, NADPH acts as one of the key modulators in the control of ROS through providing an electron for both ROS generation and scavenging. Recently, we have reported that glucose-6-phosphate dehydrogenase (G6PD), a rate-limiting enzyme of the PPP, is implicated in adipose tissue inflammation and systemic insulin resistance in obesity. Mechanistically, G6PD potentiates generation of ROS that augments pro-inflammatory responses in adipose tissue macrophages, leading to systemic insulin resistance. Here, we provide an overview of cell type- specific roles of G6PD in the regulation of ROS balance as well as additional details on the significance of G6PD that contributes to pro-oxidant NADPH generation in obesity-related chronic inflammation and insulin resistance.

  16. Hyperhomocysteinemia Promotes Insulin Resistance and Adipose Tissue Inflammation in PCOS Mice Through Modulating M2 Macrophage Polarization via Estrogen Suppression.

    PubMed

    Qi, Xinyu; Zhang, Bochun; Zhao, Yue; Li, Rong; Chang, Hsun-Ming; Pang, Yanli; Qiao, Jie

    2017-05-01

    It has been shown that serum homocysteine (Hcy) levels are higher in women with polycystic ovary syndrome (PCOS). However, the specific role of hyperhomocysteinemia (HHcy) in the development of PCOS has never been reported. Adipose tissue inflammation is featured by the infiltration of macrophages, which plays a critical role in the pathogenesis of glucose and insulin intolerance. In this study, C57BL/6 mice were treated with dehydroepiandrosterone (DHEA) and/or a high methionine diet to induce PCOS and HHcy mice models. We showed that DHEA induced a PCOS-like phenotypes, irregular estrous cycles, weight gain, abnormal sex hormone production, glucose and insulin resistance, and polycystic ovaries. HHcy further intensified the effects DHEA on the metabolic, endocrinal, hormonal, and morphological changes in PCOS-like mice. In addition, HHcy attenuated the DHEA-induced increase in serum estrogen levels in mice. Furthermore, HHcy may exacerbate the insulin resistance in PCOS-like mice, most likely through modulating the macrophage M1/M2 polarization pathways via the suppression of estrogen. Most important, our clinical data showed that there were increases in serum Hcy levels in patients with PCOS. These findings deepen our understanding of the pathological roles of HHcy in the development of PCOS and provide a promising target for PCOS therapy in clinical application. Copyright © 2017 Endocrine Society.

  17. Caveolin-1 Deficiency Leads to Increased Susceptibility to Cell Death and Fibrosis in White Adipose Tissue: Characterization of a Lipodystrophic Model

    PubMed Central

    Stanley, Amanda C.; Bastiani, Michele; Okano, Satomi; Nixon, Susan J.; Thomas, Gethin; Stow, Jennifer L.; Parton, Robert G.

    2012-01-01

    Caveolin-1 (CAV1) is an important regulator of adipose tissue homeostasis. In the present study we examined the impact of CAV1 deficiency on the properties of mouse adipose tissue both in vivo and in explant cultures during conditions of metabolic stress. In CAV1−/− mice fasting caused loss of adipose tissue mass despite a lack of hormone-sensitive lipase (HSL) phosphorylation. In addition, fasting resulted in increased macrophage infiltration, enhanced deposition of collagen, and a reduction in the level of the lipid droplet protein perilipin A (PLIN1a). Explant cultures of CAV1−/− adipose tissue also showed a loss of PLIN1a during culture, enhanced secretion of IL-6, increased release of lactate dehydrogenase, and demonstrated increased susceptibility to cell death upon collagenase treatment. Attenuated PKA-mediated signaling to HSL, loss of PLIN1a and increased secretion of IL-6 were also observed in adipose tissue explants of CAV1+/+ mice with diet-induced obesity. Together these results suggest that while alterations in adipocyte lipid droplet biology support adipose tissue metabolism in the absence of PKA-mediated pro-lipolytic signaling in CAV1−/− mice, the tissue is intrinsically unstable resulting in increased susceptibility to cell death, which we suggest underlies the development of fibrosis and inflammation during periods of metabolic stress. PMID:23049990

  18. Rapid Alterations in Perirenal Adipose Tissue Transcriptomic Networks with Cessation of Voluntary Running

    PubMed Central

    Toedebusch, Ryan G.; Roberts, Christian K.; Roberts, Michael D.; Booth, Frank W.

    2015-01-01

    In maturing rats, the growth of abdominal fat is attenuated by voluntary wheel running. After the cessation of running by wheel locking, a rapid increase in adipose tissue growth to a size that is similar to rats that have never run (i.e. catch-up growth) has been previously reported by our lab. In contrast, diet-induced increases in adiposity have a slower onset with relatively delayed transcriptomic responses. The purpose of the present study was to identify molecular pathways associated with the rapid increase in adipose tissue after ending 6 wks of voluntary running at the time of puberty. Age-matched, male Wistar rats were given access to running wheels from 4 to 10 weeks of age. From the 10th to 11th week of age, one group of rats had continued wheel access, while the other group had one week of wheel locking. Perirenal adipose tissue was extracted, RNA sequencing was performed, and bioinformatics analyses were executed using Ingenuity Pathway Analysis (IPA). IPA was chosen to assist in the understanding of complex ‘omics data by integrating data into networks and pathways. Wheel locked rats gained significantly more fat mass and significantly increased body fat percentage between weeks 10–11 despite having decreased food intake, as compared to rats with continued wheel access. IPA identified 646 known transcripts differentially expressed (p < 0.05) between continued wheel access and wheel locking. In wheel locked rats, IPA revealed enrichment of transcripts for the following functions: extracellular matrix, macrophage infiltration, immunity, and pro-inflammatory. These findings suggest that increases in visceral adipose tissue that accompanies the cessation of pubertal physical activity are associated with the alteration of multiple pathways, some of which may potentiate the development of pubertal obesity and obesity-associated systemic low-grade inflammation that occurs later in life. PMID:26678390

  19. Rapid Alterations in Perirenal Adipose Tissue Transcriptomic Networks with Cessation of Voluntary Running.

    PubMed

    Ruegsegger, Gregory N; Company, Joseph M; Toedebusch, Ryan G; Roberts, Christian K; Roberts, Michael D; Booth, Frank W

    2015-01-01

    In maturing rats, the growth of abdominal fat is attenuated by voluntary wheel running. After the cessation of running by wheel locking, a rapid increase in adipose tissue growth to a size that is similar to rats that have never run (i.e. catch-up growth) has been previously reported by our lab. In contrast, diet-induced increases in adiposity have a slower onset with relatively delayed transcriptomic responses. The purpose of the present study was to identify molecular pathways associated with the rapid increase in adipose tissue after ending 6 wks of voluntary running at the time of puberty. Age-matched, male Wistar rats were given access to running wheels from 4 to 10 weeks of age. From the 10th to 11th week of age, one group of rats had continued wheel access, while the other group had one week of wheel locking. Perirenal adipose tissue was extracted, RNA sequencing was performed, and bioinformatics analyses were executed using Ingenuity Pathway Analysis (IPA). IPA was chosen to assist in the understanding of complex 'omics data by integrating data into networks and pathways. Wheel locked rats gained significantly more fat mass and significantly increased body fat percentage between weeks 10-11 despite having decreased food intake, as compared to rats with continued wheel access. IPA identified 646 known transcripts differentially expressed (p < 0.05) between continued wheel access and wheel locking. In wheel locked rats, IPA revealed enrichment of transcripts for the following functions: extracellular matrix, macrophage infiltration, immunity, and pro-inflammatory. These findings suggest that increases in visceral adipose tissue that accompanies the cessation of pubertal physical activity are associated with the alteration of multiple pathways, some of which may potentiate the development of pubertal obesity and obesity-associated systemic low-grade inflammation that occurs later in life.

  20. LXR activation by GW3965 alters fat tissue distribution and adipose tissue inflammation in ob/ob female mice[S

    PubMed Central

    Archer, Amena; Stolarczyk, Émilie; Doria, Maria Luisa; Helguero, Luisa; Domingues, Rosário; Howard, Jane K.; Mode, Agneta; Korach-André, Marion; Gustafsson, Jan-Åke

    2013-01-01

    To investigate the role of liver X receptor (LXR) in adipose tissue metabolism during obesity, ob/ob mice were treated for 5 weeks with the synthetic LXR agonist GW3965. MRI analysis revealed that pharmacological activation of LXR modified fat distribution by decreasing visceral (VS) fat and inversely increasing subcutaneous (SC) fat storage without affecting whole body fat content. This was concordant with opposite regulation by GW3965 of the lipolytic markers hormone-sensitive lipase (HSL) and adipose triglyceride lipase (ATGL) in the two fat depots; moreover, the expression of genes involved in lipogenesis was significantly induced in SC fat. Lipidomic analysis suggested that changes in lipid composition in response to GW3965 also varied between VS and SC fat. In both depots, the observed alteration in lipid composition indicated an overall change toward less lipotoxic lipids. Flow cytometry analysis showed decreased immune cell infiltration in adipose tissue of ob/ob mice in response to GW3965 treatment, which in VS fat mainly affected the macrophage population and in SC fat the lymphocyte population. In line with this, the expression and secretion of proinflammatory markers was decreased in both fat deposits with GW3965 treatment. PMID:23446231

  1. Androgen receptor deficiency in monocytes/macrophages does not alter adiposity or glucose homeostasis in male mice.

    PubMed

    Rubinow, Katya B; Houston, Barbara; Wang, Shari; Goodspeed, Leela; Ogimoto, Kayoko; Morton, Gregory J; McCarty, Christopher; Braun, Robert E; Page, Stephanie T

    2018-01-01

    Androgen deprivation in men leads to increased adiposity, but the mechanisms underlying androgen regulation of fat mass have not been fully defined. Androgen receptor (AR) is expressed in monocytes/macrophages, which are resident in key metabolic tissues and influence energy metabolism in surrounding cells. Male mice bearing a cell-specific knockout of the AR in monocytes/macrophages (M-ARKO) were generated to determine whether selective loss of androgen signaling in these cells would lead to altered body composition. Wild-type (WT) and M-ARKO mice (12-22 weeks of age, n = 12 per group) were maintained on a regular chow diet for 8 weeks and then switched to a high-fat diet for 8 additional weeks. At baseline and on both the regular chow and high-fat diets, no differences in lean mass or fat mass were observed between groups. Consistent with the absence of differential body weight or adiposity, no differences in food intake (3.0 ± 0.5 g per day for WT mice vs 2.8 ± 0.4 g per day for M-ARKO mice) or total energy expenditure (0.6 ± 0.1 Kcal h -1 for WT mice vs 0.5 ± 0.1 Kcal h -1 for M-ARKO mice) were evident between groups during high-fat feeding. Liver weight was greater in M-ARKO than that in WT mice (1.5 ± 0.1 g vs 1.3 ± 0.0 g, respectively, P = 0.02). Finally, M-ARKO mice did not exhibit impairments in glucose tolerance or insulin sensitivity relative to WT mice at any study time point. In aggregate, these findings suggest that AR signaling specifically in monocytes/macrophages does not contribute to the regulation of systemic energy balance, adiposity, or insulin sensitivity in male mice.

  2. Downregulation of Adipose Tissue Fatty Acid Trafficking in Obesity

    PubMed Central

    McQuaid, Siobhán E.; Hodson, Leanne; Neville, Matthew J.; Dennis, A. Louise; Cheeseman, Jane; Humphreys, Sandy M.; Ruge, Toralph; Gilbert, Marjorie; Fielding, Barbara A.; Frayn, Keith N.; Karpe, Fredrik

    2011-01-01

    OBJECTIVE Lipotoxicity and ectopic fat deposition reduce insulin signaling. It is not clear whether excess fat deposition in nonadipose tissue arises from excessive fatty acid delivery from adipose tissue or from impaired adipose tissue storage of ingested fat. RESEARCH DESIGN AND METHODS To investigate this we used a whole-body integrative physiological approach with multiple and simultaneous stable-isotope fatty acid tracers to assess delivery and transport of endogenous and exogenous fatty acid in adipose tissue over a diurnal cycle in lean (n = 9) and abdominally obese men (n = 10). RESULTS Abdominally obese men had substantially (2.5-fold) greater adipose tissue mass than lean control subjects, but the rates of delivery of nonesterified fatty acids (NEFA) were downregulated, resulting in normal systemic NEFA concentrations over a 24-h period. However, adipose tissue fat storage after meals was substantially depressed in the obese men. This was especially so for chylomicron-derived fatty acids, representing the direct storage pathway for dietary fat. Adipose tissue from the obese men showed a transcriptional signature consistent with this impaired fat storage function. CONCLUSIONS Enlargement of adipose tissue mass leads to an appropriate downregulation of systemic NEFA delivery with maintained plasma NEFA concentrations. However the implicit reduction in adipose tissue fatty acid uptake goes beyond this and shows a maladaptive response with a severely impaired pathway for direct dietary fat storage. This adipose tissue response to obesity may provide the pathophysiological basis for ectopic fat deposition and lipotoxicity. PMID:20943748

  3. Adipose tissue as an endocrine organ.

    PubMed

    McGown, Christine; Birerdinc, Aybike; Younossi, Zobair M

    2014-02-01

    Obesity is one of the most important health challenges faced by developed countries and is increasingly affecting adolescents and children. Obesity is also a considerable risk factor for the development of numerous other chronic diseases, such as insulin resistance, type 2 diabetes, heart disease and nonalcoholic fatty liver disease. The epidemic proportions of obesity and its numerous comorbidities are bringing into focus the highly complex and metabolically active adipose tissue. Adipose tissue is increasingly being considered as a functional endocrine organ. This article discusses the endocrine effects of adipose tissue during obesity and the systemic impact of this signaling. Copyright © 2014 Elsevier Inc. All rights reserved.

  4. Bone Marrow Adipose Tissue: To Be or Not To Be a Typical Adipose Tissue?

    PubMed

    Hardouin, Pierre; Rharass, Tareck; Lucas, Stéphanie

    2016-01-01

    Bone marrow adipose tissue (BMAT) emerges as a distinct fat depot whose importance has been proved in the bone-fat interaction. Indeed, it is well recognized that adipokines and free fatty acids released by adipocytes can directly or indirectly interfere with cells of bone remodeling or hematopoiesis. In pathological states, such as osteoporosis, each of adipose tissues - subcutaneous white adipose tissue (WAT), visceral WAT, brown adipose tissue (BAT), and BMAT - is differently associated with bone mineral density (BMD) variations. However, compared with the other fat depots, BMAT displays striking features that makes it a substantial actor in bone alterations. BMAT quantity is well associated with BMD loss in aging, menopause, and other metabolic conditions, such as anorexia nervosa. Consequently, BMAT is sensed as a relevant marker of a compromised bone integrity. However, analyses of BMAT development in metabolic diseases (obesity and diabetes) are scarce and should be, thus, more systematically addressed to better apprehend the bone modifications in that pathophysiological contexts. Moreover, bone marrow (BM) adipogenesis occurs throughout the whole life at different rates. Following an ordered spatiotemporal expansion, BMAT has turned to be a heterogeneous fat depot whose adipocytes diverge in their phenotype and their response to stimuli according to their location in bone and BM. In vitro, in vivo, and clinical studies point to a detrimental role of BM adipocytes (BMAs) throughout the release of paracrine factors that modulate osteoblast and/or osteoclast formation and function. However, the anatomical dissemination and the difficulties to access BMAs still hamper our understanding of the relative contribution of BMAT secretions compared with those of peripheral adipose tissues. A further characterization of the phenotype and the functional regulation of BMAs are ever more required. Based on currently available data and comparison with other fat tissues

  5. Bone Marrow Adipose Tissue: To Be or Not To Be a Typical Adipose Tissue?

    PubMed Central

    Hardouin, Pierre; Rharass, Tareck; Lucas, Stéphanie

    2016-01-01

    Bone marrow adipose tissue (BMAT) emerges as a distinct fat depot whose importance has been proved in the bone–fat interaction. Indeed, it is well recognized that adipokines and free fatty acids released by adipocytes can directly or indirectly interfere with cells of bone remodeling or hematopoiesis. In pathological states, such as osteoporosis, each of adipose tissues – subcutaneous white adipose tissue (WAT), visceral WAT, brown adipose tissue (BAT), and BMAT – is differently associated with bone mineral density (BMD) variations. However, compared with the other fat depots, BMAT displays striking features that makes it a substantial actor in bone alterations. BMAT quantity is well associated with BMD loss in aging, menopause, and other metabolic conditions, such as anorexia nervosa. Consequently, BMAT is sensed as a relevant marker of a compromised bone integrity. However, analyses of BMAT development in metabolic diseases (obesity and diabetes) are scarce and should be, thus, more systematically addressed to better apprehend the bone modifications in that pathophysiological contexts. Moreover, bone marrow (BM) adipogenesis occurs throughout the whole life at different rates. Following an ordered spatiotemporal expansion, BMAT has turned to be a heterogeneous fat depot whose adipocytes diverge in their phenotype and their response to stimuli according to their location in bone and BM. In vitro, in vivo, and clinical studies point to a detrimental role of BM adipocytes (BMAs) throughout the release of paracrine factors that modulate osteoblast and/or osteoclast formation and function. However, the anatomical dissemination and the difficulties to access BMAs still hamper our understanding of the relative contribution of BMAT secretions compared with those of peripheral adipose tissues. A further characterization of the phenotype and the functional regulation of BMAs are ever more required. Based on currently available data and comparison with other fat

  6. Abscisic acid synergizes with rosiglitazone to improve glucose tolerance and down-modulate macrophage accumulation in adipose tissue: possible action of the cAMP/PKA/PPAR γ axis.

    PubMed

    Guri, Amir J; Hontecillas, Raquel; Bassaganya-Riera, Josep

    2010-10-01

    Abscisic acid (ABA) is effective in preventing insulin resistance and obesity-related inflammation through a PPAR γ-dependent mechanism. The objective of this study was to assess the efficacy ABA in improving glucose homeostasis and suppress inflammation when administered in combination with rosiglitazone (Ros) and to determine whether PPAR γ activation by ABA is initiated via cAMP/protein kinase A (PKA) signaling. Obese db/db mice were fed high-fat diets containing 0, 10, or 70 mg/kg Ros with and without racemic ABA (100 mg/kg) for 60 days. Glucose tolerance and fasting insulin levels were assessed at 6 and 8 weeks, respectively, and adipose tissue macrophage (ATM) infiltration was examined by flow cytometry. Gene expression was examined on white adipose tissue (WAT) and stromal vascular cells (SVCs) cultured with ABA, Ros, or an ABA/Ros combination. Both Ros and ABA improved glucose tolerance, and ABA decreased plasma insulin levels while having no effect on Ros-induced weight gain. ABA in combination with low-dose Ros (10 mg/kg; Roslo) synergistically inhibited ATM infiltration. Treatment of SVCs with Ros, ABA or ABA/Ros suppressed expression of the M1 marker CCL17. ABA and Ros synergistically increased PPAR γ activity and pretreatment with a cAMP-inhibitor or a PKA-inhibitor abrogated ABA-induced PPAR γ activation. ABA and Ros act synergistically to modulate PPAR γ activity and macrophage accumulation in WAT and ABA enhances PPAR γ activity through a membrane-initiated mechanism dependent on cAMP/PKA signaling. Copyright © 2010 Elsevier Ltd and European Society for Clinical Nutrition and Metabolism. All rights reserved.

  7. Aging exacerbates obesity-induced oxidative stress and inflammation in perivascular adipose tissue in mice: a paracrine mechanism contributing to vascular redox dysregulation and inflammation.

    PubMed

    Bailey-Downs, Lora C; Tucsek, Zsuzsanna; Toth, Peter; Sosnowska, Danuta; Gautam, Tripti; Sonntag, William E; Csiszar, Anna; Ungvari, Zoltan

    2013-07-01

    Obesity in the elderly individuals is increasing at alarming rates and there is evidence suggesting that elderly individuals are more vulnerable to the deleterious cardiovascular effects of obesity than younger individuals. However, the specific mechanisms through which aging and obesity interact to promote the development of cardiovascular disease remain unclear. The present study was designed to test the hypothesis that aging exacerbates obesity-induced inflammation in perivascular adipose tissue, which contributes to increased vascular oxidative stress and inflammation in a paracrine manner. To test this hypothesis, we assessed changes in the secretome, reactive oxygen species production, and macrophage infiltration in periaortic adipose tissue of young (7 month old) and aged (24 month old) high-fat diet-fed obese C57BL/6 mice. High-fat diet-induced vascular reactive oxygen species generation significantly increased in aged mice, which was associated with exacerbation of endothelial dysfunction and vascular inflammation. In young animals, high-fat diet-induced obesity promoted oxidative stress in the perivascular adipose tissue, which was associated with a marked proinflammatory shift in the profile of secreted cytokines and chemokines. Aging exacerbated obesity-induced oxidative stress and inflammation and significantly increased macrophage infiltration in periaortic adipose tissue. Using cultured arteries isolated from young control mice, we found that inflammatory factors secreted from the perivascular fat tissue of obese aged mice promote significant prooxidative and proinflammatory phenotypic alterations in the vascular wall, mimicking the aging phenotype. Overall, our findings support an important role for localized perivascular adipose tissue inflammation in exacerbation of vascular oxidative stress and inflammation in aging, an effect that likely enhances the risk for development of cardiovascular diseases from obesity in the elderly individuals.

  8. Aging Exacerbates Obesity-Induced Oxidative Stress and Inflammation in Perivascular Adipose Tissue in Mice: A Paracrine Mechanism Contributing to Vascular Redox Dysregulation and Inflammation

    PubMed Central

    Bailey-Downs, Lora C.; Tucsek, Zsuzsanna; Toth, Peter

    2013-01-01

    Obesity in the elderly individuals is increasing at alarming rates and there is evidence suggesting that elderly individuals are more vulnerable to the deleterious cardiovascular effects of obesity than younger individuals. However, the specific mechanisms through which aging and obesity interact to promote the development of cardiovascular disease remain unclear. The present study was designed to test the hypothesis that aging exacerbates obesity-induced inflammation in perivascular adipose tissue, which contributes to increased vascular oxidative stress and inflammation in a paracrine manner. To test this hypothesis, we assessed changes in the secretome, reactive oxygen species production, and macrophage infiltration in periaortic adipose tissue of young (7 month old) and aged (24 month old) high-fat diet–fed obese C57BL/6 mice. High-fat diet–induced vascular reactive oxygen species generation significantly increased in aged mice, which was associated with exacerbation of endothelial dysfunction and vascular inflammation. In young animals, high-fat diet–induced obesity promoted oxidative stress in the perivascular adipose tissue, which was associated with a marked proinflammatory shift in the profile of secreted cytokines and chemokines. Aging exacerbated obesity-induced oxidative stress and inflammation and significantly increased macrophage infiltration in periaortic adipose tissue. Using cultured arteries isolated from young control mice, we found that inflammatory factors secreted from the perivascular fat tissue of obese aged mice promote significant prooxidative and proinflammatory phenotypic alterations in the vascular wall, mimicking the aging phenotype. Overall, our findings support an important role for localized perivascular adipose tissue inflammation in exacerbation of vascular oxidative stress and inflammation in aging, an effect that likely enhances the risk for development of cardiovascular diseases from obesity in the elderly individuals

  9. Psoriasis Skin Inflammation-Induced microRNA-26b Targets NCEH1 in Underlying Subcutaneous Adipose Tissue.

    PubMed

    Cheung, Louisa; Fisher, Rachel M; Kuzmina, Natalia; Li, Dongqing; Li, Xi; Werngren, Olivera; Blomqvist, Lennart; Ståhle, Mona; Landén, Ning Xu

    2016-03-01

    Psoriasis is an immune-mediated inflammatory disease, which is associated with a high risk of developing systemic comorbidities, such as obesity, cardiovascular disease, and diabetes mellitus. However, the mechanistic links between psoriatic skin inflammation and systemic comorbidities remain largely unknown. MicroRNAs (miRNAs) are recently discovered gene regulators that play important roles in psoriasis skin inflammation. In this study we aimed to explore whether the skin inflammation in psoriasis affects miRNA expression of the underlying subcutaneous adipose tissue and whether this may be a link between psoriasis and comorbidities. To this end, we compared the miRNA expression profile of subcutaneous adipose tissue underneath lesional and nonlesional psoriatic skin. We further validated the differential expression of several miRNAs and characterized their expression patterns in different cell types present in subcutaneous adipose tissue. We focused on miR-26b-5p, which was highly up-regulated in subcutaneous adipose tissue underneath lesional psoriasis skin. We showed that it targets and down-regulates neutral cholesterol ester hydrolase 1, an enzyme essential for cholesterol efflux, in monocytes/macrophages, adipocytes, vascular endothelial cells, and fibroblasts. We conclude that this miRNA may serve as a mechanistic link between psoriatic skin inflammation and its systemic comorbidities. Copyright © 2015 The Authors. Published by Elsevier Inc. All rights reserved.

  10. Cavin1; a Regulator of Lung Function and Macrophage Phenotype

    PubMed Central

    Govender, Praveen; Romero, Freddy; Shah, Dilip; Paez, Jesus; Ding, Shi-Ying; Liu, Libin; Gower, Adam; Baez, Elizabeth; Aly, Sherif Shawky; Pilch, Paul; Summer, Ross

    2013-01-01

    Caveolae are cell membrane invaginations that are highly abundant in adipose tissue, endothelial cells and the lung. The formation of caveolae is dependent on the expression of various structural proteins that serve as scaffolding for these membrane invaginations. Cavin1 is a newly identified structural protein whose deficiency in mice leads to loss of caveolae formation and to development of a lipodystrophic phenotype. In this study, we sought to investigate the functional role of Cavin1 in the lung. Cavin1 deficient mice possessed dramatically altered distal lung morphology and exhibited significant physiological alterations, notably, increased lung elastance. The changes in distal lung architecture were associated with hypercellularity and the accumulation of lung macrophages. The increases in lung macrophages occurred without changes to circulating numbers of mononuclear cells and without evidence for increased proliferation. However, the increases in lung macrophages were associated with higher levels of macrophage chemotactic factors CXCL2 and CCL2 in BAL fluid from Cavin1−/− mice suggesting a possible mechanism by which these cells accumulate. In addition, lung macrophages from Cavin1−/− mice were larger and displayed measurable differences in gene expression when compared to macrophages from wild-type mice. Interestingly, macrophages were also increased in adipose tissue but not in liver, kidney or skeletal muscle from Cavin1−/− mice, and similar tissue specificity for macrophage accumulation was observed in lungs and adipose tissue from Caveolin1−/− mice. In conclusion, this study demonstrates an important role for Cavin1 in lung homeostasis and suggests that caveolae structural proteins are necessary for regulating macrophage number and phenotype in the lung. PMID:23634221

  11. Functional Characterization of Preadipocytes Derived from Human Periaortic Adipose Tissue

    PubMed Central

    Camacho, Jaime; Duque, Juan; Carreño, Marisol; Acero, Edward; Pérez, Máximo; Ramirez, Sergio; Umaña, Juan; Obando, Carlos; Guerrero, Albert; Sandoval, Néstor; Rodríguez, Gina

    2017-01-01

    Adipose tissue can affect the metabolic control of the cardiovascular system, and its anatomic location can affect the vascular function differently. In this study, biochemical and phenotypical characteristics of adipose tissue from periaortic fat were evaluated. Periaortic and subcutaneous adipose tissues were obtained from areas surrounding the ascending aorta and sternotomy incision, respectively. Adipose tissues were collected from patients undergoing myocardial revascularization or mitral valve replacement surgery. Morphological studies with hematoxylin/eosin and immunohistochemical assay were performed in situ to quantify adipokine expression. To analyze adipogenic capacity, adipokine expression, and the levels of thermogenic proteins, adipocyte precursor cells were isolated from periaortic and subcutaneous adipose tissues and induced to differentiation. The precursors of adipocytes from the periaortic tissue accumulated less triglycerides than those from the subcutaneous tissue after differentiation and were smaller than those from subcutaneous adipose tissue. The levels of proteins involved in thermogenesis and energy expenditure increased significantly in periaortic adipose tissue. Additionally, the expression levels of adipokines that affect carbohydrate metabolism, such as FGF21, increased significantly in mature adipocytes induced from periaortic adipose tissue. These results demonstrate that precursors of periaortic adipose tissue in humans may affect cardiovascular events and might serve as a target for preventing vascular diseases. PMID:29209367

  12. Visualized macrophage dynamics and significance of S100A8 in obese fat

    PubMed Central

    Sekimoto, Ryohei; Fukuda, Shiro; Maeda, Norikazu; Tsushima, Yu; Matsuda, Keisuke; Mori, Takuya; Nakatsuji, Hideaki; Nishizawa, Hitoshi; Kishida, Ken; Kikuta, Junichi; Maijima, Yumiko; Funahashi, Tohru; Ishii, Masaru; Shimomura, Iichiro

    2015-01-01

    Chronic low-grade inflammation of adipose tissue plays a crucial role in the pathophysiology of obesity. Immunohistological microscopic analysis in obese fat tissue has demonstrated the infiltration of several immune cells such as macrophages, but dynamics of immune cells have not been fully elucidated and clarified. Here, by using intravital multiphoton imaging technique, to our knowledge for the first time, we analyzed and visualized the inflammatory processes in adipose tissue under high-fat and high-sucrose (HF/HS) diet with lysozyme M-EGFP transgenic (LysMEGFP) mice whose EGFP was specifically expressed in the myelomonocytic lineage. Mobility of LysMEGFP-positive macrophages was shown to be activated just 5 d after HF/HS diet, when the distinct hypertrophy of adipocytes and the accumulation of macrophages still have not become prominent. Significant increase of S100A8 was detected in mature adipocyte fraction just 5 d after HF/HS diet. Recombinant S100A8 protein stimulated chemotactic migration in vitro and in vivo, as well as induced proinflammatory molecules, both macrophages and adipocytes, such as TNF-α and chemokine (C-C motif) ligand 2. Finally, an antibody against S100A8 efficiently suppressed the HF/HS diet-induced initial inflammatory change, i.e., increased mobilization of adipose LysMEGFP-positive macrophages, and ameliorated HF/HS diet-induced insulin resistance. In conclusion, time-lapse intravital multiphoton imaging of adipose tissues identified the very early event exhibiting increased mobility of macrophages, which may be triggered by increased expression of adipose S100A8 and results in progression of chronic inflammation in situ. PMID:25848057

  13. The role of adipose tissue in cancer-associated cachexia.

    PubMed

    Vaitkus, Janina A; Celi, Francesco S

    2017-03-01

    Adipose tissue (fat) is a heterogeneous organ, both in function and histology, distributed throughout the body. White adipose tissue, responsible for energy storage and more recently found to have endocrine and inflammation-modulatory activities, was historically thought to be the only type of fat present in adult humans. The recent demonstration of functional brown adipose tissue in adults, which is highly metabolic, shifted this paradigm. Additionally, recent studies demonstrate the ability of white adipose tissue to be induced toward the brown adipose phenotype - "beige" or "brite" adipose tissue - in a process referred to as "browning." While these adipose tissue depots are under investigation in the context of obesity, new evidence suggests a maladaptive role in other metabolic disturbances including cancer-associated cachexia, which is the topic of this review. This syndrome is multifactorial in nature and is an independent factor associated with poor prognosis. Here, we review the contributions of all three adipose depots - white, brown, and beige - to the development and progression of cancer-associated cachexia. Specifically, we focus on the local and systemic processes involving these adipose tissues that lead to increased energy expenditure and sustained negative energy balance. We highlight key findings from both animal and human studies and discuss areas within the field that need further exploration. Impact statement Cancer-associated cachexia (CAC) is a complex, multifactorial syndrome that negatively impacts patient quality of live and prognosis. This work reviews a component of CAC that lacks prior discussion: adipose tissue contributions. Uniquely, it discusses all three types of adipose tissue, white, beige, and brown, their interactions, and their contributions to the development and progression of CAC. Summarizing key bench and clinical studies, it provides information that will be useful to both basic and clinical researchers in designing

  14. Thyroid hormone status defines brown adipose tissue activity and browning of white adipose tissues in mice.

    PubMed

    Weiner, Juliane; Kranz, Mathias; Klöting, Nora; Kunath, Anne; Steinhoff, Karen; Rijntjes, Eddy; Köhrle, Josef; Zeisig, Vilia; Hankir, Mohammed; Gebhardt, Claudia; Deuther-Conrad, Winnie; Heiker, John T; Kralisch, Susan; Stumvoll, Michael; Blüher, Matthias; Sabri, Osama; Hesse, Swen; Brust, Peter; Tönjes, Anke; Krause, Kerstin

    2016-12-12

    The present study aimed to determine the effect of thyroid hormone dysfunction on brown adipose tissue activity and white adipose tissue browning in mice. Twenty randomized female C57BL/6NTac mice per treatment group housed at room temperature were rendered hypothyroid or hyperthyroid. In-vivo small animal 18 F-FDG PET/MRI was performed to determine the effects of hypo- and hyperthyroidism on BAT mass and BAT activity. Ex-vivo 14 C-acetate loading assay and assessment of thermogenic gene and protein expression permitted analysis of oxidative and thermogenic capacities of WAT and BAT of eu-, hyper and hypothyroid mice. 18 F-FDG PET/MRI revealed a lack of brown adipose tissue activity in hypothyroid mice, whereas hyperthyroid mice displayed increased BAT mass alongside enhanced 18 F-FDG uptake. In white adipose tissue of both, hyper- and hypothyroid mice, we found a significant induction of thermogenic genes together with multilocular adipocytes expressing UCP1. Taken together, these results suggest that both the hyperthyroid and hypothyroid state stimulate WAT thermogenesis most likely as a consequence of enhanced adrenergic signaling or compensation for impaired BAT function, respectively.

  15. Chronic Trypanosoma cruzi infection potentiates adipose tissue macrophage polarization toward an anti-inflammatory M2 phenotype and contributes to diabetes progression in a diet-induced obesity model.

    PubMed

    Cabalén, María E; Cabral, María F; Sanmarco, Liliana M; Andrada, Marta C; Onofrio, Luisina I; Ponce, Nicolás E; Aoki, María P; Gea, Susana; Cano, Roxana C

    2016-03-22

    Chronic obesity and Chagas disease (caused by the protozoan Trypanosoma cruzi) represent serious public health concerns. The interrelation between parasite infection, adipose tissue, immune system and metabolism in an obesogenic context, has not been entirely explored. A novel diet-induced obesity model (DIO) was developed in C57BL/6 wild type mice to examine the effect of chronic infection (DIO+I) on metabolic parameters and on obesity-related disorders. Dyslipidemia, hyperleptinemia, and cardiac/hepatic steatosis were strongly developed in DIO mice. Strikingly, although these metabolic alterations were collectively improved by infection, plasmatic apoB100 levels remain significantly increased in DIO+I, suggesting the presence of pro-atherogenic small and dense LDL particles. Moreover, acute insulin resistance followed by chronic hyperglycemia with hypoinsulinemia was found, evidencing an infection-related-diabetes progression. These lipid and glucose metabolic changes seemed to be highly dependent on TLR4 expression since TLR4-/- mice were protected from obesity and its complications. Notably, chronic infection promoted a strong increase in MCP-1 producing macrophages with a M2 (F4/80+CD11c-CD206+) phenotype associated to oxidative stress in visceral adipose tissue of DIO+I mice. Importantly, infection reduced lipid content but intensified inflammatory infiltrates in target tissues. Thus, parasite persistence in an obesogenic environment and the resulting host immunometabolic dysregulation may contribute to diabetes/atherosclerosis progression.

  16. Fatty acid oxidation is required for active and quiescent brown adipose tissue maintenance and thermogenic programing.

    PubMed

    Gonzalez-Hurtado, Elsie; Lee, Jieun; Choi, Joseph; Wolfgang, Michael J

    2018-01-01

    To determine the role of fatty acid oxidation on the cellular, molecular, and physiologic response of brown adipose tissue to disparate paradigms of chronic thermogenic stimulation. Mice with an adipose-specific loss of Carnitine Palmitoyltransferase 2 (Cpt2 A-/- ), that lack mitochondrial long chain fatty acid β-oxidation, were subjected to environmental and pharmacologic interventions known to promote thermogenic programming in adipose tissue. Chronic administration of β3-adrenergic (CL-316243) or thyroid hormone (GC-1) agonists induced a loss of BAT morphology and UCP1 expression in Cpt2 A-/- mice. Fatty acid oxidation was also required for the browning of white adipose tissue (WAT) and the induction of UCP1 in WAT. In contrast, chronic cold (15 °C) stimulation induced UCP1 and thermogenic programming in both control and Cpt2 A-/- adipose tissue albeit to a lesser extent in Cpt2 A-/- mice. However, thermoneutral housing also induced the loss of UCP1 and BAT morphology in Cpt2 A-/- mice. Therefore, adipose fatty acid oxidation is required for both the acute agonist-induced activation of BAT and the maintenance of quiescent BAT. Consistent with this data, Cpt2 A-/- BAT exhibited increased macrophage infiltration, inflammation and fibrosis irrespective of BAT activation. Finally, obese Cpt2 A-/- mice housed at thermoneutrality exhibited a loss of interscapular BAT and were refractory to β3-adrenergic-induced energy expenditure and weight loss. Mitochondrial long chain fatty acid β-oxidation is critical for the maintenance of the brown adipocyte phenotype both during times of activation and quiescence. Copyright © 2017 The Authors. Published by Elsevier GmbH.. All rights reserved.

  17. Adipose-derived stem cells and periodontal tissue engineering.

    PubMed

    Tobita, Morikuni; Mizuno, Hiroshi

    2013-01-01

    Innovative developments in the multidisciplinary field of tissue engineering have yielded various implementation strategies and the possibility of functional tissue regeneration. Technologic advances in the combination of stem cells, biomaterials, and growth factors have created unique opportunities to fabricate tissues in vivo and in vitro. The therapeutic potential of human multipotent mesenchymal stem cells (MSCs), which are harvested from bone marrow and adipose tissue, has generated increasing interest in a wide variety of biomedical disciplines. These cells can differentiate into a variety of tissue types, including bone, cartilage, fat, and nerve tissue. Adipose-derived stem cells have some advantages compared with other sources of stem cells, most notably that a large number of cells can be easily and quickly isolated from adipose tissue. In current clinical therapy for periodontal tissue regeneration, several methods have been developed and applied either alone or in combination, such as enamel matrix proteins, guided tissue regeneration, autologous/allogeneic/xenogeneic bone grafts, and growth factors. However, there are various limitations and shortcomings for periodontal tissue regeneration using current methods. Recently, periodontal tissue regeneration using MSCs has been examined in some animal models. This method has potential in the regeneration of functional periodontal tissues because the various secreted growth factors from MSCs might not only promote the regeneration of periodontal tissue but also encourage neovascularization of the damaged tissues. Adipose-derived stem cells are especially effective for neovascularization compared with other MSC sources. In this review, the possibility and potential of adipose-derived stem cells for regenerative medicine are introduced. Of particular interest, periodontal tissue regeneration with adipose-derived stem cells is discussed.

  18. Tissue-specific contribution of macrophages to wound healing.

    PubMed

    Minutti, Carlos M; Knipper, Johanna A; Allen, Judith E; Zaiss, Dietmar M W

    2017-01-01

    Macrophages are present in all tissues, either as resident cells or monocyte-derived cells that infiltrate into tissues. The tissue site largely determines the phenotype of tissue-resident cells, which help to maintain tissue homeostasis and act as sentinels of injury. Both tissue resident and recruited macrophages make a substantial contribution to wound healing following injury. In this review, we evaluate how macrophages in two fundamentally distinct tissues, i.e. the lung and the skin, differentially contribute to the process of wound healing. We highlight the commonalities of macrophage functions during repair and contrast them with distinct, tissue-specific functions that macrophages fulfill during the different stages of wound healing. Copyright © 2016 The Authors. Published by Elsevier Ltd.. All rights reserved.

  19. MAP3K8 (TPL2/COT) affects obesity-induced adipose tissue inflammation without systemic effects in humans and in mice.

    PubMed

    Ballak, Dov B; van Essen, Peter; van Diepen, Janna A; Jansen, Henry; Hijmans, Anneke; Matsuguchi, Tetsuya; Sparrer, Helmut; Tack, Cees J; Netea, Mihai G; Joosten, Leo A B; Stienstra, Rinke

    2014-01-01

    Chronic low-grade inflammation in adipose tissue often accompanies obesity, leading to insulin resistance and increasing the risk for metabolic diseases. MAP3K8 (TPL2/COT) is an important signal transductor and activator of pro-inflammatory pathways that has been linked to obesity-induced adipose tissue inflammation. We used human adipose tissue biopsies to study the relationship of MAP3K8 expression with markers of obesity and expression of pro-inflammatory cytokines (IL-1β, IL-6 and IL-8). Moreover, we evaluated obesity-induced adipose tissue inflammation and insulin resistance in mice lacking MAP3K8 and WT mice on a high-fat diet (HFD) for 16 weeks. Individuals with a BMI >30 displayed a higher mRNA expression of MAP3K8 in adipose tissue compared to individuals with a normal BMI. Additionally, high mRNA expression levels of IL-1β, IL-6 and IL-8, but not TNF -α, in human adipose tissue were associated with higher expression of MAP3K8. Moreover, high plasma SAA and CRP did not associate with increased MAP3K8 expression in adipose tissue. Similarly, no association was found for MAP3K8 expression with plasma insulin or glucose levels. Mice lacking MAP3K8 had similar bodyweight gain as WT mice, yet displayed lower mRNA expression levels of IL-1β, IL-6 and CXCL1 in adipose tissue in response to the HFD as compared to WT animals. However, MAP3K8 deficient mice were not protected against HFD-induced adipose tissue macrophage infiltration or the development of insulin resistance. Together, the data in both human and mouse show that MAP3K8 is involved in local adipose tissue inflammation, specifically for IL-1β and its responsive cytokines IL-6 and IL-8, but does not seem to have systemic effects on insulin resistance.

  20. Autophagy in adipose tissue biology.

    PubMed

    Zhang, Yong; Zeng, Xiangang; Jin, Shengkan

    2012-12-01

    Obesity, which predisposes individuals to type II diabetes and cardiovascular diseases, results from accumulation of white adipose tissue (WAT). WAT comprises mainly white adipocytes that have a unique cellular structure in which almost the entire intracellular space is occupied by one single lipid droplet. The cytoplasm envelopes this lipid droplet and occupies negligible space. Differentiation of WAT, or adipogenesis, requires dramatic cytoplasmic reorganization, including a dynamic change in mitochondrial mass. Autophagy is a major cytoplasmic degradation pathway and a primary pathway for mitochondrial degradation. Recent studies indicate that autophagy is implicated in adipogenesis. In this review, we summarize our current knowledge on autophagy in adipose tissue biology, with the emphasis on its role in mitochondrial degradation. Adipose tissue is a central component for whole-body energy homeostasis regulation. Advancement in this research area may provide novel venues for the intervention of obesity and obesity related diseases. Copyright © 2012 Elsevier Ltd. All rights reserved.

  1. Alternatively activated macrophages produce catecholamines to sustain adaptive thermogenesis

    PubMed Central

    Nguyen, Khoa D.; Qiu, Yifu; Cui, Xiaojin; Goh, Y.P. Sharon; Mwangi, Julia; David, Tovo; Mukundan, Lata; Brombacher, Frank; Locksley, Richard M.; Chawla, Ajay

    2011-01-01

    All homeotherms utilize thermogenesis to maintain core body temperature, ensuring that cellular functions and physiologic processes can ensue in cold environments1-3. In the prevailing model, when the hypothalamus senses cold temperatures, it triggers sympathetic discharge, resulting in the release of noradrenaline in brown adipose tissue (BAT) and white adipose tissue (WAT)4,5. Acting via the β3-adrenergic receptors, noradrenaline induces lipolysis in white adipocytes6, whereas it stimulates the expression of thermogenic genes, such as PPARγ coactivator 1a (Ppargc1a), uncoupling protein 1 (Ucp1), and acyl-CoA synthetase long-chain family member 1 (Acsl1), in brown adipocytes7-9. However, the precise nature of all the cell types involved in this efferent loop is not well established. Here we report an unexpected requirement for the interleukin 4 (IL4)-stimulated program of alternative macrophage activation in adaptive thermogenesis. Cold exposure rapidly promoted alternative activation of adipose tissue macrophages, which secrete catecholamines to induce thermogenic gene expression in BAT and lipolysis in WAT. Absence of alternatively activated macrophages impaired metabolic adaptations to cold, whereas administration of IL4 increased thermogenic gene expression, fatty acid mobilization, and energy expenditure, all in a macrophage-dependent manner. We have thus discovered a surprising role for alternatively activated macrophages in the orchestration of an important mammalian stress response, the response to cold. PMID:22101429

  2. Adipose Tissue Angiogenesis: Impact on Obesity and Type-2 Diabetes

    PubMed Central

    Corvera, Silvia; Gealekman, Olga

    2013-01-01

    The growth and function of tissues is critically dependent on their vascularization. Adipose tissue is capable of expanding many-fold during adulthood, therefore requiring the formation of new vasculature to supply growing and proliferating adipocytes. The expansion of the vasculature in adipose tissue occurs through angiogenesis, where new blood vessels develop from those pre-existing within the tissue. Inappropriate angiogenesis may underlie adipose tissue dysfunction in obesity, which in turn increases type-2 diabetes risk. In addition, genetic and developmental factors involved in vascular patterning may define the size and expandability of diverse adipose tissue depots, which are also associated with type-2 diabetes risk. Moreover, the adipose tissue vasculature appears to be the niche for pre-adipocyte precursors, and factors that affect angiogenesis may directly impact the generation of new adipocytes. Here we review recent advances on the basic mechanisms of angiogenesis, and on the role of angiogenesis in adipose tissue development and obesity. A substantial amount of data point to a deficit in adipose tissue angiogenesis as a contributing factor to insulin resistance and metabolic disease in obesity. These emerging findings support the concept of the adipose tissue vasculature as a source of new targets for metabolic disease therapies. PMID:23770388

  3. Adipose-Derived Stem Cell Delivery for Adipose Tissue Engineering: Current Status and Potential Applications in a Tissue Engineering Chamber Model.

    PubMed

    Zhan, Weiqing; Tan, Shaun S; Lu, Feng

    2016-08-01

    In reconstructive surgery, there is a clinical need for adequate implants to repair soft tissue defects caused by traumatic injury, tumor resection, or congenital abnormalities. Adipose tissue engineering may provide answers to this increasing demand. This study comprehensively reviews current approaches to adipose tissue engineering, detailing different cell carriers under investigation, with a special focus on the application of adipose-derived stem cells (ASCs). ASCs act as building blocks for new tissue growth and as modulators of the host response. Recent studies have also demonstrated that the implantation of a hollow protected chamber, combined with a vascular pedicle within the fat flaps provides blood supply and enables the growth of large-volume of engineered soft tissue. Conceptually, it would be of value to co-regulate this unique chamber model with adipose-derived stem cells to obtain a greater volume of soft tissue constructs for clinical use. Our review provides a cogent update on these advances and details the generation of possible fat substitutes.

  4. Differential activation of Fyn kinase distinguishes saturated and unsaturated fats in mouse macrophages

    PubMed Central

    Tarabra, Elena; An Lee, Ting-Wen; Zammit, Victor A.; Vatish, Manu; Yamada, Eijiro; Pessin, Jeffrey E.; Bastie, Claire C.

    2017-01-01

    Diet-induced obesity is associated with increased adipose tissue activated macrophages. Yet, how macrophages integrate fatty acid (FA) signals remains unclear. We previously demonstrated that Fyn deficiency (fynKO) protects against high fat diet-induced adipose tissue macrophage accumulation. Herein, we show that inflammatory markers and reactive oxygen species are not induced in fynKO bone marrow-derived macrophages exposed to the saturated FA palmitate, suggesting that Fyn regulates macrophage function in response to FA signals. Palmitate activates Fyn and re-localizes Fyn into the nucleus of RAW264.7, J774 and wild-type bone marrow-derived macrophages. Similarly, Fyn activity is increased in cells of adipose tissue stromal vascular fraction of high fat-fed control mice, with Fyn protein being located in the nucleus of these cells. We demonstrate that Fyn modulates palmitate-dependent oxidative stress in macrophages. Moreover, Fyn catalytic activity is necessary for its nuclear re-localization and downstream effects, as Fyn pharmacological inhibition abolishes palmitate-induced Fyn nuclear redistribution and palmitate-dependent increase of oxidative stress markers. Importantly, mono-or polyunsaturated FAs do not activate Fyn, and fail to re-localize Fyn to the nucleus. Together these data demonstrate that macrophages integrate nutritional FA signals via a differential activation of Fyn that distinguishes, at least partly, the effects of saturated versus unsaturated fats. PMID:29156823

  5. Differential activation of Fyn kinase distinguishes saturated and unsaturated fats in mouse macrophages.

    PubMed

    Tarabra, Elena; An Lee, Ting-Wen; Zammit, Victor A; Vatish, Manu; Yamada, Eijiro; Pessin, Jeffrey E; Bastie, Claire C

    2017-10-17

    Diet-induced obesity is associated with increased adipose tissue activated macrophages. Yet, how macrophages integrate fatty acid (FA) signals remains unclear. We previously demonstrated that Fyn deficiency ( fynKO ) protects against high fat diet-induced adipose tissue macrophage accumulation. Herein, we show that inflammatory markers and reactive oxygen species are not induced in fynKO bone marrow-derived macrophages exposed to the saturated FA palmitate, suggesting that Fyn regulates macrophage function in response to FA signals. Palmitate activates Fyn and re-localizes Fyn into the nucleus of RAW264.7, J774 and wild-type bone marrow-derived macrophages. Similarly, Fyn activity is increased in cells of adipose tissue stromal vascular fraction of high fat-fed control mice, with Fyn protein being located in the nucleus of these cells. We demonstrate that Fyn modulates palmitate-dependent oxidative stress in macrophages. Moreover, Fyn catalytic activity is necessary for its nuclear re-localization and downstream effects, as Fyn pharmacological inhibition abolishes palmitate-induced Fyn nuclear redistribution and palmitate-dependent increase of oxidative stress markers. Importantly, mono-or polyunsaturated FAs do not activate Fyn, and fail to re-localize Fyn to the nucleus. Together these data demonstrate that macrophages integrate nutritional FA signals via a differential activation of Fyn that distinguishes, at least partly, the effects of saturated versus unsaturated fats.

  6. Adipose tissue branched chain amino acid (BCAA) metabolism modulates circulating BCAA levels.

    PubMed

    Herman, Mark A; She, Pengxiang; Peroni, Odile D; Lynch, Christopher J; Kahn, Barbara B

    2010-04-09

    Whereas the role of adipose tissue in glucose and lipid homeostasis is widely recognized, its role in systemic protein and amino acid metabolism is less well-appreciated. In vitro and ex vivo experiments suggest that adipose tissue can metabolize substantial amounts of branched chain amino acids (BCAAs). However, the role of adipose tissue in regulating BCAA metabolism in vivo is controversial. Interest in the contribution of adipose tissue to BCAA metabolism has been renewed with recent observations demonstrating down-regulation of BCAA oxidation enzymes in adipose tissue in obese and insulin-resistant humans. Using gene set enrichment analysis, we observe alterations in adipose-tissue BCAA enzyme expression caused by adipose-selective genetic alterations in the GLUT4 glucose-transporter expression. We show that the rate of adipose tissue BCAA oxidation per mg of tissue from normal mice is higher than in skeletal muscle. In mice overexpressing GLUT4 specifically in adipose tissue, we observe coordinate down-regulation of BCAA metabolizing enzymes selectively in adipose tissue. This decreases BCAA oxidation rates in adipose tissue, but not in muscle, in association with increased circulating BCAA levels. To confirm the capacity of adipose tissue to modulate circulating BCAA levels in vivo, we demonstrate that transplantation of normal adipose tissue into mice that are globally defective in peripheral BCAA metabolism reduces circulating BCAA levels by 30% (fasting)-50% (fed state). These results demonstrate for the first time the capacity of adipose tissue to catabolize circulating BCAAs in vivo and that coordinate regulation of adipose-tissue BCAA enzymes may modulate circulating BCAA levels.

  7. Adenovirus 36 DNA in human adipose tissue.

    PubMed

    Ponterio, E; Cangemi, R; Mariani, S; Casella, G; De Cesare, A; Trovato, F M; Garozzo, A; Gnessi, L

    2015-12-01

    Recent studies have suggested a possible correlation between obesity and adenovirus 36 (Adv36) infection in humans. As information on adenoviral DNA presence in human adipose tissue are limited, we evaluated the presence of Adv36 DNA in adipose tissue of 21 adult overweight or obese patients. Total DNA was extracted from adipose tissue biopsies. Virus detection was performed using PCR protocols with primers against specific Adv36 fiber protein and the viral oncogenic E4orf1 protein nucleotide sequences. Sequences were aligned with the NCBI database and phylogenetic analyses were carried out with MEGA6 software. Adv36 DNA was found in four samples (19%). This study indicates that some individuals carry Adv36 in the visceral adipose tissue. Further studies are needed to determine the specific effect of Adv36 infection on adipocytes, the prevalence of Adv36 infection and its relationship with obesity in the perspective of developing a vaccine that could potentially prevent or mitigate infection.

  8. Insulin action in adipose tissue and muscle in hypothyroidism.

    PubMed

    Dimitriadis, George; Mitrou, Panayota; Lambadiari, Vaia; Boutati, Eleni; Maratou, Eirini; Panagiotakos, Demosthenes B; Koukkou, Efi; Tzanela, Marinela; Thalassinos, Nikos; Raptis, Sotirios A

    2006-12-01

    Although insulin resistance in thyroid hormone excess is well documented, information on insulin action in hypothyroidism is limited. To investigate this, a meal was given to 11 hypothyroid (HO; aged 45 +/- 3 yr) and 10 euthyroid subjects (EU; aged 42 +/- 4 yr). Blood was withdrawn for 360 min from veins (V) draining the anterior abdominal sc adipose tissue and the forearm and from the radial artery (A). Blood flow (BF) in adipose tissue was measured with 133Xe and in forearm with strain-gauge plethysmography. Tissue glucose uptake was calculated as (A-V)glucose(BF), lipoprotein lipase as (A-V)Triglycerides(BF), and lipolysis as [(V-A)glycerol(BF)]-lipoprotein lipase. The HO group had higher glucose and insulin levels than the EU group (P < 0.05). In HO vs. EU after meal ingestion (area under curve 0-360 min): 1) BF (1290 +/- 79 vs. 1579 +/- 106 ml per 100 ml tissue in forearm and 706 +/- 105 vs. 1340 +/- 144 ml per 100 ml tissue in adipose tissue) and glucose uptake (464 +/- 74 vs. 850 +/- 155 micromol per 100 ml tissue in forearm and 208 +/- 42 vs. 406 +/- 47 micromol per 100 ml tissue in adipose tissue) were decreased (P < 0.05), but fractional glucose uptake was similar (28 +/- 6 vs. 33 +/- 6% per minute in forearm and 17 +/- 4 vs. 14 +/- 3% per minute in adipose tissue); 2) suppression of lipolysis by insulin was similar; and 3) plasma triglycerides were elevated (489 +/- 91 vs. 264 +/- 36 nmol/liter.min, P < 0.05), whereas adipose tissue lipoprotein lipase (42 +/- 11 vs. 80 +/- 21 micromol per 100 ml tissue) and triglyceride clearance (45 +/- 10 vs. 109 +/- 21 ml per 100 ml tissue) were decreased in HO (P < 0.05). In hypothyroidism: 1) glucose uptake in muscle and adipose tissue is resistant to insulin; 2) suppression of lipolysis by insulin is not impaired; and 3) hypertriglyceridemia is due to decreased clearance by the adipose tissue.

  9. Hydrogel derived from decellularized porcine adipose tissue as a promising biomaterial for soft tissue augmentation.

    PubMed

    Tan, Qiu-Wen; Zhang, Yi; Luo, Jing-Cong; Zhang, Di; Xiong, Bin-Jun; Yang, Ji-Qiao; Xie, Hui-Qi; Lv, Qing

    2017-06-01

    Decellularized extracellular matrix (ECM) scaffolds from human adipose tissue, characterized by impressive adipogenic induction ability, are promising for soft tissue augmentation. However, scaffolds from autologous human adipose tissue are limited by the availability of tissue resources and the time necessary for scaffold fabrication. The objective of the current study was to investigate the adipogenic properties of hydrogels of decellularized porcine adipose tissue (HDPA). HDPA induced the adipogenic differentiation of human adipose-derived stem cells (ADSCs) in vitro, with significantly increased expression of adipogenic genes. Subcutaneous injection of HDPA in immunocompetent mice induced host-derived adipogenesis without cell seeding, and adipogenesis was significantly enhanced with ADSCs seeding. The newly formed adipocytes were frequently located on the basal side in the non-seeding group, but this trend was not observed in the ADSCs seeding group. Our results indicated that, similar to human adipose tissue, the ECM scaffold derived from porcine adipose tissue could provide an adipogenic microenvironment for adipose tissue regeneration and is a promising biomaterial for soft tissue augmentation. © 2017 Wiley Periodicals, Inc. J Biomed Mater Res Part A: 105A: 1756-1764, 2017. © 2017 Wiley Periodicals, Inc.

  10. Neutron organ dose and the influence of adipose tissue

    NASA Astrophysics Data System (ADS)

    Simpkins, Robert Wayne

    Neutron fluence to dose conversion coefficients have been assessed considering the influences of human adipose tissue. Monte Carlo code MCNP4C was used to simulate broad parallel beam monoenergetic neutrons ranging in energy from thermal to 10 MeV. Simulated Irradiations were conducted for standard irradiation geometries. The targets were on gender specific mathematical anthropomorphic phantoms modified to approximate human adipose tissue distributions. Dosimetric analysis compared adipose tissue influence against reference anthropomorphic phantom characteristics. Adipose Male and Post-Menopausal Female Phantoms were derived introducing interstitial adipose tissue to account for 22 and 27 kg additional body mass, respectively, each demonstrating a Body Mass Index (BMI) of 30. An Adipose Female Phantom was derived introducing specific subcutaneous adipose tissue accounting for 15 kg of additional body mass demonstrating a BMI of 26. Neutron dose was shielded in the superficial tissues; giving rise to secondary photons which dominated the effective dose for Incident energies less than 100 keV. Adipose tissue impact on the effective dose was a 25% reduction at the anterior-posterior incidence ranging to a 10% increase at the lateral incidences. Organ dose impacts were more distinctive; symmetrically situated organs demonstrated a 15% reduction at the anterior-posterior Incidence ranging to a 2% increase at the lateral incidences. Abdominal or asymmetrically situated organs demonstrated a 50% reduction at the anterior-posterior incidence ranging to a 25% increase at the lateral incidences.

  11. Pre-Operative Diet Impacts the Adipose Tissue Response to Surgical Trauma

    PubMed Central

    Nguyen, Binh; Tao, Ming; Yu, Peng; Mauro, Christine; Seidman, Michael A.; Wang, Yaoyu E.; Mitchell, James; Ozaki, C. Keith

    2012-01-01

    Background Short-term changes in pre-operative nutrition can have profound effects on surgery related outcomes such as ischemia reperfusions injury in pre-clinical models. Dietary interventions that lend protection against stress in animal models (e.g. fasting, dietary restriction [DR]) impact adipose tissue quality/quantity. Adipose tissue holds high surgical relevance due to its anatomic location and high tissue volume, and it is ubiquitously traumatized during surgery. Yet the response of adipose tissue to trauma under clinically relevant circumstances including dietary status remains poorly defined. We hypothesized that pre-operative diet alters the adipose tissue response to surgical trauma. Methods A novel mouse model of adipose tissue surgical trauma was employed. Dietary conditions (diet induced obesity [DIO], pre-operative DR) were modulated prior to application of surgical adipose tissue trauma in the context of clinically common scenarios (different ages, simulated bacterial wound contamination). Local/distant adipose tissue phenotypic responses were measured as represented by gene expression of inflammatory, tissue remodeling/growth, and metabolic markers. Results Surgical trauma had a profound effect on adipose tissue phenotype at the site of trauma. Milder but significant distal effects on non-traumatized adipose tissue were also observed. DIO exacerbated the inflammatory aspects of this response, and pre-operative DR tended to reverse these changes. Age and LPS-simulated bacterial contamination also impacted the adipose tissue response to trauma, with young adult animals and LPS treatment exacerbating the proinflammatory response. Conclusions Surgical trauma dramatically impacts both local and distal adipose tissue biology. Short-term pre-operative DR may offer a strategy to attenuate this response. PMID:23274098

  12. Microparticles release by adipocytes act as "find-me" signals to promote macrophage migration.

    PubMed

    Eguchi, Akiko; Mulya, Anny; Lazic, Milos; Radhakrishnan, Deepa; Berk, Michael P; Povero, Davide; Gornicka, Agnieszka; Feldstein, Ariel E

    2015-01-01

    Macrophage infiltration of adipose tissue during weight gain is a central event leading to the metabolic complications of obesity. However, what are the mechanisms attracting professional phagocytes to obese adipose tissue remains poorly understood. Here, we demonstrate that adipocyte-derived microparticles (MPs) are critical "find-me" signals for recruitment of monocytes and macrophages. Supernatants from stressed adipocytes stimulated the attraction of monocyte cells and primary macrophages. The activation of caspase 3 was required for release of these signals. Adipocytes exposed to saturated fatty acids showed marked release of MPs into the supernatant while common genetic mouse models of obesity demonstrate high levels of circulating adipocyte-derived MPs. The release of MPs was highly regulated and dependent on caspase 3 and Rho-associated kinase. Further analysis identified these MPs as a central chemoattractant in vitro and in vivo. In addition, intravenously transplanting circulating MPs from the ob/ob mice lead to activation of monocytes in circulation and adipose tissue of the wild type mice. These data identify adipocyte-derived MPs as novel "find me" signals that contributes to macrophage infiltration associated with obesity.

  13. Aging and Adipose Tissue: Potential Interventions for Diabetes and Regenerative Medicine

    PubMed Central

    Palmer, Allyson K.; Kirkland, James L.

    2016-01-01

    Adipose tissue dysfunction occurs with aging and has systemic effects, including peripheral insulin resistance, ectopic lipid deposition, and inflammation. Fundamental aging mechanisms, including cellular senescence and progenitor cell dysfunction, occur in adipose tissue with aging and may serve as potential therapeutic targets in age-related disease. In this review, we examine the role of adipose tissue in healthy individuals and explore how aging leads to adipose tissue dysfunction, redistribution, and changes in gene regulation. Adipose tissue plays a central role in longevity, and interventions restricted to adipose tissue may impact lifespan. Conversely, obesity may represent a state of accelerated aging. We discuss the potential therapeutic potential of targeting basic aging mechanisms, including cellular senescence, in adipose tissue, using type II diabetes and regenerative medicine as examples. We make the case that aging should not be neglected in the study of adipose-derived stem cells for regenerative medicine strategies, as elderly patients make up a large portion of individuals in need of such therapies. PMID:26924669

  14. Resveratrol attenuates intermittent hypoxia-induced macrophage migration to visceral white adipose tissue and insulin resistance in male mice.

    PubMed

    Carreras, Alba; Zhang, Shelley X L; Almendros, Isaac; Wang, Yang; Peris, Eduard; Qiao, Zhuanhong; Gozal, David

    2015-02-01

    Chronic intermittent hypoxia during sleep (IH), as occurs in sleep apnea, promotes systemic insulin resistance. Resveratrol (Resv) has been reported to ameliorate high-fat diet-induced obesity, inflammation, and insulin resistance. To examine the effect of Resv on IH-induced metabolic dysfunction, male mice were subjected to IH or room air conditions for 8 weeks and treated with either Resv or vehicle (Veh). Fasting plasma levels of glucose, insulin, and leptin were obtained, homeostatic model assessment of insulin resistance index levels were calculated, and insulin sensitivity tests (phosphorylated AKT [also known as protein kinase B]/total AKT) were performed in 2 visceral white adipose tissue (VWAT) depots (epididymal [Epi] and mesenteric [Mes]) along with flow cytometry assessments for VWAT macrophages and phenotypes (M1 and M2). IH-Veh and IH-Resv mice showed initial reductions in food intake with later recovery, with resultant lower body weights after 8 weeks but with IH-Resv showing better increases in body weight vs IH-Veh. IH-Veh and IH-Resv mice exhibited lower fasting glucose levels, but only IH-Veh had increased homeostatic model assessment of insulin resistance index vs all 3 other groups. Leptin levels were preserved in IH-Veh but were significantly lower in IH-Resv. Reduced VWAT phosphorylated-AKT/AKT responses to insulin emerged in both Mes and Epi in IH-Veh but normalized in IH-Resv. Increases total macrophage counts and in M1 to M2 ratios occurred in IH-Veh Mes and Epi compared all other 3 groups. Thus, Resv ameliorates food intake and weight gain during IH exposures and markedly attenuates VWAT inflammation and insulin resistance, thereby providing a potentially useful adjunctive therapy for metabolic morbidity in the context of sleep apnea.

  15. Adipocyte-specific deficiency of NADPH oxidase 4 delays the onset of insulin resistance and attenuates adipose tissue inflammation in obesity

    PubMed Central

    Den Hartigh, Laura J.; Omer, Mohamed; Goodspeed, Leela; Wang, Shari; Wietecha, Tomasz; O’Brien, Kevin D.; Han, Chang Yeop

    2017-01-01

    Objective Obesity is associated with insulin resistance and adipose tissue inflammation. Reactive oxygen species (ROS) increase in adipose tissue during the development of obesity. We previously showed that in response to excess nutrients like glucose and palmitate, adipocytes generated ROS via NADPH oxidase (NOX) 4, the major adipocyte isoform, instead of using mitochondrial oxidation. However, the role of NOX4-derived ROS in the development of whole body insulin resistance, adipocyte inflammation, and recruitment of macrophages to adipose tissue during the development of obesity is unknown. Approach and Results In this study, control C57BL/6 mice and mice in which NOX4 has been deleted specifically in adipocytes were fed a high fat, high sucrose (HFHS) diet. During the development of obesity in control mice, adipocyte NOX4 and PPP activity were transiently increased. Primary adipocytes differentiated form mice with adipocytes deficient in NOX4 showed resistance against high glucose or palmitate-induced adipocyte inflammation. Mice with adipocytes deficient in NOX4 showed a delayed onset of insulin resistance during the development of obesity, with an initial reduction in adipose tissue inflammation that normalized with prolonged HFHS feeding. Conclusions These findings imply that NOX4-derived ROS may play a role in the onset of insulin resistance and adipose tissue inflammation. As such, therapeutics targeting NOX4-mediated ROS production could be effective in preventing obesity-associated conditions such as insulin resistance. PMID:28062496

  16. Adipocyte-Specific Deficiency of NADPH Oxidase 4 Delays the Onset of Insulin Resistance and Attenuates Adipose Tissue Inflammation in Obesity.

    PubMed

    Den Hartigh, Laura J; Omer, Mohamed; Goodspeed, Leela; Wang, Shari; Wietecha, Tomasz; O'Brien, Kevin D; Han, Chang Yeop

    2017-03-01

    Obesity is associated with insulin resistance and adipose tissue inflammation. Reactive oxygen species (ROS) increase in adipose tissue during the development of obesity. We previously showed that in response to excess nutrients like glucose and palmitate, adipocytes generated ROS via NADPH oxidase (NOX) 4, the major adipocyte isoform, instead of using mitochondrial oxidation. However, the role of NOX4-derived ROS in the development of whole body insulin resistance, adipocyte inflammation, and recruitment of macrophages to adipose tissue during the development of obesity is unknown. In this study, control C57BL/6 mice and mice in which NOX4 has been deleted specifically in adipocytes were fed a high-fat, high-sucrose diet. During the development of obesity in control mice, adipocyte NOX4 and pentose phosphate pathway activity were transiently increased. Primary adipocytes differentiated from mice with adipocytes deficient in NOX4 showed resistance against high glucose or palmitate-induced adipocyte inflammation. Mice with adipocytes deficient in NOX4 showed a delayed onset of insulin resistance during the development of obesity, with an initial reduction in adipose tissue inflammation that normalized with prolonged high-fat, high-sucrose feeding. These findings imply that NOX4-derived ROS may play a role in the onset of insulin resistance and adipose tissue inflammation. As such, therapeutics targeting NOX4-mediated ROS production could be effective in preventing obesity-associated conditions, such as insulin resistance. © 2016 American Heart Association, Inc.

  17. Estrogen receptor 1 (ESR1) regulates VEGFA in adipose tissue.

    PubMed

    Fatima, L A; Campello, R S; Santos, R de Souza; Freitas, H S; Frank, A P; Machado, U F; Clegg, D J

    2017-12-01

    Vascular endothelial growth factor A (VEGFA) is a key factor in the regulation of angiogenesis in adipose tissue. Poor vascularization during adipose tissue proliferation causes fibrosis and local inflammation, and is associated with insulin resistance. It is known that 17-beta estradiol (E2) regulates adipose tissue function and VEGFA expression in other tissues; however, the ability of E2 to regulate VEGFA in adipose tissue is currently unknown. In this study, we showed that, in 3T3-L1 cells, E2 and the estrogen receptor 1 (ESR1) agonist PPT induced VEGFA expression, while ESR1 antagonist (MPP), and selective knockdown of ESR1 using siRNA decreased VEGFA and prevented the ability of E2 to modulate its expression. Additionally, we found that E2 and PPT induced the binding of hypoxia inducible factor 1 alpha subunit (HIF1A) in the VEGFA gene promoter. We further found that VEGFA expression was lower in inguinal and gonadal white adipose tissues of ESR1 total body knockout female mice compared to wild type mice. In conclusion, our data provide evidence of an important role for E2/ESR1 in modulating adipose tissue VEGFA, which is potentially important to enhance angiogenesis, reduce inflammation and improve adipose tissue function.

  18. Aging and adipose tissue: potential interventions for diabetes and regenerative medicine.

    PubMed

    Palmer, Allyson K; Kirkland, James L

    2016-12-15

    Adipose tissue dysfunction occurs with aging and has systemic effects, including peripheral insulin resistance, ectopic lipid deposition, and inflammation. Fundamental aging mechanisms, including cellular senescence and progenitor cell dysfunction, occur in adipose tissue with aging and may serve as potential therapeutic targets in age-related disease. In this review, we examine the role of adipose tissue in healthy individuals and explore how aging leads to adipose tissue dysfunction, redistribution, and changes in gene regulation. Adipose tissue plays a central role in longevity, and interventions restricted to adipose tissue may impact lifespan. Conversely, obesity may represent a state of accelerated aging. We discuss the potential therapeutic potential of targeting basic aging mechanisms, including cellular senescence, in adipose tissue, using type II diabetes and regenerative medicine as examples. We make the case that aging should not be neglected in the study of adipose-derived stem cells for regenerative medicine strategies, as elderly patients make up a large portion of individuals in need of such therapies. Copyright © 2016 The Authors. Published by Elsevier Inc. All rights reserved.

  19. Magnetic Resonance Imaging of Adipose Tissue in Metabolic Dysfunction.

    PubMed

    Franz, Daniela; Syväri, Jan; Weidlich, Dominik; Baum, Thomas; Rummeny, Ernst J; Karampinos, Dimitrios C

    2018-06-06

    Adipose tissue has become an increasingly important tissue target in medicine. It plays a central role in the storage and release of energy throughout the human body and has recently gained interest for its endocrinologic function. Magnetic resonance imaging (MRI) is an established method for quantitative direct evaluation of adipose tissue distribution, and is used increasingly as the modality of choice for metabolic phenotyping. The purpose of this review was the identification and presentation of the currently available literature on MRI of adipose tissue in metabolic dysfunction.  A PubMed (http://www.ncbi.nlm.nih.gov/pubmed) keyword search up to August 2017 without starting date limitation was performed and reference lists of relevant articles were searched.  MRI provides excellent tools for the evaluation of adipose tissue distribution and further characterization of the tissue. Standard as well as newly developed MRI techniques allow a risk stratification for the development of metabolic dysfunction and enable monitoring without the use of ionizing radiation or contrast material.   · Different types of adipose tissue play a crucial role in various types of metabolic dysfunction.. · Magnetic resonance imaging (MRI) is an excellent tool for noninvasive adipose tissue evaluation with respect to distribution, composition and metabolic activity.. · Both standard and newly developed MRI techniques can be used for risk stratification for the development of metabolic dysfunction and allow monitoring without the use of ionizing radiation or contrast material.. · Franz D, Syväri J, Weidlich D et al. Magnetic Resonance Imaging of Adipose Tissue in Metabolic Dysfunction. Fortschr Röntgenstr 2018; DOI: 10.1055/a-0612-8006. © Georg Thieme Verlag KG Stuttgart · New York.

  20. Non-invasive Assessments of Adipose Tissue Metabolism In Vitro.

    PubMed

    Abbott, Rosalyn D; Borowsky, Francis E; Quinn, Kyle P; Bernstein, David L; Georgakoudi, Irene; Kaplan, David L

    2016-03-01

    Adipose tissue engineering is a diverse area of research where the developed tissues can be used to study normal adipose tissue functions, create disease models in vitro, and replace soft tissue defects in vivo. Increasing attention has been focused on the highly specialized metabolic pathways that regulate energy storage and release in adipose tissues which affect local and systemic outcomes. Non-invasive, dynamic measurement systems are useful to track these metabolic pathways in the same tissue model over time to evaluate long term cell growth, differentiation, and development within tissue engineering constructs. This approach reduces costs and time in comparison to more traditional destructive methods such as biochemical and immunochemistry assays and proteomics assessments. Towards this goal, this review will focus on important metabolic functions of adipose tissues and strategies to evaluate them with non-invasive in vitro methods. Current non-invasive methods, such as measuring key metabolic markers and endogenous contrast imaging will be explored.

  1. Non-invasive assessments of adipose tissue metabolism in vitro

    PubMed Central

    Abbott, Rosalyn D.; Borowsky, Francis E.; Quinn, Kyle P.; Bernstein, David L.; Georgakoudi, Irene; Kaplan, David L.

    2015-01-01

    Adipose tissue engineering is a diverse area of research where the developed tissues can be used to study normal adipose tissue functions, create disease models in vitro, and replace soft tissue defects in vivo. Increasing attention has been focused on the highly specialized metabolic pathways that regulate energy storage and release in adipose tissues which affect local and systemic outcomes. Non-invasive, dynamic measurement systems are useful to track these metabolic pathways in the same tissue model over time to evaluate long term cell growth, differentiation, and development within tissue engineering constructs. This approach reduces costs and time in comparison to more traditional destructive methods such as biochemical and immunochemistry assays and proteomics assessments. Towards this goal, this review will focus on important metabolic functions of adipose tissues and strategies to evaluate them with noninvasive in vitro methods. Current non-invasive methods, such as measuring key metabolic markers and endogenous contrast imaging will be explored. PMID:26399988

  2. Epigenetic regulation of depot-specific gene expression in adipose tissue.

    PubMed

    Gehrke, Sandra; Brueckner, Bodo; Schepky, Andreas; Klein, Johannes; Iwen, Alexander; Bosch, Thomas C G; Wenck, Horst; Winnefeld, Marc; Hagemann, Sabine

    2013-01-01

    In humans, adipose tissue is distributed in subcutaneous abdominal and subcutaneous gluteal depots that comprise a variety of functional differences. Whereas energy storage in gluteal adipose tissue has been shown to mediate a protective effect, an increase of abdominal adipose tissue is associated with metabolic disorders. However, the molecular basis of depot-specific characteristics is not completely understood yet. Using array-based analyses of transcription profiles, we identified a specific set of genes that was differentially expressed between subcutaneous abdominal and gluteal adipose tissue. To investigate the role of epigenetic regulation in depot-specific gene expression, we additionally analyzed genome-wide DNA methylation patterns in abdominal and gluteal depots. By combining both data sets, we identified a highly significant set of depot-specifically expressed genes that appear to be epigenetically regulated. Interestingly, the majority of these genes form part of the homeobox gene family. Moreover, genes involved in fatty acid metabolism were also differentially expressed. Therefore we suppose that changes in gene expression profiles might account for depot-specific differences in lipid composition. Indeed, triglycerides and fatty acids of abdominal adipose tissue were more saturated compared to triglycerides and fatty acids in gluteal adipose tissue. Taken together, our results uncover clear differences between abdominal and gluteal adipose tissue on the gene expression and DNA methylation level as well as in fatty acid composition. Therefore, a detailed molecular characterization of adipose tissue depots will be essential to develop new treatment strategies for metabolic syndrome associated complications.

  3. Altered autophagy in human adipose tissues in obesity

    USDA-ARS?s Scientific Manuscript database

    Context: Autophagy is a housekeeping mechanism, involved in metabolic regulation and stress response, shown recently to regulate lipid droplets biogenesis/breakdown and adipose tissue phenotype. Objective: We hypothesized that in human obesity autophagy may be altered in adipose tissue in a fat d...

  4. Carotenoids in Adipose Tissue Biology and Obesity.

    PubMed

    Bonet, M Luisa; Canas, Jose A; Ribot, Joan; Palou, Andreu

    2016-01-01

    Cell, animal and human studies dealing with carotenoids and carotenoid derivatives as nutritional regulators of adipose tissue biology with implications for the etiology and management of obesity and obesity-related metabolic diseases are reviewed. Most studied carotenoids in this context are β-carotene, cryptoxanthin, astaxanthin and fucoxanthin, together with β-carotene-derived retinoids and some other apocarotenoids. Studies indicate an impact of these compounds on essential aspects of adipose tissue biology including the control of adipocyte differentiation (adipogenesis), adipocyte metabolism, oxidative stress and the production of adipose tissue-derived regulatory signals and inflammatory mediators. Specific carotenoids and carotenoid derivatives restrain adipogenesis and adipocyte hypertrophy while enhancing fat oxidation and energy dissipation in brown and white adipocytes, and counteract obesity in animal models. Intake, blood levels and adipocyte content of carotenoids are reduced in human obesity. Specifically designed human intervention studies in the field, though still sparse, indicate a beneficial effect of carotenoid supplementation in the accrual of abdominal adiposity. In summary, studies support a role of specific carotenoids and carotenoid derivatives in the prevention of excess adiposity, and suggest that carotenoid requirements may be dependent on body composition.

  5. CCR7 Maintains Nonresolving Lymph Node and Adipose Inflammation in Obesity

    PubMed Central

    Hellmann, Jason; Sansbury, Brian E.; Holden, Candice R.; Tang, Yunan; Wong, Blenda; Wysoczynski, Marcin; Rodriguez, Jorge; Bhatnagar, Aruni; Hill, Bradford G.

    2016-01-01

    Accumulation of immune cells in adipose tissue promotes insulin resistance in obesity. Although innate and adaptive immune cells contribute to adipose inflammation, the processes that sustain these interactions are incompletely understood. Here we show that obesity promotes the accumulation of CD11c+ adipose tissue immune cells that express C-C chemokine receptor 7 (CCR7) in mice and humans, and that CCR7 contributes to chronic inflammation and insulin resistance. We identified that CCR7+ macrophages and dendritic cells accumulate in adipose tissue in close proximity to lymph nodes (LNs) (i.e., perinodal) and visceral adipose. Consistent with the role of CCR7 in regulating the migration of immune cells to LNs, obesity promoted the accumulation of CD11c+ cells in LNs, which was prevented by global or hematopoietic deficiency of Ccr7. Obese Ccr7−/− mice had reduced accumulation of CD8+ T cells, B cells, and macrophages in adipose tissue, which was associated with reduced inflammatory signaling. This reduction in maladaptive inflammation translated to increased insulin signaling and improved glucose tolerance in obesity. Therapeutic administration of an anti-CCR7 antibody phenocopied the effects of genetic Ccr7 deficiency in mice with established obesity. These results suggest that CCR7 plays a causal role in maintaining innate and adaptive immunity in obesity. PMID:27207557

  6. Does bariatric surgery improve adipose tissue function?

    PubMed Central

    Frikke-Schmidt, H.; O’Rourke, R. W.; Lumeng, C. N.; Sandoval, D. A.; Seeley, R. J.

    2017-01-01

    Summary Bariatric surgery is currently the most effective treatment for obesity. Not only do these types of surgeries produce significant weight loss but also they improve insulin sensitivity and whole body metabolic function. The aim of this review is to explore how altered physiology of adipose tissue may contribute to the potent metabolic effects of some of these procedures. This includes specific effects on various fat depots, the function of individual adipocytes and the interaction between adipose tissue and other key metabolic tissues. Besides a dramatic loss of fat mass, bariatric surgery shifts the distribution of fat from visceral to the subcutaneous compartment favoring metabolic improvement. The sensitivity towards lipolysis controlled by insulin and catecholamines is improved, adipokine secretion is altered and local adipose inflammation as well as systemic inflammatory markers decreases. Some of these changes have been shown to be weight loss independent, and novel hypothesis for these effects includes include changes in bile acid metabolism, gut microbiota and central regulation of metabolism. In conclusion bariatric surgery is capable of improving aspects of adipose tissue function and do so in some cases in ways that are not entirely explained by the potent effect of surgery. PMID:27272117

  7. Adipose tissue and the reproductive axis: biological aspects

    USDA-ARS?s Scientific Manuscript database

    The discovery of leptin clearly demonstrated a relationship between body fat and the neuroendocrine axis since leptin influences appetite and the reproductive axis. Since adipose tissue is a primary source of leptin, adipose tissue is no longer considered as simply a depot to store fat. Recent find...

  8. Physiological Aging: Links Among Adipose Tissue Dysfunction, Diabetes, and Frailty

    PubMed Central

    Stout, Michael B.; Justice, Jamie N.; Nicklas, Barbara J.; Kirkland, James L.

    2016-01-01

    Advancing age is associated with progressive declines in physiological function that lead to overt chronic disease, frailty, and eventual mortality. Importantly, age-related physiological changes occur in cellularity, insulin-responsiveness, secretory profiles, and inflammatory status of adipose tissue, leading to adipose tissue dysfunction. Although the mechanisms underlying adipose tissue dysfunction are multifactorial, the consequences result in secretion of proinflammatory cytokines and chemokines, immune cell infiltration, an accumulation of senescent cells, and an increase in senescence-associated secretory phenotype (SASP). These processes synergistically promote chronic sterile inflammation, insulin resistance, and lipid redistribution away from subcutaneous adipose tissue. Without intervention, these effects contribute to age-related systemic metabolic dysfunction, physical limitations, and frailty. Thus adipose tissue dysfunction may be a fundamental contributor to the elevated risk of chronic disease, disability, and adverse health outcomes with advancing age. PMID:27927801

  9. Inflammasome-driven catecholamine catabolism in macrophages blunts lipolysis in the aged

    PubMed Central

    Camell, Christina D.; Sander, Jil; Spadaro, Olga; Lee, Aileen; Nguyen, Kim Y.; Wing, Allison; Goldberg, Emily L.; Youm, Yun-Hee; Brown, Chester W.; Elsworth, John; Rodeheffer, Matthew S.; Schultze, Joachim L.; Dixit, Vishwa Deep

    2017-01-01

    Catecholamine-induced lipolysis, the first step in generation of energy substrates through hydrolysis of triglycerides (TGs) 1, declines with age 2,3. The defect in mobilization of free fatty acids (FFA) in elderly is accompanied with increased visceral adiposity, lower exercise capacity, failure to maintain core body temperature during cold stress, and reduced ability to survive starvation. While catecholamine signaling in adipocytes is normal in elderly, how lipolysis is impaired in aging remains unknown 2,4. Here we uncover that the adipose tissue macrophages (ATMs) regulate age-related reduction in adipocyte lipolysis by lowering the bioavailability of norepinephrine (NE). Unexpectedly, unbiased whole transcriptome analyses of adipose macrophages revealed that aging upregulates genes controlling catecholamine degradation in an NLRP3 inflammasome-dependent manner. Deletion of NLRP3 in aging restored catecholamine-induced lipolysis through downregulation of growth differentiation factor-3 (GDF3) and monoamine oxidase-a (MAOA) that is known to degrade NE. Consistent with this, deletion of GDF3 in inflammasome-activated macrophages improved lipolysis by decreasing MAOA and caspase-1. Furthermore, inhibition of MAOA reversed age-related reduction in adipose tissue NE concentration and restored lipolysis with increased levels of key lipolytic enzymes, adipose triglyceride lipase (ATGL) and hormone sensitive lipase (HSL). Our study reveals that targeting neuro-innate signaling between sympathetic nervous system and macrophages may offer new approaches to mitigate chronic inflammation-induced metabolic impairment and functional decline. PMID:28953873

  10. Adipose Tissue Plasticity During Catch-Up Fat Driven by Thrifty Metabolism

    PubMed Central

    Summermatter, Serge; Marcelino, Helena; Arsenijevic, Denis; Buchala, Antony; Aprikian, Olivier; Assimacopoulos-Jeannet, Françoise; Seydoux, Josiane; Montani, Jean-Pierre; Solinas, Giovanni; Dulloo, Abdul G.

    2009-01-01

    OBJECTIVE Catch-up growth, a risk factor for later type 2 diabetes, is characterized by hyperinsulinemia, accelerated body-fat recovery (catch-up fat), and enhanced glucose utilization in adipose tissue. Our objective was to characterize the determinants of enhanced glucose utilization in adipose tissue during catch-up fat. RESEARCH DESIGN AND METHODS White adipose tissue morphometry, lipogenic capacity, fatty acid composition, insulin signaling, in vivo glucose homeostasis, and insulinemic response to glucose were assessed in a rat model of semistarvation-refeeding. This model is characterized by glucose redistribution from skeletal muscle to adipose tissue during catch-up fat that results solely from suppressed thermogenesis (i.e., without hyperphagia). RESULTS Adipose tissue recovery during the dynamic phase of catch-up fat is accompanied by increased adipocyte number with smaller diameter, increased expression of genes for adipogenesis and de novo lipogenesis, increased fatty acid synthase activity, increased proportion of saturated fatty acids in triglyceride (storage) fraction but not in phospholipid (membrane) fraction, and no impairment in insulin signaling. Furthermore, it is shown that hyperinsulinemia and enhanced adipose tissue de novo lipogenesis occur concomitantly and are very early events in catch-up fat. CONCLUSIONS These findings suggest that increased adipose tissue insulin stimulation and consequential increase in intracellular glucose flux play an important role in initiating catch-up fat. Once activated, the machinery for lipogenesis and adipogenesis contribute to sustain an increased insulin-stimulated glucose flux toward fat storage. Such adipose tissue plasticity could play an active role in the thrifty metabolism that underlies glucose redistribution from skeletal muscle to adipose tissue. PMID:19602538

  11. The Phagocytic Function of Macrophage-Enforcing Innate Immunity and Tissue Homeostasis.

    PubMed

    Hirayama, Daisuke; Iida, Tomoya; Nakase, Hiroshi

    2017-12-29

    Macrophages are effector cells of the innate immune system that phagocytose bacteria and secrete both pro-inflammatory and antimicrobial mediators. In addition, macrophages play an important role in eliminating diseased and damaged cells through their programmed cell death. Generally, macrophages ingest and degrade dead cells, debris, tumor cells, and foreign materials. They promote homeostasis by responding to internal and external changes within the body, not only as phagocytes, but also through trophic, regulatory, and repair functions. Recent studies demonstrated that macrophages differentiate from hematopoietic stem cell-derived monocytes and embryonic yolk sac macrophages. The latter mainly give rise to tissue macrophages. Macrophages exist in all vertebrate tissues and have dual functions in host protection and tissue injury, which are maintained at a fine balance. Tissue macrophages have heterogeneous phenotypes in different tissue environments. In this review, we focused on the phagocytic function of macrophage-enforcing innate immunity and tissue homeostasis for a better understanding of the role of tissue macrophages in several pathological conditions.

  12. Adipose Tissue Responses to Breaking Sitting in Men and Women with Central Adiposity.

    PubMed

    Chen, Yung-Chih; Betts, James A; Walhin, Jean-Philippe; Thompson, Dylan

    2018-04-27

    Breaking prolonged sitting reduces postprandial glucose and insulin concentrations and influences skeletal muscle molecular signalling pathways but it is unknown whether breaking sitting also affects adipose tissue. Eleven central overweight participants (7 men and 4 post-menopausal women) aged 50 ± 5 years (means ± SD) completed two mixed-meal feeding trials (PROLONGED SITTING versus BREAKING SITTING) in a randomised, counterbalanced design. The BREAKING SITTING intervention comprised walking for 2 min every 20 min over 5.5 h. Blood samples were taken at regular intervals to examine metabolic biomarkers and adipokine concentrations. Adipose tissue samples were taken at baseline and at 5.5 h to examine changes in mRNA expression and secretion of selected adipokines ex-vivo. Postprandial glycaemia and insulinaemia were attenuated by approximately 50% and 40% in BREAKING SITTING compared to PROLONGED SITTING (iAUC: 359 ± 117 versus 697 ± 218 mmol·330 min·L, p = 0.001 and 202 ± 71 versus 346 ± 150 nmol·330 min·L, p = 0.001, respectively). Despite these pronounced and sustained differences in postprandial glucose and insulin concentrations, adipose tissue mRNA expression for various genes (IL-6, leptin, adiponectin, PDK4, IRS1/2, PI3K and Akt1, etc.) and ex-vivo adipose tissue secretion of IL-6, leptin and adiponectin were not different between trials. This study demonstrates that breaking sitting with short bouts of physical activity has very pronounced effects on systemic postprandial glucose and insulin concentrations but this does not translate into corresponding effects within adipose tissue.

  13. Human adipose-derived stem cells: definition, isolation, tissue-engineering applications.

    PubMed

    Nae, S; Bordeianu, I; Stăncioiu, A T; Antohi, N

    2013-01-01

    Recent researches have demonstrated that the most effective repair system of the body is represented by stem cells - unspecialized cells, capable of self-renewal through successive mitoses, which have also the ability to transform into different cell types through differentiation. The discovery of adult stem cells represented an important step in regenerative medicine because they no longer raises ethical or legal issues and are more accessible. Only in 2002, stem cells isolated from adipose tissue were described as multipotent stem cells. Adipose tissue stem cells benefits in tissue engineering and regenerative medicine are numerous. Development of adipose tissue engineering techniques offers a great potential in surpassing the existing limits faced by the classical approaches used in plastic and reconstructive surgery. Adipose tissue engineering clinical applications are wide and varied, including reconstructive, corrective and cosmetic procedures. Nowadays, adipose tissue engineering is a fast developing field, both in terms of fundamental researches and medical applications, addressing issues related to current clinical pathology or trauma management of soft tissue injuries in different body locations.

  14. Physiological Aging: Links Among Adipose Tissue Dysfunction, Diabetes, and Frailty.

    PubMed

    Stout, Michael B; Justice, Jamie N; Nicklas, Barbara J; Kirkland, James L

    2017-01-01

    Advancing age is associated with progressive declines in physiological function that lead to overt chronic disease, frailty, and eventual mortality. Importantly, age-related physiological changes occur in cellularity, insulin-responsiveness, secretory profiles, and inflammatory status of adipose tissue, leading to adipose tissue dysfunction. Although the mechanisms underlying adipose tissue dysfunction are multifactorial, the consequences result in secretion of proinflammatory cytokines and chemokines, immune cell infiltration, an accumulation of senescent cells, and an increase in senescence-associated secretory phenotype (SASP). These processes synergistically promote chronic sterile inflammation, insulin resistance, and lipid redistribution away from subcutaneous adipose tissue. Without intervention, these effects contribute to age-related systemic metabolic dysfunction, physical limitations, and frailty. Thus adipose tissue dysfunction may be a fundamental contributor to the elevated risk of chronic disease, disability, and adverse health outcomes with advancing age. ©2017 Int. Union Physiol. Sci./Am. Physiol. Soc.

  15. Intra-body microwave communication through adipose tissue.

    PubMed

    Asan, Noor Badariah; Noreland, Daniel; Hassan, Emadeldeen; Redzwan Mohd Shah, Syaiful; Rydberg, Anders; Blokhuis, Taco J; Carlsson, Per-Ola; Voigt, Thiemo; Augustine, Robin

    2017-08-01

    The human body can act as a medium for the transmission of electromagnetic waves in the wireless body sensor networks context. However, there are transmission losses in biological tissues due to the presence of water and salts. This Letter focuses on lateral intra-body microwave communication through different biological tissue layers and demonstrates the effect of the tissue thicknesses by comparing signal coupling in the channel. For this work, the authors utilise the R-band frequencies since it overlaps the industrial, scientific and medical radio (ISM) band. The channel model in human tissues is proposed based on electromagnetic simulations, validated using equivalent phantom and ex-vivo measurements. The phantom and ex-vivo measurements are compared with simulation modelling. The results show that electromagnetic communication is feasible in the adipose tissue layer with a low attenuation of ∼2 dB per 20 mm for phantom measurements and 4 dB per 20 mm for ex-vivo measurements at 2 GHz. Since the dielectric losses of human adipose tissues are almost half of ex-vivo tissue, an attenuation of around 3 dB per 20 mm is expected. The results show that human adipose tissue can be used as an intra-body communication channel.

  16. Epicardial Adipose Tissue Thickness in Patients With Subclinical Hypothyroidism and the Relationship Thereof With Visceral Adipose Tissue Thickness.

    PubMed

    Arpaci, Dilek; Gurkan Tocoglu, Aysel; Yilmaz, Sabiye; Korkmaz, Sumeyye; Ergenc, Hasan; Gunduz, Huseyin; Keser, Nurgul; Tamer, Ali

    2016-03-01

    Subclinical hypothyroidism (SH) is associated with cardiovascular metabolic syndromes, especially dislipidemia and abdominal obesity. Visceral abdominal adipose tissue (VAAT) and epicardial adipose tissue (EAT) have the same ontogenic origin and produce many proinflammatory and proatherogenic cytokines. We evaluated EAT and VAAT thickness in patients with SH. Forty-one patients with SH and 35 controls were included in the study. Demographical and anthropometric features of both patients and controls were recorded. Thyroid and metabolic parameters were measured. EAT was measured using 2D-transthoracic echocardiography. The age and gender distributions were similar in the two groups (P = 0.998 and P = 0.121, respectively). Body mass index (BMI), fat mass, waist circumference (WC), hip circumference (HC), the WC/HC ratio, and the thicknesses of VAAT and abdominal subcutaneous adipose tissue were higher in the case group than the control group (all P values < 0.01). However, both groups had similar EAT thickness (P = 0.532), which was positively correlated with BMI, fat mass, WC, HC, VAAT thickness, abdominal subcutaneous adipose tissue thickness, and serum triglyceride (TG) level (all P values < 0.01). We found no correlation between EAT thickness and thyroid-stimulating hormone (TSH) level, free thyroxine (FT4) level, or low-density lipoprotein-cholesterol (LDL-C) level, and anti-TPO level (all P values > 0.05). We found no difference between the two groups in fasting plasma glucose (FPG) level (P = 0.780), but the levels of LDL-C and TG differed significantly (P = 0.002 and P = 0.026, respectively). The serum TSH level was higher and the FT4 level was lower in the case than the control group (both P values <0.01). Increased abdominal adipose tissue thickness in patients with SH is associated with atherosclerosis. To detemine the risk of atherosclerosis in such patients, EAT measurements are valuable; such assessment is simple to perform.

  17. Deficiency in adipocyte chemokine receptor CXCR4 exacerbates obesity and compromises thermoregulatory responses of brown adipose tissue in a mouse model of diet-induced obesity

    PubMed Central

    Yao, Longbiao; Heuser-Baker, Janet; Herlea-Pana, Oana; Zhang, Nan; Szweda, Luke I.; Griffin, Timothy M.; Barlic-Dicen, Jana

    2014-01-01

    The chemokine receptor CXCR4 is expressed on adipocytes and macrophages in adipose tissue, but its role in this tissue remains unknown. We evaluated whether deficiency in either adipocyte or myeloid leukocyte CXCR4 affects body weight (BW) and adiposity in a mouse model of high-fat-diet (HFD)-induced obesity. We found that ablation of adipocyte, but not myeloid leukocyte, CXCR4 exacerbated obesity. The HFD-fed adipocyte-specific CXCR4-knockout (AdCXCR4ko) mice, compared to wild-type C57BL/6 control mice, had increased BW (average: 52.0 g vs. 35.5 g), adiposity (average: 49.3 vs. 21.0% of total BW), and inflammatory leukocyte content in white adipose tissue (WAT), despite comparable food intake. As previously reported, HFD feeding increased uncoupling protein 1 (UCP1) expression (fold increase: 3.5) in brown adipose tissue (BAT) of the C57BL/6 control mice. However, no HFD-induced increase in UCP1 expression was observed in the AdCXCR4ko mice, which were cold sensitive. Thus, our study suggests that adipocyte CXCR4 limits development of obesity by preventing excessive inflammatory cell recruitment into WAT and by supporting thermogenic activity of BAT. Since CXCR4 is conserved between mouse and human, the newfound role of CXCR4 in mouse adipose tissue may parallel the role of this chemokine receptor in human adipose tissue.—Yao, L., Heuser-Baker, J., Herlea-Pana, O., Zhang, N., Szweda, L. I., Griffin, T. M., Barlic-Dicen, J. Deficiency in adipocyte chemokine receptor CXCR4 exacerbates obesity and compromises thermoregulatory responses of brown adipose tissue in a mouse model of diet-induced obesity. PMID:25016030

  18. The sexually dimorphic role of adipose and adipocyte estrogen receptors in modulating adipose tissue expansion, inflammation, and fibrosis

    PubMed Central

    Davis, Kathryn E.; D. Neinast, Michael; Sun, Kai; M. Skiles, William; D. Bills, Jessica; A. Zehr, Jordan; Zeve, Daniel; D. Hahner, Lisa; W. Cox, Derek; M. Gent, Lana; Xu, Yong; V. Wang, Zhao; A. Khan, Sohaib; Clegg, Deborah J.

    2013-01-01

    Our data demonstrate that estrogens, estrogen receptor-α (ERα), and estrogen receptor-β (ERβ) regulate adipose tissue distribution, inflammation, fibrosis, and glucose homeostasis, by determining that αERKO mice have increased adipose tissue inflammation and fibrosis prior to obesity onset. Selective deletion of adipose tissue ERα in adult mice using a novel viral vector technology recapitulated the findings in the total body ERα null mice. Generation of a novel mouse model, lacking ERα specifically from adipocytes (AdipoERα), demonstrated increased markers of fibrosis and inflammation, especially in the males. Additionally, we found that the beneficial effects of estrogens on adipose tissue require adipocyte ERα. Lastly, we determined the role of ERβ in regulating inflammation and fibrosis, by breeding the AdipoERα into the βERKO background and found that in the absence of adipocyte ERα, ERβ has a protective role. These data suggest that adipose tissue and adipocyte ERα protects against adiposity, inflammation, and fibrosis in both males and females. PMID:24049737

  19. Obesity-induced endoplasmic reticulum stress causes chronic inflammation in adipose tissue.

    PubMed

    Kawasaki, Noritaka; Asada, Rie; Saito, Atsushi; Kanemoto, Soshi; Imaizumi, Kazunori

    2012-01-01

    Adipose tissue plays a central role in maintaining metabolic homeostasis under normal conditions. Metabolic diseases such as obesity and type 2 diabetes are often accompanied by chronic inflammation and adipose tissue dysfunction. In this study, we observed that endoplasmic reticulum (ER) stress and the inflammatory response occurred in adipose tissue of mice fed a high-fat diet for a period of 16 weeks. After 16 weeks of feeding, ER stress markers increased and chronic inflammation occurred in adipose tissue. We found that ER stress is induced by free fatty acid (FFA)-mediated reactive oxygen species (ROS) generation and up-regulated gene expression of inflammatory cytokines in 3T3-L1 adipocytes. Oral administration to obese mice of chemical chaperons, which alleviate ER stress, improved chronic inflammation in adipose tissue, followed by the suppression of increased body weight and improved insulin signaling. These results indicate that ER stress plays important pathophysiological roles in obesity-induced adipose tissue dysfunction.

  20. Inflammatory changes in adipose tissue enhance expression of GPR84, a medium-chain fatty acid receptor: TNFα enhances GPR84 expression in adipocytes.

    PubMed

    Nagasaki, Hiroshi; Kondo, Takaaki; Fuchigami, Masahiro; Hashimoto, Hiroyuki; Sugimura, Yoshihisa; Ozaki, Nobuaki; Arima, Hiroshi; Ota, Akira; Oiso, Yutaka; Hamada, Yoji

    2012-02-17

    In this study we aimed to identify the physiological roles of G protein-coupled receptor 84 (GPR84) in adipose tissue, together with medium-chain fatty acids (MCFAs), the specific ligands for GPR84. In mice, high-fat diet up-regulated GPR84 expression in fat pads. In 3T3-L1 adipocytes, co-culture with a macrophage cell line, RAW264, or TNFα remarkably enhanced GPR84 expression. In the presence of TNFα, MCFAs down-regulated adiponectin mRNA expression in 3T3-L1 adipocytes. Taken together, our results suggest that GPR84 emerges in adipocytes in response to TNFα from infiltrating macrophages and exacerbates the vicious cycle between adiposity and diabesity. Copyright © 2012 Federation of European Biochemical Societies. All rights reserved.

  1. Gene Expression Signature in Adipose Tissue of Acromegaly Patients

    PubMed Central

    Hochberg, Irit; Tran, Quynh T.; Barkan, Ariel L.; Saltiel, Alan R.; Chandler, William F.; Bridges, Dave

    2015-01-01

    To study the effect of chronic excess growth hormone on adipose tissue, we performed RNA sequencing in adipose tissue biopsies from patients with acromegaly (n = 7) or non-functioning pituitary adenomas (n = 11). The patients underwent clinical and metabolic profiling including assessment of HOMA-IR. Explants of adipose tissue were assayed ex vivo for lipolysis and ceramide levels. Patients with acromegaly had higher glucose, higher insulin levels and higher HOMA-IR score. We observed several previously reported transcriptional changes (IGF1, IGFBP3, CISH, SOCS2) that are known to be induced by GH/IGF-1 in liver but are also induced in adipose tissue. We also identified several novel transcriptional changes, some of which may be important for GH/IGF responses (PTPN3 and PTPN4) and the effects of acromegaly on growth and proliferation. Several differentially expressed transcripts may be important in GH/IGF-1-induced metabolic changes. Specifically, induction of LPL, ABHD5, and NRIP1 can contribute to enhanced lipolysis and may explain the elevated adipose tissue lipolysis in acromegalic patients. Higher expression of TCF7L2 and the fatty acid desaturases FADS1, FADS2 and SCD could contribute to insulin resistance. Ceramides were not different between the two groups. In summary, we have identified the acromegaly gene expression signature in human adipose tissue. The significance of altered expression of specific transcripts will enhance our understanding of the metabolic and proliferative changes associated with acromegaly. PMID:26087292

  2. Adaptation of human adipose tissue to hypocaloric diet.

    PubMed

    Rossmeislová, L; Mališová, L; Kračmerová, J; Štich, V

    2013-05-01

    Hypocaloric diet is a key component of the weight-reducing treatment of obesity and obesity-related disorders. Hypocaloric diets and the associated weight reduction promote improvement of metabolic profile of obese individuals. Among the mechanisms that underlie this beneficial metabolic outcome, the diet-induced modifications of morphological and functional characteristics of human adipose tissue (AT) are believed to have an important role. Prospective studies of hypocaloric weight-reducing dietary intervention demonstrate effects on adipocyte metabolism, namely lipolysis and lipogenesis, and associated changes of the adipocyte size. The endocrine function of AT, which involves cytokine and adipokine production by adipocytes, as well as by cells of stromavascular fraction, is also regulated by dietary intervention. Related inflammatory status of AT is modulated also as a consequence of the changes in recruitment of immune cells, mainly macrophages, in AT. Here, we give an overview of metabolic and endocrine modifications in human AT induced by a variety of hypocaloric diets.

  3. Androgen Effects on Adipose Tissue Architecture and Function in Nonhuman Primates

    PubMed Central

    Varlamov, Oleg; White, Ashley E.; Carroll, Julie M.; Bethea, Cynthia L.; Reddy, Arubala; Slayden, Ov; O'Rourke, Robert W.

    2012-01-01

    The differential association of hypoandrogenism in men and hyperandrogenism in women with insulin resistance and obesity suggests that androgens may exert sex-specific effects on adipose and other tissues, although the underlying mechanisms remain poorly understood. Moreover, recent studies also suggest that rodents and humans may respond differently to androgen imbalance. To achieve better insight into clinically relevant sex-specific mechanisms of androgen action, we used nonhuman primates to investigate the direct effects of gonadectomy and hormone replacement on white adipose tissue. We also employed a novel ex vivo approach that provides a convenient framework for understanding of adipose tissue physiology under a controlled tissue culture environment. In vivo androgen deprivation of males did not result in overt obesity or insulin resistance but did induce the appearance of very small, multilocular white adipocytes. Testosterone replacement restored normal cell size and a unilocular phenotype and stimulated adipogenic gene transcription and improved insulin sensitivity of male adipose tissue. Ex vivo studies demonstrated sex-specific effects of androgens on adipocyte function. Female adipose tissue treated with androgens displayed elevated basal but reduced insulin-dependent fatty acid uptake. Androgen-stimulated basal uptake was greater in adipose tissue of ovariectomized females than in adipose tissue of intact females and ovariectomized females replaced with estrogen and progesterone in vivo. Collectively, these data demonstrate that androgens are essential for normal adipogenesis in males and can impair essential adipocyte functions in females, thus strengthening the experimental basis for sex-specific effects of androgens in adipose tissue. PMID:22547568

  4. Evidence for the ectopic synthesis of melanin in human adipose tissue.

    PubMed

    Randhawa, Manpreet; Huff, Tom; Valencia, Julio C; Younossi, Zobair; Chandhoke, Vikas; Hearing, Vincent J; Baranova, Ancha

    2009-03-01

    Melanin is a common pigment in animals. In humans, melanin is produced in melanocytes, in retinal pigment epithelium (RPE) cells, in the inner ear, and in the central nervous system. Previously, we noted that human adipose tissue expresses several melanogenesis-related genes. In the current study, we confirmed the expression of melanogenesis-related mRNAs and proteins in human adipose tissue using real-time polymerase chain reaction and immunohistochemical staining. TYR mRNA signals were also detected by in situ hybridization in visceral adipocytes. The presence of melanin in human adipose tissue was revealed both by Fontana-Masson staining and by permanganate degradation of melanin coupled with liquid chromatography/ultraviolet/mass spectrometry determination of the pyrrole-2,3,5-tricarboxylic acid (PTCA) derivative of melanin. We also compared melanogenic activities in adipose tissues and in other human tissues using the L-[U-(14)C] tyrosine assay. A marked heterogeneity in the melanogenic activities of individual adipose tissue extracts was noted. We hypothesize that the ectopic synthesis of melanin in obese adipose may serve as a compensatory mechanism that uses its anti-inflammatory and its oxidative damage-absorbing properties. In conclusion, our study demonstrates for the first time that the melanin biosynthesis pathway is functional in adipose tissue.

  5. Adipose-derived cells.

    PubMed

    Meliga, Emanuele; Strem, Brian M; Duckers, H J; Serruys, Patrick W

    2007-01-01

    Heart failure is by far the most common cause of hospitalization in Western countries, with onerous economic consequences. Cell therapy holds great promise for use in tissue regeneration and is increasingly used in an effort to improve outcomes in cardiac disease. Recently it has been shown that adipose tissue, in addition to committed adipogenic, endothelial progenitor cells and pluripotent vascular progenitor cells, also contains multipotent cell types (adipose-derived stem cells, ADSCs) that, in cell culture conditions, have shown to have an impressive developmental plasticity including the ability to undergo multilineage differentiation and self-renewal. ADSCs express multiple CD marker antigens similar to those observed on MSCs and are also capable of secreting a large number of angiogenesis-related cytokines, including vascular endothelial growth factor, granulocyte/macrophage colony stimulating factor, stromal-derived factor-1alpha, and hepatocyte growth factor. Adipose tissue can be harvested in large quantities with minimal morbidity in several regions of the body and, on average, 100 ml of human adipose tissue yields about 1 x 10(6) stem cells. Studies conducted in porcine AMI models have shown a significant LV functional improvement, with no report of any potentially fatal arrhythmias. The APOLLO trial, a prospective, double blind, randomized, placebo-controlled trial currently in the recruiting phase, is a "first-in-man" study that explores the safety and feasibility of ADSC transplantation in patients with acute MI.

  6. Adipose tissue stem cells in regenerative medicine

    PubMed Central

    Miana, Vanesa Verónica; González, Elio A Prieto

    2018-01-01

    Adipose tissue-derived stem cells (ADSCs) are mesenchymal cells with the capacity for self-renewal and multipotential differentiation. This multipotentiality allows them to become adipocytes, chondrocytes, myocytes, osteoblasts and neurocytes among other cell lineages. Stem cells and, in particular, adipose tissue-derived cells, play a key role in reconstructive or tissue engineering medicine as they have already proven effective in developing new treatments. The purpose of this work is to review the applications of ADSCs in various areas of regenerative medicine, as well as some of the risks associated with treatment with ADSCs in neoplastic disease. PMID:29662535

  7. Fish Oil-Derived Long-Chain n-3 Polyunsaturated Fatty Acids Reduce Expression of M1-Associated Macrophage Markers in an ex vivo Adipose Tissue Culture Model, in Part through Adiponectin.

    PubMed

    De Boer, Anna A; Monk, Jennifer M; Liddle, Danyelle M; Power, Krista A; Ma, David W L; Robinson, Lindsay E

    2015-01-01

    Adipose tissue (AT) macrophages (ATM) play a key role in obesity-associated pathologies, and their phenotype can be influenced by the local tissue microenvironment. Interestingly, long-chain n-3 polyunsaturated fatty acids (LC n-3 PUFA) and the LC n-3 PUFA-upregulated adipokine, adiponectin (Ad), may mitigate excessive ATM inflammatory M1-polarization responses. However, to what extent LC n-3 PUFA and Ad work in concert to affect macrophage phenotype has not been examined. Thus, we used an established ex vivo AT organ culture model using visceral AT from mice fed a control (CON; 10% w/w safflower oil) n-6 PUFA-rich diet or an isocaloric fish oil (FO; 3% w/w menhaden oil + 7% w/w safflower oil)-derived LC n-3 PUFA-rich diet to generate AT conditioned media (ACM). We then evaluated if CON or FO ACM affected macrophage polarization markers in a model designed to mimic acute [18 h ACM plus lipopolysaccharide (LPS) for the last 6 h] or chronic (macrophages treated with LPS-challenged CON or FO ACM for 24 h) inflammation ± Ad-neutralizing antibody and the LPS-neutralizing agent, polymyxin B. In the acute inflammation model, macrophages treated with FO ACM had decreased lipid uptake and mRNA expression of M1 markers (Nos2, Nfκb, Il6, Il18, Ccl2, and Ccl5) compared with CON ACM (p ≤ 0.05); however, these effects were largely attenuated when Ad was neutralized (p > 0.05). Furthermore, in the chronic inflammation model, macrophages treated with FO ACM had decreased mRNA expression of M1 markers (Nos2, Tnfα, Ccl2, and Il1β) and IL-6 and CCL2 secretion (p ≤ 0.05); however, some of these effects were lost when Ad was neutralized, and were further exacerbated when both Ad and LPS were neutralized. Taken together, this work shows that LC n-3 PUFA and Ad work in concert to suppress certain M1 macrophage responses. Thus, future strategies to modulate the ATM phenotype should consider the role of both LC n-3 PUFA and Ad in mitigating obese AT

  8. Fish Oil-Derived Long-Chain n-3 Polyunsaturated Fatty Acids Reduce Expression of M1-Associated Macrophage Markers in an ex vivo Adipose Tissue Culture Model, in Part through Adiponectin

    PubMed Central

    De Boer, Anna A.; Monk, Jennifer M.; Liddle, Danyelle M.; Power, Krista A.; Ma, David W. L.; Robinson, Lindsay E.

    2015-01-01

    Adipose tissue (AT) macrophages (ATM) play a key role in obesity-associated pathologies, and their phenotype can be influenced by the local tissue microenvironment. Interestingly, long-chain n-3 polyunsaturated fatty acids (LC n-3 PUFA) and the LC n-3 PUFA-upregulated adipokine, adiponectin (Ad), may mitigate excessive ATM inflammatory M1-polarization responses. However, to what extent LC n-3 PUFA and Ad work in concert to affect macrophage phenotype has not been examined. Thus, we used an established ex vivo AT organ culture model using visceral AT from mice fed a control (CON; 10% w/w safflower oil) n-6 PUFA-rich diet or an isocaloric fish oil (FO; 3% w/w menhaden oil + 7% w/w safflower oil)-derived LC n-3 PUFA-rich diet to generate AT conditioned media (ACM). We then evaluated if CON or FO ACM affected macrophage polarization markers in a model designed to mimic acute [18 h ACM plus lipopolysaccharide (LPS) for the last 6 h] or chronic (macrophages treated with LPS-challenged CON or FO ACM for 24 h) inflammation ± Ad-neutralizing antibody and the LPS-neutralizing agent, polymyxin B. In the acute inflammation model, macrophages treated with FO ACM had decreased lipid uptake and mRNA expression of M1 markers (Nos2, Nfκb, Il6, Il18, Ccl2, and Ccl5) compared with CON ACM (p ≤ 0.05); however, these effects were largely attenuated when Ad was neutralized (p > 0.05). Furthermore, in the chronic inflammation model, macrophages treated with FO ACM had decreased mRNA expression of M1 markers (Nos2, Tnfα, Ccl2, and Il1β) and IL-6 and CCL2 secretion (p ≤ 0.05); however, some of these effects were lost when Ad was neutralized, and were further exacerbated when both Ad and LPS were neutralized. Taken together, this work shows that LC n-3 PUFA and Ad work in concert to suppress certain M1 macrophage responses. Thus, future strategies to modulate the ATM phenotype should consider the role of both LC n-3 PUFA and Ad in mitigating obese AT

  9. Protein Kinase A Regulatory Subunits in Human Adipose Tissue

    PubMed Central

    Mantovani, Giovanna; Bondioni, Sara; Alberti, Luisella; Gilardini, Luisa; Invitti, Cecilia; Corbetta, Sabrina; Zappa, Marco A.; Ferrero, Stefano; Lania, Andrea G.; Bosari, Silvano; Beck-Peccoz, Paolo; Spada, Anna

    2009-01-01

    OBJECTIVE—In human adipocytes, the cAMP-dependent pathway mediates signals originating from β-adrenergic activation, thus playing a key role in the regulation of important metabolic processes, i.e., lipolysis and thermogenesis. Cyclic AMP effects are mainly mediated by protein kinase A (PKA), whose R2B regulatory isoform is the most expressed in mouse adipose tissue, where it protects against diet-induced obesity and fatty liver development. The aim of the study was to investigate possible differences in R2B expression, PKA activity, and lipolysis in adipose tissues from obese and nonobese subjects. RESEARCH DESIGN AND METHODS—The expression of the different PKA regulatory subunits was evaluated by immunohistochemistry, Western blot, and real-time PCR in subcutaneous and visceral adipose tissue samples from 20 nonobese and 67 obese patients. PKA activity and glycerol release were evaluated in total protein extract and adipocytes isolated from fresh tissue samples, respectively. RESULTS—Expression techniques showed that R2B was the most abundant regulatory protein, both at mRNA and protein level. Interestingly, R2B mRNA levels were significantly lower in both subcutaneous and visceral adipose tissues from obese than nonobese patients and negatively correlated with BMI, waist circumference, insulin levels, and homeostasis model assessment of insulin resistance. Moreover, both basal and stimulated PKA activity and glycerol release were significantly lower in visceral adipose tissue from obese patients then nonobese subjects. CONCLUSIONS—Our results first indicate that, in human adipose tissue, there are important BMI-related differences in R2B expression and PKA activation, which might be included among the multiple determinants involved in the different lipolytic response to β-adrenergic activation in obesity. PMID:19095761

  10. MKK6 controls T3-mediated browning of white adipose tissue.

    PubMed

    Matesanz, Nuria; Bernardo, Edgar; Acín-Pérez, Rebeca; Manieri, Elisa; Pérez-Sieira, Sonia; Hernández-Cosido, Lourdes; Montalvo-Romeral, Valle; Mora, Alfonso; Rodríguez, Elena; Leiva-Vega, Luis; Lechuga-Vieco, Ana Victoria; Ruiz-Cabello, Jesús; Torres, Jorge L; Crespo-Ruiz, Maria; Centeno, Francisco; Álvarez, Clara V; Marcos, Miguel; Enríquez, Jose Antonio; Nogueiras, Ruben; Sabio, Guadalupe

    2017-10-11

    Increasing the thermogenic capacity of adipose tissue to enhance organismal energy expenditure is considered a promising therapeutic strategy to combat obesity. Here, we report that expression of the p38 MAPK activator MKK6 is elevated in white adipose tissue of obese individuals. Using knockout animals and shRNA, we show that Mkk6 deletion increases energy expenditure and thermogenic capacity of white adipose tissue, protecting mice against diet-induced obesity and the development of diabetes. Deletion of Mkk6 increases T3-stimulated UCP1 expression in adipocytes, thereby increasing their thermogenic capacity. Mechanistically, we demonstrate that, in white adipose tissue, p38 is activated by an alternative pathway involving AMPK, TAK, and TAB. Our results identify MKK6 in adipocytes as a potential therapeutic target to reduce obesity.Brown and beige adipose tissues dissipate heat via uncoupling protein 1 (UCP1). Here the authors show that the stress activated kinase MKK6 acts as a repressor of UCP1 expression, suggesting that its inhibition promotes adipose tissue browning and increases organismal energy expenditure.

  11. Regulation of macrophage development and function in peripheral tissues

    PubMed Central

    Lavin, Yonit; Mortha, Arthur; Rahman, Adeeb; Merad, Miriam

    2015-01-01

    Macrophages are immune cells of haematopoietic origin that provide crucial innate immune defence and have tissue-specific functions in the regulation and maintenance of organ homeostasis. Recent studies of macrophage ontogeny, as well as transcriptional and epigenetic identity, have started to reveal the decisive role of the tissue stroma in the regulation of macrophage function. These findings suggest that most macrophages seed the tissues during embryonic development and functionally specialize in response to cytokines and metabolites that are released by the stroma and drive the expression of unique transcription factors. In this Review, we discuss how recent insights into macrophage ontogeny and macrophage–stroma interactions contribute to our understanding of the crosstalk that shapes macrophage function and the maintenance of organ integrity. PMID:26603899

  12. Global gene expression profiling of brown to white adipose tissue transformation in sheep reveals novel transcriptional components linked to adipose remodeling.

    PubMed

    Basse, Astrid L; Dixen, Karen; Yadav, Rachita; Tygesen, Malin P; Qvortrup, Klaus; Kristiansen, Karsten; Quistorff, Bjørn; Gupta, Ramneek; Wang, Jun; Hansen, Jacob B

    2015-03-19

    Large mammals are capable of thermoregulation shortly after birth due to the presence of brown adipose tissue (BAT). The majority of BAT disappears after birth and is replaced by white adipose tissue (WAT). We analyzed the postnatal transformation of adipose in sheep with a time course study of the perirenal adipose depot. We observed changes in tissue morphology, gene expression and metabolism within the first two weeks of postnatal life consistent with the expected transition from BAT to WAT. The transformation was characterized by massively decreased mitochondrial abundance and down-regulation of gene expression related to mitochondrial function and oxidative phosphorylation. Global gene expression profiling demonstrated that the time points grouped into three phases: a brown adipose phase, a transition phase and a white adipose phase. Between the brown adipose and the transition phase 170 genes were differentially expressed, and 717 genes were differentially expressed between the transition and the white adipose phase. Thirty-eight genes were shared among the two sets of differentially expressed genes. We identified a number of regulated transcription factors, including NR1H3, MYC, KLF4, ESR1, RELA and BCL6, which were linked to the overall changes in gene expression during the adipose tissue remodeling. Finally, the perirenal adipose tissue expressed both brown and brite/beige adipocyte marker genes at birth, the expression of which changed substantially over time. Using global gene expression profiling of the postnatal BAT to WAT transformation in sheep, we provide novel insight into adipose tissue plasticity in a large mammal, including identification of novel transcriptional components linked to adipose tissue remodeling. Moreover, our data set provides a useful resource for further studies in adipose tissue plasticity.

  13. Uric Acid Secretion from Adipose Tissue and Its Increase in Obesity*

    PubMed Central

    Tsushima, Yu; Nishizawa, Hitoshi; Tochino, Yoshihiro; Nakatsuji, Hideaki; Sekimoto, Ryohei; Nagao, Hirofumi; Shirakura, Takashi; Kato, Kenta; Imaizumi, Keiichiro; Takahashi, Hiroyuki; Tamura, Mizuho; Maeda, Norikazu; Funahashi, Tohru; Shimomura, Iichiro

    2013-01-01

    Obesity is often accompanied by hyperuricemia. However, purine metabolism in various tissues, especially regarding uric acid production, has not been fully elucidated. Here we report, using mouse models, that adipose tissue could produce and secrete uric acid through xanthine oxidoreductase (XOR) and that the production was enhanced in obesity. Plasma uric acid was elevated in obese mice and attenuated by administration of the XOR inhibitor febuxostat. Adipose tissue was one of major organs that had abundant expression and activities of XOR, and adipose tissues in obese mice had higher XOR activities than those in control mice. 3T3-L1 and mouse primary mature adipocytes produced and secreted uric acid into culture medium. The secretion was inhibited by febuxostat in a dose-dependent manner or by gene knockdown of XOR. Surgical ischemia in adipose tissue increased local uric acid production and secretion via XOR, with a subsequent increase in circulating uric acid levels. Uric acid secretion from whole adipose tissue was increased in obese mice, and uric acid secretion from 3T3-L1 adipocytes was increased under hypoxia. Our results suggest that purine catabolism in adipose tissue could be enhanced in obesity. PMID:23913681

  14. Adipose tissue engineering: state of the art, recent advances and innovative approaches.

    PubMed

    Tanzi, Maria Cristina; Farè, Silvia

    2009-09-01

    Adipose tissue is a highly specialized connective tissue found either in white or brown forms, the white form being the most abundant in adult humans. Loss or damage of white adipose tissue due to aging or pathological conditions needs reconstructive approaches. To date, two main strategies are being investigated for generating functional adipose tissue: autologous tissue/cell transplantation and adipose tissue engineering. Free-fat transplantation rarely achieves sufficient tissue augmentation owing to delayed neovascularization, with subsequent cell necrosis and graft volume shrinkage. Tissue engineering approaches represent, instead, a more suitable alternative for adipose tissue regeneration; they can be performed either with in situ or de novo adipogenesis. In situ adipogenesis or transplantation of encapsulated cells can be useful in healing small-volume defects, whereas restoration of large defects, where vascularization and a rapid volumetric gain are strict requirements, needs de novo strategies with 3D scaffold/filling matrix combinations. For adipose tissue engineering, the use of adult mesenchymal stem cells (both adipose- and bone marrow-derived stem cells) or of preadipocytes is preferred to the use of mature adipocytes, which have low expandability and poor ability for volume retention. This review intends to assemble and describe recent work on this topic, critically presenting successes obtained and drawbacks faced to date.

  15. Mechanically robust cryogels with injectability and bioprinting supportability for adipose tissue engineering.

    PubMed

    Qi, Dianjun; Wu, Shaohua; Kuss, Mitchell A; Shi, Wen; Chung, Soonkyu; Deegan, Paul T; Kamenskiy, Alexey; He, Yini; Duan, Bin

    2018-05-26

    Bioengineered adipose tissues have gained increased interest as a promising alternative to autologous tissue flaps and synthetic adipose fillers for soft tissue augmentation and defect reconstruction in clinic. Although many scaffolding materials and biofabrication methods have been investigated for adipose tissue engineering in the last decades, there are still challenges to recapitulate the appropriate adipose tissue microenvironment, maintain volume stability, and induce vascularization to achieve long-term function and integration. In the present research, we fabricated cryogels consisting of methacrylated gelatin, methacrylated hyaluronic acid, and 4arm poly(ethylene glycol) acrylate (PEG-4A) by using cryopolymerization. The cryogels were repeatedly injectable and stretchable, and the addition of PEG-4A improved the robustness and mechanical properties. The cryogels supported human adipose progenitor cell (HWA) and adipose derived mesenchymal stromal cell adhesion, proliferation, and adipogenic differentiation and maturation, regardless of the addition of PEG-4A. The HWA laden cryogels facilitated the co-culture of human umbilical vein endothelial cells (HUVEC) and capillary-like network formation, which in return also promoted adipogenesis. We further combined cryogels with 3D bioprinting to generate handleable adipose constructs with clinically relevant size. 3D bioprinting enabled the deposition of multiple bioinks onto the cryogels. The bioprinted flap-like constructs had an integrated structure without delamination and supported vascularization. Adipose tissue engineering is promising for reconstruction of soft tissue defects, and also challenging for restoring and maintaining soft tissue volume and shape, and achieving vascularization and integration. In this study, we fabricated cryogels with mechanical robustness, injectability, and stretchability by using cryopolymerization. The cryogels promoted cell adhesion, proliferation, and adipogenic

  16. Adipose tissue transcriptome changes during obesity development in female dogs.

    PubMed

    Grant, Ryan W; Vester Boler, Brittany M; Ridge, Tonya K; Graves, Thomas K; Swanson, Kelly S

    2011-03-29

    During the development of obesity, adipose tissue undergoes major expansion and remodeling, but the biological processes involved in this transition are not well understood. The objective of this study was to analyze global gene expression profiles of adipose tissue in dogs, fed a high-fat diet, during the transition from a lean to obese phenotype. Nine female beagles (4.09 ± 0.64 yr; 8.48 ± 0.35 kg) were randomized to ad libitum feeding or body weight maintenance. Subcutaneous adipose tissue biopsy, blood, and dual x-ray absorptiometry measurements were collected at 0, 4, 8, 12, and 24 wk of feeding. Serum was analyzed for glucose, insulin, fructosamine, triglycerides, free fatty acids, adiponectin, and leptin. Formalin-fixed adipose tissue was used for determination of adipocyte size. Adipose RNA samples were hybridized to Affymetrix Canine 2.0 microarrays. Statistical analysis, using repeated-measures ANOVA, showed ad libitum feeding increased (P < 0.05) body weight (0 wk, 8.36 ± 0.34 kg; 24 wk, 14.64 ± 0.34 kg), body fat mass (0 wk, 1.36 ± 0.24 kg; 24 wk, 6.52 ± 0.24 kg), adipocyte size (0 wk, 114.66 ± 17.38 μm(2); 24 wk, 320.97 ± 0.18.17 μm(2)), and leptin (0 wk, 0.8 ± 1.0 ng/ml; 24 wk, 12.9 ± 1.0 ng/ml). Microarrays displayed 1,665 differentially expressed genes in adipose tissue as weight increased. Alterations were seen in adipose tissue homeostatic processes including metabolism, oxidative stress, mitochondrial homeostasis, and extracellular matrix. Adipose transcriptome changes highlight the dynamic and adaptive response to ad libitum feeding and obesity development.

  17. Enhanced glycogen metabolism in adipose tissue decreases triglyceride mobilization

    PubMed Central

    Markan, Kathleen R.; Jurczak, Michael J.; Allison, Margaret B.; Ye, Honggang; Sutanto, Maria M.; Cohen, Ronald N.

    2010-01-01

    Adipose tissue is a primary site for lipid storage containing trace amounts of glycogen. However, refeeding after a prolonged partial fast produces a marked transient spike in adipose glycogen, which dissipates in coordination with the initiation of lipid resynthesis. To further study the potential interplay between glycogen and lipid metabolism in adipose tissue, the aP2-PTG transgenic mouse line was utilized since it contains a 100- to 400-fold elevation of adipocyte glycogen levels that are mobilized upon fasting. To determine the fate of the released glucose 1-phosphate, a series of metabolic measurements were made. Basal and isoproterenol-stimulated lactate production in vitro was significantly increased in adipose tissue from transgenic animals. In parallel, basal and isoproterenol-induced release of nonesterified fatty acids (NEFAs) was significantly reduced in transgenic adipose tissue vs. control. Interestingly, glycerol release was unchanged between the genotypes, suggesting that enhanced triglyceride resynthesis was occurring in the transgenic tissue. Qualitatively similar results for NEFA and glycerol levels between wild-type and transgenic animals were obtained in vivo during fasting. Additionally, the physiological upregulation of the phosphoenolpyruvate carboxykinase cytosolic isoform (PEPCK-C) expression in adipose upon fasting was significantly blunted in transgenic mice. No changes in whole body metabolism were detected through indirect calorimetry. Yet weight loss following a weight gain/loss protocol was significantly impeded in the transgenic animals, indicating a further impairment in triglyceride mobilization. Cumulatively, these results support the notion that the adipocyte possesses a set point for glycogen, which is altered in response to nutritional cues, enabling the coordination of adipose glycogen turnover with lipid metabolism. PMID:20424138

  18. Differential effect of subcutaneous abdominal and visceral adipose tissue on cardiometabolic risk.

    PubMed

    Sam, Susan

    2018-03-09

    Metabolic and cardiovascular diseases are increasing worldwide due to the rise in the obesity epidemic. The metabolic consequences of obesity vary by distribution of adipose tissue. Visceral and ectopic adipose accumulation are associated with adverse cardiometabolic consequences, while gluteal-femoral adipose accumulation are negatively associated with these adverse complications and subcutaneous abdominal adipose accumulation is more neutral in its associations. Gender, race and ethnic differences in adipose tissue distribution have been described and could account for the observed differences in risk for cardiometabolic disease. The mechanisms behind the differential impact of adipose tissue on cardiometabolic risk have started to be unraveled and include differences in adipocyte biology, inflammatory profile, connection to systemic circulation and most importantly the inability of the subcutaneous adipose tissue to expand in response to positive energy balance.

  19. Inverse association between brown adipose tissue activation and white adipose tissue accumulation in successfully treated pediatric malignancy1234

    PubMed Central

    Chalfant, James S; Smith, Michelle L; Hu, Houchun H; Dorey, Fred J; Goodarzian, Fariba; Fu, Cecilia H

    2012-01-01

    Background: Although the accumulation of white adipose tissue (WAT) is a risk factor for disease, brown adipose tissue (BAT) has been suggested to have a protective role against obesity. Objective: We studied whether changes in BAT were related to changes in the amounts of subcutaneous adipose tissue (SAT) and visceral adipose tissue (VAT) in children treated for malignancy. Design: We examined the effect of BAT activity on weight, SAT, and VAT in 32 pediatric patients with cancer whose positron emission tomography–computed tomography (PET-CT) scans at diagnosis showed no BAT activity. Changes in weight, SAT, and VAT from diagnosis to remission for children with metabolically active BAT at disease-free follow-up (BAT+) were compared with those in children without visualized BAT when free of disease (BAT−). Results: Follow-up PET-CT studies (4.7 ± 2.4 mo later) after successful treatment of the cancer showed BAT+ in 19 patients but no active BAT (BAT−) in 13 patients. BAT+ patients, in comparison with BAT− patients, gained significantly less weight (3.3 ± 6.6% compared with 11.0 ± 11.6%; P = 0.02) and had significantly less SAT (18.2 ± 26.5% compared with 67.4 ± 71.7%; P = 0.01) and VAT (22.6 ± 33.5% compared with 131.6 ± 171.8%; P = 0.01) during treatment. Multiple regression analysis indicated that the inverse relations between BAT activation and measures of weight, SAT, and VAT persisted even after age, glucocorticoid treatment, and the season when the PET-CT scans were obtained were accounted for. Conclusion: The activation of BAT in pediatric patients undergoing treatment of malignancy is associated with significantly less adipose accumulation. This trial was registered at clinicaltrials.gov as NCT01517581. PMID:22456659

  20. Dietary ribonucleic acid suppresses inflammation of adipose tissue and improves glucose intolerance that is mediated by immune cells in C57BL/6 mice fed a high-fat diet.

    PubMed

    Sakai, Tohru; Taki, Tomoyo; Nakamoto, Akiko; Tazaki, Shiho; Arakawa, Mai; Nakamoto, Mariko; Tsutsumi, Rie; Shuto, Emi

    2015-01-01

    Recent evidence suggests that immune cells play an important role in differentiation of inflammatory macrophages in adipose tissue, which contributes to systemic chronic inflammation. Dietary ribonucleic acid (RNA) has been shown to modulate immune function. We hypothesized that RNA affects immune cell function in adipose tissue and then improves inflammatory response in adipose tissue. C57/BL6 mice and recombination activating gene-1 (RAG-1) knockout mice on a C57BL/6 mice background were fed a high-fat diet containing 1% RNA for 12 wk. An oral glucose tolerance test was performed. Supplementation of dietary RNA in C57BL/6 mice fed a high-fat diet resulted in a smaller area under the curve (AUC) after oral glucose administration than that for control mice. The mRNA expression levels of inflammation-related cytokines in adipose tissue and serum interleukin-6 levels were reduced by dietary RNA supplementation. Interestingly, reduction of the AUC value by RNA supplementation was abolished in T and B cell-deficient RAG-1 knockout mice. These results indicate that RNA improves inflammation in adipose tissue and reduces the AUC value following oral glucose administration in a T and B cell-dependent manner.

  1. Roles of Perivascular Adipose Tissue in the Pathogenesis of Atherosclerosis

    PubMed Central

    Tanaka, Kimie; Sata, Masataka

    2018-01-01

    Traditionally, it is believed that white adipose tissues serve as energy storage, heat insulation, and mechanical cushion, whereas non-shivering thermogenesis occurs in brown adipose tissue. Recent evidence revealed that adipose tissue secretes many types of cytokines, called as adipocytokines, which modulate glucose metabolism, lipid profile, appetite, fibrinolysis, blood pressure, and inflammation. Most of the arteries are surrounded by perivascular adipose tissue (PVAT). PVAT has been thought to be simply a structurally supportive tissue for vasculature. However, recent studies showed that PVAT influences vasodilation and vasocontraction, suggesting that PVAT regulates vascular tone and diameter. Adipocytokines secreted from PVAT appear to have direct access to the adjacent arterial wall by diffusion or via vasa vasorum. In fact, PVAT around atherosclerotic lesions and mechanically-injured arteries displayed inflammatory cytokine profiles, suggesting that PVAT functions to promote vascular lesion formation. Many clinical studies revealed that increased accumulation of epicardial adipose tissue (EAT), which surrounds coronary arteries, is associated with coronary artery disease. In this review article, we will summarize recent findings about potential roles of PVAT in the pathogenesis of atherosclerosis, particularly focusing on a series of basic and clinical studies from our laboratory. PMID:29487532

  2. Effects of Rapid Weight Loss on Systemic and Adipose Tissue Inflammation and Metabolism in Obese Postmenopausal Women.

    PubMed

    Alemán, José O; Iyengar, Neil M; Walker, Jeanne M; Milne, Ginger L; Da Rosa, Joel Correa; Liang, Yupu; Giri, Dilip D; Zhou, Xi Kathy; Pollak, Michael N; Hudis, Clifford A; Breslow, Jan L; Holt, Peter R; Dannenberg, Andrew J

    2017-06-01

    Obesity is associated with subclinical white adipose tissue inflammation, as defined by the presence of crown-like structures (CLSs) consisting of dead or dying adipocytes encircled by macrophages. In humans, bariatric surgery-induced weight loss leads to a decrease in CLSs, but the effects of rapid diet-induced weight loss on CLSs and metabolism are unclear. To determine the effects of rapid very-low-calorie diet-induced weight loss on CLS density, systemic biomarkers of inflammation, and metabolism in obese postmenopausal women. Prospective cohort study. Rockefeller University Hospital, New York, NY. Ten obese, postmenopausal women with a mean age of 60.6 years (standard deviation, ±3.6 years). Effects on CLS density and gene expression in abdominal subcutaneous adipose tissue, cardiometabolic risk factors, white blood count, circulating metabolites, and oxidative stress (urinary isoprostane-M) were measured. Obese subjects lost approximately 10% body weight over a mean of 46 days. CLS density increased in subcutaneous adipose tissue without an associated increase in proinflammatory gene expression. Weight loss was accompanied by decreased fasting blood levels of high-sensitivity C-reactive protein, glucose, lactate, and kynurenine, and increased circulating levels of free fatty acids, glycerol, β -hydroxybutyrate, and 25 hydroxyvitamin D. Levels of urinary isoprostane-M declined. Rapid weight loss stimulated lipolysis and an increase in CLS density in subcutaneous adipose tissue in association with changes in levels of circulating metabolites, and improved systemic biomarkers of inflammation and insulin resistance. The observed change in levels of metabolites ( i.e. , lactate, β -hydroxybutyrate, 25 hydroxyvitamin D) may contribute to the anti-inflammatory effect of rapid weight loss.

  3. Effects of Rapid Weight Loss on Systemic and Adipose Tissue Inflammation and Metabolism in Obese Postmenopausal Women

    PubMed Central

    Iyengar, Neil M.; Walker, Jeanne M.; Milne, Ginger L.; Da Rosa, Joel Correa; Liang, Yupu; Giri, Dilip D.; Zhou, Xi Kathy; Pollak, Michael N.; Hudis, Clifford A.; Breslow, Jan L.; Holt, Peter R.; Dannenberg, Andrew J.

    2017-01-01

    Context: Obesity is associated with subclinical white adipose tissue inflammation, as defined by the presence of crown-like structures (CLSs) consisting of dead or dying adipocytes encircled by macrophages. In humans, bariatric surgery-induced weight loss leads to a decrease in CLSs, but the effects of rapid diet-induced weight loss on CLSs and metabolism are unclear. Objective: To determine the effects of rapid very-low-calorie diet-induced weight loss on CLS density, systemic biomarkers of inflammation, and metabolism in obese postmenopausal women. Design: Prospective cohort study. Setting: Rockefeller University Hospital, New York, NY. Participants: Ten obese, postmenopausal women with a mean age of 60.6 years (standard deviation, ±3.6 years). Main Outcome Measures: Effects on CLS density and gene expression in abdominal subcutaneous adipose tissue, cardiometabolic risk factors, white blood count, circulating metabolites, and oxidative stress (urinary isoprostane-M) were measured. Results: Obese subjects lost approximately 10% body weight over a mean of 46 days. CLS density increased in subcutaneous adipose tissue without an associated increase in proinflammatory gene expression. Weight loss was accompanied by decreased fasting blood levels of high-sensitivity C-reactive protein, glucose, lactate, and kynurenine, and increased circulating levels of free fatty acids, glycerol, β-hydroxybutyrate, and 25 hydroxyvitamin D. Levels of urinary isoprostane-M declined. Conclusion: Rapid weight loss stimulated lipolysis and an increase in CLS density in subcutaneous adipose tissue in association with changes in levels of circulating metabolites, and improved systemic biomarkers of inflammation and insulin resistance. The observed change in levels of metabolites (i.e., lactate, β-hydroxybutyrate, 25 hydroxyvitamin D) may contribute to the anti-inflammatory effect of rapid weight loss. PMID:29264516

  4. Brown adipose tissue and lipid metabolism.

    PubMed

    Heeren, Joerg; Scheja, Ludger

    2018-06-01

    This article explores how the interplay between lipid metabolism and thermogenic adipose tissues enables proper physiological adaptation to cold environments in rodents and humans. Cold exposure triggers systemic changes in lipid metabolism, which increases fatty acid delivery to brown adipose tissue (BAT) by various routes. Next to fatty acids generated intracellularly by de-novo lipogenesis or by lipolysis at lipid droplets, brown adipocytes utilize fatty acids released by white adipose tissue (WAT) for adaptive thermogenesis. WAT-derived fatty acids are internalized directly by BAT, or indirectly after hepatic conversion to very low-density lipoproteins and acylcarnitines. In the postprandial state, chylomicrons hydrolyzed by lipoprotein lipase - activated specifically in thermogenic adipocytes - are the predominant fatty acid source. Cholesterol-enriched chylomicron remnants and HDL generated by intravascular lipolysis in BAT are cleared more rapidly by the liver, explaining the antiatherogenic effects of BAT activation. Notably, increased cholesterol flux and elevated hepatic synthesis of bile acids under cold exposure further promote BAT-dependent thermogenesis. Although pathways providing fatty acids for activated BAT have been identified, more research is needed to understand the integration of lipid metabolism in BAT, WAT and liver, and to determine the relevance of BAT for human energy metabolism.

  5. Peritumoral adipose tissue as a source of inflammatory and angiogenic factors in colorectal cancer.

    PubMed

    Amor, S; Iglesias-de la Cruz, M C; Ferrero, E; García-Villar, O; Barrios, V; Fernandez, N; Monge, L; García-Villalón, A L; Granado, M

    2016-02-01

    Obesity is a risk factor for the development of human colorectal cancer (CC). The aim of this work is to report the inflammatory and angiogenic scenario in lean (BMI < 25 kg/m2) and obese (BMI > 30 kg/m2) patients with and without CC and to assess the role of peritumoral adipose tissue in CC-induced inflammation. Patients were divided in four experimental groups: obese patients with CC (OB-CC), lean patients with CC (LEAN-CC), obese patients without CC (OB), and lean patients without CC (LEAN). Plasma levels of pro-inflammatory cytokines (interleukin (IL)-6, IL-4, IL-8) and granulocyte-macrophage colony-stimulating factor (GM-CSF) were increased in OB-CC patients. Peritumoral adipose tissue (TF) explants and cultured mature adipocytes secreted higher amounts of nitrites and nitrates than did control and non-tumoral (NTF) adipose tissue both alone and in response to lipopolysaccharide (LPS). Nitrite and nitrate secretion was also increased in TF explants from OB-CC patients compared with that from LEAN-CC patients. Gene expression of adiponectin, tumor necrosis factor alpha (TNF-α), insulin-like growth factor type I (IGF-I), cyclooxygenase-2 (COX-2), and peroxisome proliferator-activated receptor γ (PPAR-γ) was increased in TF explants from CC patients. LPS increased the gene expression of IL-6, IL-10, TNF-α, vascular endothelial growth factor (VEGF), and COX-2 in OB and in TF explants from OB-CC patients. COX-2 and PPAR-γ inhibition further increased LPS-induced release of nitrites and nitrates in TF explants and adipocytes from OB-CC patients. In conclusion, OB-CC patients have increased plasma levels of pro-inflammatory and angiogenic factors. TF from OB-CC patients shows an increased secretion of inflammatory markers compared with both TF from LEAN-CC and non-tumoral adipose tissue (AT) through a COX-2- and PPAR-γ-independent mechanism.

  6. UCP1 in adipose tissues: two steps to full browning.

    PubMed

    Kalinovich, Anastasia V; de Jong, Jasper M A; Cannon, Barbara; Nedergaard, Jan

    2017-03-01

    The possibility that brown adipose tissue thermogenesis can be recruited in order to combat the development of obesity has led to a high interest in the identification of "browning agents", i.e. agents that increase the amount and activity of UCP1 in brown and brite/beige adipose tissues. However, functional analysis of the browning process yields confusingly different results when the analysis is performed in one of two alternative steps. Thus, in one of the steps, using cold acclimation as a potent model browning agent, we find that if the browning process is followed in mice initially housed at 21 °C (the most common procedure), there is only weak molecular evidence for increases in UCP1 gene expression or UCP1 protein abundance in classical brown adipose tissue; however, in brite/beige adipose depots, there are large increases, apparently associating functional browning with events only in the brite/beige tissues. Contrastingly, in another step, if the process is followed starting with mice initially housed at 30 °C (thermoneutrality for mice, thus similar to normal human conditions), large increases in UCP1 gene expression and UCP1 protein abundance are observed in the classical brown adipose tissue depots; there is then practically no observable UCP1 gene expression in brite/beige tissues. This apparent conundrum can be resolved when it is realized that the classical brown adipose tissue at 21 °C is already essentially fully differentiated and thus expands extensively through proliferation upon further browning induction, rather than by further enhancing cellular differentiation. When the limiting factor for thermogenesis, i.e. the total amount of UCP1 protein per depot, is analyzed, classical brown adipose tissue is by far the predominant site for the browning process, irrespective of which of the two steps is analyzed. There are to date no published data demonstrating that alternative browning agents would selectively promote brite/beige tissues

  7. The metabolic ER stress sensor IRE1α suppresses alternative activation of macrophages and impairs energy expenditure in obesity.

    PubMed

    Shan, Bo; Wang, Xiaoxia; Wu, Ying; Xu, Chi; Xia, Zhixiong; Dai, Jianli; Shao, Mengle; Zhao, Feng; He, Shengqi; Yang, Liu; Zhang, Mingliang; Nan, Fajun; Li, Jia; Liu, Jianmiao; Liu, Jianfeng; Jia, Weiping; Qiu, Yifu; Song, Baoliang; Han, Jing-Dong J; Rui, Liangyou; Duan, Sheng-Zhong; Liu, Yong

    2017-05-01

    Obesity is associated with metabolic inflammation and endoplasmic reticulum (ER) stress, both of which promote metabolic disease progression. Adipose tissue macrophages (ATMs) are key players orchestrating metabolic inflammation, and ER stress enhances macrophage activation. However, whether ER stress pathways underlie ATM regulation of energy homeostasis remains unclear. Here, we identified inositol-requiring enzyme 1α (IRE1α) as a critical switch governing M1-M2 macrophage polarization and energy balance. Myeloid-specific IRE1α abrogation in Ern1 f/f ; Lyz2-Cre mice largely reversed high-fat diet (HFD)-induced M1-M2 imbalance in white adipose tissue (WAT) and blocked HFD-induced obesity, insulin resistance, hyperlipidemia and hepatic steatosis. Brown adipose tissue (BAT) activity, WAT browning and energy expenditure were significantly higher in Ern1 f/f ; Lyz2-Cre mice. Furthermore, IRE1α ablation augmented M2 polarization of macrophages in a cell-autonomous manner. Thus, IRE1α senses protein unfolding and metabolic and immunological states, and consequently guides ATM polarization. The macrophage IRE1α pathway drives obesity and metabolic syndrome through impairing BAT activity and WAT browning.

  8. RBP4 activates antigen-presenting cells leading to adipose tissue inflammation and systemic insulin resistance

    PubMed Central

    Moraes-Vieira, Pedro M.; Yore, Mark M.; Dwyer, Peter M.; Syed, Ismail; Aryal, Pratik; Kahn, Barbara B.

    2014-01-01

    Insulin resistance is a major cause of diabetes and is highly associated with adipose tissue (AT) inflammation in obesity. RBP4, a retinol-transporter, is elevated in insulin resistance and contributes to increased diabetes risk. We aimed to determine the mechanisms for RBP4-induced insulin resistance. Here we show that RBP4 elevation causes AT inflammation by activating innate immunity which elicits an adaptive immune-response. RBP4-overexpressing mice (RBP4-Ox) are insulin-resistant and glucose-intolerant and have increased AT macrophage and CD4 T-cell infiltration. In RBP4-Ox, AT CD206+ macrophages express pro-inflammatory markers and activate CD4 T-cells while maintaining alternatively-activated macrophage markers. These effects result from direct activation of AT antigen-presenting cells (APCs) by RBP4 through a JNK-dependent pathway. Transfer of RBP4-activated APCs into normal mice is sufficient to induce AT inflammation, insulin resistance and glucose intolerance. Thus, RBP4 causes insulin resistance, at least partly, by activating AT APCs which induce CD4 T-cell Th1 polarization and AT inflammation. PMID:24606904

  9. CCR7 Maintains Nonresolving Lymph Node and Adipose Inflammation in Obesity.

    PubMed

    Hellmann, Jason; Sansbury, Brian E; Holden, Candice R; Tang, Yunan; Wong, Blenda; Wysoczynski, Marcin; Rodriguez, Jorge; Bhatnagar, Aruni; Hill, Bradford G; Spite, Matthew

    2016-08-01

    Accumulation of immune cells in adipose tissue promotes insulin resistance in obesity. Although innate and adaptive immune cells contribute to adipose inflammation, the processes that sustain these interactions are incompletely understood. Here we show that obesity promotes the accumulation of CD11c(+) adipose tissue immune cells that express C-C chemokine receptor 7 (CCR7) in mice and humans, and that CCR7 contributes to chronic inflammation and insulin resistance. We identified that CCR7(+) macrophages and dendritic cells accumulate in adipose tissue in close proximity to lymph nodes (LNs) (i.e., perinodal) and visceral adipose. Consistent with the role of CCR7 in regulating the migration of immune cells to LNs, obesity promoted the accumulation of CD11c(+) cells in LNs, which was prevented by global or hematopoietic deficiency of Ccr7 Obese Ccr7(-/-) mice had reduced accumulation of CD8(+) T cells, B cells, and macrophages in adipose tissue, which was associated with reduced inflammatory signaling. This reduction in maladaptive inflammation translated to increased insulin signaling and improved glucose tolerance in obesity. Therapeutic administration of an anti-CCR7 antibody phenocopied the effects of genetic Ccr7 deficiency in mice with established obesity. These results suggest that CCR7 plays a causal role in maintaining innate and adaptive immunity in obesity. © 2016 by the American Diabetes Association. Readers may use this article as long as the work is properly cited, the use is educational and not for profit, and the work is not altered.

  10. A FSI-based structural approach for micromechanical characterization of adipose tissue

    NASA Astrophysics Data System (ADS)

    Seyfi, Behzad; Sabzalinejad, Masoumeh; Haddad, Seyed M. H.; Fatouraee, Nasser; Samani, Abbas

    2017-03-01

    This paper presents a novel computational method for micromechanical modeling of adipose tissue. The model can be regarded as the first step for developing an inversion based framework that uses adipose stiffness data obtained from elastography to determine its microstructural alterations. Such information can be used as biomarkers for diseases associated with adipose tissue microstructure alteration (e.g. adipose tissue fibrosis and inflammation in obesity). In contrast to previous studies, the presented model follows a multiphase structure which accounts for both solid and fluid components as well as their mechanical interaction. In the model, the lipid droplets and extracellular matrix were considered as the fluid and solid phase, respectively. As such, the fluid-structure interaction (FSI) problem was solved using finite element method. In order to gain insight into how microstructural characteristics influence the macro scale mechanical properties of the adipose tissue, a compression mechanical test was simulated using the FSI model and its results were fitted to corresponding experimental data. The simulation procedure was performed for adipocytes in healthy conditions while the stiffness of extracellular matrix in normal adipose tissue was found by varying it systematically within an optimization process until the simulation response agreed with experimental data. Results obtained in this study are encouraging and show the capability of the proposed model to capture adipose tissue macroscale mechanical behavior based on its microstructure under health and different pathological conditions.

  11. Neural Stem Cells Derived Directly from Adipose Tissue.

    PubMed

    Petersen, Eric D; Zenchak, Jessica R; Lossia, Olivia V; Hochgeschwender, Ute

    2018-05-01

    Neural stem cells (NSCs) are characterized as self-renewing cell populations with the ability to differentiate into the multiple tissue types of the central nervous system. These cells can differentiate into mature neurons, astrocytes, and oligodendrocytes. This category of stem cells has been shown to be a promisingly effective treatment for neurodegenerative diseases and neuronal injury. Most treatment studies with NSCs in animal models use embryonic brain-derived NSCs. This approach presents both ethical and feasibility issues for translation to human patients. Adult tissue is a more practical source of stem cells for transplantation therapies in humans. Some adult tissues such as adipose tissue and bone marrow contain a wide variety of stem cell populations, some of which have been shown to be similar to embryonic stem cells, possessing many pluripotent properties. Of these stem cell populations, some are able to respond to neuronal growth factors and can be expanded in vitro, forming neurospheres analogous to cells harvested from embryonic brain tissue. In this study, we describe a method for the collection and culture of cells from adipose tissue that directly, without going through intermediates such as mesenchymal stem cells, results in a population of NSCs that are able to be expanded in vitro and be differentiated into functional neuronal cells. These adipose-derived NSCs display a similar phenotype to those directly derived from embryonic brain. When differentiated into neurons, cells derived from adipose tissue have spontaneous spiking activity with network characteristics similar to that of neuronal cultures.

  12. Gut microbiota-derived lipopolysaccharide uptake and trafficking to adipose tissue: implications for inflammation and obesity.

    PubMed

    Hersoug, L-G; Møller, P; Loft, S

    2016-04-01

    The composition of the gut microbiota and excessive ingestion of high-fat diets (HFD) are considered to be important factors for development of obesity. In this review we describe a coherent mechanism of action for the development of obesity, which involves the composition of gut microbiota, HFD, low-grade inflammation, expression of fat translocase and scavenger receptor CD36, and the scavenger receptor class B type 1 (SR-BI). SR-BI binds to both lipids and lipopolysaccharide (LPS) from Gram-negative bacteria, which may promote incorporation of LPS in chylomicrons (CMs). These CMs are transported via lymph to the circulation, where LPS is transferred to other lipoproteins by translocases, preferentially to HDL. LPS increases the SR-BI binding, transcytosis of lipoproteins over the endothelial barrier,and endocytosis in adipocytes. Especially large size adipocytes with high metabolic activity absorb LPS-rich lipoproteins. In addition, macrophages in adipose tissue internalize LPS-lipoproteins. This may contribute to the polarization from M2 to M1 phenotype, which is a consequence of increased LPS delivery into the tissue during hypertrophy. In conclusion, evidence suggests that LPS is involved in the development of obesity as a direct targeting molecule for lipid delivery and storage in adipose tissue. © 2015 World Obesity.

  13. Acute Hypercortisolemia Exerts Depot-Specific Effects on Abdominal and Femoral Adipose Tissue Function

    PubMed Central

    O’Reilly, Michael W.; Bujalska, Iwona J.; Tomlinson, Jeremy W.; Arlt, Wiebke

    2017-01-01

    Context: Glucocorticoids have pleiotropic metabolic functions, and acute glucocorticoid excess affects fatty acid metabolism, increasing systemic lipolysis. Whether glucocorticoids exert adipose tissue depot-specific effects remains unclear. Objective: To provide an in vivo assessment of femoral and abdominal adipose tissue responses to acute glucocorticoid administration. Design and Outcome Measures: Nine healthy male volunteers were studied on two occasions, after a hydrocortisone infusion (0.2 mg/kg/min for 14 hours) and a saline infusion, respectively, given in randomized double-blind order. The subjects were studied in the fasting state and after a 75-g glucose drink with an in vivo assessment of femoral adipose tissue blood flow (ATBF) using radioactive xenon washout and of lipolysis and glucose uptake using the arteriovenous difference technique. In a separate study (same infusion design), eight additional healthy male subjects underwent assessment of fasting abdominal ATBF and lipolysis only. Lipolysis was assessed as the net release of nonesterified fatty acids (NEFAs) from femoral and abdominal subcutaneous adipose tissue. Results: Acute hypercortisolemia significantly increased basal and postprandial ATBF in femoral adipose tissue, but the femoral net NEFA release did not change. In abdominal adipose tissue, hypercortisolemia induced substantial increases in basal ATBF and NEFA release. Conclusions: Acute hypercortisolemia induces differential lipolysis and ATBF responses in abdominal and femoral adipose tissue, suggesting depot-specific glucocorticoid effects. Abdominal, but not femoral, adipose tissue contributes to the hypercortisolemia-induced systemic NEFA increase, with likely contributions from other adipose tissue sources and intravascular triglyceride hydrolysis. PMID:28323916

  14. Adipose tissue content and distribution in children and adolescents with bronchial asthma.

    PubMed

    Umławska, Wioleta

    2015-02-01

    The excess of adipose tissue and the pattern of adipose tissue distribution in the body seem to play an important role in the complicated dependencies between obesity and risk of developing asthma. The aim of the present study was to determine nutritional status in children and adolescents with bronchial asthma with special emphasis on adipose tissue distribution evaluated on the basis of skin-fold thicknesses, and to determine the relationships between patterns of adipose tissue distribution and the course of the disease. Anthropometric data on height, weight, circumferences and skin-fold thicknesses were extracted from the medical histories of 261 children diagnosed with asthma bronchitis. Values for children with asthma were compared to Polish national growth reference charts. Distribution of subcutaneous adipose tissue was evaluated using principal components analysis (PCA). Multivariate linear regression analyses tested the effect of three factors on subcutaneous adipose tissue distribution: type of asthma, the severity of the disease and the duration of the disease. Mean body height in the children examined in this study was lower than in their healthy peers. Mean BMI and skin-fold thicknesses were significantly higher and lean body mass was lower in the study group. Excess body fat was noted, especially in girls. Adipose tissue was preferentially deposited in the trunk in girls with severe asthma, as well as in those who had been suffering from asthma for a longer time. The type of asthma, atopic or non-atopic, had no observable effect on subcutaneous adipose tissue distribution in children examined. The data suggest that long-treated subjects and those with severe bronchial asthma accumulate more adipose tissue on the trunk. It is important to regularly monitor nutritional status in children with asthma, especially in those receiving high doses of systemic or inhaled glucocorticosteroids, and long-term treatment as well. Copyright © 2014 Elsevier Ltd. All

  15. Helminth antigens counteract a rapid high-fat diet-induced decrease in adipose tissue eosinophils.

    PubMed

    van den Berg, Susan M; van Dam, Andrea D; Kusters, Pascal J H; Beckers, Linda; den Toom, Myrthe; van der Velden, Saskia; Van den Bossche, Jan; van Die, Irma; Boon, Mariëtte R; Rensen, Patrick C N; Lutgens, Esther; de Winther, Menno P J

    2017-10-01

    Brown adipose tissue (BAT) activation and white adipose tissue (WAT) beiging can increase energy expenditure and have the potential to reduce obesity and associated diseases. The immune system is a potential target in mediating brown and beige adipocyte activation. Type 2 and anti-inflammatory immune cells contribute to metabolic homeostasis within lean WAT, with a prominent role for eosinophils and interleukin (IL)-4-induced anti-inflammatory macrophages. We determined eosinophil numbers in epididymal WAT (EpAT), subcutaneous WAT (ScAT) and BAT after 1 day, 3 days or 1 week of high-fat diet (HFD) feeding in C57Bl/6 mice. One day of HFD resulted in a rapid drop in eosinophil numbers in EpAT and BAT, and after 3 days, in ScAT. In an attempt to restore this HFD-induced drop in adipose tissue eosinophils, we treated 1-week HFD-fed mice with helminth antigens from Schistosoma mansoni or Trichuris suis and evaluated whether the well-known protective metabolic effects of helminth antigens involves BAT activation or beiging. Indeed, antigens of both helminth species induced high numbers of eosinophils in EpAT, but failed to induce beiging. In ScAT, Schistosoma mansoni antigens induced mild eosinophilia, which was accompanied by slightly more beiging. No effects were observed in BAT. To study type 2 responses on brown adipocytes directly, T37i cells were stimulated with IL-4. This increased Ucp1 expression and strongly induced the production of eosinophil chemoattractant CCL11 (+26-fold), revealing that brown adipocytes themselves can attract eosinophils. Our findings indicate that helminth antigen-induced eosinophilia fails to induce profound beiging of white adipocytes. © 2017 Society for Endocrinology.

  16. High intensity interval training improves liver and adipose tissue insulin sensitivity

    PubMed Central

    Marcinko, Katarina; Sikkema, Sarah R.; Samaan, M. Constantine; Kemp, Bruce E.; Fullerton, Morgan D.; Steinberg, Gregory R.

    2015-01-01

    Objective Endurance exercise training reduces insulin resistance, adipose tissue inflammation and non-alcoholic fatty liver disease (NAFLD), an effect often associated with modest weight loss. Recent studies have indicated that high-intensity interval training (HIIT) lowers blood glucose in individuals with type 2 diabetes independently of weight loss; however, the organs affected and mechanisms mediating the glucose lowering effects are not known. Intense exercise increases phosphorylation and inhibition of acetyl-CoA carboxylase (ACC) by AMP-activated protein kinase (AMPK) in muscle, adipose tissue and liver. AMPK and ACC are key enzymes regulating fatty acid metabolism, liver fat content, adipose tissue inflammation and insulin sensitivity but the importance of this pathway in regulating insulin sensitivity with HIIT is unknown. Methods In the current study, the effects of 6 weeks of HIIT were examined using obese mice with serine–alanine knock-in mutations on the AMPK phosphorylation sites of ACC1 and ACC2 (AccDKI) or wild-type (WT) controls. Results HIIT lowered blood glucose and increased exercise capacity, food intake, basal activity levels, carbohydrate oxidation and liver and adipose tissue insulin sensitivity in HFD-fed WT and AccDKI mice. These changes occurred independently of weight loss or reductions in adiposity, inflammation and liver lipid content. Conclusions These data indicate that HIIT lowers blood glucose levels by improving adipose and liver insulin sensitivity independently of changes in adiposity, adipose tissue inflammation, liver lipid content or AMPK phosphorylation of ACC. PMID:26909307

  17. High intensity interval training improves liver and adipose tissue insulin sensitivity.

    PubMed

    Marcinko, Katarina; Sikkema, Sarah R; Samaan, M Constantine; Kemp, Bruce E; Fullerton, Morgan D; Steinberg, Gregory R

    2015-12-01

    Endurance exercise training reduces insulin resistance, adipose tissue inflammation and non-alcoholic fatty liver disease (NAFLD), an effect often associated with modest weight loss. Recent studies have indicated that high-intensity interval training (HIIT) lowers blood glucose in individuals with type 2 diabetes independently of weight loss; however, the organs affected and mechanisms mediating the glucose lowering effects are not known. Intense exercise increases phosphorylation and inhibition of acetyl-CoA carboxylase (ACC) by AMP-activated protein kinase (AMPK) in muscle, adipose tissue and liver. AMPK and ACC are key enzymes regulating fatty acid metabolism, liver fat content, adipose tissue inflammation and insulin sensitivity but the importance of this pathway in regulating insulin sensitivity with HIIT is unknown. In the current study, the effects of 6 weeks of HIIT were examined using obese mice with serine-alanine knock-in mutations on the AMPK phosphorylation sites of ACC1 and ACC2 (AccDKI) or wild-type (WT) controls. HIIT lowered blood glucose and increased exercise capacity, food intake, basal activity levels, carbohydrate oxidation and liver and adipose tissue insulin sensitivity in HFD-fed WT and AccDKI mice. These changes occurred independently of weight loss or reductions in adiposity, inflammation and liver lipid content. These data indicate that HIIT lowers blood glucose levels by improving adipose and liver insulin sensitivity independently of changes in adiposity, adipose tissue inflammation, liver lipid content or AMPK phosphorylation of ACC.

  18. Adipose tissue and inflammatory bowel disease pathogenesis.

    PubMed

    Fink, Christopher; Karagiannides, Iordanes; Bakirtzi, Kyriaki; Pothoulakis, Charalabos

    2012-08-01

    Creeping fat has long been recognized as an indicator of Crohn's disease (CD) activity. Although most patients with CD have normal or low body mass index (BMI), the ratio of intraabdominal fat to total abdominal fat is far greater than that of controls. The obesity epidemic has instructed us on the inflammatory nature of hypertrophic adipose tissue and similarities between mesenteric depots in obese and CD patients can be drawn. However, several important physiological differences exist between these two depots as well. While the molecular basis of the crosstalk between mesenteric adipose and the inflamed intestine in CD is largely unknown, novel evidence implicates neuropeptides along with adipocyte-derived paracrine mediators (adipokines) as potential targets for future investigations and highlight adipose tissue physiology as a potential important determinant in the course of IBD. Copyright © 2012 Crohn's & Colitis Foundation of America, Inc.

  19. Macrophage heterogeneity in tissues: phenotypic diversity and functions

    PubMed Central

    Gordon, Siamon; Plüddemann, Annette; Martinez Estrada, Fernando

    2014-01-01

    During development and throughout adult life, macrophages derived from hematopoietic progenitors are seeded throughout the body, initially in the absence of inflammatory and infectious stimuli as tissue-resident cells, with enhanced recruitment, activation, and local proliferation following injury and pathologic insults. We have learned a great deal about macrophage properties ex vivo and in cell culture, but their phenotypic heterogeneity within different tissue microenvironments remains poorly characterized, although it contributes significantly to maintaining local and systemic homeostasis, pathogenesis, and possible treatment. In this review, we summarize the nature, functions, and interactions of tissue macrophage populations within their microenvironment and suggest questions for further investigation. PMID:25319326

  20. Insulin and Metformin Regulate Circulating and Adipose Tissue Chemerin

    PubMed Central

    Tan, Bee K.; Chen, Jing; Farhatullah, Syed; Adya, Raghu; Kaur, Jaspreet; Heutling, Dennis; Lewandowski, Krzysztof C.; O'Hare, J. Paul; Lehnert, Hendrik; Randeva, Harpal S.

    2009-01-01

    OBJECTIVE To assess chemerin levels and regulation in sera and adipose tissue from women with polycystic ovary syndrome (PCOS) and matched control subjects. RESEARCH DESIGN AND METHODS Real-time RT-PCR and Western blotting were used to assess mRNA and protein expression of chemerin. Serum chemerin was measured by enzyme-linked immunosorbent assay. We investigated the in vivo effects of insulin on serum chemerin levels via a prolonged insulin-glucose infusion. Ex vivo effects of insulin, metformin, and steroid hormones on adipose tissue chemerin protein production and secretion into conditioned media were assessed by Western blotting and enzyme-linked immunosorbent assay, respectively. RESULTS Serum chemerin, subcutaneous, and omental adipose tissue chemerin were significantly higher in women with PCOS (n = 14; P < 0.05, P < 0.01). Hyperinsulinemic induction in human subjects significantly increased serum chemerin levels (n = 6; P < 0.05, P < 0.01). In adipose tissue explants, insulin significantly increased (n = 6; P < 0.05, P < 0.01) whereas metformin significantly decreased (n = 6; P < 0.05, P < 0.01) chemerin protein production and secretion into conditioned media, respectively. After 6 months of metformin treatment, there was a significant decrease in serum chemerin (n = 21; P < 0.01). Importantly, changes in homeostasis model assessment–insulin resistance were predictive of changes in serum chemerin (P = 0.046). CONCLUSIONS Serum and adipose tissue chemerin levels are increased in women with PCOS and are upregulated by insulin. Metformin treatment decreases serum chemerin in these women. PMID:19502420

  1. Role of adipose tissue-derived stem cells in the progression of renal disease.

    PubMed

    Donizetti-Oliveira, Cassiano; Semedo, Patricia; Burgos-Silva, Marina; Cenedeze, Marco Antonio; Malheiros, Denise Maria Avancini Costa; Reis, Marlene Antônia Dos; Pacheco-Silva, Alvaro; Câmara, Niels Olsen Saraiva

    2011-03-01

    To analyze the role of adipose tissue-derived stem cells in reducing the progression of renal fibrosis. adipose tissue-derived stem cells were isolated from C57Bl/6 mice and characterized by cytometry and differentiation. Renal fibrosis was established after unilateral clamping of the renal pedicle for 1 hour. Four hours after reperfusion, 2.105 adipose tissue-derived stem cells were administered intraperitoneally and the animals were followed for 24 hours during 6 weeks. In another experimental group, 2.105adipose tissue-derived stem cells were administered only after 6 weeks of reperfusion, and they were euthanized and studied 4 weeks later. Twenty-four hours after reperfusion, the animals treated with adipose tissue-derived stem cells displayed reduced renal and tubular dysfunction and an increase of the regenerative process. Renal expression of IL-6 and TNF mRNA were decreased in the animals treated with adipose tissue-derived stem cells, while the levels of IL-4, IL-10, and HO-1 were increased, despite the fact that adipose tissue-derived stem cells were not observed in the kidneys via SRY analysis. In 6 weeks, the kidneys of non-treated animals decreased in size, and the kidneys of the animals treated with adipose tissue-derived stem cells remained at normal size and display less deposition of type 1 collagen and FSP-1. The renal protection observed in animals treated with adipose tissue-derived stem cells was followed by a drop in serum levels of TNF-α, KC, RANTES, and IL-1a. Treatment with adipose tissue-derived stem cells after 6 weeks, when the animals already displayed established fibrosis, demonstrated an improvement in functional parameters and less fibrosis analyzed by Picrosirius stain, as well as a reduction of the expression of type 1 collagen and vimentin mRNA. Treatment with adipose tissue-derived stem cells may deter the progression of renal fibrosis by modulation of the early inflammatory response, likely via reduction of the epithelial

  2. Systems biology of adipose tissue metabolism: regulation of growth, signaling and inflammation.

    PubMed

    Manteiga, Sara; Choi, Kyungoh; Jayaraman, Arul; Lee, Kyongbum

    2013-01-01

    Adipose tissue (AT) depots actively regulate whole body energy homeostasis by orchestrating complex communications with other physiological systems as well as within the tissue. Adipocytes readily respond to hormonal and nutritional inputs to store excess nutrients as intracellular lipids or mobilize the stored fat for utilization. Co-ordinated regulation of metabolic pathways balancing uptake, esterification, and hydrolysis of lipids is accomplished through positive and negative feedback interactions of regulatory hubs comprising several pleiotropic protein kinases and nuclear receptors. Metabolic regulation in adipocytes encompasses biogenesis and remodeling of uniquely large lipid droplets (LDs). The regulatory hubs also function as energy and nutrient sensors, and integrate metabolic regulation with intercellular signaling. Over-nutrition causes hypertrophic expansion of adipocytes, which, through incompletely understood mechanisms, initiates a cascade of metabolic and signaling events leading to tissue remodeling and immune cell recruitment. Macrophage activation and polarization toward a pro-inflammatory phenotype drives a self-reinforcing cycle of pro-inflammatory signals in the AT, establishing an inflammatory state. Sustained inflammation accelerates lipolysis and elevates free fatty acids in circulation, which robustly correlates with development of obesity-related diseases. The adipose regulatory network coupling metabolism, growth, and signaling of multiple cell types is exceedingly complex. While components of the regulatory network have been individually studied in exquisite detail, systems approaches have rarely been utilized to comprehensively assess the relative engagements of the components. Thus, need and opportunity exist to develop quantitative models of metabolic and signaling networks to achieve a more complete understanding of AT biology in both health and disease. Copyright © 2013 Wiley Periodicals, Inc.

  3. Chikusetsu saponin IVa ameliorates high fat diet-induced inflammation in adipose tissue of mice through inhibition of NLRP3 inflammasome activation and NF-κB signaling

    PubMed Central

    Yuan, Chengfu; Liu, Chaoqi; Wang, Ting; He, Yumin; Zhou, Zhiyong; Dun, Yaoyan; Zhao, Haixia; Ren, Dongming; Wang, Junjie; Zhang, Changcheng; Yuan, Ding

    2017-01-01

    Chronic metabolic inflammation in adipose tissue plays an important role in the development of obesity-associated diseases. Our previous study indicated that total saponins of Panax japonicus (SPJ) rhizoma and Chikusetsu saponin V, one main component of SPJ, could exert the anti-oxidative and anti-inflammatory effects. The present study aimed to investigate the in vivo and Ex vivo anti-inflammatory activities of another main component of SPJ, namely Chikusetsu saponin IVa (CS). CS could significantly inhibited HFD-induced lipid homeostasis, and inhibited inflammation in adipose tissue, as reflected by the decreased mRNA expression levels of inflammation-related genes and secretion of the chemokines/cytokines, inhibited the accumulation of adipose tissue macrophages (ATMs) and shifted their polarization from M1 to M2, suppressed HFD-induced expression of NLRP3 inflammasome component genes and decreased IL-1β and Caspase-1 production in mice. Moreover, CS treatment also inhibited the activation of NLRP3 inflammasome in bone marrow-derived macrophages (BMDMs). Meanwhile, CS treatment inhibited an NLRP3-induced ASC pyroptosome formation and lipopolysaccharide (LPS)-induced pyroptosis. Furthermore, CS treatment suppressed HFD-induced NF-κB signaling in vivo and LPS-induced NF-κB activation as reflected by the fact that their phosphorylated forms and the ratios of pNF-κB/NF-κB, pIKK/IKK, and pIκB/IκB were all decreased in EAT from HFD-fed mice treated with CS as compared with those of HFD mice. Taking together, this study has revealed that CS effectively inhibits HFD-induced inflammation in adipose tissue of mice through inhibiting both NLRP3 inflammasome activation and NF-κB signaling. Thus, CS can serve as a potential therapeutic drug in the prevention and treatment of inflammation-associated diseases. PMID:28415686

  4. Chikusetsu saponin IVa ameliorates high fat diet-induced inflammation in adipose tissue of mice through inhibition of NLRP3 inflammasome activation and NF-κB signaling.

    PubMed

    Yuan, Chengfu; Liu, Chaoqi; Wang, Ting; He, Yumin; Zhou, Zhiyong; Dun, Yaoyan; Zhao, Haixia; Ren, Dongming; Wang, Junjie; Zhang, Changcheng; Yuan, Ding

    2017-05-09

    Chronic metabolic inflammation in adipose tissue plays an important role in the development of obesity-associated diseases. Our previous study indicated that total saponins of Panax japonicus (SPJ) rhizoma and Chikusetsu saponin V, one main component of SPJ, could exert the anti-oxidative and anti-inflammatory effects. The present study aimed to investigate the in vivo and Ex vivo anti-inflammatory activities of another main component of SPJ, namely Chikusetsu saponin IVa (CS). CS could significantly inhibited HFD-induced lipid homeostasis, and inhibited inflammation in adipose tissue, as reflected by the decreased mRNA expression levels of inflammation-related genes and secretion of the chemokines/cytokines, inhibited the accumulation of adipose tissue macrophages (ATMs) and shifted their polarization from M1 to M2, suppressed HFD-induced expression of NLRP3 inflammasome component genes and decreased IL-1β and Caspase-1 production in mice. Moreover, CS treatment also inhibited the activation of NLRP3 inflammasome in bone marrow-derived macrophages (BMDMs). Meanwhile, CS treatment inhibited an NLRP3-induced ASC pyroptosome formation and lipopolysaccharide (LPS)-induced pyroptosis. Furthermore, CS treatment suppressed HFD-induced NF-κB signaling in vivo and LPS-induced NF-κB activation as reflected by the fact that their phosphorylated forms and the ratios of pNF-κB/NF-κB, pIKK/IKK, and pIκB/IκB were all decreased in EAT from HFD-fed mice treated with CS as compared with those of HFD mice. Taking together, this study has revealed that CS effectively inhibits HFD-induced inflammation in adipose tissue of mice through inhibiting both NLRP3 inflammasome activation and NF-κB signaling. Thus, CS can serve as a potential therapeutic drug in the prevention and treatment of inflammation-associated diseases.

  5. The ubiquitin ligase Siah2 regulates obesity-induced adipose tissue inflammation.

    PubMed

    Kilroy, Gail; Carter, Lauren E; Newman, Susan; Burk, David H; Manuel, Justin; Möller, Andreas; Bowtell, David D; Mynatt, Randall L; Ghosh, Sujoy; Floyd, Z Elizabeth

    2015-11-01

    Chronic, low-grade adipose tissue inflammation associated with adipocyte hypertrophy is an important link in the relationship between obesity and insulin resistance. Although ubiquitin ligases regulate inflammatory processes, the role of these enzymes in metabolically driven adipose tissue inflammation is relatively unexplored. Herein, the effect of the ubiquitin ligase Siah2 on obesity-related adipose tissue inflammation was examined. Wild-type and Siah2KO mice were fed a low- or high-fat diet for 16 weeks. Indirect calorimetry, body composition, and glucose and insulin tolerance were assayed along with glucose and insulin levels. Gene and protein expression, immunohistochemistry, adipocyte size distribution, and lipolysis were also analyzed. Enlarged adipocytes in obese Siah2KO mice were not associated with obesity-induced insulin resistance. Proinflammatory gene expression, stress kinase signaling, fibrosis, and crown-like structures were reduced in the Siah2KO adipose tissue, and Siah2KO adipocytes were more responsive to insulin-dependent inhibition of lipolysis. Loss of Siah2 increased expression of PPARγ target genes involved in lipid metabolism and decreased expression of proinflammatory adipokines regulated by PPARγ. Siah2 links adipocyte hypertrophy with adipocyte dysfunction and recruitment of proinflammatory immune cells to adipose tissue. Selective regulation of PPARγ activity is a Siah2-mediated mechanism contributing to obesity-induced adipose tissue inflammation. © 2015 The Obesity Society.

  6. Plasticity of adipose tissue in response to fasting and refeeding in male mice.

    PubMed

    Tang, Hao-Neng; Tang, Chen-Yi; Man, Xiao-Fei; Tan, Shu-Wen; Guo, Yue; Tang, Jun; Zhou, Ci-La; Zhou, Hou-De

    2017-01-01

    Fasting is the most widely prescribed and self-imposed strategy for treating excessive weight gain and obesity, and has been shown to exert a number of beneficial effects. The aim of the present study was to determine the exact role of fasting and subsequent refeeding on fat distribution in mice. C57/BL6 mice fasted for 24 to 72 h and were then subjected to refeeding for 72 h. At 24, 48 and 72 h of fasting, and 12, 24, 48 and 72 h of refeeding, the mice were sacrificed, and serum and various adipose tissues were collected. Serum biochemical parameters, adipose tissue masses and histomorphological analysis of different depots were detected. MRNA was isolated from various adipose tissues, and the expressions of thermogenesis, visceral signature and lipid metabolism-related genes were examined. The phenotypes of adipose tissues between juvenile and adult mice subjected to fasting and refeeding were also compared. Fasting preferentially consumed mesenteric fat mass and decreased the cell size of mesenteric depots; however, refeeding recovered the mass and morphology of inguinal adipose tissues preferentially compared with visceral depots. Thermogenesis-related gene expression in the inguinal WAT and interscapular BAT were suppressed. Mitochondrial biogenesis was affected by fasting in a depot-specific manner. Furthermore, a short period of fasting led to an increase in visceral signature genes ( Wt1, Tcf21 ) in subcutaneous adipose tissue, while the expression of these genes decreased sharply as the fasting time increased. Additionally, lipogenesis-related markers were enhanced to a greater extent greater in subcutaneous depots compared with those in visceral adipose tissues by refeeding. Although similar phenotypic changes in adipose tissue were observed between juvenile mice and adult mice subjected to fasting and refeeding, the alterations appeared earlier and more sensitively in juvenile mice. Fasting preferentially consumes lipids in visceral adipose tissues

  7. Myocardial regeneration potential of adipose tissue-derived stem cells

    DOE Office of Scientific and Technical Information (OSTI.GOV)

    Bai, Xiaowen, E-mail: baixw01@yahoo.com; Alt, Eckhard, E-mail: ealt@mdanderson.org

    Research highlights: {yields} Various tissue resident stem cells are receiving tremendous attention from basic scientists and clinicians and hold great promise for myocardial regeneration. {yields} For practical reasons, human adipose tissue-derived stem cells are attractive stem cells for future clinical application in repairing damaged myocardium. {yields} This review summarizes the characteristics of cultured and freshly isolated stem cells obtained from adipose tissue, their myocardial regeneration potential and the, underlying mechanisms, and safety issues. -- Abstract: Various tissue resident stem cells are receiving attention from basic scientists and clinicians as they hold promise for myocardial regeneration. For practical reasons, adipose tissue-derivedmore » stem cells (ASCs) are attractive cells for clinical application in repairing damaged myocardium based on the following advantages: abundant adipose tissue in most patients and easy accessibility with minimally invasive lipoaspiration procedure. Several recent studies have demonstrated that both cultured and freshly isolated ASCs could improve cardiac function in animal model of myocardial infarction. The mechanisms underlying the beneficial effect of ASCs on myocardial regeneration are not fully understood. Growing evidence indicates that transplantation of ASCs improve cardiac function via the differentiation into cardiomyocytes and vascular cells, and through paracrine pathways. Paracrine factors secreted by injected ASCs enhance angiogenesis, reduce cell apoptosis rates, and promote neuron sprouts in damaged myocardium. In addition, Injection of ASCs increases electrical stability of the injured heart. Furthermore, there are no reported cases of arrhythmia or tumorigenesis in any studies regarding myocardial regeneration with ASCs. This review summarizes the characteristics of both cultured and freshly isolated stem cells obtained from adipose tissue, their myocardial regeneration potential, and

  8. Depot-specific differences in angiogenic capacity of adipose tissue in differential susceptibility to diet-induced obesity.

    PubMed

    Song, Mun-Gyu; Lee, Hye-Jin; Jin, Bo-Yeong; Gutierrez-Aguilar, Ruth; Shin, Kyung-Ho; Choi, Sang-Hyun; Um, Sung Hee; Kim, Dong-Hoon

    2016-11-01

    Adipose tissue (AT) expansion requires AT remodeling, which depends on AT angiogenesis. Modulation of AT angiogenesis could have therapeutic promise for the treatment of obesity. However, it is unclear how the capacity of angiogenesis in each adipose depot is affected by over-nutrition. Therefore, we investigated the angiogenic capacity (AC) of subcutaneous and visceral fats in lean and obese mice. We compared the AC of epididymal fat (EF) and inguinal fat (IF) using an angiogenesis assay in diet-induced obese (DIO) mice and diet-resistant (DR) mice fed a high-fat diet (HFD). Furthermore, we compared the expression levels of genes related to angiogenesis, macrophage recruitment, and inflammation using RT-qPCR in the EF and IF of lean mice fed a low-fat diet (LFD), DIO mice, and DR mice fed a HFD. DIO mice showed a significant increase in the AC of EF only at 22 weeks of age compared to DR mice. The expression levels of genes related to angiogenesis, macrophage recruitment, and inflammation were significantly higher in the EF of DIO mice than in those of LFD mice and DR mice, while expression levels of genes related to macrophages and their recruitment were higher in the IF of DIO mice than in those of LFD and DR mice. Expression of genes related to angiogenesis (including Hif1a , Vegfa , Fgf1 , Kdr , and Pecam1 ), macrophage recruitment, and inflammation (including Emr1 , Ccr2 , Itgax , Ccl2 , Tnf , and Il1b ) correlated more strongly with body weight in the EF of HFD-fed obese mice compared to that of IF. These results suggest depot-specific differences in AT angiogenesis and a potential role in the susceptibility to diet-induced obesity.

  9. Glyceroneogenesis is inhibited through HIV protease inhibitor-induced inflammation in human subcutaneous but not visceral adipose tissue

    PubMed Central

    Leroyer, Stéphanie; Vatier, Camille; Kadiri, Sarah; Quette, Joëlle; Chapron, Charles; Capeau, Jacqueline; Antoine, Bénédicte

    2011-01-01

    Glyceroneogenesis, a metabolic pathway that participates during lipolysis in the recycling of free fatty acids to triglycerides into adipocytes, contributes to the lipid-buffering function of adipose tissue. We investigated whether glyceroneogenesis could be affected by human immunodeficiency virus (HIV) protease inhibitors (PIs) responsible or not for dyslipidemia in HIV-infected patients. We treated explants obtained from subcutaneous adipose tissue (SAT) and visceral adipose tissue (VAT) depots from lean individuals. We observed that the dyslipidemic PIs nelfinavir, lopinavir and ritonavir, but not the lipid-neutral PI atazanavir, increased lipolysis and decreased glyceroneogenesis, leading to an increased release of fatty acids from SAT but not from VAT. At the same time, dyslipidemic PIs decreased the amount of perilipin and increased interleukin-6 (IL-6) and tumor necrosis factor-α (TNF-α) secretion in SAT but not in VAT. Parthenolide, an inhibitor of the NFκB pathway, counteracted PI-induced increased inflammation and decreased glyceroneogenesis. IL-6 (100 ng) inhibited the activity of phosphoenolpyruvate carboxykinase, the key enzyme of glyceroneogenesis, in SAT but not in VAT. Our data show that dyslipidemic but not lipid-neutral PIs decreased glyceroneogenesis as a consequence of PI-induced increased inflammation in SAT that could have an affect on adipocytes and/or macrophages. These results add a new link between fat inflammation and increased fatty acids release and suggest a greater sensitivity of SAT than VAT to PI-induced inflammation. PMID:21068005

  10. Abalation of ghrelin receptor reduces adiposity and improves insulin sensitivity during aging by regulating fat metabolism in white and brown adipose tissues

    USDA-ARS?s Scientific Manuscript database

    Aging is associated with increased adiposity in white adipose tissues and impaired thermogenesis in brown adipose tissues; both contribute to increased incidences of obesity and type 2 diabetes. Ghrelin is the only known circulating orexigenic hormone that promotes adiposity. In this study, we show ...

  11. Surgical reduction of adipose tissue in the male Sprague-Dawley rat.

    PubMed

    Kral, J G

    1976-10-01

    The lipostatic theory of regulation of adipose tissue mass was tested by a method for surgical reduction (adipectomy) of 24% of the total body fat of nonobese adult Sprague-Dawley rats, as judged from carcass analyses. The reduction persisted during an observation period of 12 wk without any evidence of altered food intake, weight gain, or compensatory hypertrophy or hyperplasia of adipose tissue compared with sham-operated controls. No changes were found in serum free fatty acids, glycerol, triglycerides, cholesterol, or insulin between adipectomized and control animals, implying an intact quantitative function of the remaining adipose tissue. It is concluded that the size of the adipocytes rather than the number is important for a presumed lipostatic regulation of adipose tissue mass in the adult male Sprague-Dawley rat.

  12. Cell supermarket: Adipose tissue as a source of stem cells

    USDA-ARS?s Scientific Manuscript database

    Adipose tissue is derived from numerous sources, and in recent years has been shown to provide numerous cells from what seemingly was a population of homogeneous adipocytes. Considering the types of cells that adipose tissue-derived cells may form, these cells may be useful in a variety of clinical ...

  13. An alternative splicing program promotes adipose tissue thermogenesis

    PubMed Central

    Vernia, Santiago; Edwards, Yvonne JK; Han, Myoung Sook; Cavanagh-Kyros, Julie; Barrett, Tamera; Kim, Jason K; Davis, Roger J

    2016-01-01

    Alternative pre-mRNA splicing expands the complexity of the transcriptome and controls isoform-specific gene expression. Whether alternative splicing contributes to metabolic regulation is largely unknown. Here we investigated the contribution of alternative splicing to the development of diet-induced obesity. We found that obesity-induced changes in adipocyte gene expression include alternative pre-mRNA splicing. Bioinformatics analysis associated part of this alternative splicing program with sequence specific NOVA splicing factors. This conclusion was confirmed by studies of mice with NOVA deficiency in adipocytes. Phenotypic analysis of the NOVA-deficient mice demonstrated increased adipose tissue thermogenesis and improved glycemia. We show that NOVA proteins mediate a splicing program that suppresses adipose tissue thermogenesis. Together, these data provide quantitative analysis of gene expression at exon-level resolution in obesity and identify a novel mechanism that contributes to the regulation of adipose tissue function and the maintenance of normal glycemia. DOI: http://dx.doi.org/10.7554/eLife.17672.001 PMID:27635635

  14. Interaction of differentiated human adipocytes with macrophages leads to trogocytosis and selective IL-6 secretion

    PubMed Central

    Sárvári, A K; Doan-Xuan, Q-M; Bacsó, Z; Csomós, I; Balajthy, Z; Fésüs, L

    2015-01-01

    Obesity leads to adipose tissue inflammation that is characterized by increased release of proinflammatory molecules and the recruitment of activated immune cells. Although macrophages are present in the highest number among the immune cells in obese adipose tissue, not much is known about their direct interaction with adipocytes. We have introduced an ex vivo experimental system to characterize the cellular interactions and the profile of secreted cytokines in cocultures of macrophages and human adipocytes differentiated from either mesenchymal stem cells or a preadipocyte cell line. As observed by time-lapse microscopy, flow, and laser-scanning cytometry, macrophages phagocytosed bites of adipocytes (trogocytosis), which led to their de novo, phagocytosis and NF-κB-dependent synthesis, then release of interleukin (IL)-6 and monocyte chemoattractant protein (MCP)-1. IL-6 secretion was not accompanied by secretion of other proinflammatory cytokines, such as tumor necrosis factor (TNF)-α and IL-8, except MCP-1. LPS-induced release of TNF-α, IL-8 and MCP-1 was decreased in the presence of the differentiated adipocytes but the IL-6 level did not subside suggesting that phagocytosis-dependent IL-6 secretion may have significant regulatory function in the inflamed adipose tissue. PMID:25611388

  15. Interaction of differentiated human adipocytes with macrophages leads to trogocytosis and selective IL-6 secretion.

    PubMed

    Sárvári, A K; Doan-Xuan, Q-M; Bacsó, Z; Csomós, I; Balajthy, Z; Fésüs, L

    2015-01-22

    Obesity leads to adipose tissue inflammation that is characterized by increased release of proinflammatory molecules and the recruitment of activated immune cells. Although macrophages are present in the highest number among the immune cells in obese adipose tissue, not much is known about their direct interaction with adipocytes. We have introduced an ex vivo experimental system to characterize the cellular interactions and the profile of secreted cytokines in cocultures of macrophages and human adipocytes differentiated from either mesenchymal stem cells or a preadipocyte cell line. As observed by time-lapse microscopy, flow, and laser-scanning cytometry, macrophages phagocytosed bites of adipocytes (trogocytosis), which led to their de novo, phagocytosis and NF-κB-dependent synthesis, then release of interleukin (IL)-6 and monocyte chemoattractant protein (MCP)-1. IL-6 secretion was not accompanied by secretion of other proinflammatory cytokines, such as tumor necrosis factor (TNF)-α and IL-8, except MCP-1. LPS-induced release of TNF-α, IL-8 and MCP-1 was decreased in the presence of the differentiated adipocytes but the IL-6 level did not subside suggesting that phagocytosis-dependent IL-6 secretion may have significant regulatory function in the inflamed adipose tissue.

  16. From the Cover: Adipose tissue mass can be regulated through the vasculature

    NASA Astrophysics Data System (ADS)

    Rupnick, Maria A.; Panigrahy, Dipak; Zhang, Chen-Yu; Dallabrida, Susan M.; Lowell, Bradford B.; Langer, Robert; Judah Folkman, M.

    2002-08-01

    Tumor growth is angiogenesis dependent. We hypothesized that nonneoplastic tissue growth also depends on neovascularization. We chose adipose tissue as an experimental system because of its remodeling capacity. Mice from different obesity models received anti-angiogenic agents. Treatment resulted in dose-dependent, reversible weight reduction and adipose tissue loss. Marked vascular remodeling was evident in adipose tissue sections, which revealed decreased endothelial proliferation and increased apoptosis in treated mice compared with controls. Continuous treatment maintained mice near normal body weights for age without adverse effects. Metabolic adaptations in food intake, metabolic rate, and energy substrate utilization were associated with anti-angiogenic weight loss. We conclude that adipose tissue mass is sensitive to angiogenesis inhibitors and can be regulated by its vasculature.

  17. The transcriptional coregulator GRIP1 controls macrophage polarization and metabolic homeostasis

    PubMed Central

    Coppo, Maddalena; Chinenov, Yurii; Sacta, Maria A.; Rogatsky, Inez

    2016-01-01

    Diet-induced obesity causes chronic macrophage-driven inflammation in white adipose tissue (WAT) leading to insulin resistance. WAT macrophages, however, differ in their origin, gene expression and activities: unlike infiltrating monocyte-derived inflammatory macrophages, WAT-resident macrophages counteract inflammation and insulin resistance, yet, the mechanisms underlying their transcriptional programming remain poorly understood. We recently reported that a nuclear receptor cofactor—glucocorticoid receptor (GR)-interacting protein (GRIP)1—cooperates with GR to repress inflammatory genes. Here, we show that GRIP1 facilitates macrophage programming in response to IL4 via a GR-independent pathway by serving as a coactivator for Kruppel-like factor (KLF)4—a driver of tissue-resident macrophage differentiation. Moreover, obese mice conditionally lacking GRIP1 in macrophages develop massive macrophage infiltration and inflammation in metabolic tissues, fatty livers, hyperglycaemia and insulin resistance recapitulating metabolic disease. Thus, GRIP1 is a critical regulator of immunometabolism, which engages distinct transcriptional mechanisms to coordinate the balance between macrophage populations and ultimately promote metabolic homeostasis. PMID:27464507

  18. Inhibition of myostatin in mice improves insulin sensitivity via irisin-mediated cross talk between muscle and adipose tissues

    PubMed Central

    Dong, Yanlan; Chen, Fang; Mitch, William E.; Zhang, Liping

    2015-01-01

    Background/Objective In mice, a high fat diet (HFD) induces obesity, insulin resistance and myostatin production. We tested whether inhibition of myostatin in mice can reverse these HFD-induced abnormalities. Subjects/Methods C57BL/6 mice were fed a HFD for 16 weeks including the final 4 weeks some mice were treated with an anti-myostatin peptibody. Body composition, the respiratory exchange ratio plus glucose and insulin tolerance tests were examined. Myostatin knock down in C2C12 cells was performed using ShRNA lentivirus. Adipose tissue-derived stem cells were cultured to measure their reponses to conditioned media from C2C12 cells lacking myostatin, or to recombinant myostatin or Irisin. Isolated peritoneal macrophages were treated with myostatin or Irisin to determine if myostatin or Irisin induce inflammatory mechanisms. Results In HFD-fed mice, peptibody treatment stimulated muscle growth and improved insulin resistance. The improved glucose and insulin tolerances were confirmed when we found increased muscle expression of p-Akt and the glucose transporter, Glut4. In mice fed the HFD, the peptibody suppressed macrophage infiltration and the expression of proinflammatory cytokines in both muscle and adipocytes. Inhibition of myostatin caused the conversion of white (WAT) to brown adipose tissue (BAT) while stimulating fatty acid oxidation and increasing energy expenditure. The related mechanism is a muscle-to-fat cross talk mediated by Irisin. Myostatin inhibition increased PGC-1α expression and Irisin production in muscle. Irisin then stimulated WAT browning. Irisin also suppresses inflammation and stimulates macrophage polarization from M1 to M2 types. Concusion these results uncover a metabolic pathway from an increase in myostatin that suppresses Irisin leading to activation of inflammatory cytokines and insulin resistance. Thus, myostatin is a potential therapeutic target to treat insulin resistance of type II diabetes as well as the shortage of brown

  19. Inhibition of myostatin in mice improves insulin sensitivity via irisin-mediated cross talk between muscle and adipose tissues.

    PubMed

    Dong, Jiangling; Dong, Yanjun; Dong, Yanlan; Chen, Fang; Mitch, William E; Zhang, Liping

    2016-03-01

    In mice, a high-fat diet (HFD) induces obesity, insulin resistance and myostatin production. We tested whether inhibition of myostatin in mice can reverse these HFD-induced abnormalities. C57BL/6 mice were fed a HFD for 16 weeks including the final 4 weeks some mice were treated with an anti-myostatin peptibody. Body composition, the respiratory exchange ratio plus glucose and insulin tolerance tests were examined. Myostatin knock down in C2C12 cells was performed using small hairpin RNA lentivirus. Adipose tissue-derived stem cells were cultured to measure their responses to conditioned media from C2C12 cells lacking myostatin, or to recombinant myostatin or irisin. Isolated peritoneal macrophages were treated with myostatin or irisin to determine whether myostatin or irisin induce inflammatory mechanisms. In HFD-fed mice, peptibody treatment stimulated muscle growth and improved insulin resistance. The improved glucose and insulin tolerances were confirmed when we found increased muscle expression of p-Akt and the glucose transporter, Glut4. In HFD-fed mice, the peptibody suppressed macrophage infiltration and the expression of proinflammatory cytokines in both the muscle and adipocytes. Inhibition of myostatin caused the conversion of white (WAT) to brown adipose tissue, whereas stimulating fatty acid oxidation and increasing energy expenditure. The related mechanism is a muscle-to-fat cross talk mediated by irisin. Myostatin inhibition increased peroxisome proliferator-activated receptor gamma, coactivator 1α expression and irisin production in the muscle. Irisin then stimulated WAT browning. Irisin also suppresses inflammation and stimulates macrophage polarization from M1 to M2 types. These results uncover a metabolic pathway from an increase in myostatin that suppresses irisin leading to the activation of inflammatory cytokines and insulin resistance. Thus, myostatin is a potential therapeutic target to treat insulin resistance of type II diabetes as well

  20. Vitamin A mediates conversion of monocyte-derived macrophages into tissue resident macrophages during alternative activation

    PubMed Central

    Gundra, Uma Mahesh; Girgis, Natasha M; Gonzalez, Michael A; Tang, Mei San; Van Der Zande, Hendrik J P; Lin, Jian-Da; Ouimet, Mireille; Ma, Lily J; Poles, Jordan A; Vozhilla, Nikollaq; Fisher, Edward A; Moore, Kathryn J; Loke, P’ng

    2017-01-01

    Whether activated inflammatory macrophages can adopt features of tissue resident macrophages and what mechanisms mediate this phenotypic conversion remain unclear. Here we show that vitamin A was required for phenotypic conversion of interleukin 4 (IL-4)-activated monocyte-derived F4/80intCD206+PD-L2+MHCII+ macrophages into macrophages with a tissue-resident F4/80hiCD206−PD-L2−MHCII−UCP1+ phenotype in the peritoneal cavity of mice and during liver granuloma formation in mice infected with Schistosoma mansoni. Phenotypic conversion of F4/80intCD206+ macrophages into F4/80hiCD206− macrophages was associated with almost complete remodeling of the chromatin landscape, as well as alteration of the transcriptional profiles. Vitamin A deficient mice infected with S. mansoni had disrupted liver granuloma architecture and increased mortality, indicating that failure to convert from F4/80intCD206+ macrophages to F4/80hiCD206− macrophages may lead to dysregulated inflammation during helminth infection. PMID:28436955

  1. Adipose tissue MRI for quantitative measurement of central obesity.

    PubMed

    Poonawalla, Aziz H; Sjoberg, Brett P; Rehm, Jennifer L; Hernando, Diego; Hines, Catherine D; Irarrazaval, Pablo; Reeder, Scott B

    2013-03-01

    To validate adipose tissue magnetic resonance imaging (atMRI) for rapid, quantitative volumetry of visceral adipose tissue (VAT) and total adipose tissue (TAT). Data were acquired on normal adults and clinically overweight girls with Institutional Review Board (IRB) approval/parental consent using sagittal 6-echo 3D-spoiled gradient-echo (SPGR) (26-sec single-breath-hold) at 3T. Fat-fraction images were reconstructed with quantitative corrections, permitting measurement of a physiologically based fat-fraction threshold in normals to identify adipose tissue, for automated measurement of TAT, and semiautomated measurement of VAT. TAT accuracy was validated using oil phantoms and in vivo TAT/VAT measurements validated with manual segmentation. Group comparisons were performed between normals and overweight girls using TAT, VAT, VAT-TAT-ratio (VTR), body-mass-index (BMI), waist circumference, and waist-hip-ratio (WHR). Oil phantom measurements were highly accurate (<3% error). The measured adipose fat-fraction threshold was 96% ± 2%. VAT and TAT correlated strongly with manual segmentation (normals r(2) ≥ 0.96, overweight girls r(2) ≥ 0.99). VAT segmentation required 30 ± 11 minutes/subject (14 ± 5 sec/slice) using atMRI, versus 216 ± 73 minutes/subject (99 ± 31 sec/slice) manually. Group discrimination was significant using WHR (P < 0.001) and VTR (P = 0.004). The atMRI technique permits rapid, accurate measurements of TAT, VAT, and VTR. Copyright © 2012 Wiley Periodicals, Inc.

  2. Matrix-Assisted Transplantation of Functional Beige Adipose Tissue

    PubMed Central

    Tharp, Kevin M.; Jha, Amit K.; Kraiczy, Judith; Yesian, Alexandra; Karateev, Grigory; Sinisi, Riccardo; Dubikovskaya, Elena A.

    2015-01-01

    Novel, clinically relevant, approaches to shift energy balance are urgently needed to combat metabolic disorders such as obesity and diabetes. One promising approach has been the expansion of brown adipose tissues that express uncoupling protein (UCP) 1 and thus can uncouple mitochondrial respiration from ATP synthesis. While expansion of UCP1-expressing adipose depots may be achieved in rodents via genetic and pharmacological manipulations or the transplantation of brown fat depots, these methods are difficult to use for human clinical intervention. We present a novel cell scaffold technology optimized to establish functional brown fat–like depots in vivo. We adapted the biophysical properties of hyaluronic acid–based hydrogels to support the differentiation of white adipose tissue–derived multipotent stem cells (ADMSCs) into lipid-accumulating, UCP1-expressing beige adipose tissue. Subcutaneous implantation of ADMSCs within optimized hydrogels resulted in the establishment of distinct UCP1-expressing implants that successfully attracted host vasculature and persisted for several weeks. Importantly, implant recipients demonstrated elevated core body temperature during cold challenges, enhanced respiration rates, improved glucose homeostasis, and reduced weight gain, demonstrating the therapeutic merit of this highly translatable approach. This novel approach is the first truly clinically translatable system to unlock the therapeutic potential of brown fat–like tissue expansion. PMID:26293504

  3. Inhibition of NET Release Fails to Reduce Adipose Tissue Inflammation in Mice.

    PubMed

    Braster, Quinte; Silvestre Roig, Carlos; Hartwig, Helene; Beckers, Linda; den Toom, Myrthe; Döring, Yvonne; Daemen, Mat J; Lutgens, Esther; Soehnlein, Oliver

    2016-01-01

    Obesity-associated diseases such as Type 2 diabetes, liver disease and cardiovascular diseases are profoundly mediated by low-grade chronic inflammation of the adipose tissue. Recently, the importance of neutrophils and neutrophil-derived myeloperoxidase and neutrophil elastase on the induction of insulin resistance has been established. Since neutrophil elastase and myeloperoxidase are critically involved in the release of neutrophil extracellular traps (NETs), we here hypothesized that NETs may be relevant to early adipose tissue inflammation. Thus, we tested the effect of the Peptidyl Arginine Deiminase 4 inhibitor Cl-amidine, a compound preventing histone citrullination and subsequent NET release, in a mouse model of adipose tissue inflammation. C57BL6 mice received a 60% high fat diet for 10 weeks and were treated with either Cl-amidine or vehicle. Flow cytometry of adipose tissue and liver, immunohistological analysis and glucose and insulin tolerance tests were performed to determine the effect of the treatment and diet. Although high fat diet feeding induced insulin resistance no significant effect was observed between the treatment groups. In addition no effect was found in leukocyte infiltration and activation in the adipose tissue and liver. Therefore we concluded that inhibition of neutrophil extracellular trap formation may have no clinical relevance for early obesity-mediated pathogenesis of the adipose tissue and liver.

  4. The effect of diabetes on the wound healing potential of adipose-tissue derived stem cells.

    PubMed

    Kim, Sue Min; Kim, Yun Ho; Jun, Young Joon; Yoo, Gyeol; Rhie, Jong Won

    2016-03-01

    To investigate whether diabetes mellitus affects the wound-healing-promoting potential of adipose tissue-derived stem cells, we designed a wound-healing model using diabetic mice. We compared the degree of wound healing between wounds treated with normal adipose tissue-derived stem cells and wounds treated with diabetic adipose tissue-derived stem cells. We evaluated the wound-healing rate, the epithelial tongue distance, the area of granulation tissue, the number of capillary and the number of Ki-67-stained cells. The wound-healing rate was significantly higher in the normal adipose tissue-derived stem cells group than in the diabetic adipose tissue-derived stem cells group; it was also significantly higher in the normal adipose tissue-derived stem cells group than in the control group. Although the diabetic adipose tissue-derived stem cells group showed a better wound-healing rate than the control group, the difference was not statistically significant. Similar trends were observed for the other parameters examined: re-epithelisation and keratinocyte proliferation; granulation tissue formation; and dermal regeneration. However, with regard to the number of capillary, diabetic adipose tissue-derived stem cells retained their ability to promote neovasculisation and angiogenesis. These results reflect the general impairment of the therapeutic potential of diabetic adipose tissue-derived stem cells in vivo. © 2016 Medicalhelplines.com Inc and John Wiley & Sons Ltd.

  5. Identification of a Lipokine, a Lipid Hormone Linking Adipose Tissue to Systemic Metabolism

    PubMed Central

    Cao, Haiming; Gerhold, Kristin; Mayers, Jared R.; Wiest, Michelle M.; Watkins, Steve M.; Hotamisligil, Gökhan S.

    2008-01-01

    Dysregulation of lipid metabolism in individual tissues can lead to systemic disruption of insulin action and glucose metabolism. Utilizing a comprehensive lipidomic platform and mice deficient in adipose tissue lipid chaperones aP2 and mal1, we explored how metabolic alterations in adipose tissue are linked to whole-body metabolism through lipid signals. A robust increase in de novo lipogenesis rendered the adipose tissue of these mice resistant to the deleterious systemic effects of dietary lipid exposure. Systemic lipid profiling also led to identification of C16:1n7-palmitoleate as an adipose tissue-derived lipid hormone that strongly stimulates muscle insulin action and suppresses hepatosteatosis. Our data reveal a novel, lipid-mediated endocrine network and demonstrate that adipose tissue uses lipokines such as C16:1n7-palmitoleate to communicate with distant organs and regulate systemic metabolic homeostasis. PMID:18805087

  6. Adipose tissue metabolic and inflammatory responses to a mixed meal in lean, overweight and obese men.

    PubMed

    Travers, Rebecca L; Motta, Alexandre C; Betts, James A; Thompson, Dylan

    2017-02-01

    Most of what we know about adipose tissue is restricted to observations derived after an overnight fast. However, humans spend the majority of waking hours in a postprandial (fed) state, and it is unclear whether increasing adiposity impacts adipose tissue responses to feeding. The aim of this research was to investigate postprandial responses in adipose tissue across varying degrees of adiposity. Thirty males aged 35-55 years with waist circumference 81-118 cm were divided equally into groups categorized as either lean, overweight or obese. Participants consumed a meal and insulinaemic, glycaemic and lipidaemic responses were monitored over 6 h. Subcutaneous adipose tissue samples were obtained at baseline and after 6 h to examine changes in gene expression and adipose tissue secretion of various adipokines. Following consumption of the meal, insulin and glucose responses were higher with increased adiposity (total AUC effects of group; p = 0.058 and p = 0.027, respectively). At 6 h, significant time effects reflected increases in IL-6 (F = 14.7, p = 0.001) and MCP-1 (F = 10.7, p = 0.003) and reduction in IRS2 adipose tissue gene expression (F = 24.6, p < 0.001), all independent of adiposity. Ex vivo adipokine secretion from adipose tissue explants remained largely unchanged after feeding. Increased systemic measures of postprandial metabolism with greater adiposity do not translate into increased inflammatory responses within adipose tissue. Instead, postprandial adipose tissue changes may represent a normal response to feeding or a (relatively) normalized response with increased adiposity due to either similar net exposure (i.e. per g of adipose) or reduced adipose tissue responsiveness.

  7. Soft tissue fillers for adipose tissue regeneration: From hydrogel development toward clinical applications.

    PubMed

    Van Nieuwenhove, I; Tytgat, L; Ryx, M; Blondeel, P; Stillaert, F; Thienpont, H; Ottevaere, H; Dubruel, P; Van Vlierberghe, S

    2017-11-01

    There is a clear and urgent clinical need to develop soft tissue fillers that outperform the materials currently used for adipose tissue reconstruction. Recently, extensive research has been performed within this field of adipose tissue engineering as the commercially available products and the currently existing techniques are concomitant with several disadvantages. Commercial products are highly expensive and associated with an imposing need for repeated injections. Lipofilling or free fat transfer has an unpredictable outcome with respect to cell survival and potential resorption of the fat grafts. Therefore, researchers are predominantly investigating two challenging adipose tissue engineering strategies: in situ injectable materials and porous 3D printed scaffolds. The present work provides an overview of current research encompassing synthetic, biopolymer-based and extracellular matrix-derived materials with a clear focus on emerging fabrication technologies and developments realized throughout the last decade. Moreover, clinical relevance of the most promising materials will be discussed, together with potential concerns associated with their application in the clinic. Copyright © 2017 Acta Materialia Inc. Published by Elsevier Ltd. All rights reserved.

  8. PVAT and Its Relation to Brown, Beige, and White Adipose Tissue in Development and Function

    PubMed Central

    Hildebrand, Staffan; Stümer, Jasmin; Pfeifer, Alexander

    2018-01-01

    Adipose tissue is commonly categorized into three types with distinct functions, phenotypes, and anatomical localizations. White adipose tissue (WAT) is the major energy store; the largest depots of WAT are found in subcutaneous or intravisceral sites. Brown adipose tissue (BAT) is responsible for energy dissipation during cold-exposure (i.e., non-shivering thermogenesis) and is primarily located in the interscapular region. Beige or brite (brown-in-white) adipose tissue can be found interspersed in WAT and can attain a brown-like phenotype. These three types of tissues also have endocrine functions and play major roles in whole body metabolism especially in obesity and its co-morbidities, such as cardiovascular disease. Over the last years, perivascular adipose tissue (PVAT) has emerged as an adipose organ with endocrine and paracrine functions. Pro and anti-inflammatory agents released by PVAT affect vascular health, and are implicated in the inflammatory aspects of atherosclerosis. PVAT shares several of the defining characteristics of brown adipose tissue, including its cellular morphology and expression of thermogenic genes characteristic for brown adipocytes. However, PVATs from different vessels are phenotypically different, and significant developmental differences exist between PVAT and other adipose tissues. Whether PVAT represents classical BAT, beige adipose tissue, or WAT with changing characteristics, is unclear. In this review, we summarize the current knowledge on how PVAT relates to other types of adipose tissue, both in terms of functionality, developmental origins, and its role in obesity-related cardiovascular disease and inflammation. PMID:29467675

  9. [Isolation,culture and identification of adipose-derived stem cells from SD rat adipose tissues subjected to long-term cryopreservation].

    PubMed

    Liu, Qin; Wang, Liping; Chen, Fang; Zhang, Yi

    2017-02-01

    To study the feasibility of isolation and culture of adipose-derived stem cells( ADSCs) from SD rat adipose tissues subjected to long-term cryopreservation. We took inguinal fat pads from healthy SD rats. Adipose tissues were stored with 100 m L / L dimethyl sulfoxide( DMSO) combined with 900 m L / L fetal bovine serum( FBS) in liquid nitrogen. Three months later,the adipose tissues were resuscitated for the isolation and culture of ADSCs. The growth status and morphology were observed. The growth curve and cell surface markers CD29,CD45,CD90 of the 3rd passage cells were analyzed respectively by CCK-8 assay and immunocytochemistry. The 3rd passage cells were induced towards adipogenic lineages and osteogenic lineages by different inducers,and the resulting cells were examined separately by oil red O staining and alizarin red staining. The ADSCs obtained from SD rat adipose tissues subjected to long-term cryopreservation showed a spindle-shape appearance and had a good proliferation ability. The cell growth curve was typical "S " curve.Immunocytochemistry showed that the 3rd passage cells were positive for CD29 and CD90,while negative for CD45. The cells were positive for oil red O staining after adipogenic induction,and also positive for alizarin red staining after osteogenic induction. The ADSCs can be isolated from SD rat adipose tissues subjected to long-term cryopreservation.

  10. Visceral Adiposity Index: An Indicator of Adipose Tissue Dysfunction

    PubMed Central

    2014-01-01

    The Visceral Adiposity Index (VAI) has recently proven to be an indicator of adipose distribution and function that indirectly expresses cardiometabolic risk. In addition, VAI has been proposed as a useful tool for early detection of a condition of cardiometabolic risk before it develops into an overt metabolic syndrome. The application of the VAI in particular populations of patients (women with polycystic ovary syndrome, patients with acromegaly, patients with NAFLD/NASH, patients with HCV hepatitis, patients with type 2 diabetes, and general population) has produced interesting results, which have led to the hypothesis that the VAI could be considered a marker of adipose tissue dysfunction. Unfortunately, in some cases, on the same patient population, there is conflicting evidence. We think that this could be mainly due to a lack of knowledge of the application limits of the index, on the part of various authors, and to having applied the VAI in non-Caucasian populations. Future prospective studies could certainly better define the possible usefulness of the VAI as a predictor of cardiometabolic risk. PMID:24829577

  11. Early overfeed-induced obesity leads to brown adipose tissue hypoactivity in rats.

    PubMed

    de Almeida, Douglas L; Fabrício, Gabriel S; Trombini, Amanda B; Pavanello, Audrei; Tófolo, Laize P; da Silva Ribeiro, Tatiane A; de Freitas Mathias, Paulo C; Palma-Rigo, Kesia

    2013-01-01

    Brown adipose tissue activation has been considered a potential anti-obesity mechanism because it is able to expend energy through thermogenesis. In contrast, white adipose tissue stores energy, contributing to obesity. We investigated whether the early programming of obesity by overfeeding during lactation changes structure of interscapular brown adipose tissue in adulthood and its effects on thermogenesis. Birth of litters was considered day 0. On day 2, litter size was adjusted to normal (9 pups) and small (3 pups) litters. On day 21, the litters were weaned. A temperature transponder was implanted underneath interscapular brown adipose tissue pads of 81-day-old animals; local temperature was measured during light and dark periods between days 87 and 90. The animals were euthanized, and tissue and blood samples were collected for further analysis. The vagus and retroperitoneal sympathetic nerve activity was recorded. Small litter rats presented significant lower interscapular brown adipose tissue temperature during the light (NL 37.6°C vs. SL 37.2°C) and dark (NL 38°C vs. SL 37.6°C) periods compared to controls. Morphology of small litter brown adipose tissue showed fewer lipid droplets in the tissue center and more and larger in the periphery. The activity of vagus nerve was 19,9% greater in the small litter than in control (p<0.01), and no difference was observed in the sympathetic nerve activity. In adulthood, the small litter rats were 11,7% heavier than the controls and presented higher glycemia 13,1%, insulinemia 70% and corticosteronemia 92,6%. Early overfeeding programming of obesity changes the interscapular brown adipose tissue structure in adulthood, leading to local thermogenesis hypoactivity, which may contribute to obesity in adults. © 2013 S. Karger AG, Basel.

  12. Optimized adipose tissue engineering strategy based on a neo-mechanical processing method.

    PubMed

    He, Yunfan; Lin, Maohui; Wang, Xuecen; Guan, Jingyan; Dong, Ziqing; Feng, Lu; Xing, Malcolm; Feng, Chuanbo; Li, Xiaojian

    2018-05-26

    Decellularized adipose tissue (DAT) represents a promising scaffold for adipose tissue engineering. However, the unique and prolonged lipid removal process required for adipose tissue can damage extracellular matrix (ECM) constituents. Moreover, inadequate vascularization limits the recellularization of DAT in vivo. We proposed a neo-mechanical protocol for rapidly breaking adipocytes and removing lipid content from adipose tissue. The lipid-depleted adipose tissue was then subjected to a fast and mild decellularization to fabricate high-quality DAT (M-DAT). Adipose liquid extract (ALE) derived from this mechanical process was collected and incorporated into M-DAT to further optimize in vivo recellularization. Ordinary DAT was fabricated and served as a control. This developed strategy was evaluated based on decellularization efficiency, ECM quality, and recellularization efficiency. Angiogenic factor components and angiogenic potential of ALE were evaluated in vivo and in vitro. M-DAT achieved the same decellularization efficiency, but exhibited better retention of ECM components and recellularization, compared to those with ordinary DAT. Protein quantification revealed considerable levels of angiogenic factors (basic fibroblast growth factor, epidermal growth factor, transforming growth factor-β1, and vascular endothelial growth factor) in ALE. ALE promoted tube formation in vitro and induced intense angiogenesis in M-DAT in vivo; furthermore, higher expression of the adipogenic factor PPARγ and greater numbers of adipocytes were evident following ALE treatment, compared to those in the M-DAT group. Mechanical processing of adipose tissue led to the production of high-quality M-DAT and angiogenic factor-enriched ALE. The combination of ALE and M-DAT could be a promising strategy for engineered adipose tissue construction. This article is protected by copyright. All rights reserved. © 2018 by the Wound Healing Society.

  13. Phytochemicals and their impact on adipose tissue inflammation and diabetes.

    PubMed

    Leiherer, Andreas; Mündlein, Axel; Drexel, Heinz

    2013-01-01

    Type 2 diabetes mellitus is an inflammatory disease and the mechanisms that underlie this disease, although still incompletely understood, take place in the adipose tissue of obese subjects. Concurrently, the prevalence of obesity caused by Western diet's excessive energy intake and the lack of exercise escalates, and is believed to be causative for the chronic inflammatory state in adipose tissue. Overnutrition itself as an overload of energy may induce the adipocytes to secrete chemokines activating and attracting immune cells to adipose tissue. But also inflammation-mediating food ingredients like saturated fatty acids are believed to directly initiate the inflammatory cascade. In addition, hypoxia in adipose tissue as a direct consequence of obesity, and its effect on gene expression in adipocytes and surrounding cells in fat tissue of obese subjects appears to play a central role in this inflammatory response too. In contrast, revisiting diet all over the world, there are also some natural food products and beverages which are associated with curative effects on human health. Several natural compounds known as spices such as curcumin, capsaicin, and gingerol, or secondary plant metabolites catechin, resveratrol, genistein, and quercetin have been reported to provide an improved health status to their consumers, especially with regard to diabetes, and therefore have been investigated for their anti-inflammatory effect. In this review, we will give an overview about these phytochemicals and their role to interfere with inflammatory cascades in adipose tissue and their potential for fighting against inflammatory diseases like diabetes as investigated in vivo. Copyright © 2012 Elsevier Inc. All rights reserved.

  14. Relationship between reflection spectra of breast adipose tissue with histologic grade

    NASA Astrophysics Data System (ADS)

    Muñoz Morales, Aarón; Vázquez Y Montiel, Sergio; Reigosa, Aldo

    2011-08-01

    Optical spectroscopy allows the characterization, recognition and differentiation of subcutaneous tissues healthy and no-healthy, to facilitate the diagnosis or early detection for breast cancer are studied white adipose tissue by the subcutaneous region with the help of the diffuse reflection spectroscopy in the visible areas (400 to 700 nm) of electromagnetic spectrum for them using a spectrometer portable of integrating sphere, Hunter lab Model Mini-Scan. The problem to be solved for cancer detection by optical techniques is to find the solution to the inverse problem of scattering of radiation in tissue where it is necessary to solve the equation of energy transfer. us through the trigonometric interpolation and by the data adjustment by least squares using Fourier series expansion to parameterize the spectral response curves of each sample of breast adipose tissue then correlated with histological grades established by the optical biopsy for each one of the samples, allowing use this technique to the study of anomalies in White Adipose Tissue Breast, changes are evident in the spectral response for Breast Adipose Tissue carcinogens with respect to healthy tissues and for the different histological grades.

  15. Effect of luminescence transport through adipose tissue on measurement of tissue temperature by using ZnCdS nanothermometers

    NASA Astrophysics Data System (ADS)

    Volkova, Elena K.; Yanina, Irina Yu.; Sagaydachnaya, Elena; Konyukhova, Julia G.; Kochubey, Vyacheslav I.; Tuchin, Valery V.

    2018-02-01

    The spectra of luminescence of ZnCdS nanoparticles (ZnCdS NPs) were measured and analyzed in a wide temperature range: from room to human body and further to a hyperthermic temperature resulting in tissue morphology change. The results show that the signal of luminescence of ZnCdS NPs placed within the tissue is reasonably good sensitive to temperature change and accompanied by phase transitions of lipid structures of adipose tissue. It is shown that the presence of a phase transition in adipose tissue upon its heating (polymorphic transformations of lipids) leads to a nonmonotonic temperature dependence of the intensity of luminescence for the nanoparticles introduced into adipose tissue. This is due to a change in the light scattering by the tissue. The light scattering of adipose tissue greatly distorts the results of temperature measurements. The application of these nanoparticles is possible for temperature measurements in very thin or weakly scattering samples.

  16. Physiological regulation and metabolic role of browning in white adipose tissue.

    PubMed

    Jankovic, Aleksandra; Otasevic, Vesna; Stancic, Ana; Buzadzic, Biljana; Korac, Aleksandra; Korac, Bato

    2017-09-01

    Great progress has been made in our understanding of the browning process in white adipose tissue (WAT) in rodents. The recognition that i) adult humans have physiologically inducible brown adipose tissue (BAT) that may facilitate resistance to obesity and ii) that adult human BAT molecularly and functionally resembles beige adipose tissue in rodents, reignited optimism that obesity and obesity-related diabetes type 2 can be battled by controlling the browning of WAT. In this review the main cellular mechanisms and molecular mediators of browning of WAT in different physiological states are summarized. The relevance of browning of WAT in metabolic health is considered primarily through a modulation of biological role of fat tissue in overall metabolic homeostasis.

  17. Opposite Effects of Soluble Factors Secreted by Adipose Tissue on Proliferating and Quiescent Osteosarcoma Cells.

    PubMed

    Avril, Pierre; Duteille, Franck; Ridel, Perrine; Heymann, Marie-Françoise; De Pinieux, Gonzague; Rédini, Françoise; Blanchard, Frédéric; Heymann, Dominique; Trichet, Valérie; Perrot, Pierre

    2016-03-01

    Autologous adipose tissue transfer may be performed for aesthetic needs following resection of osteosarcoma, the most frequent primary malignant tumor of bone, excluding myeloma. The safety of autologous adipose tissue transfer regarding the potential risk of cancer recurrence must be addressed. Adipose tissue injection was tested in a human osteosarcoma preclinical model induced by MNNG-HOS cells. Culture media without growth factors from fetal bovine serum were conditioned with adipose tissue samples and added to two osteosarcoma cell lines (MNNG-HOS and MG-63) that were cultured in monolayer or maintained in nonadherent spheres, favoring a proliferation or quiescent stage, respectively. Proliferation and cell cycle were analyzed. Adipose tissue injection increased local growth of osteosarcoma in mice but was not associated with aggravation of lung metastasis or osteolysis. Adipose tissue-derived soluble factors increased the in vitro proliferation of osteosarcoma cells up to 180 percent. Interleukin-6 and leptin were measured in higher concentrations in adipose tissue-conditioned medium than in osteosarcoma cell-conditioned medium, but the authors' results indicated that they were not implicated alone. Furthermore, adipose tissue-derived soluble factors did not favor a G0-to-G1 phase transition of MNNG-HOS cells in nonadherent oncospheres. This study indicates that adipose tissue-soluble factors activate osteosarcoma cell cycle from G1 to mitosis phases, but do not promote the transition from quiescent G0 to G1 phases. Autologous adipose tissue transfer may not be involved in the activation of dormant tumor cells or cancer stem cells.

  18. Weight loss induced by bariatric surgery restores adipose tissue PNPLA3 expression.

    PubMed

    Wieser, Verena; Adolph, Timon E; Enrich, Barbara; Moser, Patrizia; Moschen, Alexander R; Tilg, Herbert

    2017-02-01

    Obesity and its related co-morbidities such as non-alcoholic fatty liver disease (NAFLD) are increasing dramatically worldwide. The genetic variation in Patatin-like phospholipase domain-containing protein 3 (PNPLA3), which is also called adiponutrin (ADPN), in residue 148 (I148M, rs738409) has been associated with NAFLD. However, the regulation and function of PNPLA3 in metabolic diseases remains unclear. Laparoscopic gastric banding (LAGB) of severely obese patients reduces body weight, liver and adipose tissue inflammation. In this study, we investigated whether weight loss induced by LAGB affected PNPLA3 expression in hepatic and adipose tissue. Liver and subcutaneous adipose tissue samples were collected from 28 severely obese patients before and 6 months after LAGB. PNPLA3 expression was assessed by quantitative real-time PCR. To understand whether inflammatory stimuli regulated PNPLA3 expression, we studied the effect of tumour necrosis factor alpha (TNFα) and lipopolysaccharide (LPS) on PNPLA3 expression in human adipocytes and hepatocytes. PNPLA3 was strongly expressed in the liver and clearly detectable in subcutaneous adipose tissue of obese patients. Weight loss induced by LAGB of severely obese patients led to significantly increased adipose, but not hepatic, tissue expression of PNPLA3. Subcutaneous PNPLA3 expression negatively correlated with body-mass-index, fasting glucose and fasting insulin. TNFα potently suppressed PNPLA3 expression in adipocytes but not hepatocytes. Weight loss induced by LAGB restored adipose tissue PNPLA3 expression which is suppressed by TNFα. Further studies will be required to determine the functional impact of PNPLA3 and its related genetic variation on adipose tissue inflammation and NAFLD. © 2016 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

  19. Characterization of Visceral and Subcutaneous Adipose Tissue Transcriptome and Biological Pathways in Pregnant and Non-Pregnant Women: Evidence for Pregnancy-Related Regional-Specific Differences in Adipose Tissue

    PubMed Central

    Mazaki-Tovi, Shali; Vaisbuch, Edi; Tarca, Adi L.; Kusanovic, Juan Pedro; Than, Nandor Gabor; Chaiworapongsa, Tinnakorn; Dong, Zhong; Hassan, Sonia S.; Romero, Roberto

    2015-01-01

    Objective The purpose of this study was to compare the transcriptome of visceral and subcutaneous adipose tissues between pregnant and non-pregnant women. Study Design The transcriptome of paired visceral and abdominal subcutaneous adipose tissues from pregnant women at term and matched non-pregnant women (n = 11) was profiled with the Affymetrix Human Exon 1.0 ST array. Differential expression of selected genes was validated with the use of quantitative reverse transcription–polymerase chain reaction. Results Six hundred forty-four transcripts from 633 known genes were differentially expressed (false discovery rate (FDR) <0.1; fold-change >1.5), while 42 exons from 36 genes showed differential usage (difference in FIRMA scores >2 and FDR<0.1) between the visceral and subcutaneous fat of pregnant women. Fifty-six known genes were differentially expressed between pregnant and non-pregnant subcutaneous fat and three genes in the visceral fat. Enriched biological processes in the subcutaneous adipose tissue of pregnant women were mostly related to inflammation. Conclusion The transcriptome of visceral and subcutaneous fat depots reveals pregnancy-related gene expression and splicing differences in both visceral and subcutaneous adipose tissue. Furthermore, for the first time, alternative splicing in adipose tissue has been associated with regional differences and human parturition. PMID:26636677

  20. Feast and famine: Adipose tissue adaptations for healthy aging.

    PubMed

    Lettieri Barbato, Daniele; Aquilano, Katia

    2016-07-01

    Proper adipose tissue function controls energy balance with favourable effects on metabolic health and longevity. The molecular and metabolic asset of adipose tissue quickly and dynamically readapts in response to nutrient fluctuations. Once delivered into cells, nutrients are managed by mitochondria that represent a key bioenergetics node. A persistent nutrient overload generates mitochondrial exhaustion and uncontrolled reactive oxygen species ((mt)ROS) production. In adipocytes, metabolic/molecular reorganization is triggered culminating in the acquirement of a hypertrophic and hypersecretory phenotype that accelerates aging. Conversely, dietary regimens such as caloric restriction or time-controlled fasting endorse mitochondrial functionality and (mt)ROS-mediated signalling, thus promoting geroprotection. In this perspective view, we argued some important molecular and metabolic aspects related to adipocyte response to nutrient stress. Finally we delineated hypothetical routes by which molecularly and metabolically readapted adipose tissue promotes healthy aging. Copyright © 2016 Elsevier B.V. All rights reserved.

  1. Adipose tissue lipolysis and energy metabolism in early cancer cachexia in mice

    PubMed Central

    Kliewer, Kara L; Ke, Jia-Yu; Tian, Min; Cole, Rachel M; Andridge, Rebecca R; Belury, Martha A

    2015-01-01

    Cancer cachexia is a progressive metabolic disorder that results in depletion of adipose tissue and skeletal muscle. A growing body of literature suggests that maintaining adipose tissue mass in cachexia may improve quality-of-life and survival outcomes. Studies of lipid metabolism in cachexia, however, have generally focused on later stages of the disorder when severe loss of adipose tissue has already occurred. Here, we investigated lipid metabolism in adipose, liver and muscle tissues during early stage cachexia – before severe fat loss – in the colon-26 murine model of cachexia. White adipose tissue mass in cachectic mice was moderately reduced (34–42%) and weight loss was less than 10% of initial body weight in this study of early cachexia. In white adipose depots of cachectic mice, we found evidence of enhanced protein kinase A - activated lipolysis which coincided with elevated total energy expenditure and increased expression of markers of brown (but not white) adipose tissue thermogenesis and the acute phase response. Total lipids in liver and muscle were unchanged in early cachexia while markers of fatty oxidation were increased. Many of these initial metabolic responses contrast with reports of lipid metabolism in later stages of cachexia. Our observations suggest intervention studies to preserve fat mass in cachexia should be tailored to the stage of cachexia. Our observations also highlight a need for studies that delineate the contribution of cachexia stage and animal model to altered lipid metabolism in cancer cachexia and identify those that most closely mimic the human condition. PMID:25457061

  2. Endoplasmic reticulum stress in perivascular adipose tissue promotes destabilization of atherosclerotic plaque by regulating GM-CSF paracrine.

    PubMed

    Ying, Ru; Li, Sheng-Wei; Chen, Jia-Yuan; Zhang, Hai-Feng; Yang, Ying; Gu, Zhen-Jie; Chen, Yang-Xin; Wang, Jing-Feng

    2018-04-18

    Perivascular adipose tissue (PVAT) accelerates plaque progression and increases cardiovascular risk. We tested the hypothesis that PVAT contributed to plaque vulnerability and investigated whether endoplasmic reticulum stress (ER stress) in PVAT played an important role in vulnerable plaque. We transplanted thoracic aortic PVAT or subcutaneous adipose tissue as a control, from donor mice to carotid arteries of recipient apolipoprotein E deficient (apoE -/- ) mice after removing carotid artery collar placed for 6 weeks. Two weeks after transplantation, ER stress inhibitor 4-phenyl butyric acid (4-PBA) was locally administrated to the transplanted PVAT and then animals were euthanized after 4 weeks. Immunohistochemistry was performed to quantify plaque composition and neovascularization. Mouse angiogenesis antibody array kit was used to test the angiogenic factors produced by transplanted adipose tissue. In vitro tube formation assay, scratch wound migration assay and mouse aortic ring assay were used to assess the angiogenic capacity of supernatant of transplanted PVAT. Ultrastructural detection by transmission electron microscopy showed transplanted PVAT was a mixed population of white and brown adipocytes with abundant mitochondria. Transplanted PVAT increased the intraplaque macrophage infiltration, lipid core, intimal and vasa vasorum neovascularization and MMP2/9 expression in plaque while decreased smooth muscle cells and collagen in atherosclerotic plaque, which were restored by local 4-PBA-treatment. Antibody array analysis showed that 4-PBA reduced several angiogenic factors [Granulocyte Macrophage Colony Stimulating Factor (GM-CSF), MCP-1, IL-6] secreted by PVAT. Besides, conditioned medium from 4-PBA treated-PVAT inhibited tube formation and migration capacity of endothelial cells and ex vivo mouse aortic ring angiogenesis compared to conditioned medium from transplanted PVAT. mRNA expression and protein levels of GM-CSF were markedly elevated in

  3. Disconnect Between Adipose Tissue Inflammation and Cardiometabolic Dysfunction in Ossabaw Pigs

    PubMed Central

    Vieira-Potter, Victoria J.; Lee, Sewon; Bayless, David S.; Scroggins, Rebecca J.; Welly, Rebecca J.; Fleming, Nicholas J.; Smith, Thomas N.; Meers, Grace M.; Hill, Michael A.; Rector, R. Scott; Padilla, Jaume

    2015-01-01

    Objective The Ossabaw pig is emerging as an attractive model of human cardiometabolic disease due to its size and susceptibility to atherosclerosis, among other characteristics. Here we investigated the relationship between adipose tissue inflammation and metabolic dysfunction in this model. Methods Young female Ossabaw pigs were fed a western-style high-fat diet (HFD) (n=4) or control low-fat diet (LFD) (n=4) for a period of 9 months and compared for cardiometabolic outcomes and adipose tissue inflammation. Results The HFD-fed “OBESE” pigs were 2.5 times heavier (p<0.001) than LFD-fed “LEAN” pigs and developed severe obesity. HFD-feeding caused pronounced dyslipidemia, hypertension, insulin resistance (systemic and adipose) as well as induction of inflammatory genes, impairments in vasomotor reactivity to insulin and atherosclerosis in the coronary arteries. Remarkably, visceral, subcutaneous and perivascular adipose tissue inflammation (via FACS analysis and RT-PCR) was not increased in OBESE pigs, nor were circulating inflammatory cytokines. Conclusions These findings reveal a disconnect between adipose tissue inflammation and cardiometabolic dysfunction induced by western diet feeding in the Ossabaw pig model. PMID:26524201

  4. Macrophage activation is responsible for loss of anticontractile function in inflamed perivascular fat.

    PubMed

    Withers, Sarah B; Agabiti-Rosei, Claudia; Livingstone, Daniel M; Little, Matthew C; Aslam, Rehima; Malik, Rayaz A; Heagerty, Anthony M

    2011-04-01

    The aim of this study was to determine whether macrophages dispersed throughout perivascular fat are crucial to the loss of anticontractile function when healthy adipose tissue becomes inflamed and to gain an understanding of the mechanisms involved. Pharmacological studies on in vitro small arterial segments from a mouse model of inducible macrophage ablation and on wild-type animals were carried out with and without perivascular fat using 2 physiological stimuli of inflammation: aldosterone and hypoxia. Both inflammatory insults caused a similar loss of anticontractile capacity of perivascular fat and increased macrophage activation. Aldosterone receptor antagonism and free radical scavengers were able to restore this capacity and reduce macrophage activation. However, in a mouse deficient of macrophages CD11b-diptheria toxin receptor (CD11b-DTR), there was no increase in contractility of arteries following aldosterone incubation or hypoxia. The presence and activation of macrophages in adipose tissue is the key modulator of the increase in contractility in arteries with perivascular fat following induction of inflammation. Despite multiple factors that may be involved in bringing about the vascular consequences of obesity, the ability of eplerenone to ameliorate the inflammatory effects of both aldosterone and hypoxia may be of potential therapeutic interest.

  5. Obesity-induced Changes in Adipose Tissue Microenvironment and Their Impact on Cardiovascular Disease

    PubMed Central

    Fuster, Jose J.; Ouchi, Noriyuki; Gokce, Noyan; Walsh, Kenneth

    2016-01-01

    Obesity is causally linked with the development of cardiovascular disorders. Accumulating evidence indicates that cardiovascular disease is the “collateral damage” of obesity-driven adipose tissue dysfunction that promotes a chronic inflammatory state within the organism. Adipose tissues secrete bioactive substances, referred to as adipokines, which largely function as modulators of inflammation. The microenvironment of adipose tissue will affect the adipokine secretome, having actions on remote tissues. Obesity typically leads to the upregulation of pro-inflammatory adipokines and the downregulation of anti-inflammatory adipokines, thereby contributing to the pathogenesis of cardiovascular diseases. In this review, we focus on the microenvironment of adipose tissue and how it influences cardiovascular disorders, including atherosclerosis and ischemic heart diseases, through the systemic actions of adipokines. PMID:27230642

  6. Abdominal subcutaneous adipose tissue: a favorable adipose depot for diabetes?

    PubMed

    Chen, Peizhu; Hou, Xuhong; Hu, Gang; Wei, Li; Jiao, Lei; Wang, Hongmei; Chen, Siyu; Wu, Jingzhu; Bao, Yuqian; Jia, Weiping

    2018-06-26

    Previous studies have documented that visceral adipose tissue is positively associated with the risk of diabetes. However, the association of subcutaneous adipose tissue with diabetes risk is still in dispute. We aimed to assess the associations between different adipose distributions and the risk of newly diagnosed diabetes in Chinese adults. The Shanghai Nicheng Cohort Study was conducted among Chinese adults aged 45-70 years. The baseline data of 12,137 participants were analyzed. Subcutaneous and visceral fat area (SFA and VFA) were measured by magnetic resonance imaging. Diabetes was newly diagnosed using a 75 g oral glucose tolerance test. The multivariable-adjusted odds ratios (OR) and 95% confidence intervals (CI) of newly diagnosed diabetes per 1-standard deviation increase in SFA and VFA were 1.29 (1.19-1.39) and 1.61 (1.49-1.74) in men, and 1.10 (1.03-1.18) and 1.56 (1.45-1.67) in women, respectively. However, the association between SFA and newly diagnosed diabetes disappeared in men and was reversed in women (OR 0.86 [95% CI, 0.78-0.94]) after additional adjustment for body mass index (BMI) and VFA. The positive association between VFA and newly diagnosed diabetes remained significant in both sexes after further adjustment for BMI and SFA. Areas under the receiver operating characteristic curve of newly diagnosed diabetes predicted by VFA (0.679 [95% CI, 0.659-0.699] for men and 0.707 [95% CI, 0.690-0.723] for women) were significantly larger than by the other adiposity indicators. SFA was beneficial for lower risk of newly diagnosed diabetes in women but was not associated with newly diagnosed diabetes in men after taking general obesity and visceral obesity into account. VFA, however, was associated with likelihood of newly diagnosed diabetes in both Chinese men and women.

  7. Visceral and subcutaneous adipose tissue express and secrete functional alpha2hsglycoprotein (fetuin a) especially in obesity.

    PubMed

    Pérez-Sotelo, Diego; Roca-Rivada, Arturo; Larrosa-García, María; Castelao, Cecilia; Baamonde, Iván; Baltar, Javier; Crujeiras, Ana Belen; Seoane, Luisa María; Casanueva, Felipe F; Pardo, María

    2017-02-01

    The secretion of the hepatokine alpha-2-Heremans-Schmid glycoprotein/Fetuin A, implicated in pathological processes including systemic insulin resistance, by adipose tissue has been recently described. Thus, we have recently identified its presence in white adipose tissue secretomes by mass spectrometry. However, the secretion pattern and function of adipose-derived alpha-2-Heremans-Schmid glycoprotein are poorly understood. The aim of this study is to evaluate the expression and secretion of total and active phosphorylated alpha-2-Heremans-Schmid glycoprotein by adipose tissue from visceral and subcutaneous localizations in animals at different physiological and nutritional status including anorexia and obesity. Alpha-2-Heremans-Schmid glycoprotein expression and secretion in visceral adipose tissue and subcutaneous adipose tissue explants from animals under fasting and exercise training, at pathological situations such as anorexia and obesity, and from human obese individuals were assayed by immunoblotting, quantitative real-time polymerase chain reaction and enzyme-linked immunosorbent assay. We reveal that visceral adipose tissue expresses and secretes more alpha-2-Heremans-Schmid glycoprotein than subcutaneous adipose tissue, and that this secretion is diminished after fasting and exercise training. Visceral adipose tissue from anorectic animals showed reduced alpha-2-Heremans-Schmid glycoprotein secretion; on the contrary, alpha-2-Heremans-Schmid glycoprotein is over-secreted by visceral adipose tissue in the occurrence of obesity. While secretion of active-PhophoSer321α2HSG by visceral adipose tissue is independent of body mass index, we found that the fraction of active-alpha-2-Heremans-Schmid glycoprotein secreted by subcutaneous adipose tissue increments significantly in situations of obesity. Functional studies show that the inhibition of adipose-derived alpha-2-Heremans-Schmid glycoprotein increases insulin sensitivity in differentiated adipocytes. In

  8. How does temperature affect the function of tissue macrophages?

    NASA Astrophysics Data System (ADS)

    Lee, Chen-Ting; Repasky, Elizabeth A.

    2011-03-01

    Macrophages create a major danger signal following injury or infection and upon activation release pro-inflammatory cytokines, which in turn help to generate febrile conditions. Thus, like other cells of the body, tissue macrophages are often exposed to naturally occurring elevations in tissue temperature during inflammation and fever. However, whether macrophages sense and respond to temperature changes in a specific manner which modulates their function is still not clear. In this brief review, we highlight recent studies which have analyzed the effects of temperatures on macrophage function, and summarize the possible underlying molecular mechanisms which have been identified. Mild, physiological range hyperthermia has been shown to have both pro- and anti-inflammatory roles in regulating macrophage inflammatory cytokine production and at the meeting presentation, we will show new data demonstrating that hyperthermia can indeed exert both positive and negative signals to macrophages. While some thermal effects are correlated with the induction of heat shock factors/heat shock proteins, overall it is not clear how mild hyperthermia can exert both pro- and anti-inflammatory functions. We also summarize data which shows that hyperthermia can affect other macrophage effector functions, including the anti-tumor cytotoxicity. Overall, these studies may help us to better understand the immunological role of tissue temperature and may provide important information needed to maximize the application of heat in the treatment of various diseases including cancer.

  9. Epicardial adipose tissue volume and adipocytokine imbalance are strongly linked to human coronary atherosclerosis.

    PubMed

    Shimabukuro, Michio; Hirata, Yoichiro; Tabata, Minoru; Dagvasumberel, Munkhbaatar; Sato, Hiromi; Kurobe, Hirotsugu; Fukuda, Daiju; Soeki, Takeshi; Kitagawa, Tetsuya; Takanashi, Shuichiro; Sata, Masataka

    2013-05-01

    The impact of epicardial adipose tissue (EAT) over abdominal or overall adiposity on coronary artery disease (CAD) is currently unknown. We compared the association among EAT volume (EATV), cytokine/adipocytokine profiles in EAT and subcutaneous fat, and atherogenic CAD. Paired samples were obtained from EAT and subcutaneous adipose tissue during elective cardiac surgery for CAD (n=50) or non-CAD (n=50). EATV was the sum of cross-sectional EAT areas, and visceral and subcutaneous fat areas were determined at the umbilicus level on computed tomography scans. CD68(+), CD11c(+), and CD206(+) cells were counted using immunohistochemical staining. Cytokine/adipocytokine expression was evaluated using quantitative real-time polymerase chain reaction. Multivariate analysis indicated that male sex, age, diabetes mellitus, high triglycerides, and low high-density lipoprotein cholesterol, and EATV index (EATV/body surface area, cm(3)/m(2)) were significant CAD predictors (corrected R(2)=0.401; P<0.001); visceral fat area, hypertension, smoking, low-density lipoprotein cholesterol (140 mg/dL [3.63 mmol/L]) or statin use were not predictors. The EATV index positively correlated with the CD68(+) and CD11c(+) cell numbers and nucleotide-binding domain, leucine-rich-containing family, pyrin domain-containing-3 (NLRP3), interleukin-1β, and interleukin-1R expression; and negatively correlated with adiponectin expression in EAT. A multivariate analysis model, including CD68(+) cells and interleukin-1β, and adiponectin expression in EAT strongly predicted CAD (corrected R(2)=0.756; P<0.001). EATV and macrophage and cytokine/adipocytokine signals in EAT strongly correlated with CAD. Our findings suggest that EATV and adipocytokine imbalance are strongly linked to human coronary atherosclerosis.

  10. Methods for quantifying adipose tissue insulin resistance in overweight/obese humans.

    PubMed

    Ter Horst, K W; van Galen, K A; Gilijamse, P W; Hartstra, A V; de Groot, P F; van der Valk, F M; Ackermans, M T; Nieuwdorp, M; Romijn, J A; Serlie, M J

    2017-08-01

    Insulin resistance of adipose tissue is an important feature of obesity-related metabolic disease. However, assessment of lipolysis in humans requires labor-intensive and expensive methods, and there is limited validation of simplified measurement methods. We aimed to validate simplified methods for the quantification of adipose tissue insulin resistance against the assessment of insulin sensitivity of lipolysis suppression during hyperinsulinemic-euglycemic clamp studies. We assessed the insulin-mediated suppression of lipolysis by tracer-dilution of [1,1,2,3,3- 2 H 5 ]glycerol during hyperinsulinemic-euglycemic clamp studies in 125 overweight or obese adults (85 men, 40 women; age 50±11 years; body mass index 38±7 kg m -2 ). Seven indices of adipose tissue insulin resistance were validated against the reference measurement method. Low-dose insulin infusion resulted in suppression of the glycerol rate of appearance ranging from 4% (most resistant) to 85% (most sensitive), indicating a good range of adipose tissue insulin sensitivity in the study population. The reference method correlated with (1) insulin-mediated suppression of plasma glycerol concentrations (r=0.960, P<0.001), (2) suppression of plasma non-esterified fatty acid (NEFA) concentrations (r=0.899, P<0.001), (3) the Adipose tissue Insulin Resistance (Adipo-IR) index (fasting plasma insulin-NEFA product; r=-0.526, P<0.001), (4) the fasting plasma insulin-glycerol product (r=-0.467, P<0.001), (5) the Adipose Tissue Insulin Resistance Index (fasting plasma insulin-basal lipolysis product; r=0.460, P<0.001), (6) the Quantitative Insulin Sensitivity Check Index (QUICKI)-NEFA index (r=0.621, P<0.001), and (7) the QUICKI-glycerol index (r=0.671, P<0.001). Bland-Altman plots showed no systematic errors for the suppression indices but proportional errors for all fasting indices. Receiver-operator characteristic curves confirmed that all indices were able to detect adipose tissue insulin resistance (area

  11. Adiposity, lipogenesis, and fatty acid composition of subcutaneous and intramuscular adipose tissues of Brahman and Angus crossbred cattle.

    PubMed

    Campbell, E M G; Sanders, J O; Lunt, D K; Gill, C A; Taylor, J F; Davis, S K; Riley, D G; Smith, S B

    2016-04-01

    The objective of this study was to demonstrate differences in aspects of adipose tissue cellularity, lipid metabolism, and fatty and cholesterol composition in Angus and Brahman crossbred cattle. We hypothesized that in vitro measures of lipogenesis would be greater in three-fourths Angus progeny than in three-fourths Brahman progeny, especially in intramuscular (i.m.) adipose tissue. Progeny ( = 227) were fed a standard, corn-based diet for approximately 150 d before slaughter. Breed was considered to be the effect of interest and was forced into the model. There were 9 breed groups including all 4 kinds of three-fourths Angus calves: Angus bulls Angus-sired F cows ( = 32), Angus bulls Brahman-sired F cows ( = 20), Brahman-sired F bulls Angus cows ( = 24), and Angus-sired F bulls Angus cows ( = 20). There were all 4 kinds of three-fourths Brahman calves: Brahman bulls Brahman-sired F cows ( = 21), Brahman bulls Angus-sired F cows ( = 43), Brahman-sired F bulls Brahman cows ( = 26), and Angus-sired F bulls Brahman cows ( = 13). Additionally, F calves (one-half Brahman and one-half Angus) were produced only from Brahman-sired F bulls Angus-sired F cows ( = 28). Contrasts were calculated when breed was an important fixed effect, using the random effect family(breed) as the error term. Most contrasts were nonsignificant ( > 0.10). Those that were significant ( < 0.05) included cholesterol concentration of subcutaneous (s.c.) adipose tissue (three-fourths Angus > F, three-fourths Brahman > F, and three-fourths crossbred progeny combined > F), s.c. adipocyte volume (three-fourths Angus > F and three-fourths bloods combined > F), lipogenesis from acetate in s.c. adipose tissue (three-fourths Brahman calves from Brahman dams > three-fourths Brahman calves from F dams), and percentage 18:3-3 in s.c. adipose tissue (three-fourths Brahman calves from Brahman-sired F dams < three-fourths Brahman calves from Angus-sired F dams). Intramuscular adipocyte volume ( < 0.001) was

  12. Magnetic Resonance Imaging of Human Tissue-Engineered Adipose Substitutes

    PubMed Central

    Proulx, Maryse; Aubin, Kim; Lagueux, Jean; Audet, Pierre; Auger, Michèle

    2015-01-01

    Adipose tissue (AT) substitutes are being developed to answer the strong demand in reconstructive surgery. To facilitate the validation of their functional performance in vivo, and to avoid resorting to excessive number of animals, it is crucial at this stage to develop biomedical imaging methodologies, enabling the follow-up of reconstructed AT substitutes. Until now, biomedical imaging of AT substitutes has scarcely been reported in the literature. Therefore, the optimal parameters enabling good resolution, appropriate contrast, and graft delineation, as well as blood perfusion validation, must be studied and reported. In this study, human adipose substitutes produced from adipose-derived stem/stromal cells using the self-assembly approach of tissue engineering were implanted into athymic mice. The fate of the reconstructed AT substitutes implanted in vivo was successfully followed by magnetic resonance imaging (MRI), which is the imaging modality of choice for visualizing soft ATs. T1-weighted images allowed clear delineation of the grafts, followed by volume integration. The magnetic resonance (MR) signal of reconstructed AT was studied in vitro by proton nuclear magnetic resonance (1H-NMR). This confirmed the presence of a strong triglyceride peak of short longitudinal proton relaxation time (T1) values (200±53 ms) in reconstructed AT substitutes (total T1=813±76 ms), which establishes a clear signal difference between adjacent muscle, connective tissue, and native fat (total T1 ∼300 ms). Graft volume retention was followed up to 6 weeks after implantation, revealing a gradual resorption rate averaging at 44% of initial substitute's volume. In addition, vascular perfusion measured by dynamic contrast-enhanced-MRI confirmed the graft's vascularization postimplantation (14 and 21 days after grafting). Histological analysis of the grafted tissues revealed the persistence of numerous adipocytes without evidence of cysts or tissue necrosis. This study

  13. The role of adenosine monophosphate kinase in remodeling white adipose tissue metabolism.

    PubMed

    Gaidhu, Mandeep Pinky; Ceddia, Rolando Bacis

    2011-04-01

    Recent evidence indicates that the enzyme adenosine monophosphate (AMP) kinase exerts important fat-reducing effects in the adipose tissue, which has created great interest in this enzyme as a potential target for obesity treatment. This review summarizes our findings that chronic AMP kinase activation remodels adipocyte glucose and lipid metabolism and enhances the ability of adipose tissue to dissipate energy within itself and reduce adiposity.

  14. [Cancer cachexia and white adipose tissue browning].

    PubMed

    Zhang, S T; Yang, H M

    2016-08-01

    Cancer cachexia occurs in a majority of advanced cancer patients. These patients with impaired physical function are unable to tolerance cancer treatment well and have a significantly reduced survival rate. Currently, there is no effective clinical treatment available for cancer cachexia, therefore, it is necessary to clarify the molecular mechanisms of cancer cachexia, moreover, new therapeutic targets for cancer cachexia treatment are urgently needed. Very recent studies suggest that, during cancer cachexia, white adipose tissue undergo a 'browning' process, resulting in increased lipid mobilization and energy expenditure, which may be necessary for the occurrence of cancer cachexia. In this article, we summarize the definition and characteristics of cancer cachexia and adipose tissue 'browning', then, we discuss the new study directions presented in latest research.

  15. Adipose tissue-derived stem cells enhance bioprosthetic mesh repair of ventral hernias.

    PubMed

    Altman, Andrew M; Abdul Khalek, Feras J; Alt, Eckhard U; Butler, Charles E

    2010-09-01

    Bioprosthetic mesh used for ventral hernia repair becomes incorporated into the musculofascial edge by cellular infiltration and vascularization. Adipose tissue-derived stem cells promote tissue repair and vascularization and may increase the rate or degree of tissue incorporation. The authors hypothesized that introducing these cells into bioprosthetic mesh would result in adipose tissue-derived stem cell engraftment and proliferation and enhance incorporation of the bioprosthetic mesh. Adipose tissue-derived stem cells were isolated from the subcutaneous adipose tissue of syngeneic Brown Norway rats, expanded in vitro, and labeled with green fluorescent protein. Thirty-six additional rats underwent inlay ventral hernia repair with porcine acellular dermal matrix. Two 12-rat groups had the cells (1.0 x 10(6)) injected directly into the musculofascial/porcine acellular dermal matrix interface after repair or received porcine acellular dermal matrix on which the cells had been preseeded; the 12-rat control group received no stem cells. At 2 weeks, adipose tissue-derived stem cells in both stem cell groups engrafted, survived, migrated, and proliferated. Mean cellular infiltration into porcine acellular dermal matrix at the musculofascial/graft interface was significantly greater in the preseeded and injected stem cell groups than in the control group. Mean vascular infiltration of the porcine acellular dermal matrix was significantly greater in both stem cell groups than in the control group. Preseeded and injected adipose tissue-derived stem cells engraft, migrate, proliferate, and enhance the vascularity of porcine acellular dermal matrix grafts at the musculofascial/graft interface. These cells can thus enhance incorporation of porcine acellular dermal matrix into the abdominal wall after repair of ventral hernias.

  16. Global adiposity and thickness of intraperitoneal and mesenteric adipose tissue depots are increased in women with polycystic ovary syndrome (PCOS).

    PubMed

    Borruel, Susana; Fernández-Durán, Elena; Alpañés, Macarena; Martí, David; Alvarez-Blasco, Francisco; Luque-Ramírez, Manuel; Escobar-Morreale, Héctor F

    2013-03-01

    Sexual dimorphism suggests a role for androgens in body fat distribution. Women with polycystic ovary syndrome (PCOS), a mainly androgen excess disorder, often present with abdominal obesity and visceral adiposity. We hypothesized that women with PCOS have a masculinized body fat distribution favoring the deposition of fat in visceral and organ-specific adipose tissue depots. This was a case-control study. The study was conducted at an academic hospital. Women with PCOS (n = 55), women without androgen excess (n = 25), and men (n = 26) presenting with similar body mass index participated in the study. There were no interventions. Ultrasound measurements of adipose tissue depots including sc (minimum and maximum), preperitoneal, ip, mesenteric, epicardial, and perirenal fat thickness were obtained and total body fat mass was estimated using a body fat monitor. Men and patients with PCOS had increased amounts of total body fat compared with control women. Men had increased thickness of intraabdominal adipose tissue depots compared with the control women, with the women with PCOS showing intermediate values that were also higher than those of control women in the case of ip and mesenteric fat thickness and was close to reaching statistical significance in the case of epicardial fat thickness. Women with PCOS also showed increased minimum sc fat thickness compared with the control women. Obesity increased the thickness of all of the adipose tissue depots in the 3 groups of subjects. Women with PCOS have higher global adiposity and increased amounts of visceral adipose tissue compared with control women, especially in the ip and mesenteric depots.

  17. White Adipose Tissue Is a Reservoir for Memory T Cells and Promotes Protective Memory Responses to Infection.

    PubMed

    Han, Seong-Ji; Glatman Zaretsky, Arielle; Andrade-Oliveira, Vinicius; Collins, Nicholas; Dzutsev, Amiran; Shaik, Jahangheer; Morais da Fonseca, Denise; Harrison, Oliver J; Tamoutounour, Samira; Byrd, Allyson L; Smelkinson, Margery; Bouladoux, Nicolas; Bliska, James B; Brenchley, Jason M; Brodsky, Igor E; Belkaid, Yasmine

    2017-12-19

    White adipose tissue bridges body organs and plays a fundamental role in host metabolism. To what extent adipose tissue also contributes to immune surveillance and long-term protective defense remains largely unknown. Here, we have shown that at steady state, white adipose tissue contained abundant memory lymphocyte populations. After infection, white adipose tissue accumulated large numbers of pathogen-specific memory T cells, including tissue-resident cells. Memory T cells in white adipose tissue expressed a distinct metabolic profile, and white adipose tissue from previously infected mice was sufficient to protect uninfected mice from lethal pathogen challenge. Induction of recall responses within white adipose tissue was associated with the collapse of lipid metabolism in favor of antimicrobial responses. Our results suggest that white adipose tissue represents a memory T cell reservoir that provides potent and rapid effector memory responses, positioning this compartment as a potential major contributor to immunological memory. Published by Elsevier Inc.

  18. Quantifying the effect of adipose tissue in muscle oximetry by near infrared spectroscopy

    PubMed Central

    Nasseri, Nassim; Kleiser, Stefan; Ostojic, Daniel; Karen, Tanja; Wolf, Martin

    2016-01-01

    Change of muscle tissue oxygen saturation (StO2), due to exercise, measured by near infrared spectroscopy (NIRS) is known to be lower for subjects with higher adipose tissue thickness. This is most likely not physiological but caused by the superficial fat and adipose tissue. In this paper we assessed, in vitro, the influence of adipose tissue thickness on muscle StO2, measured by NIRS oximeters. We measured StO2 of a liquid phantom by 3 continuous wave (CW) oximeters (Sensmart Model X-100 Universal Oximetry System, INVOS 5100C, and OxyPrem v1.3), as well as a frequency-domain oximeter, OxiplexTS, through superficial layers with 4 different thicknesses. Later, we employed the results to calibrate OxyPrem v1.3 for adipose tissue thickness in-vivo. PMID:27895999

  19. Adipose Fatty Acid Binding Protein Promotes Saturated Fatty Acid-induced Macrophage Cell Death through Enhancing Ceramide Production

    PubMed Central

    Zhang, Yuwen; Rao, Enyu; Zeng, Jun; Hao, Jiaqing; Sun, Yanwen; Liu, Shujun; Sauter, Edward R.; Bernlohr, David A.; Cleary, Margot P.; Suttles, Jill; Li, Bing

    2016-01-01

    Macrophages play a critical role in obesity-associated chronic inflammation and disorders. However, the molecular mechanisms underlying the response of macrophages to elevated fatty acids (FAs) and their contribution to metabolic inflammation in obesity remain to be fully elucidated. Here, we report a new mechanism by which dietary FAs, in particular saturated FAs, are able to directly trigger macrophage cell death. We demonstrated that excess saturated FAs, but not unsaturated FAs, induced the production of cytotoxic ceramides in macrophage cell lines. Most importantly, expression of adipose fatty acid binding protein (A-FABP) in macrophages facilitated metabolism of excess saturated FAs for ceramide synthesis. Inhibition or deficiency of A-FABP in macrophage cell lines decreased saturated FA-induced ceramide production, thereby resulting in reduced cell death. Furthermore, we validated the role of A-FABP in promoting saturated FA-induced macrophage cell death with primary bone-marrow derived macrophages and high-fat diet-induced obese mice. Altogether, our data reveal that excess dietary saturated FAs may serve as direct triggers in induction of ceramide production and macrophage cell death through elevated expression of A-FABP, thus establishing A-FABP as a new molecular sensor in triggering macrophage-associated sterile inflammation in obesity. PMID:27920274

  20. The preferred magnetic resonance imaging planes in quantifying visceral adipose tissue and evaluating cardiovascular risk.

    PubMed

    Liu, K H; Chan, Y L; Chan, J C N; Chan, W B; Kong, M O; Poon, M Y

    2005-09-01

    Magnetic Resonance Imaging (MRI) is a well-accepted non-invasive method in the quantification of visceral adipose tissue. However, a standard method of measurement has not yet been universally agreed. The objectives of the present study were 2-fold, firstly, to identify the imaging plane in the Chinese population which gives the best correlation with total visceral adipose tissue volume and cardiovascular risk factors; and secondly to compare the correlations between single-slice and multiple-slice approach with cardiovascular risk factors. Thirty-seven Chinese subjects with no known medical history underwent MRI examination for quantifying total visceral adipose tissue volume. The visceral adipose tissue area at five axial imaging levels within abdomen and pelvis were determined. All subjects had blood pressure measured and fasting blood taken for analysis of cardiovascular risk factors. Framingham risk score for each subject was calculated. The imaging plane at the level of 'lower costal margin' (LCM) in both men and women had the highest correlation with total visceral adipose tissue volume (r = 0.97 and 0.99 respectively). The visceral adipose tissue area at specific imaging levels showed higher correlations with various cardiovascular risk factors and Framingham risk score than total visceral adipose tissue volume. The visceral adipose tissue area at 'umbilicus' (UMB) level in men (r = 0.88) and LCM level in women (r = 0.70) showed the best correlation with Framingham risk score. The imaging plane at the level of LCM is preferred for reflecting total visceral adipose tissue volume in Chinese subjects. For investigating the association of cardiovascular risk with visceral adipose tissue in MRI-obesity research, the single-slice approach is superior to the multiple-slice approach, with the level of UMB in men and LCM in women as the preferred imaging planes.

  1. Defining adipose tissue-derived stem cells in tissue and in culture.

    PubMed

    Lin, Ching-Shwun; Xin, Zhong-Cheng; Deng, Chun-Hua; Ning, Hongxiu; Lin, Guiting; Lue, Tom F

    2010-06-01

    Adipose tissue-derived stem cells (ADSC) are routinely isolated from the stromal vascular fraction (SVF) of homogenized adipose tissue. Similar to other types of mesenchymal stem cells (MSC), ADSC remain difficult to define due to the lack of definitive cellular markers. Still, many types of MSC, including ADSC, have been shown to reside in a perivascular location, and increasing evidence shows that both MSC and ADSC may in fact be vascular stem cells (VSC). Locally, these cells differentiate into smooth muscle and endothelial cells that are assembled into newly formed blood vessels during angiogenesis and neovasculogenesis. Additionally, MSC or ADSC can also differentiate into tissue cells such as adipocytes in the adipose tissue. Systematically, MSC or ADSC are recruited to injury sites where they participate in the repair/regeneration of the injured tissue. Due to the vasculature's dynamic capacity for growth and multipotential nature for diversification, VSC in tissue are individually at various stages and on different paths of differentiation. Therefore, when isolated and put in culture, these cells are expected to be heterogeneous in marker expression, renewal capacity, and differentiation potential. Although this heterogeneity of VSC does impose difficulties and cause confusions in basic science studies, its impact on the development of VSC as a therapeutic cell source has not been as apparent, as many preclinical and clinical trials have reported favorable outcomes. With this understanding, ADSC are generally defined as CD34+CD31- although loss of CD34 expression in culture is well documented. In adipose tissue, CD34 is localized to the intima and adventitia of blood vessels but not the media where cells expressing alpha-smooth muscle actin (SMA) exist. By excluding the intima, which contains the CD34+CD31+ endothelial cells, and the media, which contains the CD34-CD31- smooth muscle cells, it leaves the adventitia as the only possible location for the CD34

  2. White adipose tissue coloring by intermittent fasting.

    PubMed

    Kivelä, Riikka; Alitalo, Kari

    2017-11-01

    Intermittent fasting (IF) has been shown to promote metabolic health in several organisms. Two recent papers show that IF induces white adipose tissue beiging and increases thermogenesis, which improves metabolic health in mice.

  3. Osteopontin: Relation between Adipose Tissue and Bone Homeostasis.

    PubMed

    De Fusco, Carolina; Messina, Antonietta; Monda, Vincenzo; Viggiano, Emanuela; Moscatelli, Fiorenzo; Valenzano, Anna; Esposito, Teresa; Sergio, Chieffi; Cibelli, Giuseppe; Monda, Marcellino; Messina, Giovanni

    2017-01-01

    Osteopontin (OPN) is a multifunctional protein mainly associated with bone metabolism and remodeling. Besides its physiological functions, OPN is implicated in the pathogenesis of a variety of disease states, such as obesity and osteoporosis. Importantly, during the last decades obesity and osteoporosis have become among the main threats to health worldwide. Because OPN is a protein principally expressed in cells with multifaceted effects on bone morphogenesis and remodeling and because it seems to be one of the most overexpressed genes in the adipose tissue of the obese contributing to osteoporosis, this mini review will highlight recent insights about relation between adipose tissue and bone homeostasis.

  4. Adipocyte cannabinoid receptor CB1 regulates energy homeostasis and alternatively activated macrophages

    PubMed Central

    Mancini, Giacomo; Rey, Alejandro Aparisi; Cardinal, Pierre; Tedesco, Laura; Zingaretti, Cristina Maria; Sassmann, Antonia; Quarta, Carmelo; Schwitter, Claudia; Conrad, Andrea; Wettschureck, Nina; Vemuri, V. Kiran; Makriyannis, Alexandros; Hartwig, Jens; Mendez-Lago, Maria; Monory, Krisztina; Giordano, Antonio; Cinti, Saverio; Marsicano, Giovanni; Offermanns, Stefan; Pagotto, Uberto; Cota, Daniela

    2017-01-01

    Dysregulated adipocyte physiology leads to imbalanced energy storage, obesity, and associated diseases, imposing a costly burden on current health care. Cannabinoid receptor type-1 (CB1) plays a crucial role in controlling energy metabolism through central and peripheral mechanisms. In this work, adipocyte-specific inducible deletion of the CB1 gene (Ati-CB1–KO) was sufficient to protect adult mice from diet-induced obesity and associated metabolic alterations and to reverse the phenotype in already obese mice. Compared with controls, Ati-CB1–KO mice showed decreased body weight, reduced total adiposity, improved insulin sensitivity, enhanced energy expenditure, and fat depot–specific cellular remodeling toward lowered energy storage capacity and browning of white adipocytes. These changes were associated with an increase in alternatively activated macrophages concomitant with enhanced sympathetic tone in adipose tissue. Remarkably, these alterations preceded the appearance of differences in body weight, highlighting the causal relation between the loss of CB1 and the triggering of metabolic reprogramming in adipose tissues. Finally, the lean phenotype of Ati-CB1–KO mice and the increase in alternatively activated macrophages in adipose tissue were also present at thermoneutral conditions. Our data provide compelling evidence for a crosstalk among adipocytes, immune cells, and the sympathetic nervous system (SNS), wherein CB1 plays a key regulatory role. PMID:29035280

  5. IL-15 concentrations in skeletal muscle and subcutaneous adipose tissue in lean and obese humans: local effects of IL-15 on adipose tissue lipolysis

    PubMed Central

    Pierce, Joseph R.; Maples, Jill M.

    2015-01-01

    Animal/cell investigations indicate that there is a decreased adipose tissue mass resulting from skeletal muscle (SkM) IL-15 secretion (e.g., SkM-blood-adipose tissue axis). IL-15 could regulate fat mass accumulation in obesity via lipolysis, although this has not been investigated in humans. Therefore, the purpose was to examine whether SkM and/or subcutaneous adipose tissue (SCAT) IL-15 concentrations were correlated with SCAT lipolysis in lean and obese humans and determine whether IL-15 perfusion could induce lipolysis in human SCAT. Local SkM and abdominal SCAT IL-15 (microdialysis) and circulating IL-15 (blood) were sampled in lean (BMI: 23.1 ± 1.9 kg/m2; n = 10) and obese (BMI: 34.7 ± 3.5 kg/m2; n = 10) subjects at rest/during 1-h cycling exercise. Lipolysis (SCAT interstitial glycerol concentration) was compared against local/systemic IL-15. An additional probe in SCAT was perfused with IL-15 to assess direct lipolytic responses. SkM IL-15 was not different between lean and obese subjects (P = 0.45), whereas SCAT IL-15 was higher in obese vs. lean subjects (P = 0.02) and was correlated with SCAT lipolysis (r = 0.45, P = 0.05). Exercise increased SCAT lipolysis in lean and obese (P < 0.01), but exercise-induced SCAT lipolysis changes were not correlated with exercise-induced SCAT IL-15 changes. Microdialysis perfusion resulting in physiological IL-15 concentrations in the adipose tissue interstitium increased lipolysis in lean (P = 0.04) but suppressed lipolysis in obese (P < 0.01). Although we found no support for a human IL-15 SkM-blood-adipose tissue axis, IL-15 may be produced in/act on the abdominal SCAT depot. The extent to which this autocrine/paracrine IL-15 action regulates human body composition remains unknown. PMID:25921578

  6. Exercise-induced adaptations to white and brown adipose tissue.

    PubMed

    Lehnig, Adam C; Stanford, Kristin I

    2018-03-07

    The beneficial effects of exercise on skeletal muscle and the cardiovascular system have long been known. Recent studies have focused on investigating the effects of exercise on adipose tissue and the effects that these exercise-induced adaptations have on overall metabolic health. Examination of exercise-induced adaptations in both white adipose tissue (WAT) and brown adipose tissue (BAT) has revealed marked differences in each tissue with exercise. In WAT, there are changes to both subcutaneous WAT (scWAT) and visceral WAT (vWAT), including decreased adipocyte size and lipid content, increased expression of metabolic genes, altered secretion of adipokines and increased mitochondrial activity. Adaptations specific to scWAT include lipidomic remodeling of phospholipids and, in rodents, the beiging of scWAT. The changes to BAT are less clear: studies evaluating the effect of exercise on the BAT of humans and rodents have revealed contradictory data, making this an important area of current investigation. In this Review, we discuss the exercise-induced changes to WAT and BAT that have been reported by different studies and highlight the current questions in this field. © 2018. Published by The Company of Biologists Ltd.

  7. Adipose tissue lymphocytes: types and roles.

    PubMed

    Caspar-Bauguil, S; Cousin, B; Bour, S; Casteilla, L; Castiella, L; Penicaud, L; Carpéné, C

    2009-12-01

    Besides adipocytes, specialized in lipid handling and involved in energy balance regulation, white adipose tissue (WAT) is mainly composed of other cell types among which lymphocytes represent a non-negligible proportion. Different types of lymphocytes (B, alphabetaT, gammadeltaT, NK and NKT) have been detected in WAT of rodents or humans, and vary in their relative proportion according to the fat pad anatomical location. The lymphocytes found in intra-abdominal, visceral fat pads seem representative of innate immunity, while those present in subcutaneous fat depots are part of adaptive immunity, at least in mice. Both the number and the activity of the different lymphocyte classes, except B lymphocytes, are modified in obesity. Several of these modifications in the relative proportions of the lymphocyte classes depend on the degree of obesity, or on leptin concentration, or even fat depot anatomical location. Recent studies suggest that alterations of lymphocyte number and composition precede the macrophage increase and the enhanced inflammatory state of WAT found in obesity. Lymphocytes express receptors to adipokines while several proinflammatory chemokines are produced in WAT, rendering intricate crosstalk between fat and immune cells. However, the evidences and controversies available so far are in favour of an involvement of lymphocytes in the control of the number of other cells in WAT, either adipocytes or immune cells and of their secretory and metabolic activities. Therefore, immunotherapy deserves to be considered as a promising approach to treat the endocrino-metabolic disorders associated to excessive fat mass development.

  8. Adipose tissue and breast epithelial cells: a dangerous dynamic duo in breast cancer.

    PubMed

    Wang, Yuan-Yuan; Lehuédé, Camille; Laurent, Victor; Dirat, Béatrice; Dauvillier, Stéphanie; Bochet, Ludivine; Le Gonidec, Sophie; Escourrou, Ghislaine; Valet, Philippe; Muller, Catherine

    2012-11-28

    Among the many different cell types surrounding breast cancer cells, the most abundant are those that compose mammary adipose tissue, mainly mature adipocytes and progenitors. New accumulating recent evidences bring the tumor-surrounding adipose tissue into the light as a key component of breast cancer progression. The purpose of this review is to emphasize the role that adipose tissue might play by locally affecting breast cancer cell behavior and subsequent clinical consequences arising from this dialog. Two particular clinical aspects are addressed: obesity that was identified as an independent negative prognostic factor in breast cancer and the oncological safety of autologous fat transfer used in reconstructive surgery for breast cancer patients. This is preceded by the overall description of adipose tissue composition and function with special emphasis on the specificity of adipose depots and the species differences, key experimental aspects that need to be taken in account when cancer is considered. Copyright © 2012 Elsevier Ireland Ltd. All rights reserved.

  9. Macrophage PPARγ is required for normal skeletal muscle and hepatic insulin sensitivity and full antidiabetic effects of thiazolidinediones

    PubMed Central

    Hevener, Andrea L.; Olefsky, Jerrold M.; Reichart, Donna; Nguyen, M.T. Audrey; Bandyopadyhay, Gautam; Leung, Ho-Yin; Watt, Matthew J.; Benner, Chris; Febbraio, Mark A.; Nguyen, Anh-Khoi; Folian, Brian; Subramaniam, Shankar; Gonzalez, Frank J.; Glass, Christopher K.; Ricote, Mercedes

    2007-01-01

    PPARγ is required for fat cell development and is the molecular target of antidiabetic thiazolidinediones (TZDs), which exert insulin-sensitizing effects in adipose tissue, skeletal muscle, and liver. Unexpectedly, we found that inactivation of PPARγ in macrophages results in the development of significant glucose intolerance plus skeletal muscle and hepatic insulin resistance in lean mice fed a normal diet. This phenotype was associated with increased expression of inflammatory markers and impaired insulin signaling in adipose tissue, muscle, and liver. PPARγ-deficient macrophages secreted elevated levels of factors that impair insulin responsiveness in muscle cells in a manner that was enhanced by exposure to FFAs. Consistent with this, the relative degree of insulin resistance became more severe in mice lacking macrophage PPARγ following high-fat feeding, and these mice were only partially responsive to TZD treatment. These findings reveal an essential role of PPARγ in macrophages for the maintenance of whole-body insulin action and in mediating the antidiabetic actions of TZDs. PMID:17525798

  10. Three-Dimensional Magnetic Levitation Culture System Simulating White Adipose Tissue.

    PubMed

    Tseng, Hubert; Daquinag, Alexes C; Souza, Glauco R; Kolonin, Mikhail G

    2018-01-01

    White adipose tissue (WAT) has attracted interest for tissue engineering and cell-based therapies as an abundant source of adipose stem/stromal cells (ASC). However, technical challenges in WAT cell culture have limited its applications in regenerative medicine. Traditional two-dimensional (2D) cell culture models, which are essentially monolayers of cells on glass or plastic substrates, inadequately represent tissue architecture, biochemical concentration gradients, substrate stiffness, and most importantly for WAT research, cell phenotypic heterogeneity. Physiological cell culture platforms for WAT modeling must recapitulate the native diversity of cell types and their coordination within the organ. For this purpose, we developed a three-dimensional (3D) model using magnetic levitation. Here, we describe our protocol that we successfully employed to build adipose tissue organoids (adipospheres) that preserve the heterogeneity of the constituent cell types in vitro. We demonstrate the capacity of assembling adipospheres from multiple cell types, including ASCs, endohtelial cells, and leukocytes that recreate tissue organization. These adipospheres mimicked WAT organogenesis in that they enabled the formation of vessel-like endothelial structures with lumens and differentiation of unilocular adipocytes. Altogether, magnetic levitation is a cell culture platform that recreates tissue structure, function, and heterogeneity in vitro, and serves as a foundation for high-throughput WAT tissue culture and analysis.

  11. Reduction of Adipose Tissue Mass by the Angiogenesis Inhibitor ALS-L1023 from Melissa officinalis

    PubMed Central

    Park, Byung Young; Lee, Hyunghee; Woo, Sangee; Yoon, Miso; Kim, Jeongjun; Hong, Yeonhee; Lee, Hee Suk; Park, Eun Kyu; Hahm, Jong Cheon; Kim, Jin Woo; Shin, Soon Shik; Kim, Min-Young; Yoon, Michung

    2015-01-01

    It has been suggested that angiogenesis modulates adipogenesis and obesity. This study was undertaken to determine whether ALS-L1023 (ALS) prepared by a two-step organic solvent fractionation from Melissa leaves, which exhibits antiangiogenic activity, can regulate adipose tissue growth. The effects of ALS on angiogenesis and extracellular matrix remodeling were measured using in vitro assays. The effects of ALS on adipose tissue growth were investigated in high fat diet-induced obese mice. ALS inhibited VEGF- and bFGF-induced endothelial cell proliferation and suppressed matrix metalloproteinase (MMP) activity in vitro. Compared to obese control mice, administration of ALS to obese mice reduced body weight gain, adipose tissue mass and adipocyte size without affecting appetite. ALS treatment decreased blood vessel density and MMP activity in adipose tissues. ALS reduced the mRNA levels of angiogenic factors (VEGF-A and FGF-2) and MMPs (MMP-2 and MMP-9), whereas ALS increased the mRNA levels of angiogenic inhibitors (TSP-1, TIMP-1, and TIMP-2) in adipose tissues. The protein levels of VEGF, MMP-2 and MMP-9 were also decreased by ALS in adipose tissue. Metabolic changes in plasma lipids, liver triglycerides, and hepatic expression of fatty acid oxidation genes occurred during ALS-induced weight loss. These results suggest that ALS, which has antiangiogenic and MMP inhibitory activities, reduces adipose tissue mass in nutritionally obese mice, demonstrating that adipose tissue growth can be regulated by angiogenesis inhibitors. PMID:26599360

  12. The Metabolic Phenotype in Obesity: Fat Mass, Body Fat Distribution, and Adipose Tissue Function.

    PubMed

    Goossens, Gijs H

    2017-01-01

    The current obesity epidemic poses a major public health issue since obesity predisposes towards several chronic diseases. BMI and total adiposity are positively correlated with cardiometabolic disease risk at the population level. However, body fat distribution and an impaired adipose tissue function, rather than total fat mass, better predict insulin resistance and related complications at the individual level. Adipose tissue dysfunction is determined by an impaired adipose tissue expandability, adipocyte hypertrophy, altered lipid metabolism, and local inflammation. Recent human studies suggest that adipose tissue oxygenation may be a key factor herein. A subgroup of obese individuals - the 'metabolically healthy obese' (MHO) - have a better adipose tissue function, less ectopic fat storage, and are more insulin sensitive than obese metabolically unhealthy persons, emphasizing the central role of adipose tissue function in metabolic health. However, controversy has surrounded the idea that metabolically healthy obesity may be considered really healthy since MHO individuals are at increased (cardio)metabolic disease risk and may have a lower quality of life than normal weight subjects due to other comorbidities. Detailed metabolic phenotyping of obese persons will be invaluable in understanding the pathophysiology of metabolic disturbances, and is needed to identify high-risk individuals or subgroups, thereby paving the way for optimization of prevention and treatment strategies to combat cardiometabolic diseases. © 2017 The Author(s) Published by S. Karger GmbH, Freiburg.

  13. Leptin Aggravates Reflux Esophagitis by Increasing Tissue Levels of Macrophage Migration Inhibitory Factor in Rats.

    PubMed

    Murata, Tsugihiro; Asanuma, Kiyotaka; Ara, Nobuyuki; Iijima, Katsunori; Hatta, Waku; Hamada, Shin; Asano, Naoki; Koike, Tomoyuki; Imatani, Akira; Masamune, Atsushi; Shimosegawa, Tooru

    2018-05-01

    Leptin, produced primarily by the adipose tissue, acts as a pro-inflammatory modulator, thereby contributing to the development of obesity-related disease. Although high levels of leptin in the obese are closely related to gastroesophageal reflux disease, the mechanism by which leptin influences esophageal inflammation remains unknown. Macrophage migration inhibitory factor (MIF) is produced by immune cells, such as T lymphocytes and macrophages, and MIF is known to induce the production of tumor necrosis factor α (TNF-α), interleukin 1β (IL-1β) and interleukin 6 (IL-6). We therefore investigated the mechanism whereby leptin aggravates reflux esophagitis, by focusing on esophageal tissue levels of MIF and CD3+ T lymphocytes, both of which are crucial for the reflux-induced epithelial damage. Esophageal inflammation was surgically induced in male Wistar rats by ligating the forestomach and narrowing the duodenum to facilitate gastroesophageal reflux, followed by administration of leptin or vehicle with an osmotic pump system for 1 week. We demonstrated that the administration of leptin exacerbated the reflux esophagitis with the apparent infiltration of CD3+ T lymphocytes and caused the significant increase in the esophageal tissue levels of MIF. Moreover, the leptin caused increases in the esophageal tissue levels of TNF-α, IL-1β and IL-6, downstream targets of MIF. Importantly, the increases in these pro-inflammatory cytokines were accompanied by increased protein levels of phospho-STAT3 and phospho-AKT, pivotal molecules of leptin signaling pathways. In conclusion, through enhancing the MIF-induced inflammatory signaling, leptin could contribute to the development of gastroesophageal reflux disease.

  14. The effect of hypokinesia on lipid metabolism in adipose tissue

    NASA Astrophysics Data System (ADS)

    Macho, Ladislav; Kvetn̆anský, Richard; Ficková, Mária

    The increase of nonesterified fatty acid (NEFA) concentration in plasma was observed in rats subjected to hypokinesia for 1-60 days. In the period of recovery (7 and 21 days after 60 days immobilization) the content of NEFA returned to control values. The increase of fatty acid release from adipose tissue was observed in hypokinetic rats, however the stimulation of lipolysis by norepinephrine was lower in rats exposed to hypokinesis. The decrease of the binding capacity and a diminished number of beta-adrenergic receptors were found in animals after hypokinesia. The augmentation of the incorporation of glucose into lipids and the marked increase in the stimulation of lipogenesis by insulin were found in adipose tissue of rats subjected to long-term hypokinesia. These results showed an important effect of hypokinesia on lipid mobilization, on lipogenesis and on the processes of hormone regulation in adipose tissue.

  15. Effect of the anatomical site on telomere length and pref-1 gene expression in bovine adipose tissues

    DOE Office of Scientific and Technical Information (OSTI.GOV)

    Yamada, Tomoya, E-mail: toyamada@affrc.go.jp; Higuchi, Mikito; Nakanishi, Naoto

    Adipose tissue growth is associated with preadipocyte proliferation and differentiation. Telomere length is a biological marker for cell proliferation. Preadipocyte factor-1 (pref-1) is specifically expressed in preadipocytes and acts as a molecular gatekeeper of adipogenesis. In the present study, we investigated the fat depot-specific differences in telomere length and pref-1 gene expression in various anatomical sites (subcutaneous, intramuscular and visceral) of fattening Wagyu cattle. Visceral adipose tissue expressed higher pref-1 mRNA than did subcutaneous and intramuscular adipose tissues. The telomere length in visceral adipose tissue tended to be longer than that of subcutaneous and intramuscular adipose tissues. The telomere lengthmore » of adipose tissue was not associated with adipocyte size from three anatomical sites. No significant correlation was found between the pref-1 mRNA level and the subcutaneous adipocyte size. In contrast, the pref-1 mRNA level was negatively correlated with the intramuscular and visceral adipocyte size. These results suggest that anatomical sites of adipose tissue affect the telomere length and expression pattern of the pref-1 gene in a fat depot-specific manner. - Highlights: • Visceral adipose tissue express higher pref-1 mRNA than other anatomical sites. • Telomere length in visceral adipose tissue is longer than other anatomical sites. • Telomere length of adipose tissue is not associated with adipocyte size. • Pref-1 mRNA is negatively correlated with intramuscular and visceral adipocyte size.« less

  16. Automated adipose study for assessing cancerous human breast tissue using optical coherence tomography (Conference Presentation)

    NASA Astrophysics Data System (ADS)

    Gan, Yu; Yao, Xinwen; Chang, Ernest W.; Bin Amir, Syed A.; Hibshoosh, Hanina; Feldman, Sheldon; Hendon, Christine P.

    2017-02-01

    Breast cancer is the third leading cause of death in women in the United States. In human breast tissue, adipose cells are infiltrated or replaced by cancer cells during the development of breast tumor. Therefore, an adipose map can be an indicator of identifying cancerous region. We developed an automated classification method to generate adipose map within human breast. To facilitate the automated classification, we first mask the B-scans from OCT volumes by comparing the signal noise ratio with a threshold. Then, the image was divided into multiple blocks with a size of 30 pixels by 30 pixels. In each block, we extracted texture features such as local standard deviation, entropy, homogeneity, and coarseness. The features of each block were input to a probabilistic model, relevance vector machine (RVM), which was trained prior to the experiment, to classify tissue types. For each block within the B-scan, RVM identified the region with adipose tissue. We calculated the adipose ratio as the number of blocks identified as adipose over the total number of blocks within the B-scan. We obtained OCT images from patients (n = 19) in Columbia medical center. We automatically generated the adipose maps from 24 B-scans including normal samples (n = 16) and cancerous samples (n = 8). We found the adipose regions show an isolated pattern that in cancerous tissue while a clustered pattern in normal tissue. Moreover, the adipose ratio (52.30 ± 29.42%) in normal tissue was higher than the that in cancerous tissue (12.41 ± 10.07%).

  17. Cellular and molecular players in adipose tissue inflammation in the development of obesity-induced insulin resistance.

    PubMed

    Lee, Byung-Cheol; Lee, Jongsoon

    2014-03-01

    There is increasing evidence showing that inflammation is an important pathogenic mediator of the development of obesity-induced insulin resistance. It is now generally accepted that tissue-resident immune cells play a major role in the regulation of this obesity-induced inflammation. The roles that adipose tissue (AT)-resident immune cells play have been particularly extensively studied. AT contains most types of immune cells and obesity increases their numbers and activation levels, particularly in AT macrophages (ATMs). Other pro-inflammatory cells found in AT include neutrophils, Th1 CD4 T cells, CD8 T cells, B cells, DCs, and mast cells. However, AT also contains anti-inflammatory cells that counter the pro-inflammatory immune cells that are responsible for the obesity-induced inflammation in this tissue. These anti-inflammatory cells include regulatory CD4 T cells (Tregs), Th2 CD4 T cells, and eosinophils. Hence, AT inflammation is shaped by the regulation of pro- and anti-inflammatory immune cell homeostasis, and obesity skews this balance towards a more pro-inflammatory status. Recent genetic studies revealed several molecules that participate in the development of obesity-induced inflammation and insulin resistance. In this review, the cellular and molecular players that participate in the regulation of obesity-induced inflammation and insulin resistance are discussed, with particular attention being placed on the roles of the cellular players in these pathogeneses. This article is part of a Special Issue entitled: Modulation of Adipose Tissue in Health and Disease. Copyright © 2013 Elsevier B.V. All rights reserved.

  18. Breast Cancer and Estrogen Biosynthesis in Adipose Tissue

    DTIC Science & Technology

    1998-10-01

    transferred to a nitrocellulose mem - brane. The transferred proteins were subjected to a denaturation/rena- turation process and hybridized to the 32P...aromatase expression in adipose tissue has been recently observed to be regulated by mem - bers of the interleukin-6 (IL-6) cytokine family. Based on...shown in human adipose stromal cells that the stimulatory effects of serum on aromatase expression can be mimicked by mem - bers of the interleukin-6

  19. Adiponectin/resistin interplay in serum and in adipose tissue of obese and normal-weight individuals.

    PubMed

    Jonas, Marta Izabela; Kurylowicz, Alina; Bartoszewicz, Zbigniew; Lisik, Wojciech; Jonas, Maurycy; Domienik-Karlowicz, Justyna; Puzianowska-Kuznicka, Monika

    2017-01-01

    The interplay between adiponectin and resistin, the two adipokines of opposite effects, may determine the metabolic profile of obese individuals and development of obesity-related complications. The current study was conducted to assess how adiponectin/resistin interplay in sera and adipose tissues may influence the metabolic profile of obese and normal-weight subjects. Concentrations of adiponectin and resistin were measured on protein level by immunoassay in visceral and subcutaneous adipose tissues from 50 obese (body mass index > 40 kg/m 2 ) and 28 normal-weight (body mass index 20-24.9 kg/m 2 ) individuals. Simultaneously expression of ADIPOQ and RETN (encoding adiponectin and resistin, respectively) was assessed on mRNA level by real-time PCR. ADIPOQ mRNA (P = 0.0001) and adiponectin protein (P = 0.0013) levels were lower, while RETN mRNA (P = 0.0338) and resistin (P < 0.0001)-higher in subcutaneous adipose tissues of obese subjects. ADIPOQ and RETN mRNA levels did not correlate with protein concentrations in the investigated adipose tissues. In obesity adiponectin serum concentrations correlated positively with ADIPOQ mRNA in subcutaneous adipose tissue (P = 0.005) and negatively with protein levels in visceral adipose tissue (P = 0.001). Obesity was associated with higher adiponectin-resistin index value in sera (P < 0.0001) and decreased in subcutaneous adipose tissue (P < 0.001), but only adiponectin-resistin index measured in sera was significantly higher in obese with the metabolic syndrome (P = 0.04). Obesity affects synthesis of adiponectin and resistin mainly in subcutaneous adipose tissue. The adiponectin-resistin index assessed in the adipose tissues has a different prognostic value compared to the adiponectin-resistin index in serum and does not reflect a metabolic risk in obese individuals.

  20. Insulin resistance, hepatic lipid and adipose tissue distribution in HIV-infected men.

    PubMed

    He, Qing; Engelson, Ellen S; Ionescu, Gabriel; Glesby, Marshall J; Albu, Jeanine B; Kotler, Donald P

    2008-01-01

    A large proportion of HIV-infected patients on antiretroviral medication develop insulin resistance, especially in the context of fat redistribution. This study investigates the interrelationships among fat distribution, hepatic lipid content, and insulin resistance in HIV-infected men. We performed a cross-sectional analysis of baseline data from 23 HIV-infected participants in three prospective clinical studies. Magnetic resonance spectroscopy was used to quantify hepatic lipid concentrations. Magnetic resonance imaging was used to quantify whole-body adipose tissue compartments: that is, subcutaneous adipose tissue (SAT) and visceral adipose tissue (VAT) volumes, as well as the intermuscular adipose tissue (IMAT) subcompartment and the omental-mesenteric adipose tissue (OMAT) and retroperitoneal adipose tissue (RPAT) subcompartments of VAT. The homeostasis model for assessment of insulin resistance (HOMA-IR) was calculated from fasting glucose and insulin concentrations. Hepatic lipid content correlated significantly with total VAT (r = 0.62, P = 0.0014), but not with SAT (r = 0.053, P = 0.81). In univariate analysis, hepatic lipid content was associated with the OMAT (r = 0.67, P = 0.0004) and RPAT (r = 0.53, P = 0.009) subcompartments; HOMA-IR correlated with both VAT and hepatic lipid contents (r = 0.61, P = 0.057 and r = 0.68, P = 0.0012, respectively). In stepwise linear regression models, hepatic lipid had the strongest associations with OMAT and with HOMA-IR. Hepatic lipid content is associated with VAT volume, especially the OMAT subcompartment, in HIV-infected men. Hepatic lipid content is associated with insulin resistance in HIV-infected men. Hepatic lipid content might mediate the relationship between VAT and insulin resistance among treated, HIV-infected men.

  1. Insulin resistance, hepatic lipid and adipose tissue distribution in HIV infected men

    PubMed Central

    He, Qing; Engelson, Ellen S.; Ionescu, Gabriel; Glesby, Marshall J.; Albu, Jeanine B.; Kotler, Donald P.

    2010-01-01

    Background A large proportion of HIV-infected subjects on antiretroviral medication develop insulin resistance, especially in the context of fat redistribution. This study investigates the interrelationships among fat distribution, hepatic lipid content, and insulin resistance in HIV-infected men. Design and methods We performed a cross-sectional analysis of baseline data from twenty-three HIV-infected participants in 3 prospective clinical studies. Magnetic resonance spectroscopy was applied to quantify hepatic lipid concentrations. Magnetic resonance imaging was used to quantify whole body adipose tissue compartments, i.e., subcutaneous adipose tissue (SAT) and visceral adipose tissue (VAT) volumes as well as inter-muscular adipose tissue (IMAT) subcompartment, and omental-mesenteric adipose tissue (OMAT) and retroperitoneal adipose tissue (RPAT) subcompartments of VAT. Homeostasis model for assessment of insulin resistance (HOMA-IR) was calculated from fasting glucose and insulin concentrations. Results Hepatic lipid content correlated significantly with total VAT (r=0.62, p=0.0014) but not with SAT (r=0.053, p=0.81). In univariate analysis, hepatic lipid content was associated with the OMAT (r=0.67, p=0.0004) and RPAT (r=0.53, p=0.009) subcompartments; HOMA-IR correlated with both VAT and hepatic lipid contents (r=0.61, p=0.057 and 0.68, p=0.0012, respectively). In stepwise linear regression models, hepatic lipid had the strongest associations with OMAT and with HOMA-IR. Conclusion Hepatic lipid content is associated with VAT volume, especially the omental-mesenteric subcompartment, in HIV-infected men. Hepatic lipid content is associated with insulin resistance in HIV-infected men. Hepatic lipid content might mediate the relationship between VAT and insulin resistance among treated, HIV-infected men. PMID:18572755

  2. Assessing the effect of a high-fat diet on rodents' adipose tissue using Brillouin and Raman spectroscopy

    NASA Astrophysics Data System (ADS)

    Troyanova-Wood, Maria; Gobbell, Cassidy; Meng, Zhaokai; Yakovlev, Vladislav V.

    2016-03-01

    The purpose of this study is to evaluate the effect of a high-lipid diet on elasticity of adipose tissue. We employed dual Raman/Brillouin microspectroscopy to analyze brown and white adipose tissues obtained from adult rats. The rats were divided into two groups, one of which received a high-fat feed, while the other served as a control. We hypothesized that the changes in the elasticity of adipose tissues between the two groups can be successfully assessed using Brillouin spectroscopy. We found that the brown adipose tissue possessed a lesser Brillouin shift than the white adipose within each group and that the elastic modulus of both adipose tissues increases in the high-fat diet group. The Raman spectra provided supplementary chemical information and indicated an increase in the lipid-to-protein ratio in the brown adipose, but not in the white adipose.

  3. Differences in prostate and adipose tissue basic fibroblast growth factor: analysis of preliminary results.

    PubMed

    Mydlo, J H; Kral, J G; Macchia, R J

    1997-09-01

    Basic fibroblast growth factor (bFGF or FGF-2) is mitogenic to human prostate epithelial and stromal cells, and it is reported to be elevated in the serum and urine of patients with various cancers, including prostate cancer. Obesity, with increased body fat, is a risk factor for prostate cancer through unknown mechanisms. Because adipose tissue is a source of FGF-2, we determined the quantity and quality of activity of FGF-2 in omental adipose tissue and compared it with normal and cancerous prostate tissues. Using heparin-Sepharose chromatography, we extracted proteins from human omental adipose tissue, adenocarcinoma of the prostate, and benign prostatic hypertrophic (BPH) tissues. Each of the mitogenic proteins eluted with NaCl concentrations between 1.4 M and 1.8 M, similar to control FGF-2. Using FGF-2 antisera (which inhibited the mitogenic activity of the proteins), we performed Western blot analysis to confirm their homology to FGF-2. We also assessed recovery, mitogenicity, and angiogenicity of each of the proteins using thymidine incorporation into human umbilical vein endothelial cells and the chorioallantoic membrane assay. There was greater recovery of FGF-2 from omental adipose tissue compared with cancerous or BPH homogenates (40 micrograms [2.0 micrograms/g] versus 25 micrograms [1.25 micrograms/g] and 20 micrograms [1.0 microgram/g], respectively). Moreover. FGF-2 from adipose tissue had greater mitogenic activity (96.2% versus 74.8% and 54%; P < 0.05) and a greater angiogenic activity (5.1 vessels versus 2.9 and 1.8 vessels; P < 0.05) on the chorioallantoic assay. We suggest that human omental adipose tissue FGF-2 may demonstrate greater mitogenic and angiogenic activity than either BPH or prostate cancer tissue FGF-2. It is not known whether FGF-2 from adipose tissue qualitatively or quantitatively may underlie the relationship between obesity and prostate cancer.

  4. Adipose Tissue in Metabolic Syndrome: Onset and Progression of Atherosclerosis.

    PubMed

    Luna-Luna, María; Medina-Urrutia, Aida; Vargas-Alarcón, Gilberto; Coss-Rovirosa, Fernanda; Vargas-Barrón, Jesús; Pérez-Méndez, Óscar

    2015-07-01

    Metabolic syndrome (MetS) should be considered a clinical entity when its different symptoms share a common etiology: obesity/insulin resistance as a result of a multi-organ dysfunction. The main interest in treating MetS as a clinical entity is that the addition of its components drastically increases the risk of atherosclerosis. In MetS, the adipose tissue plays a central role along with an unbalanced gut microbiome, which has become relevant in recent years. Once visceral adipose tissue (VAT) increases, dyslipidemia and endothelial dysfunction follow as additive risk factors. However, when the nonalcoholic fatty liver is present, risk of a cardiovascular event is highly augmented. Epicardial adipose tissue (EAT) seems to increase simultaneously with the VAT. In this context, the former may play a more important role in the development of the atherosclerotic plaque than the latter. Hence, EAT may act as a paracrine tissue vis-à-vis the coronary arteries favoring the local inflammation and the atheroma calcification. Copyright © 2015 IMSS. Published by Elsevier Inc. All rights reserved.

  5. Short-term oleoyl-estrone treatment affects capacity to manage lipids in rat adipose tissue

    PubMed Central

    Salas, Anna; Noé, Véronique; Ciudad, Carlos J; Romero, M Mar; Remesar, Xavier; Esteve, Montserrat

    2007-01-01

    Background Short-term OE (oleoyl-estrone) treatment causes significant decreases in rat weight mainly due to adipose tissue loss. The aim of this work was to determine if OE treatment affects the expression of genes that regulate lipid metabolism in white adipose tissue. Results Gene expression in adipose tissue from female treated rats (48 hours) was analysed by hybridization to cDNA arrays and levels of specific mRNAs were determined by real-time PCR. Treatment with OE decreased the expression of 232 genes and up-regulated 75 other genes in mesenteric white adipose tissue. The use of real-time PCR validate that, in mesenteric white adipose tissue, mRNA levels for Lipoprotein Lipase (LPL) were decreased by 52%, those of Fatty Acid Synthase (FAS) by 95%, those of Hormone Sensible Lipase (HSL) by 32%, those of Acetyl CoA Carboxylase (ACC) by 92%, those of Carnitine Palmitoyltransferase 1b (CPT1b) by 45%, and those of Fatty Acid Transport Protein 1 (FATP1) and Adipocyte Fatty Acid Binding Protein (FABP4) by 52% and 49%, respectively. Conversely, Tumour Necrosis Factor (TNFα) values showed overexpression (198%). Conclusion Short-term treatment with OE affects adipose tissue capacity to extract fatty acids from lipoproteins and to deal with fatty acid transport and metabolism. PMID:17725831

  6. Short-term oleoyl-estrone treatment affects capacity to manage lipids in rat adipose tissue.

    PubMed

    Salas, Anna; Noé, Véronique; Ciudad, Carlos J; Romero, M Mar; Remesar, Xavier; Esteve, Montserrat

    2007-08-28

    Short-term OE (oleoyl-estrone) treatment causes significant decreases in rat weight mainly due to adipose tissue loss. The aim of this work was to determine if OE treatment affects the expression of genes that regulate lipid metabolism in white adipose tissue. Gene expression in adipose tissue from female treated rats (48 hours) was analysed by hybridization to cDNA arrays and levels of specific mRNAs were determined by real-time PCR. Treatment with OE decreased the expression of 232 genes and up-regulated 75 other genes in mesenteric white adipose tissue. The use of real-time PCR validate that, in mesenteric white adipose tissue, mRNA levels for Lipoprotein Lipase (LPL) were decreased by 52%, those of Fatty Acid Synthase (FAS) by 95%, those of Hormone Sensible Lipase (HSL) by 32%, those of Acetyl CoA Carboxylase (ACC) by 92%, those of Carnitine Palmitoyltransferase 1b (CPT1b) by 45%, and those of Fatty Acid Transport Protein 1 (FATP1) and Adipocyte Fatty Acid Binding Protein (FABP4) by 52% and 49%, respectively. Conversely, Tumour Necrosis Factor (TNFalpha) values showed overexpression (198%). Short-term treatment with OE affects adipose tissue capacity to extract fatty acids from lipoproteins and to deal with fatty acid transport and metabolism.

  7. White adipose tissue cells and the progression of cachexia: inflammatory pathways

    PubMed Central

    Neves, Rodrigo X.; Rosa‐Neto, José Cesar; Yamashita, Alex S.; Matos‐Neto, Emidio M.; Riccardi, Daniela M. R.; Lira, Fabio S.; Batista, Miguel L.

    2015-01-01

    Abstract Background Cachexia is a systemic syndrome leading to body wasting, systemic inflammation, and to metabolic chaos. It is a progressive condition, and little is known about its dynamics. Detection of the early signs of the disease may lead to the attenuation of the associated symptoms. The white adipose tissue is an organ with endocrine functions, capable of synthesising and secreting a plethora of proteins, including cytokines, chemokines, and adipokines. It is well established that different adipose tissue depots demonstrate heterogeneous responses to physiological and pathological stimuli. The present study aimed at providing insight into adipocyte involvement in inflammation along the progression of cachexia. Methods Eight‐weeks‐old male rats were subcutaneously inoculated with a Walker 256 carcinosarcoma cell suspension (2 × 107 cells in 1.0 mL; tumour‐bearing, T) or Phosphate‐buffered saline (control, C). The retroperitoneal, epididymal, and mesenteric adipose pads were excised on Days 0, 7, and 14 post‐tumour cell injection, and the adipocytes were isolated. Results Mesenteric and epididymal adipocytes showed up‐regulation of IL‐1β protein expression and activation of the inflammasome pathway, contributing for whole tissue inflammation. The stromal vascular fraction of the retroperitoneal adipose tissue, on the other hand, seems to be the major contributor for the inflammation in this specific pad. Conclusion Adipocytes seem to play a relevant role in the establishment of white adipose tissue inflammation, through the activation of the NF‐κB and inflammasome pathways. In epididymal adipocytes, induction of the inflammasome may be detected already on Day 7 post‐tumour cell inoculation. PMID:27493872

  8. Preliminary results comparing the recovery of basic fibroblast growth factor (FGF-2) in adipose tissue and benign and malignant renal tissue.

    PubMed

    Mydlo, J H; Kral, J G; Macchia, R J

    1998-06-01

    Basic fibroblast growth factor (bFGF or FGF-2) is mitogenic to numerous epithelial, mesodermal and endothelial cells, and thus may play a role in the neovascularity and progression of several tumors. Furthermore, FGF-2 is reported to be elevated in the serum and urine of patients with various cancers, including renal cancer. Obesity, with increased body fat, is a risk factor for renal cancer through unknown mechanisms. Since adipose tissue is a source of FGF-2, we determined the quantity and quality of activity of FGF-2 in omental adipose tissue and compared it to normal and cancerous renal tissue. Using heparin-Sepharose chromatography we extracted proteins from human omental adipose tissue, renal cell carcinoma (RCC) and benign renal tissue (BRT). Using FGF-2 antisera we performed western blot analysis to confirm their homology to FGF-2. We also assessed recovery, mitogenicity and angiogenicity of each of the proteins using thymidine incorporation into human umbilical vein endothelial cells (HUVEC) and the chorioallantoic membrane (CAM) assay. Each of the three purified mitogenic proteins eluted with NaCl concentrations between 1.4 M. and 1.8 M., similar to control FGF-2. There was greater recovery of FGF-2 from omental adipose tissue compared with renal cell carcinoma or benign renal tissue (42 microg. vs. 24 microg. and 18 microg., respectively; ANOVA p <0.05). Moreover, FGF-2 from adipose tissue had greater mitogenic activity (96.% versus 68% and 38%; p <0.05) and greater angiogenic activity (5.5 vessels versus 2.7 and 1.6 vessels; p <0.05) on the CAM assay. We suggest that human omental adipose tissue FGF-2 may demonstrate greater mitogenic and angiogenic activity than either benign or cancerous renal tissue FGF-2. It is not known if FGF-2 from adipose tissue may play a role in the relationship between obesity and renal cancer.

  9. Modal response of a computational vocal fold model with a substrate layer of adipose tissue.

    PubMed

    Jones, Cameron L; Achuthan, Ajit; Erath, Byron D

    2015-02-01

    This study demonstrates the effect of a substrate layer of adipose tissue on the modal response of the vocal folds, and hence, on the mechanics of voice production. Modal analysis is performed on the vocal fold structure with a lateral layer of adipose tissue. A finite element model is employed, and the first six mode shapes and modal frequencies are studied. The results show significant changes in modal frequencies and substantial variation in mode shapes depending on the strain rate of the adipose tissue. These findings highlight the importance of considering adipose tissue in computational vocal fold modeling.

  10. Adipose Tissue: Sanctuary for HIV/SIV Persistence and Replication.

    PubMed

    Pallikkuth, Suresh; Mohan, Mahesh

    2015-12-01

    This commentary highlights new findings from a recent study identifying adipose tissue as a potential HIV reservoir and a major site of inflammation during chronic human/simian immunodeficiency virus (HIV/SIV) infection. A concise discussion about upcoming challenges and new research avenues for reducing chronic adipose inflammation during HIV/SIV infection is presented. Copyright © 2015 Elsevier Ltd. All rights reserved.

  11. One in vitro model for visceral adipose-derived fibroblasts in chronic inflammation

    DOE Office of Scientific and Technical Information (OSTI.GOV)

    Yue Guiping; Du Lirui; Xia Tao

    2005-08-05

    One pathogenesis of the obesity-associated complications is that consistent with increased body fat mass, the elevation of adipose tissue-derived cytokines inflicts a low-grade chronic inflammation, which ultimately leads to metabolic disorders. Adipocytes and macrophages in visceral adipose (VA) have been confirmed to contribute to the chronic inflammation; however, the role of the resident fibroblasts is still unknown. We established one VA fibroblast cell line, termed VAFC. Morphological analysis indicated that there were large numbers of pits at the cell plasma membrane. In vitro VAFC cells promoted bone marrow cells to differentiate into macrophages and protected them from apoptosis in themore » serum-free conditions. Additionally, they also interfered in lymphocytes proliferation. On the basis of these results, this cell line might be an in vitro model for understanding the role of adipose-derived fibroblasts in obesity-associated chronic inflammation.« less

  12. Characterization of visceral and subcutaneous adipose tissue transcriptome in pregnant women with and without spontaneous labor at term: implication of alternative splicing in the metabolic adaptations of adipose tissue to parturition.

    PubMed

    Mazaki-Tovi, Shali; Tarca, Adi L; Vaisbuch, Edi; Kusanovic, Juan Pedro; Than, Nandor Gabor; Chaiworapongsa, Tinnakorn; Dong, Zhong; Hassan, Sonia S; Romero, Roberto

    2016-10-01

    The aim of this study was to determine gene expression and splicing changes associated with parturition and regions (visceral vs. subcutaneous) of the adipose tissue of pregnant women. The transcriptome of visceral and abdominal subcutaneous adipose tissue from pregnant women at term with (n=15) and without (n=25) spontaneous labor was profiled with the Affymetrix GeneChip Human Exon 1.0 ST array. Overall gene expression changes and the differential exon usage rate were compared between patient groups (unpaired analyses) and adipose tissue regions (paired analyses). Selected genes were tested by quantitative reverse transcription-polymerase chain reaction. Four hundred and eighty-two genes were differentially expressed between visceral and subcutaneous fat of pregnant women with spontaneous labor at term (q-value <0.1; fold change >1.5). Biological processes enriched in this comparison included tissue and vasculature development as well as inflammatory and metabolic pathways. Differential splicing was found for 42 genes [q-value <0.1; differences in Finding Isoforms using Robust Multichip Analysis scores >2] between adipose tissue regions of women not in labor. Differential exon usage associated with parturition was found for three genes (LIMS1, HSPA5, and GSTK1) in subcutaneous tissues. We show for the first time evidence of implication of mRNA splicing and processing machinery in the subcutaneous adipose tissue of women in labor compared to those without labor.

  13. Characterization of visceral and subcutaneous adipose tissue transcriptome in pregnant women with and without spontaneous labor at term: Implication of alternative splicing in the metabolic adaptations of adipose tissue to parturition

    PubMed Central

    Mazaki-Tovi, Shali; Tarca, Adi L.; Vaisbuch, Edi; Kusanovic, Juan Pedro; Than, Nandor Gabor; Chaiworapongsa, Tinnakorn; Dong, Zhong; Hassan, Sonia S; Romero, Roberto

    2018-01-01

    OBJECTIVE The aim of this study was to determine gene expression and splicing changes associated with parturition and regions (visceral vs subcutaneous) of the adipose tissue of pregnant women. STUDY DESIGN The transcriptome of visceral and abdominal subcutaneous adipose tissue from pregnant women at term with (n=15) and without (n=25) spontaneous labor was profiled with Affymetrix GeneChip Human Exon 1.0 ST array. Overall gene expression changes and differential exon usage rate were compared between patient groups and adipose tissue regions (paired analyses). Selected genes were tested by quantitative reverse transcription–polymerase chain reaction. RESULTS Four hundred eighty-two genes were differentially expressed between visceral and subcutaneous fat of pregnant women with spontaneous labor at term (q-value <0.1; fold change >1.5). Biological processes enriched in this comparison included tissue and vasculature development, inflammatory and metabolic pathways. Differential splicing was found for 42 genes (q-value <0.1; difference FIRMA scores >2) between adipose tissue regions of women not in labor. Differential exon usage associated with parturition was found for three genes (LIMS1, HSPA5 and GSTK1) in subcutaneous tissues. CONCLUSION We show for the first time evidence of implication of mRNA splicing and processing machinery in the subcutaneous adipose tissue of women in labor compared to those without labor. PMID:26994472

  14. Adipose tissue endocannabinoid system gene expression: depot differences and effects of diet and exercise

    PubMed Central

    2011-01-01

    Background Alterations of endocannabinoid system in adipose tissue play an important role in lipid regulation and metabolic dysfunction associated with obesity. The purpose of this study was to determine whether gene expression levels of cannabinoid type 1 receptor (CB1) and fatty acid amide hydrolase (FAAH) are different in subcutaneous abdominal and gluteal adipose tissue, and whether hypocaloric diet and aerobic exercise influence subcutaneous adipose tissue CB1 and FAAH gene expression in obese women. Methods Thirty overweight or obese, middle-aged women (BMI = 34.3 ± 0.8 kg/m2, age = 59 ± 1 years) underwent one of three 20-week weight loss interventions: caloric restriction only (CR, N = 9), caloric restriction plus moderate-intensity aerobic exercise (CRM, 45-50% HRR, N = 13), or caloric restriction plus vigorous-intensity aerobic exercise (CRV, 70-75% HRR, N = 8). Subcutaneous abdominal and gluteal adipose tissue samples were collected before and after the interventions to measure CB1 and FAAH gene expression. Results At baseline, FAAH gene expression was higher in abdominal, compared to gluteal adipose tissue (2.08 ± 0.11 vs. 1.78 ± 0.10, expressed as target gene/β-actin mRNA ratio × 10-3, P < 0.05). Compared to pre-intervention, CR did not change abdominal, but decreased gluteal CB1 (Δ = -0.82 ± 0.25, P < 0.05) and FAAH (Δ = -0.49 ± 0.14, P < 0.05) gene expression. CRM or CRV alone did not change adipose tissue CB1 and FAAH gene expression. However, combined CRM and CRV (CRM+CRV) decreased abdominal adipose tissue FAAH gene expression (Δ = -0.37 ± 0.18, P < 0.05). The changes in gluteal CB1 and abdominal FAAH gene expression levels in the CR alone and the CRM+CRV group were different (P < 0.05) or tended to be different (P = 0.10). Conclusions There are depot differences in subcutaneous adipose tissue endocannabinoid system gene expression in obese individuals. Aerobic exercise training may preferentially modulate abdominal adipose tissue

  15. Fully automated adipose tissue measurement on abdominal CT

    NASA Astrophysics Data System (ADS)

    Yao, Jianhua; Sussman, Daniel L.; Summers, Ronald M.

    2011-03-01

    Obesity has become widespread in America and has been associated as a risk factor for many illnesses. Adipose tissue (AT) content, especially visceral AT (VAT), is an important indicator for risks of many disorders, including heart disease and diabetes. Measuring adipose tissue (AT) with traditional means is often unreliable and inaccurate. CT provides a means to measure AT accurately and consistently. We present a fully automated method to segment and measure abdominal AT in CT. Our method integrates image preprocessing which attempts to correct for image artifacts and inhomogeneities. We use fuzzy cmeans to cluster AT regions and active contour models to separate subcutaneous and visceral AT. We tested our method on 50 abdominal CT scans and evaluated the correlations between several measurements.

  16. Succination of Thiol Groups in Adipose Tissue Proteins in Diabetes

    PubMed Central

    Frizzell, Norma; Rajesh, Mathur; Jepson, Matthew J.; Nagai, Ryoji; Carson, James A.; Thorpe, Suzanne R.; Baynes, John W.

    2009-01-01

    S-(2-Succinyl)cysteine (2SC) is formed by reaction of the Krebs cycle intermediate fumarate with cysteine residues in protein, a process termed succination of protein. Both fumarate and succination of proteins are increased in adipocytes cultured in high glucose medium (Nagai, R., Brock, J. W., Blatnik, M., Baatz, J. E., Bethard, J., Walla, M. D., Thorpe, S. R., Baynes, J. W., and Frizzell, N. (2007) J. Biol. Chem. 282, 34219–34228). We show here that succination of protein is also increased in epididymal, mesenteric, and subcutaneous adipose tissue of diabetic (db/db) mice and that adiponectin is a major target for succination in both adipocytes and adipose tissue. Cys-39, which is involved in cross-linking of adiponectin monomers to form trimers, was identified as a key site of succination of adiponectin in adipocytes. 2SC was detected on two of seven monomeric forms of adiponectin immunoprecipitated from adipocytes and epididymal adipose tissue. Based on densitometry, 2SC-adiponectin accounted for ∼7 and 8% of total intracellular adiponectin in cells and tissue, respectively. 2SC was found only in the intracellular, monomeric forms of adiponectin and was not detectable in polymeric forms of adiponectin in cell culture medium or plasma. We conclude that succination of adiponectin blocks its incorporation into trimeric and higher molecular weight, secreted forms of adiponectin. We propose that succination of proteins is a biomarker of mitochondrial stress and accumulation of Krebs cycle intermediates in adipose tissue in diabetes and that succination of adiponectin may contribute to the decrease in plasma adiponectin in diabetes. PMID:19592500

  17. Maternal high-fat diet modulates brown adipose tissue response to B-adrenergic agonist

    USDA-ARS?s Scientific Manuscript database

    Maternal obesity increases offspring risk for several metabolic diseases. We previously showed that offspring of obese dams are predisposed to obesity, liver and adipose tissue anomalies. However, the effect of maternal obesity on developmental programing brown adipose tissue (BAT) is poorly underst...

  18. Association between subcutaneous white adipose tissue and serum 25-hydroxyvitamin D in overweight and obese adults

    USDA-ARS?s Scientific Manuscript database

    Background: Cholecalciferol is known to be deposited in human adipose tissue, but the distribution of 25-hydroxyvitamin D (25(OH)D) in adipose tissue is not known. Objectives: To determine whether 25(OH)D is detectable in subcutaneous white adipose tissue (SWAT) in overweight and obese persons an...

  19. Implication of low level inflammation in the insulin resistance of adipose tissue at late pregnancy.

    PubMed

    de Castro, J; Sevillano, J; Marciniak, J; Rodriguez, R; González-Martín, C; Viana, M; Eun-suk, O H; de Mouzon, S Hauguel; Herrera, E; Ramos, M P

    2011-11-01

    Insulin resistance is a characteristic of late pregnancy, and adipose tissue is one of the tissues that most actively contributes to the reduced maternal insulin sensitivity. There is evidence that pregnancy is a condition of moderate inflammation, although the physiological role of this low-grade inflammation remains unclear. The present study was designed to validate whether low-grade inflammation plays a role in the development of insulin resistance in adipose tissue during late pregnancy. To this end, we analyzed proinflammatory adipokines and kinases in lumbar adipose tissue of nonpregnant and late pregnant rats at d 18 and 20 of gestation. We found that circulating and tissue levels of adipokines, such as IL-1β, plasminogen activator inhibitor-1, and TNF-α, were increased at late pregnancy, which correlated with insulin resistance. The observed increase in adipokines coincided with an enhanced activation of p38 MAPK in adipose tissue. Treatment of pregnant rats with the p38 MAPK inhibitor SB 202190 increased insulin-stimulated tyrosine phosphorylation of the insulin receptor (IR) and IR substrate-1 in adipose tissue, which was paralleled by a reduction of IR substrate-1 serine phosphorylation and an enhancement of the metabolic actions of insulin. These results indicate that activation of p38 MAPK in adipose tissue contributes to adipose tissue insulin resistance at late pregnancy. Furthermore, the results of the present study support the hypothesis that physiological low-grade inflammation in the maternal organism is relevant to the development of pregnancy-associated insulin resistance.

  20. Implication of Low Level Inflammation in the Insulin Resistance of Adipose Tissue at Late Pregnancy

    PubMed Central

    de Castro, J.; Sevillano, J.; Marciniak, J.; Rodriguez, R.; González-Martín, C.; Viana, M.; Eun-suk, O. H.; de Mouzon, S. Hauguel; Herrera, E.

    2011-01-01

    Insulin resistance is a characteristic of late pregnancy, and adipose tissue is one of the tissues that most actively contributes to the reduced maternal insulin sensitivity. There is evidence that pregnancy is a condition of moderate inflammation, although the physiological role of this low-grade inflammation remains unclear. The present study was designed to validate whether low-grade inflammation plays a role in the development of insulin resistance in adipose tissue during late pregnancy. To this end, we analyzed proinflammatory adipokines and kinases in lumbar adipose tissue of nonpregnant and late pregnant rats at d 18 and 20 of gestation. We found that circulating and tissue levels of adipokines, such as IL-1β, plasminogen activator inhibitor-1, and TNF-α, were increased at late pregnancy, which correlated with insulin resistance. The observed increase in adipokines coincided with an enhanced activation of p38 MAPK in adipose tissue. Treatment of pregnant rats with the p38 MAPK inhibitor SB 202190 increased insulin-stimulated tyrosine phosphorylation of the insulin receptor (IR) and IR substrate-1 in adipose tissue, which was paralleled by a reduction of IR substrate-1 serine phosphorylation and an enhancement of the metabolic actions of insulin. These results indicate that activation of p38 MAPK in adipose tissue contributes to adipose tissue insulin resistance at late pregnancy. Furthermore, the results of the present study support the hypothesis that physiological low-grade inflammation in the maternal organism is relevant to the development of pregnancy-associated insulin resistance. PMID:21914778

  1. Culture and Sampling of Primary Adipose Tissue in Practical Microfluidic Systems.

    PubMed

    Brooks, Jessica C; Judd, Robert L; Easley, Christopher J

    2017-01-01

    Microfluidic culture of primary adipose tissue allows for reduced sample and reagent volumes as well as constant media perfusion of the cells. By continuously flowing media over the tissue, microfluidic sampling systems can more accurately mimic vascular flow in vivo. Quantitative measurements can be performed on or off chip to provide time-resolved secretion data, furthering insight into the dynamics of the function of adipose tissue. Buoyancy resulting from the large lipid storage capacity in this tissue presents a unique challenge for culture, and it is important to account for this buoyancy during microdevice design. Herein, we describe approaches for microfluidic device fabrication that utilize 3D-printed interface templating to help counteract cell buoyancy. We apply such methods to the culture of both isolated, dispersed primary adipocytes and epididymal adipose explants. To facilitate more widespread adoption of the methodology, the devices presented here are designed for user-friendly operation. Only handheld syringes are needed to control flow, and devices are inexpensive and disposable.

  2. Targeting obesity-related adipose tissue dysfunction to prevent cancer development and progression

    PubMed Central

    Gucalp, Ayca; Iyengar, Neil M.; Hudis, Clifford A.; Dannenberg, Andrew J.

    2016-01-01

    The incidence of obesity, a leading modifiable risk factor for common solid tumors, is increasing. Effective interventions are needed to minimize the public health implications of obesity. Although the mechanisms linking increased adiposity to malignancy are incompletely understood, growing evidence points to complex interactions among multiple systemic and tissue-specific pathways including inflamed white adipose tissue. The metabolic and inflammatory consequences of white adipose tissue dysfunction collectively provide a plausible explanation for the link between overweight/obesity and carcinogenesis. Gaining a better understanding of these underlying molecular pathways and developing risk assessment tools that identify at-risk populations will be critical in implementing effective and novel cancer prevention and management strategies. PMID:26970134

  3. Dietary Quercetin Attenuates Adipose Tissue Expansion and Inflammation and Alters Adipocyte Morphology in a Tissue-Specific Manner

    PubMed Central

    Forney, Laura A.; Lenard, Natalie R.; Stewart, Laura K.

    2018-01-01

    Chronic inflammation in adipose tissue may contribute to depot-specific adipose tissue expansion, leading to obesity and insulin resistance. Dietary supplementation with quercetin or botanical extracts containing quercetin attenuates high fat diet (HFD)-induced obesity and insulin resistance and decreases inflammation. Here, we determined the effects of quercetin and red onion extract (ROE) containing quercetin on subcutaneous (inguinal, IWAT) vs. visceral (epididymal, EWAT) white adipose tissue morphology and inflammation in mice fed low fat, high fat, high fat plus 50 μg/day quercetin or high fat plus ROE containing 50 μg/day quercetin equivalents for 9 weeks. Quercetin and ROE similarly ameliorated HFD-induced increases in adipocyte size and decreases in adipocyte number in IWAT and EWAT. Furthermore, quercetin and ROE induced alterations in adipocyte morphology in IWAT. Quercetin and ROE similarly decreased HFD-induced IWAT inflammation. However, quercetin and red onion differentially affected HFD-induced EWAT inflammation, with quercetin decreasing and REO increasing inflammatory marker gene expression. Quercetin and REO also differentially regulated circulating adipokine levels. These results show that quercetin or botanical extracts containing quercetin induce white adipose tissue remodeling which may occur through inflammatory-related mechanisms. PMID:29562620

  4. Invited review: Pre- and postnatal adipose tissue development in farm animals: from stem cells to adipocyte physiology.

    PubMed

    Louveau, I; Perruchot, M-H; Bonnet, M; Gondret, F

    2016-11-01

    Both white and brown adipose tissues are recognized to be differently involved in energy metabolism and are also able to secrete a variety of factors called adipokines that are involved in a wide range of physiological and metabolic functions. Brown adipose tissue is predominant around birth, except in pigs. Irrespective of species, white adipose tissue has a large capacity to expand postnatally and is able to adapt to a variety of factors. The aim of this review is to update the cellular and molecular mechanisms associated with pre- and postnatal adipose tissue development with a special focus on pigs and ruminants. In contrast to other tissues, the embryonic origin of adipose cells remains the subject of debate. Adipose cells arise from the recruitment of specific multipotent stem cells/progenitors named adipose tissue-derived stromal cells. Recent studies have highlighted the existence of a variety of those cells being able to differentiate into white, brown or brown-like/beige adipocytes. After commitment to the adipocyte lineage, progenitors undergo large changes in the expression of many genes involved in cell cycle arrest, lipid accumulation and secretory functions. Early nutrition can affect these processes during fetal and perinatal periods and can also influence or pre-determinate later growth of adipose tissue. How these changes may be related to adipose tissue functional maturity around birth and can influence newborn survival is discussed. Altogether, a better knowledge of fetal and postnatal adipose tissue development is important for various aspects of animal production, including neonatal survival, postnatal growth efficiency and health.

  5. Regional Differences in Adipose Tissue Hormone/Cytokine Production Before and After Weight Loss in Abdominally Obese Women

    PubMed Central

    You, Tongjian; Wang, Xuewen; Murphy, Karin M.; Lyles, Mary F.; Demons, Jamehl L.; Yang, Rongze; Gong, Da-Wei; Nicklas, Barbara J.

    2014-01-01

    Objective To compare the regional differences in subcutaneous adipose tissue hormone/cytokine production in abdominally obese women during weight loss. Design and Methods Forty-two abdominally obese, older women underwent a 20-week weight loss intervention composed of hypocaloric diet with or without aerobic exercise (total energy expenditure: ~2800 kcal/week). Subcutaneous (gluteal and abdominal) adipose tissue biopsies were conducted before and after the intervention. Results Adipose tissue gene expression and release of leptin, adiponectin, and interleukin 6 (IL-6) were determined. The intervention resulted in significant weight loss (−10.1 ±0.7 kg, P<0.001). At baseline, gene expression of adiponectin were higher (P<0.01), and gene expression and release of IL-6 were lower (both P<0.05) in abdominal than in gluteal adipose tissue. After intervention, leptin gene expression and release were lower in both gluteal and abdominal adipose tissue compared to baseline (P<0.05 to P<0.01). Abdominal, but not gluteal, adipose tissue adiponectin gene expression and release increased after intervention (both P<0.05). Conclusion A 20-week weight loss program decreased leptin production in both gluteal and abdominal adipose tissue, but only increased adiponectin production from abdominal adipose tissue in obese women. This depot-specific effect may be of importance for the treatment of health complications associated with abdominal adiposity. PMID:24634403

  6. FABP4 dynamics in obesity: discrepancies in adipose tissue and liver expression regarding circulating plasma levels.

    PubMed

    Queipo-Ortuño, María Isabel; Escoté, Xavier; Ceperuelo-Mallafré, Victoria; Garrido-Sanchez, Lourdes; Miranda, Merce; Clemente-Postigo, Mercedes; Pérez-Pérez, Rafael; Peral, Belen; Cardona, Fernando; Fernández-Real, Jose Manuel; Tinahones, Francisco J; Vendrell, Joan

    2012-01-01

    FABP4 is predominantly expressed in adipose tissue, and its circulating levels are linked with obesity and a poor atherogenic profile. In patients with a wide BMI range, we analyze FABP4 expression in adipose and hepatic tissues in the settings of obesity and insulin resistance. Associations between FABP4 expression in adipose tissue and the FABP4 plasma level as well as the main adipogenic and lipolytic genes expressed in adipose tissue were also analyzed. The expression of several lipogenic, lipolytic, PPAR family and FABP family genes was analyzed by real time PCR. FABP4 protein expression in total adipose tissues and its fractions were determined by western blot. In obesity FABP4 expression was down-regulated (at both mRNA and protein levels), with its levels mainly predicted by ATGL and inversely by the HOMA-IR index. The BMI appeared as the only determinant of the FABP4 variation in both adipose tissue depots. FABP4 plasma levels showed a significant progressive increase according to BMI but no association was detected between FABP4 circulating levels and SAT or VAT FABP4 gene expression. The gene expression of FABP1, FABP4 and FABP5 in hepatic tissue was significantly higher in tissue from the obese IR patients compared to the non-IR group. The inverse pattern in FABP4 expression between adipose and hepatic tissue observed in morbid obese patients, regarding the IR context, suggests that both tissues may act in a balanced manner. These differences may help us to understand the discrepancies between circulating plasma levels and adipose tissue expression in obesity.

  7. FABP4 Dynamics in Obesity: Discrepancies in Adipose Tissue and Liver Expression Regarding Circulating Plasma Levels

    PubMed Central

    Ceperuelo-Mallafré, Victoria; Garrido-Sanchez, Lourdes; Miranda, Merce; Clemente-Postigo, Mercedes; Pérez-Pérez, Rafael; Peral, Belen; Cardona, Fernando; Fernández-Real, Jose Manuel; Tinahones, Francisco J.; Vendrell, Joan

    2012-01-01

    Background FABP4 is predominantly expressed in adipose tissue, and its circulating levels are linked with obesity and a poor atherogenic profile. Objective In patients with a wide BMI range, we analyze FABP4 expression in adipose and hepatic tissues in the settings of obesity and insulin resistance. Associations between FABP4 expression in adipose tissue and the FABP4 plasma level as well as the main adipogenic and lipolytic genes expressed in adipose tissue were also analyzed. Methods The expression of several lipogenic, lipolytic, PPAR family and FABP family genes was analyzed by real time PCR. FABP4 protein expression in total adipose tissues and its fractions were determined by western blot. Results In obesity FABP4 expression was down-regulated (at both mRNA and protein levels), with its levels mainly predicted by ATGL and inversely by the HOMA-IR index. The BMI appeared as the only determinant of the FABP4 variation in both adipose tissue depots. FABP4 plasma levels showed a significant progressive increase according to BMI but no association was detected between FABP4 circulating levels and SAT or VAT FABP4 gene expression. The gene expression of FABP1, FABP4 and FABP5 in hepatic tissue was significantly higher in tissue from the obese IR patients compared to the non-IR group. Conclusion The inverse pattern in FABP4 expression between adipose and hepatic tissue observed in morbid obese patients, regarding the IR context, suggests that both tissues may act in a balanced manner. These differences may help us to understand the discrepancies between circulating plasma levels and adipose tissue expression in obesity. PMID:23139800

  8. Plasma and white adipose tissue lipid composition in marmots.

    PubMed

    Florant, G L; Nuttle, L C; Mullinex, D E; Rintoul, D A

    1990-05-01

    White adipose tissue biopsies and plasma samples were obtained from hibernating yellow-bellied marmots (Marmota flaviventris) maintained in the laboratory. In addition, biopsies and plasma samples were obtained from normothermic animals in the field and laboratory. Measurement of plasma free fatty acid (FA) levels indicated that winter laboratory animals exhibited increased lipolysis. Additionally, analysis of white adipose tissue triacylglycerol revealed that the FA composition of the storage fat in animals maintained on the standard laboratory diet is remarkably simple and uniform between different adipose depots in the same animal. Three FAs (palmitic, oleic, and linoleic acids) made up greater than 95% of the total. Triene (alpha-linolenate) was found in newly captured animals, but the percentage of this FA decreased rapidly when the animals were maintained on the standard laboratory diet. Throughout the hibernation season (October to April), white adipose tissue-saturated FA percentage decreased, monoene percentage remained constant, and diene percentage increased. Analysis of plasma FA composition suggested that these animals tended to metabolize saturated FAs from stored lipid during hibernation and that dienes were mobilized briefly after the last arousal from hibernation in spring. From these observations, we hypothesize that marmots preferentially metabolize saturated fats during the hibernation period and that essential FAs of the omega 6 series tend to be metabolized more slowly than other FAs. These characteristics suggest that marmots are a valuable animal model in which to study lipid metabolism.

  9. Oxidative stress accumulates in adipose tissue during aging and inhibits adipogenesis.

    PubMed

    Findeisen, Hannes M; Pearson, Kevin J; Gizard, Florence; Zhao, Yue; Qing, Hua; Jones, Karrie L; Cohn, Dianne; Heywood, Elizabeth B; de Cabo, Rafael; Bruemmer, Dennis

    2011-04-14

    Aging constitutes a major independent risk factor for the development of type 2 diabetes and is accompanied by insulin resistance and adipose tissue dysfunction. One of the most important factors implicitly linked to aging and age-related chronic diseases is the accumulation of oxidative stress. However, the effect of increased oxidative stress on adipose tissue biology remains elusive. In this study, we demonstrate that aging in mice results in a loss of fat mass and the accumulation of oxidative stress in adipose tissue. In vitro, increased oxidative stress through glutathione depletion inhibits preadipocyte differentiation. This inhibition of adipogenesis is at least in part the result of reduced cell proliferation and an inhibition of G(1)→S-phase transition during the initial mitotic clonal expansion of the adipocyte differentiation process. While phosphorylation of the retinoblastoma protein (Rb) by cyclin/cdk complexes remains unaffected, oxidative stress decreases the expression of S-phase genes downstream of Rb. This silencing of S phase gene expression by increased oxidative stress is mediated through a transcriptional mechanism involving the inhibition of E2F recruitment and transactivation of its target promoters. Collectively, these data demonstrate a previously unrecognized role of oxidative stress in the regulation of adipogenesis which may contribute to age-associated adipose tissue dysfunction.

  10. Oxidative Stress Accumulates in Adipose Tissue during Aging and Inhibits Adipogenesis

    PubMed Central

    Findeisen, Hannes M.; Pearson, Kevin J.; Gizard, Florence; Zhao, Yue; Qing, Hua; Jones, Karrie L.; Cohn, Dianne; Heywood, Elizabeth B.; de Cabo, Rafael; Bruemmer, Dennis

    2011-01-01

    Aging constitutes a major independent risk factor for the development of type 2 diabetes and is accompanied by insulin resistance and adipose tissue dysfunction. One of the most important factors implicitly linked to aging and age-related chronic diseases is the accumulation of oxidative stress. However, the effect of increased oxidative stress on adipose tissue biology remains elusive. In this study, we demonstrate that aging in mice results in a loss of fat mass and the accumulation of oxidative stress in adipose tissue. In vitro, increased oxidative stress through glutathione depletion inhibits preadipocyte differentiation. This inhibition of adipogenesis is at least in part the result of reduced cell proliferation and an inhibition of G1→S-phase transition during the initial mitotic clonal expansion of the adipocyte differentiation process. While phosphorylation of the retinoblastoma protein (Rb) by cyclin/cdk complexes remains unaffected, oxidative stress decreases the expression of S-phase genes downstream of Rb. This silencing of S phase gene expression by increased oxidative stress is mediated through a transcriptional mechanism involving the inhibition of E2F recruitment and transactivation of its target promoters. Collectively, these data demonstrate a previously unrecognized role of oxidative stress in the regulation of adipogenesis which may contribute to age-associated adipose tissue dysfunction. PMID:21533223

  11. Ontogenesis of muscle and adipose tissues and their interactions in ruminants and other species.

    PubMed

    Bonnet, M; Cassar-Malek, I; Chilliard, Y; Picard, B

    2010-07-01

    The lean-to-fat ratio, that is, the relative masses of muscle and adipose tissue, is a criterion for the yield and quality of bovine carcasses and meat. This review describes the interactions between muscle and adipose tissue (AT) that may regulate the dynamic balance between the number and size of muscle v. adipose cells. Muscle and adipose tissue in cattle grow by an increase in the number of cells (hyperplasia), mainly during foetal life. The total number of muscle fibres is set by the end of the second trimester of gestation. By contrast, the number of adipocytes is never set. Number of adipocytes increases mainly before birth until 1 year of age, depending on the anatomical location of the adipose tissue. Hyperplasia concerns brown pre-adipocytes during foetal life and white pre-adipocytes from a few weeks after birth. A decrease in the number of secondary myofibres and an increase in adiposity in lambs born from mothers severely underfed during early pregnancy suggest a balance in the commitment of a common progenitor into the myogenic or adipogenic lineages, or a reciprocal regulation of the commitment of two distinct progenitors. The developmental origin of white adipocytes is a subject of debate. Molecular and histological data suggested a possible transdifferentiation of brown into white adipocytes, but this hypothesis has now been challenged by the characterization of distinct precursor cells for brown and white adipocytes in mice. Increased nutrient storage in fully differentiated muscle fibres and adipocytes, resulting in cell enlargement (hypertrophy), is thought to be the main mechanism, whereby muscle and fat masses increase in growing cattle. Competition or prioritization between adipose and muscle cells for the uptake and metabolism of nutrients is suggested, besides the successive waves of growth of muscle v. adipose tissue, by the inhibited or delayed adipose tissue growth in bovine genotypes exhibiting strong muscular development. This

  12. The FGF21-CCL11 Axis Mediates Beiging of White Adipose Tissues by Coupling Sympathetic Nervous System to Type 2 Immunity.

    PubMed

    Huang, Zhe; Zhong, Ling; Lee, Jimmy Tsz Hang; Zhang, Jialiang; Wu, Donghai; Geng, Leiluo; Wang, Yu; Wong, Chi-Ming; Xu, Aimin

    2017-09-05

    Type 2 cytokines are important signals triggering biogenesis of thermogenic beige adipocytes in white adipose tissue (WAT) during cold acclimation. However, how cold activates type 2 immunity in WAT remains obscure. Here we show that cold-induced type 2 immune responses and beiging in subcutaneous WAT (scWAT) are abrogated in mice with adipose-selective ablation of FGF21 or its co-receptor β-Klotho, whereas such impairments are reversed by replenishment with chemokine CCL11. Mechanistically, FGF21 acts on adipocytes in an autocrine manner to promote the expression and secretion of CCL11 via activation of ERK1/2, which drives recruitment of eosinophils into scWAT, leading to increases in accumulation of M2 macrophages, and proliferation and commitment of adipocyte precursors into beige adipocytes. These FGF21-elicited type 2 immune responses and beiging are blocked by CCL11 neutralization. Thus, the adipose-derived FGF21-CCL11 axis triggers cold-induced beiging and thermogenesis by coupling sympathetic nervous system to activation of type 2 immunity in scWAT. Copyright © 2017 Elsevier Inc. All rights reserved.

  13. A role of low dose chemical mixtures in adipose tissue in carcinogenesis.

    PubMed

    Lee, Duk-Hee; Jacobs, David R; Park, Ho Yong; Carpenter, David O

    2017-11-01

    The Halifax project recently hypothesized a composite carcinogenic potential of the mixture of low dose chemicals which are commonly encountered environmentally, yet which are not classified as human carcinogens. A long neglected but important fact is that adipose tissue is an important exposure source for chemical mixtures. In fact, findings from human studies based on several persistent organic pollutants in general populations with only background exposure should be interpreted from the viewpoint of chemical mixtures because serum concentrations of these chemicals can be seen as surrogates for chemical mixtures in adipose tissue. Furthermore, in conditions such as obesity with dysfunctional adipocytes or weight loss in which lipolysis is increased, the amount of the chemical mixture released from adipose tissue to circulation is increased. Thus, both obesity and weight loss can enhance the chance of chemical mixtures reaching critical organs, however paradoxical this idea may be when fat mass is the only factor considered. The complicated, interrelated dynamics of adipocytes and chemical mixtures can explain puzzling findings related to body weight among cancer patients, including the obesity paradox. The contamination of fat in human diet with chemical mixtures, occurring for reasons similar to contamination of human adipose tissue, may be a missing factor which affects the association between dietary fat intake and cancer. The presence of chemical mixtures in adipose tissue should be considered in future cancer research, including clinical trials on weight management among cancer survivors. Copyright © 2017 Elsevier Ltd. All rights reserved.

  14. Minimally invasive collection of adipose tissue facilitates the study of eco-physiology in small-bodied mammals

    Treesearch

    Jeff Clerc; Theodore J. Weller; Jeffrey B. Schineller; Joseph M. Szewczak; Diana Fisher

    2016-01-01

    Adipose tissue is the primary fuel storage for vertebrates and is an important component of energy budgets during periods of peak energetic demands. Investigating the composition of adipose tissue can provide information about energetics, migration, reproduction, and other life-history traits. Until now, most field methods for sampling the adipose tissue of...

  15. Regulation of metabolic health and adipose tissue function by group 2 innate lymphoid cells.

    PubMed

    Cautivo, Kelly M; Molofsky, Ari B

    2016-06-01

    Adipose tissue (AT) is home to an abundance of immune cells. With chronic obesity, inflammatory immune cells accumulate and promote insulin resistance and the progression to type 2 diabetes mellitus. In contrast, recent studies have highlighted the regulation and function of immune cells in lean, healthy AT, including those associated with type 2 or "allergic" immunity. Although traditionally activated by infection with multicellular helminthes, AT type 2 immunity is active independently of infection, and promotes tissue homeostasis, AT "browning," and systemic insulin sensitivity, protecting against obesity-induced metabolic dysfunction and type 2 diabetes mellitus. In particular, group 2 innate lymphoid cells (ILC2s) are integral regulators of AT type 2 immunity, producing the cytokines interleukin-5 and IL-13, promoting eosinophils and alternatively activated macrophages, and cooperating with and promoting AT regulatory T (Treg) cells. In this review, we focus on the recent developments in our understanding of group 2 innate lymphoid cell cells and type 2 immunity in AT metabolism and homeostasis. © 2016 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

  16. [Construction of injectable tissue engineered adipose tissue with fibrin glue scaffold and human adipose-derived stem cells transfected by lentivirus vector expressing hepatocyte growth factor].

    PubMed

    Zhu, Yuanzheng; Yi, Yangyan; Yang, Shuifa; Zhang, Jing; Wu, Shu; Wang, Zhaohui

    2017-09-01

    To discuss the possibility of constructing injectable tissue engineered adipose tissue, and to provide a new approach for repairing soft tissue defects. Human adipose-derived stem cells (hADSCs) were extracted from the lipid part of human liposuction aspirate by enzymatic digestion and identified by morphological observation, flow cytometry, and adipogenic induction. The hADSCs underwent transfection by lentivirus vector expressing hepatocyte growth factor and green fluorescent protein (HGF-GFP-LVs) of different multiplicity of infection (MOI, 10, 30, 50, and 100), the transfection efficiency was calculated to determine the optimum MOI. The hADSCs transfected by HGF-GFP-LVs of optimal MOI and being adipogenic inducted were combined with injectable fibrin glue scaffold, and were injected subcutaneously into the right side of the low back of 10 T-cell deficiency BALB/c female nude mice (transfected group); non-HGF-GFP-LVs transfected hADSCs (being adipogenic inducted) combined with injectable fibrin glue scaffold were injected subcutaneously into the left side of the low back (untransfected group); and injectable fibrin glue scaffold were injected subcutaneously into the middle part of the neck (blank control group); 0.4 mL at each point. Twelve weeks later the mice were killed and the implants were taken out. Gross observation, wet weight measurement, HE staining, GFP fluorescence labeling, and immunofluorescence staining were performed to assess the in vivo adipogenic ability of the seed cells and the neovascularization of the grafts. The cultured cells were identified as hADSCs. Poor transfection efficiency was observed in MOI of 10 and 30, the transfection efficiency of MOI of 50 and 100 was more than 80%, so the optimum MOI was 50. Adipose tissue-like new-born tissues were found in the injection sites of the transfected and untransfected groups after 12 weeks of injection, and no new-born tissues was found in the blank control group. The wet-weight of new

  17. Dynamic, M2-like remodeling phenotypes of CD11c+ adipose tissue macrophages during high-fat diet--induced obesity in mice.

    PubMed

    Shaul, Merav E; Bennett, Grace; Strissel, Katherine J; Greenberg, Andrew S; Obin, Martin S

    2010-05-01

    To identify, localize, and determine M1/M2 polarization of epidydimal adipose tissue (eAT) macrophages (Phis) during high-fat diet (HFD)-induced obesity. Male C57BL/6 mice were fed an HFD (60% fat kcal) or low-fat diet (LFD) (10% fat kcal) for 8 or 12 weeks. eATMPhis (F4/80(+) cells) were characterized by in vivo fluorescent labeling, immunohistochemistry, fluorescence-activated cell sorting, and quantitative PCR. Recruited interstitial macrophage galactose-type C-type lectin (MGL)1(+)/CD11c(-) and crown-like structure-associated MGL1(-)/CD11c(+) and MGL1(med)/CD11c(+) eATMPhis were identified after 8 weeks of HFD. MGL1(med)/CD11c(+) cells comprised approximately 65% of CD11c(+) eATMPhis. CD11c(+) eATMPhis expressed a mixed M1/M2 profile, with some M1 transcripts upregulated (IL-12p40 and IL-1beta), others downregulated (iNOS, caspase-1, MCP-1, and CD86), and multiple M2 and matrix remodeling transcripts upregulated (arginase-1, IL-1Ra, MMP-12, ADAM8, VEGF, and Clec-7a). At HFD week 12, each eATMPhi subtype displayed an enhanced M2 phenotype as compared with HFD week 8. CD11c(+) subtypes downregulated IL-1beta and genes mediating antigen presentation (I-a, CD80) and upregulated the M2 hallmark Ym-1 and genes promoting oxidative metabolism (PGC-1alpha) and adipogenesis (MMP-2). MGL1(med)/CD11c(+) eATMPhis upregulated additional M2 genes (IL-13, SPHK1, CD163, LYVE-1, and PPAR-alpha). MGL1(med)/CD11c(+) ATMPhis expressing elevated PGC-1alpha, PPAR-alpha, and Ym-1 transcripts were selectively enriched in eAT of obese mice fed pioglitazone for 6 days, confirming the M2 features of the MGL1(med)/CD11c(+) eATMPhi transcriptional profile and implicating PPAR activation in its elicitation. These results 1) redefine the phenotypic potential of CD11c(+) eATMPhis and 2) suggest previously unappreciated phenotypic and functional commonality between murine and human ATMPhis in the development of obesity and its complications.

  18. Parallels in Immunometabolic Adipose Tissue Dysfunction with Ageing and Obesity

    PubMed Central

    Trim, William; Turner, James E.; Thompson, Dylan

    2018-01-01

    Ageing, like obesity, is often associated with alterations in metabolic and inflammatory processes resulting in morbidity from diseases characterised by poor metabolic control, insulin insensitivity, and inflammation. Ageing populations also exhibit a decline in immune competence referred to as immunosenescence, which contributes to, or might be driven by chronic, low-grade inflammation termed “inflammageing”. In recent years, animal and human studies have started to uncover a role for immune cells within the stromal fraction of adipose tissue in driving the health complications that come with obesity, but relatively little work has been conducted in the context of immunometabolic adipose function in ageing. It is now clear that aberrant immune function within adipose tissue in obesity—including an accumulation of pro-inflammatory immune cell populations—plays a major role in the development of systemic chronic, low-grade inflammation, and limiting the function of adipocytes leading to an impaired fat handling capacity. As a consequence, these changes increase the chance of multiorgan dysfunction and disease onset. Considering the important role of the immune system in obesity-associated metabolic and inflammatory diseases, it is critically important to further understand the interplay between immunological processes and adipose tissue function, establishing whether this interaction contributes to age-associated immunometabolic dysfunction and inflammation. Therefore, the aim of this article is to summarise how the interaction between adipose tissue and the immune system changes with ageing, likely contributing to the age-associated increase in inflammatory activity and loss of metabolic control. To understand the potential mechanisms involved, parallels will be drawn to the current knowledge derived from investigations in obesity. We also highlight gaps in research and propose potential future directions based on the current evidence. PMID:29479350

  19. Trypanosoma brucei parasites occupy and functionally adapt to the adipose tissue in mice

    DOE Office of Scientific and Technical Information (OSTI.GOV)

    Trindade, Sandra; Rijo-Ferreira, Filipa; Carvalho, Tania

    Trypanosoma brucei is an extracellular parasite that causes sleeping sickness. In mammalian hosts, trypanosomes are thought to exist in two major niches: early in infection, they populate the blood; later, they breach the blood-brain barrier. Working with a well-established mouse model, we discovered that adipose tissue constitutes a third major reservoir for T. brucei. Parasites from adipose tissue, here termed adipose tissue forms (ATFs), can replicate and were capable of infecting a naive animal. ATFs were transcriptionally distinct from bloodstream forms, and the genes upregulated included putative fatty acid β-oxidation enzymes. Consistent with this, ATFs were able to utilize exogenousmore » myristate and form β-oxidation intermediates, suggesting that ATF parasites can use fatty acids as an external carbon source. Lastly, these findings identify the adipose tissue as a niche for T. brucei during its mammalian life cycle and could potentially explain the weight loss associated with sleeping sickness.« less

  20. Trypanosoma brucei parasites occupy and functionally adapt to the adipose tissue in mice

    DOE PAGES

    Trindade, Sandra; Rijo-Ferreira, Filipa; Carvalho, Tania; ...

    2016-05-26

    Trypanosoma brucei is an extracellular parasite that causes sleeping sickness. In mammalian hosts, trypanosomes are thought to exist in two major niches: early in infection, they populate the blood; later, they breach the blood-brain barrier. Working with a well-established mouse model, we discovered that adipose tissue constitutes a third major reservoir for T. brucei. Parasites from adipose tissue, here termed adipose tissue forms (ATFs), can replicate and were capable of infecting a naive animal. ATFs were transcriptionally distinct from bloodstream forms, and the genes upregulated included putative fatty acid β-oxidation enzymes. Consistent with this, ATFs were able to utilize exogenousmore » myristate and form β-oxidation intermediates, suggesting that ATF parasites can use fatty acids as an external carbon source. Lastly, these findings identify the adipose tissue as a niche for T. brucei during its mammalian life cycle and could potentially explain the weight loss associated with sleeping sickness.« less

  1. ABCD2 identifies a subclass of peroxisomes in mouse adipose tissue

    DOE Office of Scientific and Technical Information (OSTI.GOV)

    Liu, Xiaoxi, E-mail: xiaoxi.liu@uky.edu; Liu, Jingjing, E-mail: jingjing.liu0@gmail.com; Lester, Joshua D., E-mail: joshua.lester@uky.edu

    2015-01-02

    Highlights: • We examined the D2 localization and the proteome of D2-containing compartment in mouse adipose tissue. • We confirmed the presence of D2 on a subcellular compartment that has typical structure as a microperoxisome. • We demonstrated the scarcity of peroxisome markers on D2-containing compartment. • The D2-containing compartment may be a subpopulation of peroxisome in mouse adipose tissue. • Proteomic data suggests potential association between D2-containing compartment and mitochondria and ER. - Abstract: ATP-binding cassette transporter D2 (D2) is an ABC half transporter that is thought to promote the transport of very long-chain fatty acyl-CoAs into peroxisomes. Bothmore » D2 and peroxisomes increase during adipogenesis. Although peroxisomes are essential to both catabolic and anabolic lipid metabolism, their function, and that of D2, in adipose tissues remain largely unknown. Here, we investigated the D2 localization and the proteome of D2-containing organelles, in adipose tissue. Centrifugation of mouse adipose homogenates generated a fraction enriched with D2, but deficient in peroxisome markers including catalase, PEX19, and ABCD3 (D3). Electron microscopic imaging of this fraction confirmed the presence of D2 protein on an organelle with a dense matrix and a diameter of ∼200 nm, the typical structure and size of a microperoxisome. D2 and PEX19 antibodies recognized distinct structures in mouse adipose. Immunoisolation of the D2-containing compartment confirmed the scarcity of PEX19 and proteomic profiling revealed the presence of proteins associated with peroxisome, endoplasmic reticulum (ER), and mitochondria. D2 is localized to a distinct class of peroxisomes that lack many peroxisome proteins, and may associate physically with mitochondria and the ER.« less

  2. Lipocalin 2, a Regulator of Retinoid Homeostasis and Retinoid-mediated Thermogenic Activation in Adipose Tissue*

    PubMed Central

    Guo, Hong; Foncea, Rocio; O'Byrne, Sheila M.; Jiang, Hongfeng; Zhang, Yuanyuan; Deis, Jessica A.; Blaner, William S.; Bernlohr, David A.; Chen, Xiaoli

    2016-01-01

    We have recently characterized the role of lipocalin 2 (Lcn2) as a new adipose-derived cytokine in the regulation of adaptive thermogenesis via a non-adrenergic pathway. Herein, we explored a potential non-adrenergic mechanism by which Lcn2 regulates thermogenesis and lipid metabolism. We found that Lcn2 is a retinoic acid target gene, and retinoic acid concurrently stimulated UCP1 and Lcn2 expression in adipocytes. Lcn2 KO mice exhibited a blunted effect of all-trans-retinoic acid (ATRA) on body weight and fat mass, lipid metabolism, and retinoic acid signaling pathway activation in adipose tissue under the high fat diet-induced obese condition. We further demonstrated that Lcn2 is required for the full action of ATRA on the induction of UCP1 and PGC-1α expression in brown adipocytes and the restoration of cold intolerance in Lcn2 KO mice. Interestingly, we discovered that Lcn2 KO mice have decreased levels of retinoic acid and retinol in adipose tissue. The protein levels of STRA6 responsible for retinol uptake were significantly decreased in adipose tissue. The retinol transporter RBP4 was increased in adipose tissue but decreased in the circulation, suggesting the impairment of RBP4 secretion in Lcn2 KO adipose tissue. Moreover, Lcn2 deficiency abolished the ATRA effect on RBP4 expression in adipocytes. All the data suggest that the decreased retinoid level and action are associated with impaired retinol transport and storage in adipose tissue in Lcn2 KO mice. We conclude that Lcn2 plays a critical role in regulating metabolic homeostasis of retinoids and retinoid-mediated thermogenesis in adipose tissue. PMID:27008859

  3. FABP4 attenuates PPARγ and adipogenesis and is inversely correlated with PPARγ in adipose tissues.

    PubMed

    Garin-Shkolnik, Tali; Rudich, Assaf; Hotamisligil, Gökhan S; Rubinstein, Menachem

    2014-03-01

    Fatty acid binding protein 4 (FABP4, also known as aP2) is a cytoplasmic fatty acid chaperone expressed primarily in adipocytes and myeloid cells and implicated in the development of insulin resistance and atherosclerosis. Here we demonstrate that FABP4 triggers the ubiquitination and subsequent proteasomal degradation of peroxisome proliferator-activated receptor γ (PPARγ), a master regulator of adipogenesis and insulin responsiveness. Importantly, FABP4-null mouse preadipocytes as well as macrophages exhibited increased expression of PPARγ, and complementation of FABP4 in the macrophages reversed the increase in FABP4 expression. The FABP4-null preadipocytes exhibited a remarkably enhanced adipogenesis compared with wild-type cells, indicating that FABP4 regulates adipogenesis by downregulating PPARγ. We found that the FABP4 level was higher and PPARγ level was lower in human visceral fat and mouse epididymal fat compared with their subcutaneous fat. Furthermore, FABP4 was higher in the adipose tissues of obese diabetic individuals compared with healthy ones. Suppression of PPARγ by FABP4 in visceral fat may explain the reported role of FABP4 in the development of obesity-related morbidities, including insulin resistance, diabetes, and atherosclerosis.

  4. Rutin suppresses palmitic acids-triggered inflammation in macrophages and blocks high fat diet-induced obesity and fatty liver in mice.

    PubMed

    Gao, Mingming; Ma, Yongjie; Liu, Dexi

    2013-11-01

    To elucidate the mechanism of rutin in blocking macrophage-mediated inflammation and high fat diet-induced obesity and fatty liver. Both in vitro and in vivo approaches were taken in evaluating the effects of rutin on palmitic acids-triggered inflammation in cultured macrophages, and on weight gain and development of fatty liver of mice fed a high fat diet. Palmitic acids increase mRNA levels of pro-inflammatory cytokines, and elevate the production of TNFα in cultured macrophages. Pre-exposure of rutin to cells greatly suppressed these elevations. The suppressed inflammation by rutin was correlated with a decrease in transcription of genes responsible for ER stress and production of reactive oxygen species. In vivo, rutin protects mice from high fat diet-induced obesity, fatty liver and insulin resistance. The protective effects were associated with lack of hypertrophy and crown-like structures in the white adipose tissue, decreased mRNA levels of marker genes for macrophages including F4/80, Cd11c and Cd68, and repressed transcription of genes involved in chronic inflammation such as Mcp1 and Tnfα in white adipose tissue. In addition, rutin increases the expression of genes responsible for energy expenditure in brown adipose tissue including Pgc1α and Dio2. Furthermore, rutin suppresses transcription of Srebp1c and Cd36 in the liver, leading to a blockade of fatty liver development. These results suggest that supplementation of rutin is a promising strategy for blocking macrophage-mediated inflammation and inflammation-induced obesity and its associated complications.

  5. Brazilian propolis ethanol extract and its component kaempferol induce myeloid-derived suppressor cells from macrophages of mice in vivo and in vitro.

    PubMed

    Kitamura, Hiroshi; Saito, Natsuko; Fujimoto, Junpei; Nakashima, Ken-Ichi; Fujikura, Daisuke

    2018-05-02

    Brazilian green propolis is produced by mixing secretions from Africanized honey bees with exudate, mainly from Baccharis dracunculifolia. Brazilian propolis is especially rich in flavonoids and cinammic acid derivatives, and it has been widely used in folk medicine owing to its anti-inflammatory, anti-viral, tumoricidal, and analgesic effects. Moreover, it is applied to prevent metabolic disorders, such as type 2 diabetes and arteriosclerosis. Previously, we demonstrated that propolis ethanol extract ameliorated type 2 diabetes in a mouse model through the resolution of adipose tissue inflammation. The aims of this study were to identify the immunosuppressive cells directly elicited by propolis extract and to evaluate the flavonoids that induce such cells. Ethanol extract of Brazilian propolis (PEE; 100 mg/kg i.p., twice a week) was injected into lean or high fat-fed obese C57BL/6 mice or C57BL/6 ob/ob mice for one month. Subsequently, immune cells in visceral adipose tissue and the peritoneal cavity were monitored using FACS analysis. Isolated macrophages and the macrophage-like cell line J774.1 were treated with PEE and its constituent components, and the expression of immune suppressive myeloid markers were evaluated. Finally, we injected one of the identified compounds, kaempferol, into C57BL/6 mice and performed FACS analysis on the adipose tissue. Intraperitoneal treatment of PEE induces CD11b + , Gr-1 + myeloid-derived suppressor cells (MDSCs) in visceral adipose tissue and the peritoneal cavity of lean and obese mice. PEE directly stimulates cultured M1 macrophages to transdifferentiate into MDSCs. Among twelve compounds isolated from PEE, kaempferol has an exclusive effect on MDSCs induction in vitro. Accordingly, intraperitoneal injection of kaempferol causes accumulation of MDSCs in the visceral adipose tissue of mice. Brazilian PEE and its compound kaempferol strongly induce MDSCs in visceral adipose tissue at a relatively early phase of inflammation

  6. Bone Marrow Adipose Tissue and Skeletal Health.

    PubMed

    Muruganandan, Shanmugam; Govindarajan, Rajgopal; Sinal, Christopher J

    2018-05-31

    To summarize and discuss recent progress and novel signaling mechanisms relevant to bone marrow adipocyte formation and its physiological/pathophysiological implications for bone remodeling. Skeletal remodeling is a coordinated process entailing removal of old bone and formation of new bone. Several bone loss disorders such as osteoporosis are commonly associated with increased bone marrow adipose tissue. Experimental and clinical evidence supports that a reduction in osteoblastogenesis from mesenchymal stem cells at the expense of adipogenesis, as well as the deleterious effects of adipocyte-derived signaling, contributes to the etiology of osteoporosis as well as bone loss associated with aging, diabetes mellitus, post-menopause, and chronic drug therapy. However, this view is challenged by findings indicating that, in some contexts, bone marrow adipose tissue may have a beneficial impact on skeletal health. Further research is needed to better define the role of marrow adipocytes in bone physiology/pathophysiology and to determine the therapeutic potential of manipulating mesenchymal stem cell differentiation.

  7. Diet and adipose tissue distributions: The Multi-Ethnic Study of Atherosclerosis

    USDA-ARS?s Scientific Manuscript database

    Dietary quality affects cardiometabolic risk, yet its pathways of influence on regional adipose tissue depots involved in metabolic and diabetes risk are not well established. We aimed to investigate the relationship between dietary quality and regional adiposity. We investigated 5079 individuals in...

  8. Obesity Disrupts Rhythmic Clock Gene Expression in Maternal Adipose Tissue during Rat Pregnancy.

    PubMed

    Crew, Rachael C; Mark, Peter J; Waddell, Brendan J

    2018-06-01

    Obesity during pregnancy causes numerous maternal and fetal health complications, but the underlying mechanisms remain unclear. Adipose tissue dysfunction in obesity has previously been linked to disruption of the intrinsic adipose clock gene network that is crucial for normal metabolic function. This adipose clock also undergoes major change as part of the maternal metabolic adaptation to pregnancy, but whether this is affected by maternal obesity is unknown. Consequently, in this study we tested the hypothesis that obesity disturbs rhythmic gene expression in maternal adipose tissue across pregnancy. A rat model of maternal obesity was established by cafeteria (CAF) feeding, and adipose expression of clock genes and associated nuclear receptors ( Ppars and Pgc1α) was measured across days 15-16 and 21-22 of gestation (term = 23 days). CAF feeding suppressed the mesor and/or amplitude of adipose tissue clock genes (most notably Bmal1, Per2, and Rev-erbα) relative to chow-fed controls (CON) across both days of gestation. On day 15, the CAF diet also induced adipose Pparα, Pparδ, and Pgc1α rhythmicity but repressed that of Pparγ, while expression of Pparα, Pparδ, and Pgc1α was reduced at select time points. CAF mothers were hyperleptinemic at both stages of gestation, and at day 21 this effect was time-of-day dependent. Fetal plasma leptin exhibited clear rhythmicity, albeit with low amplitude, but interestingly these levels were unaffected by CAF feeding. Our data show that maternal obesity disrupts rhythmic expression of clock and metabolic genes in maternal adipose tissue and leads to maternal but not fetal hyperleptinemia.

  9. Cold-Induced Changes in Gene Expression in Brown Adipose Tissue, White Adipose Tissue and Liver

    PubMed Central

    Shore, Andrew M.; Karamitri, Angeliki; Kemp, Paul; Speakman, John R.; Graham, Neil S.; Lomax, Michael A.

    2013-01-01

    Cold exposure imposes a metabolic challenge to mammals that is met by a coordinated response in different tissues to prevent hypothermia. This study reports a transcriptomic analysis in brown adipose tissue (BAT), white adipose (WAT) and liver of mice in response to 24 h cold exposure at 8°C. Expression of 1895 genes were significantly (P<0.05) up- or down-regulated more than two fold by cold exposure in all tissues but only 5 of these genes were shared by all three tissues, and only 19, 14 and 134 genes were common between WAT and BAT, WAT and liver, and BAT and liver, respectively. We confirmed using qRT-PCR, the increased expression of a number of characteristic BAT genes during cold exposure. In both BAT and the liver, the most common direction of change in gene expression was suppression (496 genes in BAT and 590 genes in liver). Gene ontology analysis revealed for the first time significant (P<0.05) down regulation in response to cold, of genes involved in oxidoreductase activity, lipid metabolic processes and protease inhibitor activity, in both BAT and liver, but not WAT. The results reveal an unexpected importance of down regulation of cytochrome P450 gene expression and apolipoprotein, in both BAT and liver, but not WAT, in response to cold exposure. Pathway analysis suggests a model in which down regulation of the nuclear transcription factors HNF4α and PPARα in both BAT and liver may orchestrate the down regulation of genes involved in lipoprotein and steroid metabolism as well as Phase I enzymes belonging to the cytochrome P450 group in response to cold stress in mice. We propose that the response to cold stress involves decreased gene expression in a range of cellular processes in order to maximise pathways involved in heat production. PMID:23894377

  10. Inflammation and Fibrosis in Perirenal Adipose Tissue of Patients With Aldosterone-Producing Adenoma.

    PubMed

    Wu, Chunyan; Zhang, Huijian; Zhang, Jiajun; Xie, Cuihua; Fan, Cunxia; Zhang, Hongbin; Wu, Peng; Wei, Qiang; Tan, Wanlong; Xu, Lingling; Wang, Ling; Xue, Yaoming; Guan, Meiping

    2018-01-01

    The prevalence of primary aldosteronism is much higher than previously thought. Recent studies have shown that primary aldosteronism is related to a higher risk of cardiovascular events. However, the underlying mechanism is not yet clear. Here we investigate the characteristics, including inflammation, fibrosis, and adipokine expression, of adipose tissues from different deposits in patients with aldosterone-producing adenoma (APA). Inflammation and fibrosis changes were evaluated in perirenal and subcutaneous adipose tissues obtained from patients with APA (n = 16), normotension (NT; n = 10), and essential hypertension (EH; n = 5) undergoing laparoscopic surgery. We also evaluated the effect of aldosterone in isolated human perirenal adipose tissue stromal vascular fraction (SVF) cells and investigated the effect of aldosterone in mouse 3T3-L1 and brown preadipocytes. Compared with the EH group, significantly higher levels of interleukin-6 (IL-6) and tumor necrosis factor-α messenger RNA (mRNA) and protein were observed in perirenal adipose tissue of patients with APA. Expression of genes related to fibrosis and adipogenesis in perirenal adipose tissue was notably higher in patients with APA than in patients with NT and EH. Aldosterone significantly induced IL-6 and fibrosis gene mRNA expression in differentiated SVF cells. Aldosterone treatment enhanced mRNA expression of genes associated with inflammation and fibrosis and stimulated differentiation of 3T3-L1 and brown preadipocytes. In conclusion, these data indicate that high aldosterone in patients with APA may induce perirenal adipose tissue dysfunction and lead to inflammation and fibrosis, which may be involved in the high risk of cardiovascular events observed in patients with primary aldosteronism. Copyright © 2018 Endocrine Society.

  11. Targeting the NO/superoxide ratio in adipose tissue: relevance to obesity and diabetes management.

    PubMed

    Jankovic, Aleksandra; Korac, Aleksandra; Buzadzic, Biljana; Stancic, Ana; Otasevic, Vesna; Ferdinandy, Péter; Daiber, Andreas; Korac, Bato

    2017-06-01

    Insulin sensitivity and metabolic homeostasis depend on the capacity of adipose tissue to take up and utilize excess glucose and fatty acids. The key aspects that determine the fuel-buffering capacity of adipose tissue depend on the physiological levels of the small redox molecule, nitric oxide (NO). In addition to impairment of NO synthesis, excessive formation of the superoxide anion (О 2 •- ) in adipose tissue may be an important interfering factor diverting the signalling of NO and other reactive oxygen and nitrogen species in obesity, resulting in metabolic dysfunction of adipose tissue over time. Besides its role in relief from superoxide burst, enhanced NO signalling may be responsible for the therapeutic benefits of different superoxide dismutase mimetics, in obesity and experimental diabetes models. This review summarizes the role of NO in adipose tissue and highlights the effects of NO/О 2 •- ratio 'teetering' as a promising pharmacological target in the metabolic syndrome. This article is part of a themed section on Redox Biology and Oxidative Stress in Health and Disease. To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v174.12/issuetoc. © 2016 The British Pharmacological Society.

  12. Fatty acid metabolism and the basis of brown adipose tissue function

    PubMed Central

    Calderon-Dominguez, María; Mir, Joan F.; Fucho, Raquel; Weber, Minéia; Serra, Dolors; Herrero, Laura

    2016-01-01

    ABSTRACT Obesity has reached epidemic proportions, leading to severe associated pathologies such as insulin resistance, cardiovascular disease, cancer and type 2 diabetes. Adipose tissue has become crucial due to its involvement in the pathogenesis of obesity-induced insulin resistance, and traditionally white adipose tissue has captured the most attention. However in the last decade the presence and activity of heat-generating brown adipose tissue (BAT) in adult humans has been rediscovered. BAT decreases with age and in obese and diabetic patients. It has thus attracted strong scientific interest, and any strategy to increase its mass or activity might lead to new therapeutic approaches to obesity and associated metabolic diseases. In this review we highlight the mechanisms of fatty acid uptake, trafficking and oxidation in brown fat thermogenesis. We focus on BAT's morphological and functional characteristics and fatty acid synthesis, storage, oxidation and use as a source of energy. PMID:27386151

  13. Technical note: Alternatives to reduce adipose tissue sampling bias.

    PubMed

    Cruz, G D; Wang, Y; Fadel, J G

    2014-10-01

    Understanding the mechanisms by which nutritional and pharmaceutical factors can manipulate adipose tissue growth and development in production animals has direct and indirect effects in the profitability of an enterprise. Adipocyte cellularity (number and size) is a key biological response that is commonly measured in animal science research. The variability and sampling of adipocyte cellularity within a muscle has been addressed in previous studies, but no attempt to critically investigate these issues has been proposed in the literature. The present study evaluated 2 sampling techniques (random and systematic) in an attempt to minimize sampling bias and to determine the minimum number of samples from 1 to 15 needed to represent the overall adipose tissue in the muscle. Both sampling procedures were applied on adipose tissue samples dissected from 30 longissimus muscles from cattle finished either on grass or grain. Briefly, adipose tissue samples were fixed with osmium tetroxide, and size and number of adipocytes were determined by a Coulter Counter. These results were then fit in a finite mixture model to obtain distribution parameters of each sample. To evaluate the benefits of increasing number of samples and the advantage of the new sampling technique, the concept of acceptance ratio was used; simply stated, the higher the acceptance ratio, the better the representation of the overall population. As expected, a great improvement on the estimation of the overall adipocyte cellularity parameters was observed using both sampling techniques when sample size number increased from 1 to 15 samples, considering both techniques' acceptance ratio increased from approximately 3 to 25%. When comparing sampling techniques, the systematic procedure slightly improved parameters estimation. The results suggest that more detailed research using other sampling techniques may provide better estimates for minimum sampling.

  14. Adipose tissue in muscle: a novel depot similar in size to visceral adipose tissue1-3

    PubMed Central

    Gallagher, Dympna; Kuznia, Patrick; Heshka, Stanley; Albu, Jeanine; Heymsfield, Steven B; Goodpaster, Bret; Visser, Marjolein; Harris, Tamara B

    2006-01-01

    Background The manner in which fat depot volumes and distributions, particularly the adipose tissue (AT) between the muscles, vary by race is unknown. Objective The objective was to quantify a previously unstudied and novel intermuscular AT (IMAT) depot and subcutaneous AT, visceral AT (VAT), and total-body skeletal muscle mass in healthy sedentary African American (AA), Asian, and white adults by whole-body magnetic resonance imaging. IMAT is the AT between muscles and within the boundary of the muscle fascia. Design Analyses were conducted on 227 women [AA (n = 79): body mass index (BMI; in kg/m2), 29.0 ± 5.5; age, 45.7 ± 16.9 y; Asian (n = 38): BMI, 21.7 ± 2.9; age, 47.2 ± 19.9 y; whites (n = 110): BMI, 24.9 ± 5.4; age, 43.7 ± 16.2 y]) and 111 men [AA (n = 39): BMI, 25.6 ± 3.2; age, 45.5 ± 18.8 y; Asian (n = 13): BMI, 24.9 ± 2.5; age, 45.6 ± 25.0 y; white (n = 59): BMI, 25.8 ± 3.8; age 44.5 ± 16.3 y]. Results IMAT depots were not significantly different in size between race groups at low levels of adiposity; however, with increasing adiposity, AAs had a significantly greater increment in the proportion of total AT (TAT) than did the whites and Asians (58, 46, and 44 g IMAT/kg TAT, respectively; P = 0.001). VAT depots were not significantly different in size at low levels of adiposity but, with increasing adiposity, VAT accumulation was greater than IMAT accumulation in the Asians and whites; no significant differences were observed in AAs. Conclusion Race differences in AT distribution extend to IMAT, a depot that may influence race-ethnicity differences in dysglycemia. PMID:15817870

  15. Breast Cancer Cell Colonization of the Human Bone Marrow Adipose Tissue Niche.

    PubMed

    Templeton, Zach S; Lie, Wen-Rong; Wang, Weiqi; Rosenberg-Hasson, Yael; Alluri, Rajiv V; Tamaresis, John S; Bachmann, Michael H; Lee, Kitty; Maloney, William J; Contag, Christopher H; King, Bonnie L

    2015-12-01

    Bone is a preferred site of breast cancer metastasis, suggesting the presence of tissue-specific features that attract and promote the outgrowth of breast cancer cells. We sought to identify parameters of human bone tissue associated with breast cancer cell osteotropism and colonization in the metastatic niche. Migration and colonization patterns of MDA-MB-231-fLuc-EGFP (luciferase-enhanced green fluorescence protein) and MCF-7-fLuc-EGFP breast cancer cells were studied in co-culture with cancellous bone tissue fragments isolated from 14 hip arthroplasties. Breast cancer cell migration into tissues and toward tissue-conditioned medium was measured in Transwell migration chambers using bioluminescence imaging and analyzed as a function of secreted factors measured by multiplex immunoassay. Patterns of breast cancer cell colonization were evaluated with fluorescence microscopy and immunohistochemistry. Enhanced MDA-MB-231-fLuc-EGFP breast cancer cell migration to bone-conditioned versus control medium was observed in 12/14 specimens (P = .0014) and correlated significantly with increasing levels of the adipokines/cytokines leptin (P = .006) and IL-1β (P = .001) in univariate and multivariate regression analyses. Fluorescence microscopy and immunohistochemistry of fragments underscored the extreme adiposity of adult human bone tissues and revealed extensive breast cancer cell colonization within the marrow adipose tissue compartment. Our results show that breast cancer cells migrate to human bone tissue-conditioned medium in association with increasing levels of leptin and IL-1β, and colonize the bone marrow adipose tissue compartment of cultured fragments. Bone marrow adipose tissue and its molecular signals may be important but understudied components of the breast cancer metastatic niche. Copyright © 2015 The Authors. Published by Elsevier Inc. All rights reserved.

  16. Allele compensation in tip60+/- mice rescues white adipose tissue function in vivo.

    PubMed

    Gao, Yuan; Hamers, Nicole; Rakhshandehroo, Maryam; Berger, Ruud; Lough, John; Kalkhoven, Eric

    2014-01-01

    Adipose tissue is a key regulator of energy homestasis. The amount of adipose tissue is largely determined by adipocyte differentiation (adipogenesis), a process that is regulated by the concerted actions of multiple transcription factors and cofactors. Based on in vitro studies in murine 3T3-L1 preadipocytes and human primary preadipocytes, the transcriptional cofactor and acetyltransferase Tip60 was recently identified as an essential adipogenic factor. We therefore investigated the role of Tip60 on adipocyte differentiation and function, and possible consequences on energy homeostasis, in vivo. Because homozygous inactivation results in early embryonic lethality, Tip60+/- mice were used. Heterozygous inactivation of Tip60 had no effect on body weight, despite slightly higher food intake by Tip60+/- mice. No major effects of heterozygous inactivation of Tip60 were observed on adipose tissue and liver, and Tip60+/- displayed normal glucose tolerance, both on a low fat and a high fat diet. While Tip60 mRNA was reduced to 50% in adipose tissue, the protein levels were unaltered, suggesting compensation by the intact allele. These findings indicate that the in vivo role of Tip60 in adipocyte differentiation and function cannot be properly addressed in Tip60+/- mice, but requires the generation of adipose tissue-specific knock out animals or specific knock-in mice.

  17. Adipose Tissues Characteristics of Normal, Obesity, and Type 2 Diabetes in Uygurs Population

    PubMed Central

    Zhang, Jun; Zhang, Zhiwei; Ding, Yulei; Xu, Peng; Wang, Tingting; Xu, Wenjing; Lu, Huan; Li, Jun; Wang, Yan; Li, Siyuan; Liu, Zongzhi; An, Na; Yang, Li; Xie, Jianxin

    2015-01-01

    Our results showed that, at the same BMI level, Uygurs have greater WHR values, abdominal visceral fat content, and diabetes risks than Kazaks. In addition, values of HDL-C in Uygur subjects were lower than those in Kazak subjects, and values of creatinine, uric acid, diastolic blood pressure, blood glucose, and fructosamine in Uygur male subjects were lower than those in Kazak male subjects. In contrast, systolic blood pressure values in Uygur subjects were greater than those in Kazak subjects, and blood glucose values were greater in Uygur female subjects than in Kazak female subjects. Additionally, in Uygurs, visceral adipose tissue expression levels of TBX1 and TCF21 were greater in obesity group than in normal and T2DM groups and lower in T2DM group than in normal group (P < 0.01). The visceral adipose tissue expression levels of APN in normal group was greater than those in obesity and T2DM groups, and visceral adipose tissue expression levels of TNF-α and MCP-1 in normal group were lower than those in obesity and T2DM groups (P < 0.01). In conclusion, T2DM in Uygurs was mainly associated with not only distribution of adipose tissue in body, but also change in metabolic activity and adipocytokines secretion of adipose tissue. PMID:26273678

  18. A low-protein, high-carbohydrate diet increases browning in perirenal adipose tissue but not in inguinal adipose tissue.

    PubMed

    Pereira, Mayara P; Ferreira, Laís A A; da Silva, Flávia H S; Christoffolete, Marcelo A; Metsios, George S; Chaves, Valéria E; de França, Suélem A; Damazo, Amílcar S; Flouris, Andreas D; Kawashita, Nair H

    2017-10-01

    The aim of this study was to evaluate the browning and origin of fatty acids (FAs) in the maintenance of triacylglycerol (TG) storage and/or as fuel for thermogenesis in perirenal adipose tissue (periWAT) and inguinal adipose tissue (ingWAT) of rats fed a low-protein, high-carbohydrate (LPHC) diet. LPHC (6% protein, 74% carbohydrate) or control (C; 17% protein, 63% carbohydrate) diets were administered to rats for 15 d. The tissues were stained with hematoxylin and eosin for histologic analysis. The content of uncoupling protein 1 (UCP1) was determined by immunofluorescence. Levels of T-box transcription factor (TBX1), PR domain containing 16 (PRDM16), adipose triacylglycerol lipase (ATGL), hormone-sensitive lipase, lipoprotein lipase (LPL), glycerokinase, phosphoenolpyruvate carboxykinase (PEPCK), glucose transporter 4, β 3 -adrenergic receptor (AR), β 1 -AR, protein kinase A (PKA), adenosine-monophosphate-activated protein kinase (AMPK), and phospho-AMPK were determined by immunoblotting. Serum fibroblast growth factor 21 (FGF21) was measured using a commercial kit (Student's t tests, P < 0.05). The LPHC diet increased FGF21 levels by 150-fold. The presence of multilocular adipocytes, combined with the increased contents of UCP1, TBX1, and PRDM16 in periWAT of LPHC-fed rats, suggested the occurrence of browning. The contents of β 1 -AR and LPL were increased in the periWAT. The ingWAT showed higher ATGL and PEPCK levels, phospho-AMPK/AMPK ratio, and reduced β 3 -AR and PKA levels. These findings suggest that browning occurred only in the periWAT and that higher utilization of FAs from blood lipoproteins acted as fuel for thermogenesis. Increased glycerol 3-phosphate generation by glyceroneogenesis increased FAs reesterification from lipolysis, explaining the increased TG storage in the ingWAT. Copyright © 2017 Elsevier Inc. All rights reserved.

  19. Extracellular cyclic AMP-adenosine pathway in isolated adipocytes and adipose tissue.

    PubMed

    Strouch, Marci B; Jackson, Edwin K; Mi, Zaichuan; Metes, Nicole A; Carey, Gale B

    2005-06-01

    Our goal was to evaluate the presence and lipolytic impact of the extracellular cyclic adenosine monophosphate (AMP)-adenosine pathway in adipose tissue. Sixteen miniature Yucatan swine (Sus scrofa) were used for these in vitro and in situ experiments. Four microdialysis probes were implanted into subcutaneous adipose tissue and perfused at 2 microL/min with Ringer's solution containing no addition, varying levels of cyclic AMP, 10 microM isoproterenol, or 10 microM isoproterenol plus 1 mM alpha,beta-methylene adenosine 5'-diphosphate (AMPCP), a 5'-nucleotidase inhibitor. Dialysate was assayed for AMP, adenosine, inosine, hypoxanthine, and glycerol. Freshly isolated adipocytes were incubated with buffer, 1 microM isoproterenol, or 1 microM isoproterenol plus 0.1 mM AMPCP, and extracellular levels of AMP, adenosine, inosine, hypoxanthine, and glycerol were measured. Perfusion of adipose tissue with exogenous cyclic AMP caused a significant increase in AMP and adenosine appearance. Perfusion with AMPCP, in the presence or absence of isoproterenol, significantly increased the levels of AMP and glycerol, whereas it significantly reduced the level of adenosine and its metabolites. However, the AMPCP-provoked increase in lipolysis observed in situ and in vitro was not temporally associated with a decrease in adenosine. These data suggest the existence of a cyclic AMP-adenosine pathway in adipocytes and adipose tissue. The role of this pathway in the regulation of lipolysis remains to be clarified.

  20. Lipolytic and thermogenic depletion of adipose tissue in cancer cachexia.

    PubMed

    Tsoli, Maria; Swarbrick, Michael M; Robertson, Graham R

    2016-06-01

    Although muscle wasting is the obvious manifestation of cancer cachexia that impacts on patient quality of life, the loss of lipid reserves and metabolic imbalance in adipose tissue also contribute to the devastating impact of cachexia. Depletion of fat depots in cancer patients is more pronounced than loss of muscle and often precedes, or even occurs in the absence of, reduced lean body mass. Rapid mobilisation of triglycerides stored within adipocytes to supply the body with fatty acids in periods of high-energy demand is normally mediated through a well-defined process of lipolysis involving the lipases ATGL, HSL and MGL. Studies into how these lipases contribute to fat loss in cancer cachexia have revealed the prominent role for ATGL in initiating lipolysis during adipose tissue atrophy, together with links between tumour-derived factors and the signalling pathways that control lipid flux within fat cells. The recent findings of increased thermogenesis in brown fat during cancer cachexia indicate that metabolically active adipose tissue contributes to the imbalance in energy homeostasis involved in catabolic wasting. Such energetically futile use of fatty acids liberated from adipose tissue to generate heat represents a maladaptive response in conjunction with anorexia experienced by cancer patients. As IL-6 release by tumours provokes lipolysis and activates the thermogenic programme in brown fat, this review explores the overlap in dysregulated metabolic processes due to inflammatory mediators in cancer cachexia and other disease states characterised by elevated cytokines such as obesity and diabetes. Crown Copyright © 2015. Published by Elsevier Ltd. All rights reserved.

  1. Brown Adipose Tissue Bioenergetics: A New Methodological Approach

    PubMed Central

    Calderon‐Dominguez, María; Alcalá, Martín; Sebastián, David; Zorzano, Antonio; Viana, Marta; Serra, Dolors

    2017-01-01

    The rediscovery of brown adipose tissue (BAT) in humans and its capacity to oxidize fat and dissipate energy as heat has put the spotlight on its potential as a therapeutic target in the treatment of several metabolic conditions including obesity and diabetes. To date the measurement of bioenergetics parameters has required the use of cultured cells or extracted mitochondria with the corresponding loss of information in the tissue context. Herein, we present a method to quantify mitochondrial bioenergetics directly in BAT. Based on XF Seahorse Technology, we assessed the appropriate weight of the explants, the exact concentration of each inhibitor in the reaction, and the specific incubation time to optimize bioenergetics measurements. Our results show that BAT basal oxygen consumption is mostly due to proton leak. In addition, BAT presents higher basal oxygen consumption than white adipose tissue and a positive response to b‐adrenergic stimulation. Considering the whole tissue and not just subcellular populations is a direct approach that provides a realistic view of physiological respiration. In addition, it can be adapted to analyze the effect of potential activators of thermogenesis, or to assess the use of fatty acids or glucose as a source of energy. PMID:28435771

  2. ERα upregulates Phd3 to ameliorate HIF-1 induced fibrosis and inflammation in adipose tissue

    PubMed Central

    Kim, Min; Neinast, Michael D.; Frank, Aaron P.; Sun, Kai; Park, Jiyoung; Zehr, Jordan A.; Vishvanath, Lavanya; Morselli, Eugenia; Amelotte, Mason; Palmer, Biff F.; Gupta, Rana K.; Scherer, Philipp E.; Clegg, Deborah J.

    2014-01-01

    Hypoxia Inducible Factor 1 (HIF-1) promotes fibrosis and inflammation in adipose tissues, while estrogens and Estrogen Receptor α (ERα) have the opposite effect. Here we identify an Estrogen Response Element (ERE) in the promoter of Phd3, which is a negative regulatory enzyme of HIF-1, and we demonstrate HIF-1α is ubiquitinated following 17-β estradiol (E2)/ERα mediated Phd3 transcription. Manipulating ERα in vivo increases Phd3 transcription and reduces HIF-1 activity, while addition of PHD3 ameliorates adipose tissue fibrosis and inflammation. Our findings outline a novel regulatory relationship between E2/ERα, PHD3 and HIF-1 in adipose tissues, providing a mechanistic explanation for the protective effect of E2/ERα in adipose tissue. PMID:25161887

  3. Effect of Gender on the Total Abdominal Fat, Intra-Abdominal Adipose Tissue and Abdominal Sub-Cutaneous Adipose Tissue among Indian Hypertensive Patients.

    PubMed

    Sahoo, Jaya Prakash; Kumari, Savita; Jain, Sanjay

    2016-04-01

    Abdominal obesity is a better marker of adverse metabolic profile than generalized obesity in hypertensive subjects. Further, gender has effect on adiposity and its distribution. Effect of gender on obesity and the distribution of fat in different sub-compartments of abdomen among Indian hypertensive subjects. This observational study included 278 adult subjects (Males-149 & Females-129) with essential hypertension from a tertiary care centre in north India over one year. A detailed history taking and physical examination including anthropometry were performed in all patients. Total Abdominal Fat (TAF) and abdominal adipose tissue sub-compartments like Intra-Abdominal Adipose Tissue (IAAT) and Sub-Cutaneous Adipose Tissue (SCAT) were measured using the predictive equations developed for Asian Indians. Female hypertensive subjects had higher Body Mass Index (BMI) with more overweight (BMI ≥ 23kg/m(2)), and obesity (BMI≥ 25 kg/m(2)). Additionally, they had higher prevalence of central obesity based on both Waist Circumference (WC) criteria (WC≥ 90 cm in males and WC≥ 80 cm in females) and TAF criteria {≥245.6 cm(2) (males) and ≥203.46 cm(2) (females)} than male patients. But there was no difference in the prevalence of central obesity based on Waist Hip Ratio (WHR) criteria (WHR ≥0.90 in males and WHR ≥ 0.85 in females) between two genders. High TAF & IAAT were present in more females although there was no difference in the distribution of high SCAT between two genders. Female hypertensive subjects were more obese with higher abnormal TAF & IAAT compared to male patients. However, there was no difference in the distribution of high SCAT among them.

  4. Human skeletal muscles replaced to a high degree by white adipose tissue.

    PubMed

    Ina, Keisuke; Kitamura, Hirokazu; Masaki, Takayuki; Tatsukawa, Shuji; Yoshimatsu, Hironobu; Fujikura, Yoshihisa

    2011-02-01

    Extreme replacement of skeletal muscles by adipose tissue was found in an 86-year old Japanese male cadaver during dissection practice for medical students at Oita University School of Medicine. Especially, the bilateral sartorius muscles looked overall like adipose tissue. The man had suffered from diabetes mellitus, renal failure, hypertension and hypothyroidism before his death. He was also an alcohol drinker. He had been bedridden late in life. The cause of death was renal failure. In microscopy, the adipose tissue-like sartorius muscle was shown to consist of leptin-positive adipocytes with a small number of degenerated muscle fibers. Fatty replacement, or fatty degeneration, appears to result from endocrine and metabolic disorders, and being bedridden leads to muscle atrophy and damage, although the origin of the adipocytes which emerged in the degenerated muscles is unknown.

  5. Modulations of calcium in adipose tissue by TRPC1: a key player in obesity

    USDA-ARS?s Scientific Manuscript database

    The disruption of metabolic homeostasis, the regulation of energy the body extracts, stores and uses, leads to excess adipose tissue accumulation and the onset of obesity. White adipose tissue (WAT) is a metabolically dynamic endocrine organ responsible for maintaining metabolic homeostasis through ...

  6. Dietary overload lithium decreases the adipogenesis in abdominal adipose tissue of broiler chickens.

    PubMed

    Bai, Shiping; Pan, Shuqin; Zhang, Keying; Ding, Xuemei; Wang, Jianping; Zeng, Qiufeng; Xuan, Yue; Su, Zuowei

    2017-01-01

    To investigate the toxic effects of dietary overload lithium on the adipogenesis in adipose tissue of chicken and the role of hypothalamic neuropeptide Y (NPY) in this process, one-day-old male chicks were fed with the basal diet added with 0 (control) or 100mg lithium/kg diet from lithium chloride (overload lithium) for 35days. Abdominal adipose tissue and hypothalamus were collected at day 6, 14, and 35. As a percentage of body weight, abdominal fat decreased (p<0.001) at day 6, 14, and 35, and feed intake and body weight gain decreased during day 7-14, and day 15-35 in overload lithium treated broilers as compared to control. Adipocyte diameter and DNA content in abdominal adipose tissue were significantly lower in overload-lithium treatment than control at day 35, although no significant differences were observed at day 6 and 14. Dietary overload lithium decreased (p<0.01) transcriptional expression of preadipocyte proliferation makers ki-67 (KI67), microtubule-associated protein homolog (TPX2), and topoisomerase 2-alpha (TOP2A), and preadipocyte differentiation transcriptional factors peroxisome proliferator-activated receptor-γ (PPARγ), and CCAAT/enhancer binding protein (C/EBP) α mRNA abundance in abdominal adipose tissue. In hypothalamus, dietary overload lithium influenced (p<0.001) NPY, and NPY receptor (NPYR) 6 mRNA abundance at day 6 and 14, but not at day 35. In conclusion, dietary overload lithium decreased the adipogenesis in abdominal adipose tissue of chicken, which was accompanied by depressing transcriptional expression of adipogenesis-associated factors. Hypothalamic NPY had a potential role in the adipogenesis in abdominal adipose tissue of broilers with a short-term overload lithium treatment. Copyright © 2016 Elsevier B.V. All rights reserved.

  7. Crif1 Deficiency Reduces Adipose OXPHOS Capacity and Triggers Inflammation and Insulin Resistance in Mice

    PubMed Central

    Ryu, Min Jeong; Kim, Soung Jung; Kim, Yong Kyung; Choi, Min Jeong; Tadi, Surendar; Lee, Min Hee; Lee, Seong Eun; Chung, Hyo Kyun; Jung, Saet Byel; Kim, Hyun-Jin; Jo, Young Suk; Kim, Koon Soon; Lee, Sang-Hee; Kim, Jin Man; Kweon, Gi Ryang; Park, Ki Cheol; Lee, Jung Uee; Kong, Young Yun; Lee, Chul-Ho; Chung, Jongkyeong; Shong, Minho

    2013-01-01

    Impaired mitochondrial oxidative phosphorylation (OXPHOS) has been proposed as an etiological mechanism underlying insulin resistance. However, the initiating organ of OXPHOS dysfunction during the development of systemic insulin resistance has yet to be identified. To determine whether adipose OXPHOS deficiency plays an etiological role in systemic insulin resistance, the metabolic phenotype of mice with OXPHOS–deficient adipose tissue was examined. Crif1 is a protein required for the intramitochondrial production of mtDNA–encoded OXPHOS subunits; therefore, Crif1 haploinsufficient deficiency in mice results in a mild, but specific, failure of OXPHOS capacity in vivo. Although adipose-specific Crif1-haploinsufficient mice showed normal growth and development, they became insulin-resistant. Crif1-silenced adipocytes showed higher expression of chemokines, the expression of which is dependent upon stress kinases and antioxidant. Accordingly, examination of adipose tissue from Crif1-haploinsufficient mice revealed increased secretion of MCP1 and TNFα, as well as marked infiltration by macrophages. These findings indicate that the OXPHOS status of adipose tissue determines its metabolic and inflammatory responses, and may cause systemic inflammation and insulin resistance. PMID:23516375

  8. Broiler chicken adipose tissue dynamics during the first two weeks post-hatch.

    PubMed

    Bai, Shiping; Wang, Guoqing; Zhang, Wei; Zhang, Shuai; Rice, Brittany Breon; Cline, Mark Andrew; Gilbert, Elizabeth Ruth

    2015-11-01

    Selection of broiler chickens for growth has led to increased adipose tissue accretion. To investigate the post-hatch development of adipose tissue, the abdominal, clavicular, and subcutaneous adipose tissue depots were collected from broiler chicks at 4 and 14 days post-hatch. As a percent of body weight, abdominal fat increased (P<0.001) with age. At day 4, clavicular and subcutaneous fat depots were heavier (P<0.003) than abdominal fat whereas at day 14, abdominal and clavicular weighed more (P<0.003) than subcutaneous fat. Adipocyte area and diameter were greater in clavicular and subcutaneous than abdominal fat at 4 and 14 days post-hatch (P<0.001). Glycerol-3-phosphate dehydrogenase (G3PDH) activity increased (P<0.001) in all depots from day 4 to 14, and at both ages was greatest in subcutaneous, intermediate in clavicular, and lowest in abdominal fat (P<0.05). In clavicular fat, peroxisome proliferator-activated receptor-γ (PPARγ), CCAAT/enhancer binding protein (CEBP)α, CEBPβ, fatty acid synthase (FASN), fatty acid binding protein 4 (FABP4), lipoprotein lipase (LPL), neuropeptide Y (NPY), and NPY receptor 5 (NPYR5) mRNA increased and NPYR2 mRNA decreased from day 4 to 14 (P<0.001). Thus, there are site-specific differences in broiler chick adipose development, with larger adipocytes and greater G3PDH activity in subcutaneous fat at day 4, more rapid growth of abdominal fat, and clavicular fat intermediate for most traits. Adipose tissue expansion was accompanied by changes in gene expression of adipose-associated factors. Copyright © 2015 Elsevier Inc. All rights reserved.

  9. Induced-Pluripotent-Stem-Cell-Derived Primitive Macrophages Provide a Platform for Modeling Tissue-Resident Macrophage Differentiation and Function.

    PubMed

    Takata, Kazuyuki; Kozaki, Tatsuya; Lee, Christopher Zhe Wei; Thion, Morgane Sonia; Otsuka, Masayuki; Lim, Shawn; Utami, Kagistia Hana; Fidan, Kerem; Park, Dong Shin; Malleret, Benoit; Chakarov, Svetoslav; See, Peter; Low, Donovan; Low, Gillian; Garcia-Miralles, Marta; Zeng, Ruizhu; Zhang, Jinqiu; Goh, Chi Ching; Gul, Ahmet; Hubert, Sandra; Lee, Bernett; Chen, Jinmiao; Low, Ivy; Shadan, Nurhidaya Binte; Lum, Josephine; Wei, Tay Seok; Mok, Esther; Kawanishi, Shohei; Kitamura, Yoshihisa; Larbi, Anis; Poidinger, Michael; Renia, Laurent; Ng, Lai Guan; Wolf, Yochai; Jung, Steffen; Önder, Tamer; Newell, Evan; Huber, Tara; Ashihara, Eishi; Garel, Sonia; Pouladi, Mahmoud A; Ginhoux, Florent

    2017-07-18

    Tissue macrophages arise during embryogenesis from yolk-sac (YS) progenitors that give rise to primitive YS macrophages. Until recently, it has been impossible to isolate or derive sufficient numbers of YS-derived macrophages for further study, but data now suggest that induced pluripotent stem cells (iPSCs) can be driven to undergo a process reminiscent of YS-hematopoiesis in vitro. We asked whether iPSC-derived primitive macrophages (iMacs) can terminally differentiate into specialized macrophages with the help of growth factors and organ-specific cues. Co-culturing human or murine iMacs with iPSC-derived neurons promoted differentiation into microglia-like cells in vitro. Furthermore, murine iMacs differentiated in vivo into microglia after injection into the brain and into functional alveolar macrophages after engraftment in the lung. Finally, iPSCs from a patient with familial Mediterranean fever differentiated into iMacs with pro-inflammatory characteristics, mimicking the disease phenotype. Altogether, iMacs constitute a source of tissue-resident macrophage precursors that can be used for biological, pathophysiological, and therapeutic studies. Copyright © 2017 Elsevier Inc. All rights reserved.

  10. Analysis of type II diabetes mellitus adipose-derived stem cells for tissue engineering applications

    PubMed Central

    Minteer, Danielle Marie; Young, Matthew T; Lin, Yen-Chih; Over, Patrick J; Rubin, J Peter; Gerlach, Jorg C

    2015-01-01

    To address the functionality of diabetic adipose-derived stem cells in tissue engineering applications, adipose-derived stem cells isolated from patients with and without type II diabetes mellitus were cultured in bioreactor culture systems. The adipose-derived stem cells were differentiated into adipocytes and maintained as functional adipocytes. The bioreactor system utilizes a hollow fiber–based technology for three-dimensional perfusion of tissues in vitro, creating a model in which long-term culture of adipocytes is feasible, and providing a potential tool useful for drug discovery. Daily metabolic activity of the adipose-derived stem cells was analyzed within the medium recirculating throughout the bioreactor system. At experiment termination, tissues were extracted from bioreactors for immunohistological analyses in addition to gene and protein expression. Type II diabetic adipose-derived stem cells did not exhibit significantly different glucose consumption compared to adipose-derived stem cells from patients without type II diabetes (p > 0.05, N = 3). Expression of mature adipocyte genes was not significantly different between diabetic/non-diabetic groups (p > 0.05, N = 3). Protein expression of adipose tissue grown within all bioreactors was verified by Western blotting.The results from this small-scale study reveal adipose-derived stem cells from patients with type II diabetes when removed from diabetic environments behave metabolically similar to the same cells of non-diabetic patients when cultured in a three-dimensional perfusion bioreactor, suggesting that glucose transport across the adipocyte cell membrane, the hindrance of which being characteristic of type II diabetes, is dependent on environment. The presented observation describes a tissue-engineered tool for long-term cell culture and, following future adjustments to the culture environment and increased sample sizes, potentially for anti-diabetic drug testing. PMID:26090087

  11. Body frame size in school children is related to the amount of adipose tissue in different depots but not to adipose distribution.

    PubMed

    Guzmán-de la Garza, Francisco J; González Ayala, Alejandra E; Gómez Nava, Marisol; Martínez Monsiváis, Leislie I; Salinas Martínez, Ana M; Ramírez López, Erik; Mathiew Quirós, Alvaro; Garcia Quintanilla, Francisco

    2017-09-10

    The main aim of this study was to test the hypothesis that body frame size is related to the amount of fat in different adipose tissue depots and to fat distribution in schoolchildren. Children aged between 5 and 10 years were included in this cross-sectional study (n = 565). Body frame size, adiposity markers (anthropometric, skinfolds thickness, and ultrasound measures), and fat distribution indices were analyzed. Correlation coefficients adjusted by reliability were estimated and analyzed by sex; the significance of the difference between two correlation coefficients was assessed using the Fisher z-transformation. The sample included primarily urban children; 58.6% were normal weight, 16.1% overweight, 19.6% obese, and the rest were underweight. Markers of subcutaneous adiposity, fat mass and fat-free mass, and preperitoneal adiposity showed higher and significant correlations with the sum of the biacromial + bitrochanteric diameter than with the elbow diameter, regardless of sex. The fat distribution conicity index presented significant but weak correlations; and visceral adipose tissue, hepatic steatosis, and the waist-for-hip ratio were not significantly correlated with body frame size measures. Body frame size in school children was related to the amount of adipose tissue in different depots, but not adipose distribution. More studies are needed to confirm this relationship and its importance to predict changes in visceral fat deposition during growth. © 2017 Wiley Periodicals, Inc.

  12. Soya protein attenuates abnormalities of the renin-angiotensin system in adipose tissue from obese rats.

    PubMed

    Frigolet, María E; Torres, Nimbe; Tovar, Armando R

    2012-01-01

    Several metabolic disturbances during obesity are associated with adipose tissue-altered functions. Adipocytes contain the renin-angiotensin system (RAS), which regulates signalling pathways that control angiogenesis via Akt in an autocrine fashion. Soya protein (Soy) consumption modifies the gene expression pattern in adipose tissue, resulting in an improved adipocyte function. Therefore, the aim of the present work is to study whether dietary Soy regulates the expression of RAS and angiogenesis-related genes and its association with the phosphorylated state of Akt in the adipose tissue of obese rats. Animals were fed a 30 % Soy or casein (Cas) diet containing 5 or 25 % fat for 160 d. mRNA abundance was studied in the adipose tissue, and Akt phosphorylation and hormone release were measured in the primary adipocyte culture. The present results show that Soy treatment in comparison with Cas consumption induces lower angiotensin release and increased insulin-stimulated Akt activation in adipocytes. Furthermore, Soy consumption varies the expression of RAS and angiogenesis-related genes, which maintain cell size and vascularity in the adipose tissue of rats fed a high-fat diet. Thus, adipocyte hypertrophy and impaired angiogenesis, which are frequently observed in dysfunctional adipose tissue, were avoided by consuming dietary Soy. Taken together, these findings suggest that Soy can be used as a dietary strategy to preserve adipocyte functionality and to prevent obesity abnormalities.

  13. Adipose tissue mitochondrial dysfunction triggers a lipodystrophic syndrome with insulin resistance, hepatosteatosis, and cardiovascular complications

    PubMed Central

    Vernochet, Cecile; Damilano, Federico; Mourier, Arnaud; Bezy, Olivier; Mori, Marcelo A.; Smyth, Graham; Rosenzweig, Anthony; Larsson, Nils-Göran; Kahn, C. Ronald

    2014-01-01

    Mitochondrial dysfunction in adipose tissue occurs in obesity, type 2 diabetes, and some forms of lipodystrophy, but whether this dysfunction contributes to or is the result of these disorders is unknown. To investigate the physiological consequences of severe mitochondrial impairment in adipose tissue, we generated mice deficient in mitochondrial transcription factor A (TFAM) in adipocytes by using mice carrying adiponectin-Cre and TFAM floxed alleles. These adiponectin TFAM-knockout (adipo-TFAM-KO) mice had a 75–81% reduction in TFAM in the subcutaneous and intra-abdominal white adipose tissue (WAT) and interscapular brown adipose tissue (BAT), causing decreased expression and enzymatic activity of proteins in complexes I, III, and IV of the electron transport chain (ETC). This mitochondrial dysfunction led to adipocyte death and inflammation in WAT and a whitening of BAT. As a result, adipo-TFAM-KO mice were resistant to weight gain, but exhibited insulin resistance on both normal chow and high-fat diets. These lipodystrophic mice also developed hypertension, cardiac hypertrophy, and cardiac dysfunction. Thus, isolated mitochondrial dysfunction in adipose tissue can lead a syndrome of lipodystrophy with metabolic syndrome and cardiovascular complications.—Vernochet, C., Damilano, F., Mourier, A., Bezy, O., Mori, M. A., Smyth, G., Rosenzweig, A., Larsson, N.-G., Kahn, C. R. Adipose tissue mitochondrial dysfunction triggers a lipodystrophic syndrome with insulin resistance, hepatosteatosis, and cardiovascular complications. PMID:25005176

  14. A microarray analysis of sexual dimorphism of adipose tissues in high-fat-diet-induced obese mice

    PubMed Central

    Grove, KL; Fried, SK; Greenberg, AS; Xiao, XQ; Clegg, DJ

    2013-01-01

    Objective A sexual dimorphism exists in body fat distribution; females deposit relatively more fat in subcutaneous/inguinal depots whereas males deposit more fat in the intra-abdominal/gonadal depot. Our objective was to systematically document depot- and sex-related differences in the accumulation of adipose tissue and gene expression, comparing differentially expressed genes in diet-induced obese mice with mice maintained on a chow diet. Research Design and Methods We used a microarray approach to determine whether there are sexual dimorphisms in gene expression in age-matched male, female or ovariectomized female (OVX) C57/BL6 mice maintained on a high-fat (HF) diet. We then compared expression of validated genes between the sexes on a chow diet. Results After exposure to a high fat diet for 12 weeks, females gained less weight than males. The microarray analyses indicate in intra-abdominal/gonadal adipose tissue in females 1642 genes differ by at least twofold between the depots, whereas 706 genes differ in subcutaneous/inguinal adipose tissue when compared with males. Only 138 genes are commonly regulated in both sexes and adipose tissue depots. Inflammatory genes (cytokine–cytokine receptor interactions and acute-phase protein synthesis) are upregulated in males when compared with females, and there is a partial reversal after OVX, where OVX adipose tissue gene expression is more ′male-like′. This pattern is not observed in mice maintained on chow. Histology of male gonadal white adipose tissue (GWAT) shows more crown-like structures than females, indicative of inflammation and adipose tissue remodeling. In addition, genes related to insulin signaling and lipid synthesis are higher in females than males, regardless of dietary exposure. Conclusions These data suggest that male and female adipose tissue differ between the sexes regardless of diet. Moreover, HF diet exposure elicits a much greater inflammatory response in males when compared with females

  15. Epicardial adipose tissue, hepatic steatosis and obesity.

    PubMed

    Cikim, A Sertkaya; Topal, E; Harputluoglu, M; Keskin, L; Zengin, Z; Cikim, K; Ozdemir, R; Aladag, M; Yologlu, S

    2007-06-01

    Hepatic steatosis is a common companion of obesity. Moreover, the measurement of epicardial adipose tissue (EAT) has been reported to be related with both obesity and insulin resistance. Therefore, we aimed to evaluate the relationship between hepatic steatosis, EAT and insulin resistance in obese patients. Sixty-three obese subjects were enrolled in the study. Patients were divided into 3 groups according to body mass index (BMI) as follows: 20 patients with 30 < or = BMI < 35 kg/m2 (Group 1, mean age 39.3+/-12.9 yr), 25 patients with 35 < or = BMI < 40 kg/m2 (Group 2, mean age 41.7+/-9.3 yr), and 18 patients with BMI > or = 40 kg/m2 (Group 3, mean age 36.8+/-13.9 yr). EAT and grade of hepatic steatosis were assessed sonographically. Anthropometrical measurements were assessed with the foot-to-foot bioelectrical impedance analysis. Insulin resistance was assessed according to basal insulin, quantitative insulin sensitivity check index (QUICKI) and homeostasis model assessment (HOMA) equations. Although EAT was similarly higher in both groups 2 and 3, these groups were found to be similar in terms of the grade of hepatic steatosis. Both EAT and the grade of hepatic steatosis were correlated with whole body fat mass, abdominal adiposity, insulin resistance, and triglyceridemia but waist circumference was the only factor affecting EAT thickness. Highly sensitive C-reactive protein (hsCRP) was the only metabolic parameter that was significantly higher in Group 3 than in Group 1 (p=0.02). Hepatic steatosis should be assessed as a valuable predictor that reflects the increments of whole body fat mass as well as abdominal adiposity. However, in an attempt to demonstrate marginal differences between patients with similar obesity levels, epicardial adipose tissue appears to be a more sensitive marker compared to hepatic steatosis.

  16. Botulinum toxin A improves adipose tissue engraftment by promoting cell proliferation, adipogenesis and angiogenesis

    PubMed Central

    Tang, Qi; Chen, Chang; Wang, Xiaqi; Li, Wei; Zhang, Yan; Wang, Muyao; Jing, Wei; Wang, Hang; Guo, Weihua; Tian, Weidong

    2017-01-01

    Adipose tissue engraftment has become a well-established therapy in plastic and reconstructive surgery used to restore age-related or injury-related soft tissue loss. However, the unpredictable absorption rates limit its further application. Some clinicians have noted that more optimal aesthetic results are achieved when botulinum toxin A (BoNTA) is applied prior to adipose tissue grafting. In the present study, we transplanted allogeneic adipose tissue treated with or without BoNTA in SD rats in vivo. We subsequently evaluated the survival rate (weight, volume, apoptosis and cellular integrity) and revascularization of the adipose tissue. The results revealed that BoNTA improved the long-term weight and volume retention of the graft, and preserved cellular integrity. BoNTA significantly increased the expression levels of CD31 and vascular endothelial growth factor (VEGF), suggesting enhanced vasodilation and endothelial cell proliferation. In vitro, adipose-derived stem cells (ASCs) were isolated, identified and induced to proliferate and differentiate with or without BoNTA. Furthermore, to evaluate the proliferative, adipogenic and angiogenic ability of the ASCs, CCK-8 assay and Oil Red O staining were conducted. Gene and protein expression levels were analyzed by RT-qPCR and western blot analysis. The results revealed that 8×10−2 U/ml BoNTA as the optimal dose increased ASC proliferation and adipogenic differentiation capacity, as well as the expression level of the key cytokine of angiogenesis. On the whole, our findings indicate that BoNTA improves adipose tissue engraftment and promotes ASC regeneration, which could benefit future clinical applications. PMID:28731141

  17. Regenerative Repair of Damaged Meniscus with Autologous Adipose Tissue-Derived Stem Cells

    PubMed Central

    Pak, Jaewoo; Lee, Jung Hun; Lee, Sang Hee

    2014-01-01

    Mesenchymal stem cells (MSCs) are defined as pluripotent cells found in numerous human tissues, including bone marrow and adipose tissue. Such MSCs, isolated from bone marrow and adipose tissue, have been shown to differentiate into bone and cartilage, along with other types of tissues. Therefore, MSCs represent a promising new therapy in regenerative medicine. The initial treatment of meniscus tear of the knee is managed conservatively with nonsteroidal anti-inflammatory drugs and physical therapy. When such conservative treatment fails, an arthroscopic resection of the meniscus is necessary. However, the major drawback of the meniscectomy is an early onset of osteoarthritis. Therefore, an effective and noninvasive treatment for patients with continuous knee pain due to damaged meniscus has been sought. Here, we present a review, highlighting the possible regenerative mechanisms of damaged meniscus with MSCs (especially adipose tissue-derived stem cells (ASCs)), along with a case of successful repair of torn meniscus with significant reduction of knee pain by percutaneous injection of autologous ASCs into an adult human knee. PMID:24592390

  18. Epicardial adipose tissue is associated with visceral fat, metabolic syndrome, and insulin resistance in menopausal women.

    PubMed

    Fernández Muñoz, María J; Basurto Acevedo, Lourdes; Córdova Pérez, Nydia; Vázquez Martínez, Ana Laura; Tepach Gutiérrez, Nayive; Vega García, Sara; Rocha Cruz, Alberto; Díaz Martínez, Alma; Saucedo García, Renata; Zárate Treviño, Arturo; González Escudero, Eduardo Alberto; Degollado Córdova, José Antonio

    2014-06-01

    Epicardial adipose tissue has been associated with several obesity-related parameters and with insulin resistance. Echocardiographic assessment of this tissue is an easy and reliable marker of cardiometabolic risk. However, there are insufficient studies on the relationship between epicardial fat and insulin resistance during the postmenopausal period, when cardiovascular risk increases in women. The objective of this study was to examine the association between epicardial adipose tissue and visceral adipose tissue, waist circumference, body mass index, and insulin resistance in postmenopausal women. A cross sectional study was conducted in 34 postmenopausal women with and without metabolic syndrome. All participants underwent a transthoracic echocardiogram and body composition analysis. A positive correlation was observed between epicardial fat and visceral adipose tissue, body mass index, and waist circumference. The values of these correlations of epicardial fat thickness overlying the aorta-right ventricle were r = 0.505 (P < .003), r = 0.545 (P < .001), and r = 0.515 (P < .003), respectively. Epicardial adipose tissue was higher in postmenopausal women with metabolic syndrome than in those without this syndrome (mean [standard deviation], 544.2 [122.9] vs 363.6 [162.3] mm(2); P = .03). Epicardial fat thickness measured by echocardiography was associated with visceral adipose tissue and other obesity parameters. Epicardial adipose tissue was higher in postmenopausal women with metabolic syndrome. Therefore, echocardiographic assessment of epicardial fat may be a simple and reliable marker of cardiovascular risk in postmenopausal women. Copyright © 2013 Sociedad Española de Cardiología. Published by Elsevier Espana. All rights reserved.

  19. WAT-on-a-chip: A physiologically relevant microfluidic system incorporating white adipose tissue

    PubMed Central

    Loskill, Peter; Sezhian, Thiagarajan; Tharp, Kevin; Lee-Montiel, Felipe T.; Jeeawoody, Shaheen; Reese, Willie Mae; Zushin, Pete-James H.; Stahl, Andreas; Healy, Kevin E.

    2017-01-01

    Organ-on-a-chip systems possess a promising future as drug screening assays and as testbeds for disease modeling in the context of both single-organ systems and multi-organ-chips. Although it comprises approximately one fourth of the body weight of a healthy human, an organ frequently overlooked in this context is white adipose tissue (WAT). WAT-on-a-chip systems are required to create safety profiles of a large number of drugs due to their interactions with adipose tissue and other organs via paracrine signals, fatty acid release, and drug levels through sequestration. We report a WAT-on-a-chip system with a footprint of less than 1 mm2 consisting of a separate media channel and WAT chamber connected via small micropores. Analogous to the in vivo blood circulation, convective transport is thereby confined to the vasculature-like structures and the tissues protected from shear stresses. Numerical and analytical modeling revealed that the flow rates in the WAT chambers are less than 1/100 of the input flow rate. Using optimized injection parameters, we were able to inject pre-adipocytes, which subsequently formed adipose tissue featuring fully functional lipid metabolism. The physiologically relevant microfluidic environment of the WAT-chip supported long term culture of the functional adipose tissue for more than two weeks. Due to its physiological, highly controlled, and computationally predictable character, the system has the potential to be a powerful tool for the study of adipose tissue associated diseases such as obesity and type 2 diabetes. PMID:28418430

  20. Milk-derived peptide Val-Pro-Pro (VPP) inhibits obesity-induced adipose inflammation via an angiotensin-converting enzyme (ACE) dependent cascade.

    PubMed

    Sawada, Yoko; Sakamoto, Yuri; Toh, Mariko; Ohara, Nozomi; Hatanaka, Yuiko; Naka, Ayano; Kishimoto, Yoshimi; Kondo, Kazuo; Iida, Kaoruko

    2015-12-01

    This study aimed to examine the effects of Val-Pro-Pro (VPP), a food-derived peptide with an angiotensin-converting enzyme (ACE) inhibitory property, on obesity-linked insulin resistance, and adipose inflammation in vivo and in vitro. C57BL/6J mice were fed high-fat high-sucrose diet and VPP (0.1% in water) for 4 months. For in vitro analysis, coculture of 3T3-L1 adipocytes overexpressing either ACE (3T3-ACE) or green fluorescent protein (3T3-GFP) and RAW264 macrophages was conducted with VPP. In diet-induced obese mice, VPP improved insulin sensitivity, concomitant with a significant decrease in tumor necrosis factor α (TNF-α) and IL-1β expression in adipose tissue, with a tendency (p = 0.06) toward decreased CC chemokine ligand 5 expression. Additionally, VPP administration inhibited macrophage accumulation and activation in fat tissues. In vitro, VPP attenuated TNF-α mRNA induced by ACE overexpression in 3T3-L1 adipocytes. TNF-α and IL-1β expression decreased following VPP treatment of RAW264 macrophage and 3T3-ACE adipocyte cocultures, but not in RAW264-3T3-GFP adipocyte cocultures. Our data suggest that VPP inhibits adipose inflammation in the interaction between adipocytes and macrophages, acting as an ACE inhibitor, thereby improving obesity-related insulin resistance. Thus, ingestion of VPP may be a viable protective and therapeutic strategy for insulin resistance and obesity-associated adipose inflammation. © 2015 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

  1. Interactions between adipose tissue and the immune system in health and malnutrition.

    PubMed

    Wensveen, Felix M; Valentić, Sonja; Šestan, Marko; Wensveen, Tamara Turk; Polić, Bojan

    2015-09-01

    Adipose tissue provides the body with a storage depot of nutrients that is drained during times of starvation and replenished when food sources are abundant. As such, it is the primary sensor for nutrient availability in the milieu of an organism, which it communicates to the body through the excretion of hormones. Adipose tissue regulates a multitude of body functions associated with metabolism, such as gluconeogenesis, feeding and nutrient uptake. The immune system forms a vital layer of protection against micro-organisms that try to gain access to the nutrients contained in the body. Because infections need to be resolved as quickly as possible, speed is favored over energy-efficiency in an immune response. Especially when immune cells are activated, they switch to fast, but energy-inefficient anaerobic respiration to fulfill their energetic needs. Despite the necessity for an effective immune system, it is not given free rein in its energy expenditure. Signals derived from adipose tissue limit immune cell numbers and activity under conditions of nutrient shortage, whereas they allow proper immune cell activity when food sources are sufficiently available. When excessive fat accumulation occurs, such as in diet-induced obesity, adipose tissue becomes the site of pathological immune cell activation, causing chronic low-grade systemic inflammation. Obesity is therefore associated with a number of disorders in which the immune system plays a central role, such as atherosclerosis and non-alcoholic steatohepatitis. In this review, we will discuss the way in which adipose tissue regulates activity of the immune system under healthy and pathological conditions. Copyright © 2015 Elsevier Ltd. All rights reserved.

  2. Atorvastatin reduces cardiac and adipose tissue inflammation in rats with metabolic syndrome.

    PubMed

    Yamada, Yuichiro; Takeuchi, Shino; Yoneda, Mamoru; Ito, Shogo; Sano, Yusuke; Nagasawa, Kai; Matsuura, Natsumi; Uchinaka, Ayako; Murohara, Toyoaki; Nagata, Kohzo

    2017-08-01

    Statins are strong inhibitors of cholesterol biosynthesis and help to prevent cardiovascular disease. They also exert additional pleiotropic effects that include an anti-inflammatory action and are independent of cholesterol, but the molecular mechanisms underlying these additional effects have remained unclear. We have now examined the effects of atorvastatin on cardiac and adipose tissue inflammation in DahlS.Z-Lepr fa /Lepr fa (DS/obese) rats, which we previously established as a model of metabolic syndrome (MetS). DS/obese rats were treated with atorvastatin (6 or 20mgkg -1 day -1 ) from 9 to 13weeks of age. Atorvastatin ameliorated cardiac fibrosis, diastolic dysfunction, oxidative stress, and inflammation as well as adipose tissue inflammation in these animals at both doses. The high dose of atorvastatin reduced adipocyte hypertrophy to a greater extent than did the low dose. Atorvastatin inhibited the up-regulation of peroxisome proliferator-activated receptor γ gene expression in adipose tissue as well as decreased the serum adiponectin concentration in DS/obese rats. It also activated AMP-activated protein kinase (AMPK) as well as inactivated nuclear factor-κB (NF-κB) in the heart of these animals. The down-regulation of AMPK and NF-κB activities in adipose tissue of DS/obese rats was attenuated and further enhanced, respectively, by atorvastatin treatment. The present results suggest that the anti-inflammatory effects of atorvastatin on the heart and adipose tissue are attributable at least partly to increased AMPK activity and decreased NF-κB activity in this rat model of MetS. Copyright © 2017 Elsevier B.V. All rights reserved.

  3. Correlation of MRI-derived adipose tissue measurements and anthropometric markers with prevalent hypertension in the community.

    PubMed

    Lorbeer, Roberto; Rospleszcz, Susanne; Schlett, Christopher L; Heber, Sophia D; Machann, Jürgen; Thorand, Barbara; Meisinger, Christa; Heier, Margit; Peters, Annette; Bamberg, Fabian; Lieb, Wolfgang

    2018-07-01

    To compare the correlations of MRI-derived adipose tissue measurements and anthropometric markers, respectively, with prevalent hypertension in a community-based sample, free of clinical cardiovascular disease. MRI-derived adipose tissue measurements were obtained in 345 participants (143 women; age 39-73 years) of the KORA FF4 survey from Southern Germany using a 3-Tesla machine and included total adipose tissue (TAT), visceral adipose tissue (VAT), subcutaneous adipose tissue (SCAT), hepatic fat fraction (HFF), pancreatic fat fraction (PFF) as well as pericardial adipose tissue (PAT). In addition, the anthropometric markers body mass index, waist circumference, hip circumference, waist-hip ratio (WHR) and waist-height ratio (WHtR) as well as blood pressure measurements were obtained. The prevalence of hypertension was 33.6% (women: 28%, men: 38%). VAT and PAT had the highest area under the curve (AUC) values for identifying individuals with prevalent hypertension (AUC: 0.75; 0.73, respectively), whereas WHtR and waist circumference were best performing anthropometric markers (AUC: 0.72; 0.70, respectively). A 1SD increment of TAT was associated with the highest odd for hypertension in the age-adjusted and sex-adjusted model (OR = 2.20, 95% CI 1.67-2.91, P < 0.001) and in the fully adjusted model (OR = 1.97, 95% CI 1.45-2.66, P < 0.001). TAT was the only MRI-derived adipose tissue measurement that was associated with hypertension independently of the best performing anthropometric marker waist circumference in the fully adjusted model (OR = 1.93, 95% CI 1.00-3.72, P = 0.049). MRI-derived adipose tissue measurements perform similarly in identifying prevalent hypertension compared with anthropometric markers. Especially, TAT, VAT and PAT as well as WHtR and waist circumference were highly correlated with prevalent hypertension.

  4. Depot differences in steroid receptor expression in adipose tissue: possible role of the local steroid milieu.

    PubMed

    Rodriguez-Cuenca, S; Monjo, M; Proenza, A M; Roca, P

    2005-01-01

    Sex hormones play an important role in adipose tissue metabolism by activating specific receptors that alter several steps of the lipolytic and lipogenic signal cascade in depot- and sex-dependent manners. However, studies focusing on steroid receptor status in adipose tissue are scarce. In the present study, we analyzed steroid content [testosterone (T), 17beta-estradiol (17beta-E2), and progesterone (P4)] and steroid receptor mRNA levels in different rat adipose tissue depots. As expected, T levels were higher in males than in females (P = 0.031), whereas the reverse trend was observed for P4 (P < 0.001). It is noteworthy that 17beta-E2 adipose tissue levels were higher in inguinal than in the rest of adipose tissues for both sexes, where no sex differences in 17beta-E2 tissue levels were noted (P = 0.010 for retroperitoneal, P = 0.005 for gonadal, P = 0.018 for mesenteric). Regarding steroid receptor levels, androgen (AR) and estrogen receptor (ER)alpha and ERbeta densities were more clearly dependent on adipose depot location than on sex, with visceral depots showing overall higher mRNA densities than their subcutaneous counterparts. Besides, expression of ERalpha predominated over ERbeta expression, and progesterone receptor (PR-B form and PR-A+B form) mRNAs were identically expressed regardless of anatomic depot and sex. In vitro studies in 3T3-L1 cells showed that 17beta-E2 increased ERalpha (P = 0.001) and AR expression (P = 0.001), indicating that estrogen can alter estrogenic and androgenic signaling in adipose tissue. The results highlighted in this study demonstrate important depot-dependent differences in the sensitivity of adipose tissues to sex hormones between visceral and subcutaneous depots that could be related to metabolic situations observed in response to sex hormones.

  5. Impairment of adipose tissue in Prader-Willi syndrome rescued by growth hormone treatment.

    PubMed

    Cadoudal, T; Buléon, M; Sengenès, C; Diene, G; Desneulin, F; Molinas, C; Eddiry, S; Conte-Auriol, F; Daviaud, D; Martin, P G P; Bouloumié, A; Salles, J-P; Tauber, M; Valet, P

    2014-09-01

    Prader-Willi syndrome (PWS) results from abnormalities in the genomic imprinting process leading to hypothalamic dysfunction with an alteration of growth hormone (GH) secretion. PWS is associated with early morbid obesity and short stature which can be efficiently improved with GH treatment. Our aims were to highlight adipose tissue structural and functional impairments in children with PWS and to study the modifications of those parameters on GH treatment. Plasma samples and adipose tissue biopsies were obtained from 23 research centers in France coordinated by the reference center for PWS in Toulouse, France. Lean controls (n=33), non-syndromic obese (n=53), untreated (n=26) and GH-treated PWS (n=43) children were enrolled in the study. Adipose tissue biopsies were obtained during scheduled surgeries from 15 lean control, 7 untreated and 8 GH-treated PWS children. Children with PWS displayed higher insulin sensitivity as shown by reduced glycemia, insulinemia and HOMA-IR compared with non-syndromic obese children. In contrast, plasma inflammatory cytokines such as TNF-α, MCP-1 and IL-8 were increased in PWS. Analysis of biopsies compared with control children revealed decreased progenitor cell content in the stromal vascular fraction of adipose tissue and an impairment of lipolytic response to β-adrenergic agonist in PWS adipocytes. Interestingly, both of these alterations in PWS seem to be ameliorated on GH treatment. Herein, we report adipose tissue dysfunctions in children with PWS which may be partially restored by GH treatment.

  6. Biologically and mechanically driven design of an RGD-mimetic macroporous foam for adipose tissue engineering applications.

    PubMed

    Rossi, Eleonora; Gerges, Irini; Tocchio, Alessandro; Tamplenizza, Margherita; Aprile, Paola; Recordati, Camilla; Martello, Federico; Martin, Ivan; Milani, Paolo; Lenardi, Cristina

    2016-10-01

    Despite clinical treatments for adipose tissue defects, in particular breast tissue reconstruction, have certain grades of efficacy, many drawbacks are still affecting the long-term survival of new formed fat tissue. To overcome this problem, in the last decades, several scaffolding materials have been investigated in the field of adipose tissue engineering. However, a strategy able to recapitulate a suitable environment for adipose tissue reconstruction and maintenance is still missing. To address this need, we adopted a biologically and mechanically driven design to fabricate an RGD-mimetic poly(amidoamine) oligomer macroporous foam (OPAAF) for adipose tissue reconstruction. The scaffold was designed to fulfil three fundamental criteria: capability to induce cell adhesion and proliferation, support of in vivo vascularization and match of native tissue mechanical properties. Poly(amidoamine) oligomers were formed into soft scaffolds with hierarchical porosity through a combined free radical polymerization and foaming reaction. OPAAF is characterized by a high water uptake capacity, progressive degradation kinetics and ideal mechanical properties for adipose tissue reconstruction. OPAAF's ability to support cell adhesion, proliferation and adipogenesis was assessed in vitro using epithelial, fibroblast and endothelial cells (MDCK, 3T3L1 and HUVEC respectively). In addition, in vivo subcutaneous implantation in murine model highlighted OPAAF potential to support both adipogenesis and vessels infiltration. Overall, the reported results support the use of OPAAF as a scaffold for engineered adipose tissue construct. Copyright © 2016 Elsevier Ltd. All rights reserved.

  7. Weight-dependent changes of immune system in adipose tissue: Importance of leptin

    DOE Office of Scientific and Technical Information (OSTI.GOV)

    Caspar-Bauguil, S.; Groupe de Recherche et d'Etude en Nutrition; Cousin, B.

    2006-07-15

    Ancestral lymphoid cells reside in adipose tissues, and their numbers are highly altered in obesity. Leptin, production of which is correlated to fat mass, is strongly involved in the relationships between adipose tissues and immune system. We investigated in epididymal (EPI) and inguinal (ING) fat pads to determine whether 1) lymphocyte phenotypes were correlated to the tissue weight and 2) leptin was involved in such relationships. Immunohistological analyses revealed a tight relationship between the T and NK lymphocytes of the stromal vascular fraction and adipocytes. We identified a significant negative and positive correlation between EPI weight and the percentage ofmore » NK and total T cells respectively by cytofluorometric analyses. The NK and ancestral {gamma}{delta} T cell contents were directly dependent of leptin since they increased significantly in high-fat (HF) diet mice but not in leptin-deficient (ob/ob) mice as compared to control. By contrast, the {alpha}{beta} T cell content seemed independent of leptin because their percentages increased significantly with the EPI weight whatever the type of mice (control, HF, ob/ob). The present study suggests that adipose tissues present, according to their localization, different immunological mechanisms that might be involved in the regulation of adipose cells functions and proliferations.« less

  8. Effects of Male Hypogonadism on Regional Adipose Tissue Fatty Acid Storage and Lipogenic Proteins

    PubMed Central

    Santosa, Sylvia; Jensen, Michael D.

    2012-01-01

    Testosterone has long been known to affect body fat distribution, although the underlying mechanisms remain elusive. We investigated the effects of chronic hypogonadism in men on adipose tissue fatty acid (FA) storage and FA storage factors. Twelve men with chronic hypogonadism and 13 control men matched for age and body composition: 1) underwent measures of body composition with dual energy x-ray absorptiometry and an abdominal CT scan; 2) consumed an experimental meal containing [3H]triolein to determine the fate of meal FA (biopsy-measured adipose storage vs. oxidation); 3) received infusions of [U-13C]palmitate and [1-14C]palmitate to measure rates of direct free (F)FA storage (adipose biopsies). Adipose tissue lipoprotein lipase, acyl-CoA synthetase (ACS), and diacylglycerol acetyl-transferase (DGAT) activities, as well as, CD36 content were measured to understand the mechanism by which alterations in fat storage occur in response to testosterone deficiency. Results of the study showed that hypogonadal men stored a greater proportion of both dietary FA and FFA in lower body subcutaneous fat than did eugonadal men (both p<0.05). Femoral adipose tissue ACS activity was significantly greater in hypogonadal than eugonadal men, whereas CD36 and DGAT were not different between the two groups. The relationships between these proteins and FA storage varied somewhat between the two groups. We conclude that chronic effects of testosterone deficiency has effects on leg adipose tissue ACS activity which may relate to greater lower body FA storage. These results provide further insight into the role of androgens in body fat distribution and adipose tissue metabolism in humans. PMID:22363653

  9. Reduced Socs3 expression in adipose tissue protects female mice against obesity-induced insulin resistance.

    PubMed

    Palanivel, R; Fullerton, M D; Galic, S; Honeyman, J; Hewitt, K A; Jorgensen, S B; Steinberg, G R

    2012-11-01

    Inflammation in obesity increases the levels of the suppressor of cytokine signalling-3 (SOCS3) protein in adipose tissue, but the physiological importance of this protein in regulating whole-body insulin sensitivity in obesity is not known. We generated Socs3 floxed (wild-type, WT) and Socs3 aP2 (also known as Fabp4)-Cre null (Socs3 AKO) mice. Mice were maintained on either a regular chow or a high-fat diet (HFD) for 16 weeks during which time body mass, adiposity, glucose homeostasis and insulin sensitivity were assessed. The HFD increased SOCS3 levels in adipose tissue of WT but not Socs3 AKO mice. WT and Socs3 AKO mice had similar body mass and adiposity, assessed using computed tomography (CT) imaging, irrespective of diet or sex. On a control chow diet there were no differences in insulin sensitivity or glucose tolerance. When fed a HFD, female but not male Socs3 AKO mice had improved glucose tolerance as well as lower fasting glucose and insulin levels compared with WT littermates. Hyperinsulinaemic-euglycaemic clamps and positron emission tomography (PET) imaging demonstrated that improved insulin sensitivity was due to elevated adipose tissue glucose uptake. Increased insulin-stimulated glucose uptake in adipose tissue was associated with enhanced levels and activating phosphorylation of insulin receptor substrate-1 (IRS1). These data demonstrate that inhibiting SOCS3 production in adipose tissue of female mice is effective for improving whole-body insulin sensitivity in obesity.

  10. Tracking of adipose tissue-derived progenitor cells using two magnetic nanoparticle types

    NASA Astrophysics Data System (ADS)

    Kasten, Annika; Siegmund, Birte J.; Grüttner, Cordula; Kühn, Jens-Peter; Frerich, Bernhard

    2015-04-01

    Magnetic resonance imaging (MRI) is to be considered as an emerging detection technique for cell tracking experiments to evaluate the fate of transplanted progenitor cells and develop successful cell therapies for tissue engineering. Adipose tissue engineering using adipose tissue-derived progenitor cells has been advocated for the cure of soft tissue defects or for persistent soft tissue augmentation. Adipose tissue-derived progenitor cells were differentiated into the adipogenic lineage and labeled with two different types of magnetic iron oxide nanoparticles in varying concentrations which resulted in a concentration-dependent reduction of gene expression of adipogenic differentiation markers, adiponectin and fatty acid-binding protein 4 (FABP4), whereas the metabolic activity was not altered. As a result, only low nanoparticle concentrations for labeling were used for in vivo experiments. Cells were seeded onto collagen scaffolds and subcutaneously implanted into severe combined immunodeficient (SCID) mice. At 24 h as well as 28 days after implantation, MRI analyses were performed visualizing nanoparticle-labeled cells using T2-weighted sequences. The quantification of absolute volume of the scaffolds revealed a decrease of volume over time in all experimental groups. The distribution of nanoparticle-labeled cells within the scaffolds varied likewise over time.

  11. Exocytosis of macrophage lysosomes leads to digestion of apoptotic adipocytes and foam cell formation[S

    PubMed Central

    Haka, Abigail S.; Barbosa-Lorenzi, Valéria C.; Lee, Hyuek Jong; Falcone, Domenick J.; Hudis, Clifford A.; Dannenberg, Andrew J.

    2016-01-01

    Many types of apoptotic cells are phagocytosed and digested by macrophages. Adipocytes can be hundreds of times larger than macrophages, so they are too large to be digested by conventional phagocytic processes. The nature of the interaction between macrophages and apoptotic adipocytes has not been studied in detail. We describe a cellular process, termed exophagy, that is important for macrophage clearance of dead adipocytes and adipose tissue homeostasis. Using mouse models of obesity, human tissue, and a cell culture model, we show that macrophages form hydrolytic extracellular compartments at points of contact with dead adipocytes using local actin polymerization. These compartments are acidic and contain lysosomal enzymes delivered by exocytosis. Uptake and complete degradation of adipocyte fragments, which are released by extracellular hydrolysis, leads to macrophage foam cell formation. Exophagy-mediated foam cell formation is a highly efficient means by which macrophages internalize large amounts of lipid, which may ultimately overwhelm the metabolic capacity of the macrophage. This process provides a mechanism for degradation of objects, such as dead adipocytes, that are too large to be phagocytosed by macrophages. PMID:27044658

  12. 4E-BP1 regulates the differentiation of white adipose tissue.

    PubMed

    Tsukiyama-Kohara, Kyoko; Katsume, Asao; Kimura, Kazuhiro; Saito, Masayuki; Kohara, Michinori

    2013-07-01

    4E Binding protein 1 (4E-BP1) suppresses translation initiation. The absence of 4E-BP1 drastically reduces the amount of adipose tissue in mice. To address the role of 4E-BP1 in adipocyte differentiation, we characterized 4E-BP1(-/-) mice in this study. The lack of 4E-BP1 decreased the amount of white adipose tissue and increased the amount of brown adipose tissue. In 4E-BP1(-/-) MEF cells, PPARγ coactivator 1 alpha (PGC-1α) expression increased and exogenous 4E-BP1 expression suppressed PGC-1α expression. The level of 4E-BP1 expression was higher in white adipocytes than in brown adipocytes and showed significantly greater up-regulation in white adipocytes than in brown adipocytes during preadipocyte differentiation into mature adipocytes. The amount of PGC-1α was consistently higher in HB cells (a brown preadipocyte cell line) than in HW cells (a white preadipocyte cell line) during differentiation. Moreover, the ectopic over-expression of 4E-BP1 suppressed PGC-1α expression in white adipocytes, but not in brown adipocytes. Thus, the results of our study indicate that 4E-BP1 may suppress brown adipocyte differentiation and PGC-1α expression in white adipose tissues. © 2013 The Authors Genes to Cells © 2013 by the Molecular Biology Society of Japan and Wiley Publishing Asia Pty Ltd.

  13. Development, regulation, metabolism and function of bone marrow adipose tissues.

    PubMed

    Li, Ziru; Hardij, Julie; Bagchi, Devika P; Scheller, Erica L; MacDougald, Ormond A

    2018-05-01

    Most adipocytes exist in discrete depots throughout the body, notably in well-defined white and brown adipose tissues. However, adipocytes also reside within specialized niches, of which the most abundant is within bone marrow. Whereas bone marrow adipose tissue (BMAT) shares many properties in common with white adipose tissue, the distinct functions of BMAT are reflected by its development, regulation, protein secretion, and lipid composition. In addition to its potential role as a local energy reservoir, BMAT also secretes proteins, including adiponectin, RANK ligand, dipeptidyl peptidase-4, and stem cell factor, which contribute to local marrow niche functions and which may also influence global metabolism. The characteristics of BMAT are also distinct depending on whether marrow adipocytes are contained within yellow or red marrow, as these can be thought of as 'constitutive' and 'regulated', respectively. The rBMAT for instance can be expanded or depleted by myriad factors, including age, nutrition, endocrine status and pharmaceuticals. Herein we review the site specificity, age-related development, regulation and metabolic characteristics of BMAT under various metabolic conditions, including the functional interactions with bone and hematopoietic cells. Copyright © 2018 Elsevier Inc. All rights reserved.

  14. The Role of Macrophage Phenotype in Vascularization of Tissue Engineering Scaffolds

    PubMed Central

    Spiller, Kara L.; Anfang, Rachel; Spiller, Krista J.; Ng, Johnathan; Nakazawa, Kenneth R.; Daulton, Jeffrey W.; Vunjak-Novakovic, Gordana

    2014-01-01

    Angiogenesis is crucial for the success of most tissue engineering strategies. The natural inflammatory response is a major regulator of vascularization, through the activity of different types of macrophages and the cytokines they secrete. Macrophages exist on a spectrum of diverse phenotypes, from “classically activated” M1 to “alternatively activated” M2 macrophages. M2 macrophages, including the subsets M2a and M2c, are typically considered to promote angiogenesis and tissue regeneration, while M1 macrophages are considered to be anti-angiogenic, although these classifications are controversial. Here we show that in contrast to this traditional paradigm, primary human M1 macrophages secrete the highest levels of potent angiogenic stimulators including VEGF; M2a macrophages secrete the highest levels of PDGF-BB, a chemoattractant stabilizing pericytes, and also promote anastomosis of sprouting endothelial cells in vitro; and M2c macrophages secrete the highest levels of MMP9, an important protease involved in vascular remodeling. In a murine subcutaneous implantation model, porous collagen scaffolds were surrounded by a fibrous capsule, coincident with high expression of M2 macrophage markers, while scaffolds coated with the bacterial lipopolysaccharide were degraded by inflammatory macrophages, and glutaraldehyde-crosslinked scaffolds were infiltrated by substantial numbers of blood vessels accompanied by high levels of M1 and M2 macrophages. These results suggest that coordinated efforts by both M1 and M2 macrophages are required for angiogenesis and scaffold vascularization, which may explain some of the controversy over which phenotype is the angiogenic phenotype. PMID:24589361

  15. Fatty Acid Composition of Lamb Liver, Muscle, And Adipose Tissues in Response to Rumen-Protected Conjugated Linoleic Acid (CLA) Supplementation Is Tissue Dependent.

    PubMed

    Schiavon, Stefano; Bergamaschi, Matteo; Pellattiero, Erika; Simonetto, Alberto; Tagliapietra, Franco

    2017-12-06

    The tissue-specific response to rumen-protected conjugated linoleic acid supply (rpCLA) of liver, two muscles, and three adipose tissues of heavy lambs was studied. Twenty-four lambs, 8 months old, divided into 4 groups of 6, were fed at libitum on a ration supplemented without or with a mixture of rpCLA. Silica and hydrogenated soybean oil was the rpCLA coating matrix. The lambs were slaughtered at 11 months of age. Tissues were collected and analyzed for their FA profiles. The dietary rpCLA supplement had no influence on carcass fatness nor on the fat content of the liver and tissues and had little influence on the FA profiles of these tissues. In the adipose tissues, rpCLA increased the proportions of saturated FAs, 18:0 and 18:2t10c12, and decreased the proportions of monounsaturated FAs in the adipose tissues. In muscles, the effects were the opposite. The results suggest that Δ9 desaturase activity is inhibited by the rpCLA mixture in adipose tissues to a greater extent than in the other tissues.

  16. Comparison of three methods for the derivation of a biologic scaffold composed of adipose tissue extracellular matrix.

    PubMed

    Brown, Bryan N; Freund, John M; Han, Li; Rubin, J Peter; Reing, Janet E; Jeffries, Eric M; Wolf, Mathew T; Tottey, Stephen; Barnes, Christopher A; Ratner, Buddy D; Badylak, Stephen F

    2011-04-01

    Extracellular matrix (ECM)-based scaffold materials have been used successfully in both preclinical and clinical tissue engineering and regenerative medicine approaches to tissue reconstruction. Results of numerous studies have shown that ECM scaffolds are capable of supporting the growth and differentiation of multiple cell types in vitro and of acting as inductive templates for constructive tissue remodeling after implantation in vivo. Adipose tissue represents a potentially abundant source of ECM and may represent an ideal substrate for the growth and adipogenic differentiation of stem cells harvested from this tissue. Numerous studies have shown that the methods by which ECM scaffold materials are prepared have a dramatic effect upon both the biochemical and structural properties of the resultant ECM scaffold material as well as the ability of the material to support a positive tissue remodeling outcome after implantation. The objective of the present study was to characterize the adipose ECM material resulting from three methods of decellularization to determine the most effective method for the derivation of an adipose tissue ECM scaffold that was largely free of potentially immunogenic cellular content while retaining tissue-specific structural and functional components as well as the ability to support the growth and adipogenic differentiation of adipose-derived stem cells. The results show that each of the decellularization methods produced an adipose ECM scaffold that was distinct from both a structural and biochemical perspective, emphasizing the importance of the decellularization protocol used to produce adipose ECM scaffolds. Further, the results suggest that the adipose ECM scaffolds produced using the methods described herein are capable of supporting the maintenance and adipogenic differentiation of adipose-derived stem cells and may represent effective substrates for use in tissue engineering and regenerative medicine approaches to soft tissue

  17. Fat body, fat pad and adipose tissues in invertebrates and vertebrates: the nexus

    PubMed Central

    2014-01-01

    The fat body in invertebrates was shown to participate in energy storage and homeostasis, apart from its other roles in immune mediation and protein synthesis to mention a few. Thus, sharing similar characteristics with the liver and adipose tissues in vertebrates. However, vertebrate adipose tissue or fat has been incriminated in the pathophysiology of metabolic disorders due to its role in production of pro-inflammatory cytokines. This has not been reported in the insect fat body. The link between the fat body and adipose tissue was examined in this review with the aim of determining the principal factors responsible for resistance to inflammation in the insect fat body. This could be the missing link in the prevention of metabolic disorders in vertebrates, occasioned by obesity. PMID:24758278

  18. Reference genes for quantitative PCR in the adipose tissue of mice with metabolic disease.

    PubMed

    Almeida-Oliveira, Fernanda; Leandro, João G B; Ausina, Priscila; Sola-Penna, Mauro; Majerowicz, David

    2017-04-01

    Obesity and diabetes are metabolic diseases and they are increasing in prevalence. The dynamics of gene expression associated with these diseases is fundamental to identifying genes involved in related biological processes. qPCR is a sensitive technique for mRNA quantification and the most commonly used method in gene-expression studies. However, the reliability of these results is directly influenced by data normalization. As reference genes are the major normalization method used, this work aims to identify reference genes for qPCR in adipose tissues of mice with type-I diabetes or obesity. We selected 12 genes that are commonly used as reference genes. The expression of these genes in the adipose tissues of mice was analyzed in the context of three different experimental protocols: 1) untreated animals; 2) high-fat-diet animals; and 3) streptozotocin-treated animals. Gene-expression stability was analyzed using four different algorithms. Our data indicate that TATA-binding protein is stably expressed across adipose tissues in control animals. This gene was also a useful reference when the brown adipose tissues of control and obese mice were analyzed. The mitochondrial ATP synthase F1 complex gene exhibits stable expression in subcutaneous and perigonadal adipose tissue from control and obese mice. Moreover, this gene is the best reference for qPCR normalization in adipose tissue from streptozotocin-treated animals. These results show that there is no perfect stable gene suited for use under all experimental conditions. In conclusion, the selection of appropriate genes is a prerequisite to ensure qPCR reliability and must be performed separately for different experimental protocols. Copyright © 2017 Elsevier Masson SAS. All rights reserved.

  19. Prognostic Effect of Low Subcutaneous Adipose Tissue on Survival Outcome in Patients With Multiple Myeloma.

    PubMed

    Takeoka, Yasunobu; Sakatoku, Kazuki; Miura, Akiko; Yamamura, Ryosuke; Araki, Taku; Seura, Hirotaka; Okamura, Terue; Koh, Hideo; Nakamae, Hirohisa; Hino, Masayuki; Ohta, Kensuke

    2016-08-01

    Increasing evidence suggests that decreased skeletal muscle mass (sarcopenia) or adipose tissue assessed using computed tomography (CT) predicts negative outcomes in patients with solid tumors. However, the prognostic value of such an assessment in multiple myeloma (MM) remains unknown. Consecutive patients with newly diagnosed symptomatic MM were retrospectively analyzed. The cross-sectional area of skeletal muscles and subcutaneous or visceral adipose tissue was measured using CT. Body composition indexes (skeletal muscle index, subcutaneous adipose tissue index [SAI], and visceral adipose tissue index) were calculated. The association between these indexes and overall survival (OS) was examined. Of 56 evaluable patients, 37 (66%) had sarcopenia. The 2-year OS in patients with SAI < median was 58% compared with 91% in those with SAI ≥ median (P = .006). In multivariate analyses, SAI < median was significantly associated with poor OS (hazard ratio, 4.05; P = .02). Sarcopenia was not associated with OS. The maximum value of the standardized uptake value was significantly higher in patients with SAI < median (P = .02). The findings of this study suggest that low subcutaneous adipose tissue at baseline predicts poor survival outcome in patients with MM. Copyright © 2016 Elsevier Inc. All rights reserved.

  20. Adipose tissue mitochondrial dysfunction triggers a lipodystrophic syndrome with insulin resistance, hepatosteatosis, and cardiovascular complications.

    PubMed

    Vernochet, Cecile; Damilano, Federico; Mourier, Arnaud; Bezy, Olivier; Mori, Marcelo A; Smyth, Graham; Rosenzweig, Anthony; Larsson, Nils-Göran; Kahn, C Ronald

    2014-10-01

    Mitochondrial dysfunction in adipose tissue occurs in obesity, type 2 diabetes, and some forms of lipodystrophy, but whether this dysfunction contributes to or is the result of these disorders is unknown. To investigate the physiological consequences of severe mitochondrial impairment in adipose tissue, we generated mice deficient in mitochondrial transcription factor A (TFAM) in adipocytes by using mice carrying adiponectin-Cre and TFAM floxed alleles. These adiponectin TFAM-knockout (adipo-TFAM-KO) mice had a 75-81% reduction in TFAM in the subcutaneous and intra-abdominal white adipose tissue (WAT) and interscapular brown adipose tissue (BAT), causing decreased expression and enzymatic activity of proteins in complexes I, III, and IV of the electron transport chain (ETC). This mitochondrial dysfunction led to adipocyte death and inflammation in WAT and a whitening of BAT. As a result, adipo-TFAM-KO mice were resistant to weight gain, but exhibited insulin resistance on both normal chow and high-fat diets. These lipodystrophic mice also developed hypertension, cardiac hypertrophy, and cardiac dysfunction. Thus, isolated mitochondrial dysfunction in adipose tissue can lead a syndrome of lipodystrophy with metabolic syndrome and cardiovascular complications. © FASEB.

  1. The Effect of Marine Derived n-3 Fatty Acids on Adipose Tissue Metabolism and Function

    PubMed Central

    Todorčević, Marijana; Hodson, Leanne

    2015-01-01

    Adipose tissue function is key determinant of metabolic health, with specific nutrients being suggested to play a role in tissue metabolism. One such group of nutrients are the n-3 fatty acids, specifically eicosapentaenoic acid (EPA; 20:5n-3) and docosahexaenoic acid (DHA; 22:6n-3). Results from studies where human, animal and cellular models have been utilised to investigate the effects of EPA and/or DHA on white adipose tissue/adipocytes suggest anti-obesity and anti-inflammatory effects. We review here evidence for these effects, specifically focusing on studies that provide some insight into metabolic pathways or processes. Of note, limited work has been undertaken investigating the effects of EPA and DHA on white adipose tissue in humans whilst more work has been undertaken using animal and cellular models. Taken together it would appear that EPA and DHA have a positive effect on lowering lipogenesis, increasing lipolysis and decreasing inflammation, all of which would be beneficial for adipose tissue biology. What remains to be elucidated is the duration and dose required to see a favourable effect of EPA and DHA in vivo in humans, across a range of adiposity. PMID:26729182

  2. HIV persistence in tissue macrophages of humanized myeloid-only mice during antiretroviral therapy

    DOE Office of Scientific and Technical Information (OSTI.GOV)

    Honeycutt, Jenna B.; Thayer, William O.; Baker, Caroline E.

    Despite years of fully suppressive antiretroviral therapy (ART), HIV persists in its hosts and is never eradicated. One major barrier to eradication is that the virus infects multiple cell types that may individually contribute to HIV persistence. Tissue macrophages are critical contributors to HIV pathogenesis; however, their specific role in HIV persistence during long-term suppressive ART has not been established. Using humanized myeloid-only mice (MoM), we demonstrate that HIV infection of tissue macrophages is rapidly suppressed by ART, as reflected by a rapid drop in plasma viral load and a dramatic decrease in the levels of cell-associated viral RNA andmore » DNA. No viral rebound was observed in the plasma of 67% of the ART-treated animals at 7 weeks after ART interruption, and no replication-competent virus was rescued from the tissue macrophages obtained from these animals. In contrast, in a subset of animals (~33%), a delayed viral rebound was observed that is consistent with the establishment of persistent infection in tissue macrophages. Furthermore, these observations represent the first direct evidence, to our knowledge, of HIV persistence in tissue macrophages in vivo.« less

  3. HIV persistence in tissue macrophages of humanized myeloid-only mice during antiretroviral therapy

    DOE PAGES

    Honeycutt, Jenna B.; Thayer, William O.; Baker, Caroline E.; ...

    2017-04-17

    Despite years of fully suppressive antiretroviral therapy (ART), HIV persists in its hosts and is never eradicated. One major barrier to eradication is that the virus infects multiple cell types that may individually contribute to HIV persistence. Tissue macrophages are critical contributors to HIV pathogenesis; however, their specific role in HIV persistence during long-term suppressive ART has not been established. Using humanized myeloid-only mice (MoM), we demonstrate that HIV infection of tissue macrophages is rapidly suppressed by ART, as reflected by a rapid drop in plasma viral load and a dramatic decrease in the levels of cell-associated viral RNA andmore » DNA. No viral rebound was observed in the plasma of 67% of the ART-treated animals at 7 weeks after ART interruption, and no replication-competent virus was rescued from the tissue macrophages obtained from these animals. In contrast, in a subset of animals (~33%), a delayed viral rebound was observed that is consistent with the establishment of persistent infection in tissue macrophages. Furthermore, these observations represent the first direct evidence, to our knowledge, of HIV persistence in tissue macrophages in vivo.« less

  4. HIV persistence in tissue macrophages of humanized myeloid only mice during antiretroviral therapy

    PubMed Central

    Honeycutt, J. B.; Thayer, W.O.; Baker, C. E.; Ribeiro, R.M.; Lada, S.M.; Cao, Y.; Cleary, R. A.; Hudgens, M. G.; Richman, D.D.; Garcia, J. V.

    2017-01-01

    Despite years of fully suppressive antiretroviral therapy (ART), HIV persists in the host and is never eradicated. One major barrier to eradication is that multiple different cell types are infected that may individually contribute to HIV persistence. Tissue macrophages are critical contributors to HIV disease (1–3); however, their specific role in HIV persistence during long-term suppressive ART has not been established (4–6). Using humanized myeloid-only mice (MoM), we demonstrate that HIV infection of tissue macrophages is rapidly suppressed by ART, as determined by a rapid drop in plasma viral load and a dramatic drop in the levels of cell-associated viral RNA and DNA. No virus rebound was observed in the plasma of 67% of the ART treated animals at seven weeks post-ART interruption, and no replication competent virus was rescued from the tissue macrophages obtained from these animals. In contrast, in a subset of animals (~33%), a significantly delayed viral rebound was observed that is consistent with the establishment of persistent infection in tissue macrophages. These observations represent the first direct evidence of HIV persistence in tissue macrophages in vivo. PMID:28414330

  5. HIV persistence in tissue macrophages of humanized myeloid-only mice during antiretroviral therapy.

    PubMed

    Honeycutt, Jenna B; Thayer, William O; Baker, Caroline E; Ribeiro, Ruy M; Lada, Steven M; Cao, Youfang; Cleary, Rachel A; Hudgens, Michael G; Richman, Douglas D; Garcia, J Victor

    2017-05-01

    Despite years of fully suppressive antiretroviral therapy (ART), HIV persists in its hosts and is never eradicated. One major barrier to eradication is that the virus infects multiple cell types that may individually contribute to HIV persistence. Tissue macrophages are critical contributors to HIV pathogenesis; however, their specific role in HIV persistence during long-term suppressive ART has not been established. Using humanized myeloid-only mice (MoM), we demonstrate that HIV infection of tissue macrophages is rapidly suppressed by ART, as reflected by a rapid drop in plasma viral load and a dramatic decrease in the levels of cell-associated viral RNA and DNA. No viral rebound was observed in the plasma of 67% of the ART-treated animals at 7 weeks after ART interruption, and no replication-competent virus was rescued from the tissue macrophages obtained from these animals. In contrast, in a subset of animals (∼33%), a delayed viral rebound was observed that is consistent with the establishment of persistent infection in tissue macrophages. These observations represent the first direct evidence, to our knowledge, of HIV persistence in tissue macrophages in vivo.

  6. Meteorin-like is a hormone that regulates immune-adipose interactions to increase beige fat thermogenesis.

    PubMed

    Rao, Rajesh R; Long, Jonathan Z; White, James P; Svensson, Katrin J; Lou, Jesse; Lokurkar, Isha; Jedrychowski, Mark P; Ruas, Jorge L; Wrann, Christiane D; Lo, James C; Camera, Donny M; Lachey, Jenn; Gygi, Steven; Seehra, Jasbir; Hawley, John A; Spiegelman, Bruce M

    2014-06-05

    Exercise training benefits many organ systems and offers protection against metabolic disorders such as obesity and diabetes. Using the recently identified isoform of PGC1-α (PGC1-α4) as a discovery tool, we report the identification of meteorin-like (Metrnl), a circulating factor that is induced in muscle after exercise and in adipose tissue upon cold exposure. Increasing circulating levels of Metrnl stimulates energy expenditure and improves glucose tolerance and the expression of genes associated with beige fat thermogenesis and anti-inflammatory cytokines. Metrnl stimulates an eosinophil-dependent increase in IL-4 expression and promotes alternative activation of adipose tissue macrophages, which are required for the increased expression of the thermogenic and anti-inflammatory gene programs in fat. Importantly, blocking Metrnl actions in vivo significantly attenuates chronic cold-exposure-induced alternative macrophage activation and thermogenic gene responses. Thus, Metrnl links host-adaptive responses to the regulation of energy homeostasis and tissue inflammation and has therapeutic potential for metabolic and inflammatory diseases. Copyright © 2014 Elsevier Inc. All rights reserved.

  7. Proliferation and differentiation of adipose tissue in prolonged lean and obese critically ill patients.

    PubMed

    Goossens, Chloë; Vander Perre, Sarah; Van den Berghe, Greet; Langouche, Lies

    2017-12-01

    In prolonged non-obese critically ill patients, preservation of adipose tissue is prioritized over that of the skeletal muscle and coincides with increased adipogenesis. However, we recently demonstrated that in obese critically ill mice, this priority was switched. In the obese, the use of abundantly available adipose tissue-derived energy substrates was preferred and counteracted muscle wasting. These observations suggest that different processes are ongoing in adipose tissue of lean vs. overweight/obese critically ill patients. We hypothesize that to preserve adipose tissue mass during critical illness, adipogenesis is increased in prolonged lean critically ill patients, but not in overweight/obese critically ill patients, who enter the ICU with excess adipose tissue. To test this, we studied markers of adipogenesis in subcutaneous and visceral biopsies of matched lean (n = 24) and overweight/obese (n = 24) prolonged critically ill patients. Secondly, to further unravel the underlying mechanism of critical illness-induced adipogenesis, local production of eicosanoid PPARγ agonists was explored, as well as the adipogenic potential of serum from matched lean (n = 20) and overweight/obese (n = 20) critically ill patients. The number of small adipocytes, PPARγ protein, and CEBPB expression were equally upregulated (p ≤ 0.05) in subcutaneous and visceral adipose tissue biopsies of lean and overweight/obese prolonged critically ill patients. Gene expression of key enzymes involved in eicosanoid production was reduced (COX1, HPGDS, LPGDS, ALOX15, all p ≤ 0.05) or unaltered (COX2, ALOX5) during critical illness, irrespective of obesity. Gene expression of PLA2G2A and ALOX15B was upregulated in lean and overweight/obese patients (p ≤ 0.05), whereas their end products, the PPARγ-activating metabolites 15s-HETE and 9-HODE, were not increased in the adipose tissue. In vitro, serum of lean and overweight/obese prolonged critically ill

  8. Roles of macrophage migration inhibitory factor in cartilage tissue engineering.

    PubMed

    Fujihara, Yuko; Hikita, Atsuhiko; Takato, Tsuyoshi; Hoshi, Kazuto

    2018-02-01

    To obtain stable outcomes in regenerative medicine, understanding and controlling immunological responses in transplanted tissues are of great importance. In our previous study, auricular chondrocytes in tissue-engineered cartilage transplanted in mice were shown to express immunological factors, including macrophage migration inhibitory factor (MIF). Since MIF exerts pleiotropic functions, in this study, we examined the roles of MIF in cartilage regenerative medicine. We made tissue-engineered cartilage consisting of auricular chondrocytes of C57BL/6J mouse, atellocollagen gel and a PLLA scaffold, and transplanted the construct subcutaneously in a syngeneic manner. Localization of MIF was prominent in cartilage areas of tissue-engineered cartilage at 2 weeks after transplantation, though it became less apparent by 8 weeks. Co-culture with RAW264 significantly increased the expression of MIF in chondrocytes, suggesting that the transplanted chondrocytes in tissue-engineered cartilage could enhance the expression of MIF by stimulation of surrounding macrophages. When MIF was added in the culture of chondrocytes, the expression of type II collagen was increased, indicating that MIF could promote the maturation of chondrocytes. Meanwhile, toluidine blue staining of constructs containing wild type (Mif+/+) chondrocytes showed increased metachromasia compared to MIF-knockout (Mif-/-) constructs at 2 weeks. However, this tendency was reversed by 8 weeks, suggesting that the initial increase in cartilage maturation in Mif+/+ constructs deteriorated by 8 weeks. Since the Mif+/+ constructs included more iNOS-positive inflammatory macrophages at 2 weeks, MIF might induce an M1 macrophage-polarized environment, which may eventually worsen the maturation of tissue-engineered cartilage in the long term. © 2017 Wiley Periodicals, Inc.

  9. Gene Delivery to Adipose Tissue Using Transcriptionally Targeted rAAV8 Vectors

    PubMed Central

    Uhrig-Schmidt, Silke; Geiger, Matthias; Luippold, Gerd; Birk, Gerald; Mennerich, Detlev; Neubauer, Heike; Grimm, Dirk; Wolfrum, Christian; Kreuz, Sebastian

    2014-01-01

    In recent years, the increasing prevalence of obesity and obesity-related co-morbidities fostered intensive research in the field of adipose tissue biology. To further unravel molecular mechanisms of adipose tissue function, genetic tools enabling functional studies in vitro and in vivo are essential. While the use of transgenic animals is well established, attempts using viral and non-viral vectors to genetically modify adipocytes in vivo are rare. Therefore, we here characterized recombinant Adeno-associated virus (rAAV) vectors regarding their potency as gene transfer vehicles for adipose tissue. Our results demonstrate that a single dose of systemically applied rAAV8-CMV-eGFP can give rise to remarkable transgene expression in murine adipose tissues. Upon transcriptional targeting of the rAAV8 vector to adipocytes using a 2.2 kb fragment of the murine adiponectin (mAP2.2) promoter, eGFP expression was significantly decreased in off-target tissues while efficient transduction was maintained in subcutaneous and visceral fat depots. Moreover, rAAV8-mAP2.2-mediated expression of perilipin A – a lipid-droplet-associated protein – resulted in significant changes in metabolic parameters only three weeks post vector administration. Taken together, our findings indicate that rAAV vector technology is applicable as a flexible tool to genetically modify adipocytes for functional proof-of-concept studies and the assessment of putative therapeutic targets in vivo. PMID:25551639

  10. Vibration Training Triggers Brown Adipocyte Relative Protein Expression in Rat White Adipose Tissue

    PubMed Central

    Sun, Chao; Zeng, Ruixia; Cao, Ge; Song, Zhibang; Zhang, Yibo; Liu, Chang

    2015-01-01

    Recently, vibration training is considered as a novel strategy of weight loss; however, its mechanisms are still unclear. In this study, normal or high-fat diet-induced rats were trained by whole body vibration for 8 weeks. We observed that the body weight and fat metabolism index, blood glucose, triglyceride, cholesterol, and free fatty acid in obesity rats decreased significantly compared with nonvibration group (n = 6). Although intrascapular BAT weight did not change significantly, vibration enhanced ATP reduction and increased protein level of the key molecule of brown adipose tissue (BAT), PGC-1α, and UCP1 in BAT. Interestingly, the adipocytes in retroperitoneal white adipose tissue (WAT) became smaller due to vibration exercise and had higher protein level of the key molecule of brown adipose tissue (BAT), PGC-1α, and UCP1 and inflammatory relative proteins, IL-6 and TNFα. Simultaneously, ATP content and PPARγ protein level in WAT became less in rats compared with nonvibration group. The results indicated that vibration training changed lipid metabolism in rats and promoted brown fat-like change in white adipose tissues through triggering BAT associated gene expression, inflammatory reflect, and reducing energy reserve. PMID:26125027

  11. Allele Compensation in Tip60+/− Mice Rescues White Adipose Tissue Function In Vivo

    PubMed Central

    Gao, Yuan; Hamers, Nicole; Rakhshandehroo, Maryam; Berger, Ruud; Lough, John; Kalkhoven, Eric

    2014-01-01

    Adipose tissue is a key regulator of energy homestasis. The amount of adipose tissue is largely determined by adipocyte differentiation (adipogenesis), a process that is regulated by the concerted actions of multiple transcription factors and cofactors. Based on in vitro studies in murine 3T3-L1 preadipocytes and human primary preadipocytes, the transcriptional cofactor and acetyltransferase Tip60 was recently identified as an essential adipogenic factor. We therefore investigated the role of Tip60 on adipocyte differentiation and function, and possible consequences on energy homeostasis, in vivo. Because homozygous inactivation results in early embryonic lethality, Tip60+/− mice were used. Heterozygous inactivation of Tip60 had no effect on body weight, despite slightly higher food intake by Tip60+/− mice. No major effects of heterozygous inactivation of Tip60 were observed on adipose tissue and liver, and Tip60+/− displayed normal glucose tolerance, both on a low fat and a high fat diet. While Tip60 mRNA was reduced to 50% in adipose tissue, the protein levels were unaltered, suggesting compensation by the intact allele. These findings indicate that the in vivo role of Tip60 in adipocyte differentiation and function cannot be properly addressed in Tip60+/− mice, but requires the generation of adipose tissue-specific knock out animals or specific knock-in mice. PMID:24870614

  12. Renal injury in Seipin-deficient lipodystrophic mice and its reversal by adipose tissue transplantation or leptin administration alone: adipose tissue-kidney crosstalk.

    PubMed

    Liu, Xue-Jing; Wu, Xiao-Yue; Wang, Huan; Wang, Su-Xia; Kong, Wei; Zhang, Ling; Liu, George; Huang, Wei

    2018-05-08

    Seipin deficiency is responsible for type 2 congenital generalized lipodystrophy with severe loss of adipose tissue (AT) and could lead to renal failure in humans. However, the effect of Seipin on renal function is poorly understood. Here we report that Seipin knockout (SKO) mice exhibited impaired renal function, enlarged glomerular and mesangial surface areas, renal depositions of lipid, and advanced glycation end products. Elevated glycosuria and increased electrolyte excretion were also detected. Relative renal gene expression in fatty acid oxidation and reabsorption pathways were impaired in SKO mice. Elevated glycosuria might be associated with reduced renal glucose transporter 2 levels. To improve renal function, AT transplantation or leptin administration alone was performed. Both treatments effectively ameliorated renal injury by improving all of the parameters that were measured in the kidney. The treatments also rescued insulin resistance and low plasma leptin levels in SKO mice. Our findings demonstrate for the first time that Seipin deficiency induces renal injury, which is closely related to glucolipotoxicity and impaired renal reabsorption in SKO mice, and is primarily caused by the loss of AT and especially the lack of leptin. AT transplantation and leptin administration are two effective treatments for renal injury in Seipin-deficient mice.-Liu, X.-J., Wu, X.-Y., Wang, H., Wang, S.-X., Kong, W., Zhang, L., Liu, G., Huang, W. Renal injury in Seipin-deficient lipodystrophic mice and its reversal by adipose tissue transplantation or leptin administration alone: adipose tissue-kidney crosstalk.

  13. Reduced Socs3 expression in adipose tissue protects female mice against obesity-induced insulin resistance

    PubMed Central

    Palanivel, R.; Fullerton, M. D.; Galic, S.; Honeyman, J.; Hewitt, K. A.; Jorgensen, S. B.; Steinberg, G. R.

    2017-01-01

    Aims/hypothesis Inflammation in obesity increases the levels of the suppressor of cytokine signalling-3 (SOCS3) protein in adipose tissue, but the physiological importance of this protein in regulating whole-body insulin sensitivity in obesity is not known. Methods We generated Socs3 floxed (wild-type, WT) and Socs3 aP2 (also known as Fabp4)-Cre null (Socs3 AKO) mice. Mice were maintained on either a regular chow or a high-fat diet (HFD) for 16 weeks during which time body mass, adiposity, glucose homeostasis and insulin sensitivity were assessed. Results The HFD increased SOCS3 levels in adipose tissue of WT but not Socs3 AKO mice. WT and Socs3 AKO mice had similar body mass and adiposity, assessed using computed tomography (CT) imaging, irrespective of diet or sex. On a control chow diet there were no differences in insulin sensitivity or glucose tolerance. When fed a HFD, female but not male Socs3 AKO mice had improved glucose tolerance as well as lower fasting glucose and insulin levels compared with WT littermates. Hyperinsulinaemic–euglycaemic clamps and positron emission tomography (PET) imaging demonstrated that improved insulin sensitivity was due to elevated adipose tissue glucose uptake. Increased insulin-stimulated glucose uptake in adipose tissue was associated with enhanced levels and activating phosphorylation of insulin receptor substrate-1 (IRS1). Conclusions/interpretation These data demonstrate that inhibiting SOCS3 production in adipose tissue of female mice is effective for improving whole-body insulin sensitivity in obesity. PMID:22872213

  14. Liver attenuation, pericardial adipose tissue, obesity, and insulin resistance: the Multi-Ethnic Study of Atherosclerosis (MESA).

    PubMed

    McAuley, Paul A; Hsu, Fang-Chi; Loman, Kurt K; Carr, J Jeffrey; Budoff, Matthew J; Szklo, Moyses; Sharrett, A Richey; Ding, Jingzhong

    2011-09-01

    Insulin resistance is linked to general and abdominal obesity, but its relation to hepatic lipid content and pericardial adipose tissue is less clear. The purpose of this study was to examine cross-sectional associations of liver attenuation, pericardial adipose tissue, BMI, and waist circumference with insulin resistance. We measured liver attenuation and pericardial adipose tissue using the existing cardiac computed tomography scans in 5,291 individuals free of clinical cardiovascular disease and diabetes in the Multi-Ethnic Study of Atherosclerosis (MESA) during the study's baseline visit (2000-2002). Low liver attenuation was defined as the lowest quartile and high pericardial adipose tissue as the upper quartile of volume (cm(3)). We used standard clinical definitions for obesity and abdominal obesity. Insulin resistance was assessed by the homeostasis model assessment of insulin resistance (HOMA(IR)) index. In multivariate linear regression with all adiposity measures in the model simultaneously, all adiposity measures were significantly (P < 0.0001) associated with insulin resistance: regression coefficients (±s.e.) were 0.31 (±0.02) for low liver attenuation, 0.27 (±0.02) for high pericardial adipose tissue, 0.27 (±0.02) for obesity, and 0.32 (±0.02) for abdominal obesity. We found significant differences (P = 0.003) between standardized liver attenuation and insulin resistance by ethnicity: regression coefficients per 1 s.d. increment were 0.10 ± 0.01 for whites, 0.11 ± 0.02 for Chinese, 0.08 ± 0.2 for blacks, and 0.14 ± 0.01 for Hispanics. Liver attenuation and pericardial adipose tissue were associated with insulin resistance, independent of BMI and waist circumference.

  15. Uncultivated stromal vascular fraction is equivalent to adipose-derived stem and stromal cells on porous polyurethrane scaffolds forming adipose tissue in vivo.

    PubMed

    Griessl, Michael; Buchberger, Anna-Maria; Regn, Sybille; Kreutzer, Kilian; Storck, Katharina

    2018-06-01

    To find an alternative approach to contemporary techniques in tissue augmentation and reconstruction, tissue engineering strategies aim to involve adipose-derived stem and stromal cells (ASCs) harboring a strong differentiation potential into various tissue types such as bone, cartilage, and fat. Animal research. The stromal vascular fraction (SVF) was used directly as a cell source to provide a potential alternative to contemporary ASC-based adipose tissue engineering. Seeded in TissuCol fibrin, we applied ASCs or SVF cells to porous, degradable polyurethane (PU) scaffolds. We successfully demonstrated the in vivo generation of volume-stable, well-vascularized PU-based constructs containing host-derived mature fat pads. Seeded human stem cells served as modulators of host-cell migration rather than differentiating themselves. We further demonstrated that preliminary culture of SVF cells was not necessary. Our results bring adipose tissue engineering, together with automated processing devices, closer to clinical applicability. The time-consuming and cost-intensive culture and induction of the ASCs is not necessary. NA. Laryngoscope, 128:E206-E213, 2018. © 2018 The American Laryngological, Rhinological and Otological Society, Inc.

  16. Lipopolysaccharide-binding protein is a negative regulator of adipose tissue browning in mice and humans.

    PubMed

    Gavaldà-Navarro, Aleix; Moreno-Navarrete, José M; Quesada-López, Tania; Cairó, Montserrat; Giralt, Marta; Fernández-Real, José M; Villarroya, Francesc

    2016-10-01

    Adipocyte lipopolysaccharide-binding protein (LBP) biosynthesis is associated with obesity-induced adipose tissue dysfunction. Our purpose was to study the role of LBP in regulating the browning of adipose tissue. Adult mice were maintained at 4°C for 3 weeks or treated with the β3-adrenergic agonist, CL316,243, for 1 week to induce the browning of white fat. Precursor cells from brown and white adipose tissues were cultured under differentiation-inducing conditions to yield brown and beige/brite adipocytes, respectively. In vitro, Lbp was knocked down in 3T3-L1 adipocytes, and cells were treated with recombinant LBP or co-cultured in transwells with control 3T3-L1 adipocytes. Wild-type and Lbp-null mice, fed a standard or high fat diet (HFD) for 15 weeks, were also used in investigations. In humans, subcutaneous and visceral adipose tissue samples were obtained from a cohort of morbidly obese participants. The induction of white fat browning by exposure of mice to cold or CL316,243 treatment was strongly associated with decreased Lbp mRNA expression in white adipose tissue. The acquisition of the beige/brite phenotype in cultured cells was associated with downregulation of Lbp. Moreover, silencing of Lbp induced the expression of brown fat-related genes in adipocytes, whereas LBP treatment reversed this effect. Lbp-null mice exhibited the spontaneous induction of subcutaneous adipose tissue browning, as evidenced by a remarkable increase in Ucp1 and Dio2 gene expression and the appearance of multivacuolar adipocyte clusters. The amount of brown adipose tissue, and brown adipose tissue activity were also increased in Lbp-null mice. These changes were associated with decreased weight gain in Lbp-null mice and protection against HFD-induced inflammatory responses, as shown by reduced IL-6 levels. However, rather than improving glucose homeostasis, these effects led to glucose intolerance and insulin resistance. LBP is identified as a negative regulator of the

  17. Feeding feedlot steers fish oil alters the fatty acid composition of adipose and muscle tissue.

    PubMed

    Wistuba, T J; Kegley, E B; Apple, J K; Rule, D C

    2007-10-01

    Sixteen steers (441±31.7kg initial body weight) consumed two high concentrate diets with either 0 or 3% fish oil to determine the impact of fish oil, an omega-3 fatty acid source, on the fatty acid composition of beef carcasses. Collected tissue samples included the Longissimus thoracis from the 6th to 7th rib section, ground 10th to 12th rib, liver, subcutaneous adipose tissue adjacent to the 12th rib, intramuscular adipose tissue in the 6th to 7th rib sections, perirenal adipose tissue, and brisket adipose tissue. Including fish oil in the diet increased most of the saturated fatty acids (P<0.01) and proportions of polyunsaturated fatty acids (P<0.06), and decreased (P<0.01) proportions of monounsaturated fatty acids. Dietary fish oil increased (P<0.01) levels of omega-3 fatty acids in sampled tissues, resulting in lower (P<0.01) omega-6:omega-3 ratios. The weight percentages of C20:5 and C22:6 in tissue may provide the recommended daily allowance for humans. Fish oil may have a role in beef niche marketing if there are no deleterious effects on consumer satisfaction.

  18. Toll-like receptor 4 (TLR4) deficient mice are protected from adipose tissue inflammation in aging.

    PubMed

    Ghosh, Amiya K; O'Brien, Martin; Mau, Theresa; Yung, Raymond

    2017-09-07

    Adipose tissue (AT) inflammation is a central mechanism for metabolic dysfunction in both diet-induced obesity and age-associated obesity. Studies in diet-induced obesity have characterized the role of Fetuin A (Fet A) in Free Fatty Acids (FFA)-mediated TLR4 activation and adipose tissue inflammation. However, the role of Fet A & TLR4 in aging-related adipose tissue inflammation is unknown. In the current study, analysis of epidymymal fat pads of C57/Bl6 male mice, we found that, in contrast to data from diet-induced obesity models, adipose tissue from aged mice have normal Fet A and TLR4 expression. Interestingly, aged TLR4-deficient mice have diminished adipose tissue inflammation compared to normal controls. We further demonstrated that reduced AT inflammation in old TLR4-deficient mice is linked to impaired ER stress, augmented autophagy activity, and diminished senescence phenomenon. Importantly, old TLR4-deficient mice have improved glucose tolerance compared to age-matched wild type mice, suggesting that the observed reduced AT inflammation in aged TLR4-deficient mice has important physiological consequences. Taken together, our present study establishes novel aspect of aging-associated AT inflammation that is distinct from diet-induced AT inflammation. Our results also provide strong evidence that TLR4 plays a significant role in promoting aging adipose tissue inflammation.

  19. Toll-like receptor 4 (TLR4) deficient mice are protected from adipose tissue inflammation in aging

    PubMed Central

    Ghosh, Amiya K.; O'Brien, Martin; Mau, Theresa; Yung, Raymond

    2017-01-01

    Adipose tissue (AT) inflammation is a central mechanism for metabolic dysfunction in both diet-induced obesity and age-associated obesity. Studies in diet-induced obesity have characterized the role of Fetuin A (Fet A) in Free Fatty Acids (FFA)-mediated TLR4 activation and adipose tissue inflammation. However, the role of Fet A & TLR4 in aging-related adipose tissue inflammation is unknown. In the current study, analysis of epidymymal fat pads of C57/Bl6 male mice, we found that, in contrast to data from diet-induced obesity models, adipose tissue from aged mice have normal Fet A and TLR4 expression. Interestingly, aged TLR4-deficient mice have diminished adipose tissue inflammation compared to normal controls. We further demonstrated that reduced AT inflammation in old TLR4-deficient mice is linked to impaired ER stress, augmented autophagy activity, and diminished senescence phenomenon. Importantly, old TLR4-deficient mice have improved glucose tolerance compared to age-matched wild type mice, suggesting that the observed reduced AT inflammation in aged TLR4-deficient mice has important physiological consequences. Taken together, our present study establishes novel aspect of aging-associated AT inflammation that is distinct from diet-induced AT inflammation. Our results also provide strong evidence that TLR4 plays a significant role in promoting aging adipose tissue inflammation. PMID:28898202

  20. Molecular Interaction of Bone Marrow Adipose Tissue with Energy Metabolism.

    PubMed

    Suchacki, Karla J; Cawthorn, William P

    2018-01-01

    The last decade has seen a resurgence in the study of bone marrow adipose tissue (BMAT) across diverse fields such as metabolism, haematopoiesis, skeletal biology and cancer. Herein, we review the most recent developments of BMAT research in both humans and rodents, including the distinct nature of BMAT; the autocrine, paracrine and endocrine interactions between BMAT and various tissues, both in physiological and pathological scenarios; how these interactions might impact energy metabolism; and the most recent technological advances to quantify BMAT. Though still dwarfed by research into white and brown adipose tissues, BMAT is now recognised as endocrine organ and is attracting increasing attention from biomedical researchers around the globe. We are beginning to learn the importance of BMAT both within and beyond the bone, allowing us to better appreciate the role of BMAT in normal physiology and disease.

  1. Adipose Tissue and Adipokines: The Association with and Application of Adipokines in Obesity

    PubMed Central

    Khan, Muhammad; Joseph, Frank

    2014-01-01

    2014 marks the 20th anniversary of adipokines. Through the identification of leptin, our perceived understanding of adipose tissue was changed instantaneously. From a simple dormant site of energy storage, adipose tissue is now recognized as an integral hub of various hormones known as adipokines. Although great strides have been made in characterizing these hormones in health, research also shows they are significantly implicated in a series of pathologies. One such condition is obesity. Defined as an excess of adipose tissue, obesity remains one of the greatest healthcare epidemics of the 21st century. With no definitive treatment, attention has shifted to understanding the role of adipokines in obesity. This review provides an introduction to the salient obesity-related adipokines and their possible application as a treatment for obesity. PMID:25309775

  2. PCOS is associated with increased CD11c expression and crown-like structures in adipose tissue and increased central abdominal fat depots independent of obesity.

    PubMed

    Huang, Zhi Hua; Manickam, Buvana; Ryvkin, Victoria; Zhou, Xiaohong Joe; Fantuzzi, Giamila; Mazzone, Theodore; Sam, Susan

    2013-01-01

    Adipose tissue macrophage (ATM) infiltration is a major pathway for obesity-induced insulin resistance but has not been studied as a mechanism for insulin resistance in PCOS. We tested whether polycystic ovary syndrome (PCOS) is associated with increased ATM infiltration, especially of inflammatory subtype identified by the CD11c marker. We conducted a case-control study at an academic medical center in the United States. Fourteen PCOS and 14 control women of similar age and body mass index (BMI) underwent a gluteal fat biopsy. Markers of ATM, integrins, TNF-α, and adiponectin, were analyzed by quantitative RT-PCR using a standard curve method. Crown-like structures (CLS) were identified by immunohistochemistry. Abdominal magnetic resonance imaging and frequently sampled i.v. glucose tolerance test were performed to assess abdominal fat and insulin sensitivity (SI). Women with PCOS were compared with control women of similar age and BMI for ATM markers, CLS density, adipose tissue expression of inflammatory cytokines and adiponectin, SI, and abdominal fat depots. Women with PCOS had an increase in CD11c expression (P = 0.03), CLS density (P = 0.001), α5 expression (P = 0.009), borderline increase in TNF-α expression (P = 0.08), and a decrease in adiponectin expression (P = 0.02) in gluteal adipose tissue. Visceral (P = 0.009) and sc abdominal fat (P = 0.005) were increased in PCOS. SI was lower in PCOS (P = 0.008). PCOS is associated with an increase in CD11c expression and CLS density and a decrease in adiponectin expression in sc adipose tissue. Additionally, PCOS is associated with higher central abdominal fat depots independent of BMI. These alterations are present among mostly nonobese women and could represent mechanisms for insulin resistance.

  3. Exercise training attenuates neutrophil infiltration and elastase expression in adipose tissue of high-fat-diet-induced obese mice

    PubMed Central

    Kawanishi, Noriaki; Niihara, Hiroyuki; Mizokami, Tsubasa; Yada, Koichi; Suzuki, Katsuhiko

    2015-01-01

    The innate immune system is associated with the development of local inflammation. Neutrophils play an essential role in the development of the adipose tissue (AT) inflammation associated with obesity by producing elastase, which can promote the activation and infiltration of macrophages. Exercise training attenuates AT inflammation via suppression of macrophage infiltration. However, the mechanisms driving this phenomenon remains to be elucidated. Here, we evaluated the effects of exercise training on the infiltration of neutrophils and elastase expression in an obese mouse model. Four-week-old male C57BL/6J mice were randomly assigned to one of three groups that either received a normal diet (ND) plus sedentary activity (n = 15), a high-fat diet (HFD) plus sedentary activity (n = 15), or a HFD plus exercise training (n = 15). Mice were fed the ND or HFD from the age of 4 weeks until 20 weeks. Mice in the exercise group ran on a treadmill for 60 min/day, 5 days/week over the same experimental period. Mice fed with the HFD had increased content of macrophages in the AT and increased inflammatory cytokine mRNA levels, which were reduced by exercise training. Similarly, AT from the HFD sedentary mice contained more neutrophils than AT from the ND mice, and the amount of neutrophils in this tissue in HFD-fed mice was lowered by exercise training. The mRNA levels of neutrophil elastase in AT were lower in the HFD exercise-trained mice than those in the HFD sedentary mice. These results suggest that exercise training plays a critical role in reducing macrophage infiltration and AT inflammation by regulating the infiltration of neutrophils. PMID:26341995

  4. A worm of one's own: how helminths modulate host adipose tissue function and metabolism.

    PubMed

    Guigas, Bruno; Molofsky, Ari B

    2015-09-01

    Parasitic helminths have coexisted with human beings throughout time. Success in eradicating helminths has limited helminth-induced morbidity and mortality but is also correlated with increasing rates of 'western' diseases, including metabolic syndrome and type 2 diabetes. Recent studies in mice describe how type 2 immune cells, traditionally associated with helminth infection, maintain adipose tissue homeostasis and promote adipose tissue beiging, protecting against obesity and metabolic dysfunction. Here, we review these studies and discuss how helminths and helminth-derived molecules may modulate these physiologic pathways to improve metabolic functions in specific tissues, such as adipose and liver, as well as at the whole-organism level. Copyright © 2015 Elsevier Ltd. All rights reserved.

  5. Role of arsenic exposure in adipose tissue dysfunction and its possible implication in diabetes pathophysiology.

    PubMed

    Renu, Kaviyarasi; Madhyastha, Harishkumar; Madhyastha, Radha; Maruyama, Masugi; Arunachlam, Sankarganesh; V G, Abilash

    2018-03-01

    Exposure to arsenic in drinking water can stimulate a diverse number of diseases that originate from impaired lipid metabolism in adipose and glucose metabolism, leading to insulin resistance. Arsenic inhibits differentiation of adipocyte and mediates insulin resistance with diminutive information on arsenicosis on lipid storage and lipolysis. This review focused on different mechanisms and pathways involved in adipogenesis and lipolysis in adipose tissue during arsenic-induced diabetes. Though arsenic is known to cause type2 diabetes through different mechanisms, the role of adipose tissue in causing type2 diabetes is still unclear. With the existing literature, this review exhibits the effect of arsenic on adipose tissue and its signalling events such as SIRT3- FOXO3a signalling pathway, Ras -MAP -AP-1 cascade, PI(3)-K-Akt pathway, endoplasmic reticulum stress protein, C/EBP homologous protein (CHOP10) and GPCR pathway with role of adipokines. There is a need to elucidate the different types of adipokines which are involved in arsenic-induced diabetes. The exhibited information brings to light that arsenic has negative effects on a white adipose tissue (WAT) by decreasing adipogenesis and enhancing lipolysis. Some of the epidemiological studies show that arsenic would causes obesity. Few studies indicate that arsenic might induces lipodystrophy condition. Further research is needed to evaluate the mechanistic link between arsenic and adipose tissue dysfunction which leads to insulin resistance. Copyright © 2017 Elsevier B.V. All rights reserved.

  6. The tumor secretory factor ZAG promotes white adipose tissue browning and energy wasting.

    PubMed

    Elattar, Sawsan; Dimri, Manali; Satyanarayana, Ande

    2018-03-23

    Cachexia is a complex tissue-wasting syndrome characterized by inflammation, hypermetabolism, increased energy expenditure, and anorexia. Browning of white adipose tissue (WAT) is one of the significant factors that contribute to energy wasting in cachexia. By utilizing a cell implantation model, we demonstrate here that the lipid mobilizing factor zinc-α 2 -glycoprotein (ZAG) induces WAT browning in mice. Increased circulating levels of ZAG not only induced lipolysis in adipose tissues but also caused robust browning in WAT. Stimulating WAT progenitors with ZAG recombinant protein or expression of ZAG in mouse embryonic fibroblasts (MEFs) strongly enhanced brown-like differentiation. At the molecular level, ZAG stimulated peroxisome proliferator-activated receptor γ (PPARγ) and early B cell factor 2 expression and promoted their recruitment to the PR/SET domain 16 (Prdm16) promoter, leading to enhanced expression of Prdm16, which determines brown cell fate. In brown adipose tissue, ZAG stimulated the expression of PPARγ and PPARγ coactivator 1α and promoted recruitment of PPARγ to the uncoupling protein 1 (Ucp1) promoter, leading to increased expression of Ucp1. Overall, our results reveal a novel function of ZAG in WAT browning and highlight the targeting of ZAG as a potential therapeutic application in humans with cachexia.-Elattar, S., Dimri, M., Satyanarayana, A. The tumor secretory factor ZAG promotes white adipose tissue browning and energy wasting.

  7. Development of a 3D bone marrow adipose tissue model.

    PubMed

    Fairfield, Heather; Falank, Carolyne; Farrell, Mariah; Vary, Calvin; Boucher, Joshua M; Driscoll, Heather; Liaw, Lucy; Rosen, Clifford J; Reagan, Michaela R

    2018-01-26

    Over the past twenty years, evidence has accumulated that biochemically and spatially defined networks of extracellular matrix, cellular components, and interactions dictate cellular differentiation, proliferation, and function in a variety of tissue and diseases. Modeling in vivo systems in vitro has been undeniably necessary, but when simplified 2D conditions rather than 3D in vitro models are used, the reliability and usefulness of the data derived from these models decreases. Thus, there is a pressing need to develop and validate reliable in vitro models to reproduce specific tissue-like structures and mimic functions and responses of cells in a more realistic manner for both drug screening/disease modeling and tissue regeneration applications. In adipose biology and cancer research, these models serve as physiologically relevant 3D platforms to bridge the divide between 2D cultures and in vivo models, bringing about more reliable and translationally useful data to accelerate benchtop to bedside research. Currently, no model has been developed for bone marrow adipose tissue (BMAT), a novel adipose depot that has previously been overlooked as "filler tissue" but has more recently been recognized as endocrine-signaling and systemically relevant. Herein we describe the development of the first 3D, BMAT model derived from either human or mouse bone marrow (BM) mesenchymal stromal cells (MSCs). We found that BMAT models can be stably cultured for at least 3 months in vitro, and that myeloma cells (5TGM1, OPM2 and MM1S cells) can be cultured on these for at least 2 weeks. Upon tumor cell co-culture, delipidation occurred in BMAT adipocytes, suggesting a bidirectional relationship between these two important cell types in the malignant BM niche. Overall, our studies suggest that 3D BMAT represents a "healthier," more realistic tissue model that may be useful for elucidating the effects of MAT on tumor cells, and tumor cells on MAT, to identify novel therapeutic

  8. Resistin in Dairy Cows: Plasma Concentrations during Early Lactation, Expression and Potential Role in Adipose Tissue

    PubMed Central

    Reverchon, Maxime; Ramé, Christelle; Cognié, Juliette; Briant, Eric; Elis, Sébastien; Guillaume, Daniel; Dupont, Joëlle

    2014-01-01

    Resistin is an adipokine that has been implicated in energy metabolism regulation in rodents but has been little studied in dairy cows. We determined plasma resistin concentrations in early lactation in dairy cows and investigated the levels of resistin mRNA and protein in adipose tissue and the phosphorylation of several components of insulin signaling pathways one week post partum (1 WPP) and at five months of gestation (5 MG). We detected resistin in mature bovine adipocytes and investigated the effect of recombinant bovine resistin on lipolysis in bovine adipose tissue explants. ELISA showed that plasma resistin concentration was low before calving, subsequently increasing and reaching a peak at 1 WPP, decreasing steadily thereafter to reach pre-calving levels at 6 WPP. Plasma resistin concentration was significantly positively correlated with plasma non esterified fatty acid (NEFA) levels and negatively with milk yield, dry matter intake and energy balance between WPP1 to WPP22. We showed, by quantitative RT-PCR and western blotting, that resistin mRNA and protein levels in adipose tissue were higher at WPP1 than at 5 MG. The level of phosphorylation of several early and downstream insulin signaling components (IRβ, IRS-1, IRS-2, Akt, MAPK ERK1/2, P70S6K and S6) in adipose tissue was also lower at 1 WPP than at 5 MG. Finally, we showed that recombinant bovine resistin increased the release of glycerol and mRNA levels for ATGL (adipose triglyceride lipase) and HSL (hormone-sensitive lipase) in adipose tissue explants. Overall, resistin levels were high in the plasma and adipose tissue and were positively correlated with NEFA levels after calving. Resistin is expressed in bovine mature adipocytes and promotes lipid mobilization in adipose explants in vitro. PMID:24675707

  9. Maresin conjugates in tissue regeneration biosynthesis enzymes in human macrophages.

    PubMed

    Dalli, Jesmond; Vlasakov, Iliyan; Riley, Ian R; Rodriguez, Ana R; Spur, Bernd W; Petasis, Nicos A; Chiang, Nan; Serhan, Charles N

    2016-10-25

    Macrophages are central in coordinating immune responses, tissue repair, and regeneration, with different subtypes being associated with inflammation-initiating and proresolving actions. We recently identified a family of macrophage-derived proresolving and tissue regenerative molecules coined maresin conjugates in tissue regeneration (MCTR). Herein, using lipid mediator profiling we identified MCTR in human serum, lymph nodes, and plasma and investigated MCTR biosynthetic pathways in human macrophages. With human recombinant enzymes, primary cells, and enantiomerically pure compounds we found that the synthetic maresin epoxide intermediate 13S,14S-eMaR (13S,14S-epoxy- 4Z,7Z,9E,11E,16Z,19Z-docosahexaenoic acid) was converted to MCTR1 (13R-glutathionyl, 14S-hydroxy-4Z,7Z,9E,11E,13R,14S,16Z,19Z-docosahexaenoic acid) by LTC 4 S and GSTM4. Incubation of human macrophages with LTC 4 S inhibitors blocked LTC 4 and increased resolvins and lipoxins. The conversion of MCTR1 to MCTR2 (13R-cysteinylglycinyl, 14S-hydroxy-4Z,7Z,9E,11E,13R,14S,16Z,19Z-docosahexaenoic acid) was catalyzed by γ-glutamyl transferase (GGT) in human macrophages. Biosynthesis of MCTR3 was mediated by dipeptidases that cleaved the cysteinyl-glycinyl bond of MCTR2 to give 13R-cysteinyl, 14S-hydroxy-4Z,7Z,9E,11E,13R,14S,16Z,19Z-docosahexaenoic acid. Of note, both GSTM4 and GGT enzymes displayed higher affinity to 13S,14S-eMaR and MCTR1 compared with their classic substrates in the cysteinyl leukotriene metabolome. Together these results establish the MCTR biosynthetic pathway and provide mechanisms in tissue repair and regeneration.

  10. Optimizing Adipose Tissue Extract Isolation with Stirred Suspension Culture.

    PubMed

    Zhang, Yan; Yu, Mei; Zhao, Xueyong; Dai, Minjia; Chen, Chang; Tian, Weidong

    2018-05-31

    Adherent culture which is used to collect adipose tissue extract (ATE) previously brings the problem of inhomogeneity and non-repeatability. Here we aim to extract ATE with stirred suspension culture to speed up the extraction process, stabilize the yield and improve consistent potency metrics of ATE. ATE was collected with adherent culture (ATE-A) and stirred suspension culture (ATE-S) separately. Protein yield and composition were detected by SDS-PAGE while cytokines in ATE were determined with ELISA. The adipogenic and angiogenic potential of ATE were compared by Western blot and qPCR. In addition, HE staining and LDH activity assays were used to analyze the cell viability of adipose tissue cultured with different methods. The yield of ATE-S was consistent while ATE-A varied notably. Characterization of the protein composition and exosome-like vesicles (ELVs) indicated no significant difference between ATE-S and ATE-A. The concentrations of cytokines (VEGF, bFGF and IL-6) showed no significant difference while IGF in ATE-S was higher than that in ATE-A. ATE-S showed upregulated adipogenic and angiogenic potential compared to ATE-A. Morever, stirred suspension culture decreased the LDH activity of ATE while increased the number of viable adipocytes and reduced adipose tissue necrosis. Compared with adherent culture, stirred suspension culture is a reliable, time and labor-saving method to collect ATE, which might be used to improve the downstream applications of ATE.

  11. Lymphoid tissue and plasmacytoid dendritic cells and macrophages do not share a common macrophage-dendritic cell-restricted progenitor.

    PubMed

    Sathe, Priyanka; Metcalf, Donald; Vremec, David; Naik, Shalin H; Langdon, Wallace Y; Huntington, Nicholas D; Wu, Li; Shortman, Ken

    2014-07-17

    The relationship between dendritic cells (DCs) and macrophages is often debated. Here we ask whether steady-state, lymphoid-tissue-resident conventional DCs (cDCs), plasmacytoid DCs (pDCs), and macrophages share a common macrophage-DC-restricted precursor (MDP). Using new clonal culture assays combined with adoptive transfer, we found that MDP fractions isolated by previous strategies are dominated by precursors of macrophages and monocytes, include some multipotent precursors of other hematopoietic lineages, but contain few precursors of resident cDCs and pDCs and no detectable common precursors restricted to these DC types and macrophages. Overall we find no evidence for a common restricted MDP leading to both macrophages and FL-dependent, resident cDCs and pDCs. Copyright © 2014 Elsevier Inc. All rights reserved.

  12. Adipose tissue NAD+-homeostasis, sirtuins and poly(ADP-ribose) polymerases -important players in mitochondrial metabolism and metabolic health.

    PubMed

    Jokinen, Riikka; Pirnes-Karhu, Sini; Pietiläinen, Kirsi H; Pirinen, Eija

    2017-08-01

    Obesity, a chronic state of energy overload, is characterized by adipose tissue dysfunction that is considered to be the major driver for obesity associated metabolic complications. The reasons for adipose tissue dysfunction are incompletely understood, but one potential contributing factor is adipose tissue mitochondrial dysfunction. Derangements of adipose tissue mitochondrial biogenesis and pathways associate with obesity and metabolic diseases. Mitochondria are central organelles in energy metabolism through their role in energy derivation through catabolic oxidative reactions. The mitochondrial processes are dependent on the proper NAD + /NADH redox balance and NAD + is essential for reactions catalyzed by the key regulators of mitochondrial metabolism, sirtuins (SIRTs) and poly(ADP-ribose) polymerases (PARPs). Notably, obesity is associated with disturbed adipose tissue NAD + homeostasis and the balance of SIRT and PARP activities. In this review we aim to summarize existing literature on the maintenance of intracellular NAD + pools and the function of SIRTs and PARPs in adipose tissue during normal and obese conditions, with the purpose of comprehending their potential role in mitochondrial derangements and obesity associated metabolic complications. Understanding the molecular mechanisms that are the root cause of the adipose tissue mitochondrial derangements is crucial for developing new effective strategies to reverse obesity associated metabolic complications. Copyright © 2017 The Authors. Published by Elsevier B.V. All rights reserved.

  13. Extra-Virgin Olive Oil with Natural Phenolic Content Exerts an Anti-Inflammatory Effect in Adipose Tissue and Attenuates the Severity of Atherosclerotic Lesions in Ldlr-/-.Leiden Mice.

    PubMed

    Luque-Sierra, Amparo; Alvarez-Amor, Leticia; Kleemann, Robert; Martín, Franz; Varela, Lourdes M

    2018-05-15

    The present study investigates the effect of olive oils with different phenolic content in high-fat diets (HFDs) on hypertrophy and inflammation in adipose tissue and associated atherosclerosis, in the context of obesity. Ldlr-/-.Leiden mice were fed three different HFDs for 32 weeks and were compared with mice fed the standard low-fat diet (LFD). The different fats provided in the HFDs were lard (HFD-L), extra-virgin olive oil (EVOO; 79 mg kg -1 of phenolic compounds, HFD-EVOO), or EVOO rich in phenolic compounds (OL, 444 mg kg -1 of phenolic compounds, HFD-OL). All HFD-fed mice became obese, but only HFD-L-induced adipocyte hypertrophy. HFD-EVOO mice exhibited the greatest levels of Adiponectin in adipose tissue and presented atherosclerotic lesions similar to the LFD group, with a very low count of monocyte/macrophage compared with HFD-L and HFD-OL mice. Enrichment of the phenolic content of olive oil reduced the secretion of nitrites/nitrates in the aorta, but atherosclerosis was not attenuated in HFD-OL mice compared to other HFD mice. Consumption of olive oil with a natural content of phenolic compounds attenuates adipose tissue hypertrophy and inflammation and exerts antiatherosclerotic effects in mice. A higher phenolic content of olive oil did not provide further benefits in the prevention of atherosclerosis. © 2018 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

  14. Current Therapeutic Strategies for Adipose Tissue Defects/Repair Using Engineered Biomaterials and Biomolecule Formulations.

    PubMed

    Mahoney, Christopher M; Imbarlina, Cayla; Yates, Cecelia C; Marra, Kacey G

    2018-01-01

    Tissue engineered scaffolds for adipose restoration/repair has significantly evolved in recent years. Patients requiring soft tissue reconstruction, caused by defects or pathology, require biomaterials that will restore void volume with new functional tissue. The gold standard of autologous fat grafting (AFG) is not a reliable option. This review focuses on the latest therapeutic strategies for the treatment of adipose tissue defects using biomolecule formulations and delivery, and specifically engineered biomaterials. Additionally, the clinical need for reliable off-the-shelf therapies, animal models, and challenges facing current technologies are discussed.

  15. Fructose, Glucocorticoids and Adipose Tissue: Implications for the Metabolic Syndrome.

    PubMed

    Legeza, Balázs; Marcolongo, Paola; Gamberucci, Alessandra; Varga, Viola; Bánhegyi, Gábor; Benedetti, Angiolo; Odermatt, Alex

    2017-04-26

    The modern Western society lifestyle is characterized by a hyperenergetic, high sugar containing food intake. Sugar intake increased dramatically during the last few decades, due to the excessive consumption of high-sugar drinks and high-fructose corn syrup. Current evidence suggests that high fructose intake when combined with overeating and adiposity promotes adverse metabolic health effects including dyslipidemia, insulin resistance, type II diabetes, and inflammation. Similarly, elevated glucocorticoid levels, especially the enhanced generation of active glucocorticoids in the adipose tissue due to increased 11β-hydroxysteroid dehydrogenase 1 (11β-HSD1) activity, have been associated with metabolic diseases. Moreover, recent evidence suggests that fructose stimulates the 11β-HSD1-mediated glucocorticoid activation by enhancing the availability of its cofactor NADPH. In adipocytes, fructose was found to stimulate 11β-HSD1 expression and activity, thereby promoting the adipogenic effects of glucocorticoids. This article aims to highlight the interconnections between overwhelmed fructose metabolism, intracellular glucocorticoid activation in adipose tissue, and their metabolic effects on the progression of the metabolic syndrome.

  16. Fructose, Glucocorticoids and Adipose Tissue: Implications for the Metabolic Syndrome

    PubMed Central

    Legeza, Balázs; Marcolongo, Paola; Gamberucci, Alessandra; Varga, Viola; Bánhegyi, Gábor; Benedetti, Angiolo; Odermatt, Alex

    2017-01-01

    The modern Western society lifestyle is characterized by a hyperenergetic, high sugar containing food intake. Sugar intake increased dramatically during the last few decades, due to the excessive consumption of high-sugar drinks and high-fructose corn syrup. Current evidence suggests that high fructose intake when combined with overeating and adiposity promotes adverse metabolic health effects including dyslipidemia, insulin resistance, type II diabetes, and inflammation. Similarly, elevated glucocorticoid levels, especially the enhanced generation of active glucocorticoids in the adipose tissue due to increased 11β-hydroxysteroid dehydrogenase 1 (11β-HSD1) activity, have been associated with metabolic diseases. Moreover, recent evidence suggests that fructose stimulates the 11β-HSD1-mediated glucocorticoid activation by enhancing the availability of its cofactor NADPH. In adipocytes, fructose was found to stimulate 11β-HSD1 expression and activity, thereby promoting the adipogenic effects of glucocorticoids. This article aims to highlight the interconnections between overwhelmed fructose metabolism, intracellular glucocorticoid activation in adipose tissue, and their metabolic effects on the progression of the metabolic syndrome. PMID:28445389

  17. Laser light propagation in adipose tissue and laser effects on adipose cell membranes

    NASA Astrophysics Data System (ADS)

    Solarte, Efraín; Rebolledo, Aldo; Gutierrez, Oscar; Criollo, William; Neira, Rodrigo; Arroyave, José; Ramírez, Hugo

    2006-01-01

    Recently Neira et al. have presented a new liposuction technique that demonstrated the movement of fat from inside to outside of the cell, using a low-level laser device during a liposuction procedure with Ultrawet solution. The clinical observations, allowed this new surgical development, started a set of physical, histological and pharmacological studies aimed to determine the mechanisms involved in the observed fat mobilization concomitant to external laser application in liposuction procedures. Scanning and Transmission Electron Microscopy, studies show that the cellular arrangement of normal adipose tissue changes when laser light from a diode laser: 10 mW, 635 nm is applied. Laser exposures longer than 6 minutes cause the total destruction of the adipocyte panicles. Detailed observation of the adipose cells show that by short irradiation times (less than four minutes) the cell membrane exhibits dark zones, that collapse by longer laser exposures. Optical measurements show that effective penetration length depends on the laser intensity. Moreover, the light scattering is enhanced by diffraction and subsequent interference effects, and the tumescent solution produces a clearing of the tissue optical medium. Finally, isolate adipose cell observation show that fat release from adipocytes is a concomitant effect between the tumescent solution (adrenaline) and laser light, revealing a synergism which conduces to the aperture, and maybe the disruption, of the cell membrane. All these studies were consistent with a laser induced cellular process, which causes fat release from inside the adipocytes into the intercellular space, besides a strong modification of the cellular membranes.

  18. Inorganic Nitrate Promotes the Browning of White Adipose Tissue through the Nitrate-Nitrite-Nitric Oxide Pathway

    PubMed Central

    Roberts, Lee D; Ashmore, Tom; Kotwica, Aleksandra O; Murfitt, Steven A; Fernandez, Bernadette O; Feelisch, Martin; Griffin, Julian L

    2015-01-01

    Inorganic nitrate was once considered an oxidation end-product of nitric oxide metabolism with little biological activity. However, recent studies have demonstrated that dietary nitrate can modulate mitochondrial function in man and is effective in reversing features of the metabolic syndrome in mice. Using a combined histological, metabolomics, and transcriptional and protein analysis approach we mechanistically define that nitrate not only increases the expression of thermogenic genes in brown-adipose tissue but also induces the expression of brown adipocyte-specific genes and proteins in white adipose tissue, substantially increasing oxygen consumption and fatty acid β-oxidation in adipocytes. Nitrate induces these phenotypic changes through a mechanism distinct from known physiological small molecule activators of browning, the recently identified nitrate-nitrite-nitric oxide pathway. The nitrate-induced browning effect was enhanced in hypoxia, a serious co-morbidity affecting white adipose tissue in obese individuals, and corrected impaired brown adipocyte-specific gene expression in white adipose tissue in a murine model of obesity. Since resulting beige/brite cells exhibit anti-obesity and anti-diabetic effects, nitrate may be an effective means of inducing the browning response in adipose tissue to treat the metabolic syndrome. PMID:25249574

  19. Quantitative CT imaging for adipose tissue analysis in mouse model of obesity

    NASA Astrophysics Data System (ADS)

    Marchadier, A.; Vidal, C.; Tafani, J.-P.; Ordureau, S.; Lédée, R.; Léger, C.

    2011-03-01

    In obese humans CT imaging is a validated method for follow up studies of adipose tissue distribution and quantification of visceral and subcutaneous fat. Equivalent methods in murine models of obesity are still lacking. Current small animal micro-CT involves long-term X-ray exposure precluding longitudinal studies. We have overcome this limitation by using a human medical CT which allows very fast 3D imaging (2 sec) and minimal radiation exposure. This work presents novel methods fitted to in vivo investigations of mice model of obesity, allowing (i) automated detection of adipose tissue in abdominal regions of interest, (ii) quantification of visceral and subcutaneous fat. For each mouse, 1000 slices (100μm thickness, 160 μm resolution) were acquired in 2 sec using a Toshiba medical CT (135 kV, 400mAs). A Gaussian mixture model of the Hounsfield curve of 2D slices was computed with the Expectation Maximization algorithm. Identification of each Gaussian part allowed the automatic classification of adipose tissue voxels. The abdominal region of interest (umbilical) was automatically detected as the slice showing the highest ratio of the Gaussian proportion between adipose and lean tissues. Segmentation of visceral and subcutaneous fat compartments was achieved with 2D 1/2 level set methods. Our results show that the application of human clinical CT to mice is a promising approach for the study of obesity, allowing valuable comparison between species using the same imaging materials and software analysis.

  20. Reversal of Type 1 Diabetes in Mice by Brown Adipose Tissue Transplant

    PubMed Central

    Gunawardana, Subhadra C.; Piston, David W.

    2012-01-01

    Current therapies for type 1 diabetes (T1D) involve insulin replacement or transplantation of insulin-secreting tissue, both of which suffer from numerous limitations and complications. Here, we show that subcutaneous transplants of embryonic brown adipose tissue (BAT) can correct T1D in streptozotocin-treated mice (both immune competent and immune deficient) with severely impaired glucose tolerance and significant loss of adipose tissue. BAT transplants result in euglycemia, normalized glucose tolerance, reduced tissue inflammation, and reversal of clinical diabetes markers such as polyuria, polydipsia, and polyphagia. These effects are independent of insulin but correlate with recovery of the animals’ white adipose tissue. BAT transplants lead to significant increases in adiponectin and leptin, but with levels that are static and not responsive to glucose. Pharmacological blockade of the insulin receptor in BAT transplant mice leads to impaired glucose tolerance, similar to what is seen in nondiabetic animals, indicating that insulin receptor activity plays a role in the reversal of diabetes. One possible candidate for activating the insulin receptor is IGF-1, whose levels are also significantly elevated in BAT transplant mice. Thus, we propose that the combined action of multiple adipokines establishes a new equilibrium in the animal that allows for chronic glycemic control without insulin. PMID:22315305

  1. Dioxins and dibenzofurans in adipose tissue of US Vietnam veterans and controls

    DOE Office of Scientific and Technical Information (OSTI.GOV)

    Kang, H.K.; Watanabe, K.K.; Breen, J.

    1991-03-01

    The primary reason for concern about the adverse effects of exposure to Agent Orange is attributable to its toxic contaminant, 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) or dioxin. We studied adipose tissues from 36 Vietnam veterans, a similar group of 79 non-Vietnam veterans, and 80 civilians; the tissue specimens were selected from the 8,000 archived tissues collected from the non-institutionalized general population by the US Environmental Protection Agency. The geometric mean (+/- standard deviation) dioxin levels in adipose tissue for Vietnam veterans, non-Vietnam veterans, and civilian controls were 11.7 (+/- 1.7), 10.9 (+/- 1.7), and 12.4 (+/- 1.9) parts per trillion on a lipidmore » weight basis, respectively. The mean levels for these groups were not significantly different from each other with or without adjustment for age of individuals, body mass index, and specimen collection year. In addition, none of the surrogate measures of Agent Orange exposure such as military branch, service within specific geographic region, military occupation, and troop location in relation to recorded Agent Orange spray was associated with the dioxin levels in adipose tissue of Vietnam veterans. Our results suggest that heavy exposure to Agent Orange or dioxin for most US troops was unlikely.« less

  2. A worm of one’s own: how helminths modulate host adipose tissue function and metabolism

    PubMed Central

    Guigas, Bruno; Molofsky, Ari B.

    2015-01-01

    Parasitic helminths have co-existed with human beings throughout time. Success in eradicating helminths has limited helminth-induced morbidity and mortality but is also correlated with increasing rates of ‘Western’ diseases, including metabolic syndrome and type 2 diabetes. Recent studies in mice describe how type 2 immune cells, traditionally associated with helminth infection, maintain adipose tissue homeostasis and promote adipose tissue beiging, protecting against obesity and metabolic dysfunction. Here we review these studies and discuss how helminths and helminth-derived molecules may modulate these physiologic pathways to improve metabolic functions in specific tissues, such as adipose and liver, as well as at the whole-organism level. PMID:25991556

  3. Inhibition of adipose tissue PPARγ prevents increased adipocyte expansion after lipectomy and exacerbates a glucose-intolerant phenotype.

    PubMed

    Booth, A D; Magnuson, A M; Cox-York, K A; Wei, Y; Wang, D; Pagliassotti, M J; Foster, M T

    2017-04-01

    Adipose tissue plays a fundamental role in glucose homeostasis. For example, fat removal (lipectomy, LipX) in lean mice, resulting in a compensatory 50% increase in total fat mass, is associated with significant improvement in glucose tolerance. This study was designed to further examine the link between fat removal, adipose tissue compensation and glucose homeostasis using a peroxisome proliferator-activated receptor γ (PPAR γ; activator of adipogenesis) knockout mouse. The study involved PPARγ knockout (FKOγ) or control mice (CON), subdivided into groups that received LipX or Sham surgery. We reasoned that as the ability of adipose tissue to expand in response to LipX would be compromised in FKOγ mice, so would improvements in glucose homeostasis. In CON mice, LipX increased total adipose depot mass (~60%), adipocyte number (~45%) and changed adipocyte distribution to smaller cells. Glucose tolerance was improved (~30%) in LipX CON mice compared to Shams. In FKOγ mice, LipX did not result in any significant changes in adipose depot mass, adipocyte number or distribution. LipX FKOγ mice were also characterized by reduction of glucose tolerance (~30%) compared to shams. Inhibition of adipose tissue PPARγ prevented LipX-induced increases in adipocyte expansion and produced a glucose-intolerant phenotype. These data support the notion that adipose tissue expansion is critical to maintain and/or improvement in glucose homeostasis. © 2016 John Wiley & Sons Ltd.

  4. Genomic and epigenomic regulation of adipose tissue inflammation in obesity.

    PubMed

    Toubal, Amine; Treuter, Eckardt; Clément, Karine; Venteclef, Nicolas

    2013-12-01

    Chronic inflammation of adipose tissue is viewed as a hallmark of obesity and contributes to the development of type 2 diabetes and cardiovascular disease. According to current models, nutrient excess causes metabolic and structural changes in adipocytes, which initiate transcriptional programs leading to the expression of inflammatory molecules and the subsequent recruitment of immune cells. Recent advances in deciphering the underlying mechanisms revealed that key regulatory events occur at the genomic and epigenomic levels. Here we review these advances because they offer a better understanding of the mechanisms behind the complex obesogenic program in adipose tissue, and because they may help in defining new therapeutic strategies that prevent, restrict, and resolve inflammation in the context of obesity. Copyright © 2013 Elsevier Ltd. All rights reserved.

  5. Effects of endurance exercise training, metformin, and their combination on adipose tissue leptin and IL-10 secretion in OLETF rats

    PubMed Central

    Padilla, Jaume; Arce-Esquivel, Arturo A.; Bayless, David S.; Martin, Jeffrey S.; Leidy, Heather J.; Booth, Frank W.; Rector, R. Scott; Laughlin, M. Harold

    2012-01-01

    Adipose tissue inflammation plays a role in cardiovascular (CV) and metabolic diseases associated with obesity, insulin resistance, and type 2 diabetes mellitus (T2DM). The interactive effects of exercise training and metformin, two first-line T2DM treatments, on adipose tissue inflammation are not known. Using the hyperphagic, obese, insulin-resistant Otsuka Long-Evans Tokushima Fatty (OLETF) rat model, we tested the hypothesis that treadmill training, metformin, or a combination of these reduces the secretion of proinflammatory cytokines from adipose tissue. Compared with Long-Evans Tokushima Otsuka (LETO) control rats (L-Sed), sedentary OLETF (O-Sed) animals secreted significantly greater amounts of leptin from retroperitoneal adipose tissue. Conversely, secretion of interleukin (IL)-10 by O-Sed adipose tissue was lower than that in L-Sed animals. Examination of leptin and IL-10 secretion from adipose tissue in OLETF groups treated with endurance exercise training (O-EndEx), metformin treatment (O-Met), and a combination of these (O-E+M) from 20 to 32 wk of age indicated that 1) leptin secretion from adipose tissue was reduced in O-Met and O-E+M, but not O-EndEx animals; 2) adipose tissue IL-10 secretion was increased in O-EndEx and O-E+M but not in O-Met animals; and 3) only the combined treatment (O-E+M) displayed both a reduction in leptin secretion and an increase in IL-10 secretion. Leptin and IL-10 concentrations in adipose tissue–conditioned buffers were correlated with their plasma concentrations, adipocyte diameters, and total adiposity. Overall, this study indicates that exercise training and metformin have additive influences on adipose tissue secretion and plasma concentrations of leptin and IL-10. PMID:23019312

  6. Magneto-motive detection of tissue-based macrophages by differential phase optical coherence tomography.

    PubMed

    Oh, Junghwan; Feldman, Marc D; Kim, Jihoon; Kang, Hyun Wook; Sanghi, Pramod; Milner, Thomas E

    2007-03-01

    A novel method to detect tissue-based macrophages using a combination of superparamagnetic iron oxide (SPIO) nanoparticles and differential phase optical coherence tomography (DP-OCT) with an external oscillating magnetic field is reported. Magnetic force acting on iron-laden tissue-based macrophages was varied by applying a sinusoidal current to a solenoid containing a conical iron core that substantially focused and increased magnetic flux density. Nanoparticle motion was detected with DP-OCT, which can detect tissue movement with nanometer resolution. Frequency response of iron-laden tissue movement was twice the modulation frequency since the magnetic force is proportional to the product of magnetic flux density and gradient. Results of our experiments indicate that DP-OCT can be used to identify tissue-based macrophage when excited by an external focused oscillating magnetic field. (c) 2007 Wiley-Liss, Inc

  7. Defining the Adipose Tissue Proteome of Dairy Cows to Reveal Biomarkers Related to Peripartum Insulin Resistance and Metabolic Status.

    PubMed

    Zachut, Maya

    2015-07-02

    Adipose tissue is a central regulator of metabolism in dairy cows; however, little is known about the association between various proteins in adipose tissue and the metabolic status of peripartum cows. Therefore, the objectives were to (1) examine total protein expression in adipose tissue of dairy cows and (2) identify biomarkers in adipose that are linked to insulin resistance and to cows' metabolic status. Adipose tissue biopsies were obtained from eight multiparous cows at -17 and +4 days relative to parturition. Proteins were analyzed by intensity-based, label-free, quantitative shotgun proteomics (nanoLC-MS/MS). Cows were divided into groups with insulin-resistant (IR) and insulin-sensitive (IS) adipose according to protein kinase B phosphorylation following insulin stimulation. Cows with IR adipose lost more body weight postpartum compared with IS cows. Differential expression of 143 out of 586 proteins was detected in prepartum versus postpartum adipose. Comparing IR to IS adipose revealed differential expression of 18.9% of the proteins; those related to lipolysis (hormone-sensitive lipase, perilipin, monoglycerol lipase) were increased in IR adipose. In conclusion, we found novel biomarkers related to IR in adipose and to metabolic status that could be used to characterize high-yielding dairy cows that are better adapted to peripartum metabolic stress.

  8. Adipose tissue derived mesenchymal stem cells for musculoskeletal repair in veterinary medicine

    PubMed Central

    Arnhold, Stefan; Wenisch, Sabine

    2015-01-01

    Adipose tissue derived stem cells (ASCs) are mesenchymal stem cells which can be obtained from different adipose tissue sources within the body. It is an abundant cell pool, which is easy accessible and the cells can be obtained in large numbers, cultivated and expanded in vitro and prepared for tissue engineering approaches, especially for skeletal tissue repair. In the recent years this cell population has attracted a great amount of attention among researchers in human as well as in veterinary medicine. In the meantime ASCs have been well characterized and their use in regenerative medicine is very well established. This review focuses on the characterization of ASCs for their use for tissue engineering approaches especially in veterinary medicine and also highlights a selection of clinical trials on the basis of ASCs as the relevant cell source. PMID:25973326

  9. Adipose tissue derived mesenchymal stem cells for musculoskeletal repair in veterinary medicine.

    PubMed

    Arnhold, Stefan; Wenisch, Sabine

    2015-01-01

    Adipose tissue derived stem cells (ASCs) are mesenchymal stem cells which can be obtained from different adipose tissue sources within the body. It is an abundant cell pool, which is easy accessible and the cells can be obtained in large numbers, cultivated and expanded in vitro and prepared for tissue engineering approaches, especially for skeletal tissue repair. In the recent years this cell population has attracted a great amount of attention among researchers in human as well as in veterinary medicine. In the meantime ASCs have been well characterized and their use in regenerative medicine is very well established. This review focuses on the characterization of ASCs for their use for tissue engineering approaches especially in veterinary medicine and also highlights a selection of clinical trials on the basis of ASCs as the relevant cell source.

  10. The combination of high-fat diet-induced obesity and chronic ulcerative colitis reciprocally exacerbates adipose tissue and colon inflammation

    PubMed Central

    2011-01-01

    Background This study evaluated the relationship between ulcerative colitis and obesity, which are both chronic diseases characterized by inflammation and increases in immune cells and pro-inflammatory cytokines. Methods Mice with chronic ulcerative colitis induced by 2 cycles of dextran sodium sulfate (DSS) in the first and fourth week of the experiment were fed a high-fat diet (HFD) to induce obesity by 8 weeks. The animals were divided into 4 \\ groups (control, colitis, HFD and colitis + HFD). Results Obesity alone did not raise histopathology scores, but the combination of obesity and colitis worsened the scores in the colon compared to colitis group. Despite the reduction in weight gain, there was increased inflammatory infiltrate in both the colon and visceral adipose tissue of colitis + HFD mice due to increased infiltration of macrophages, neutrophils and lymphocytes. Intravital microscopy of VAT microvasculature showed an increase in leukocyte adhesion and rolling and overexpression of adhesion molecules compared to other groups. Moreover, circulating lymphocytes, monocytes and neutrophils in the spleen and cecal lymph nodes were increased in the colitis + HFD group. Conclusion Our results demonstrated the relationship between ulcerative colitis and obesity as aggravating factors for each disease, with increased inflammation in the colon and adipose tissue and systemic alterations observed in the spleen, lymph nodes and bloodstream. PMID:22073943

  11. Fibroblast Growth Factor 23 is Associated With Adiposity in Patients Receiving Hemodialysis: Possible Cross Talk Between Bone and Adipose Tissue.

    PubMed

    Chiang, Janet M; Kaysen, George A; Schafer, Anne L; Delgado, Cynthia; Johansen, Kirsten L

    2018-03-29

    Fibroblast growth factor 23 (FGF-23) may be involved in signaling between bone and adipose tissue in dialysis patients, but its role is uncertain. We sought to examine the association between FGF-23 and adiposity and whether this association is mediated in part by leptin. We performed univariate and multivariate linear regression analyses using data from 611 participants in a cohort of prevalent hemodialysis patients recruited from dialysis centers in Atlanta, GA and San Francisco, CA from 2009 to 2011. We also investigated the role of leptin in these relationships. Participants were aged ≥18 years, English or Spanish speaking, and receiving hemodialysis for at least 3 months. Outcome measures of adiposity included body mass index, waist circumference, and body fat measured by bioelectrical impedance spectroscopy. Mean age was 56 ± 14 years, 39.8% were female, and median serum FGF-23 was 807 pg/mL. In fully adjusted models, FGF-23 was inversely associated with body mass index (-0.24 kg/m 2 per 50% higher FGF-23, 95% confidence interval [CI]: -0.38 to -0.10), waist circumference (-0.44 cm per 50% higher FGF-23, 95% CI: -0.79 to -0.08), and percent body fat (-0.58% per 50% higher FGF-23, 95% CI: -0.79 to -0.37). Leptin was inversely associated with FGF-23. Addition of leptin to body composition models attenuated the associations between FGF-23 and measures of adiposity, but FGF-23 remained significantly associated with percent body fat (-0.17% per 50% higher FGF-23, 95% CI: -0.32 to -0.02). We found a negative association between FGF-23 and adiposity that appears to be mediated in part by leptin. As adipose tissue provides a "protective energy depot" for patients with chronic illness, a decrease in adipose tissue may be one mechanism in which higher FGF-23 levels may contribute to increased mortality in dialysis patients. Copyright © 2018 National Kidney Foundation, Inc. Published by Elsevier Inc. All rights reserved.

  12. Pomegranate vinegar attenuates adiposity in obese rats through coordinated control of AMPK signaling in the liver and adipose tissue

    PubMed Central

    2013-01-01

    Background The effect of pomegranate vinegar (PV) on adiposity was investigated in high-fat diet (HF)-induced obese rats. Methods The rats were divided into 5 groups and treated with HF with PV or acetic acid (0, 6.5 or 13% w/w) for 16 weeks. Statistical analyses were performed by the Statistical Analysis Systems package, version 9.2. Results Compared to control, PV supplementation increased phosphorylation of AMP-activated protein kinase (AMPK), leading to changes in mRNA expressions: increases for hormone sensitive lipase and mitochondrial uncoupling protein 2 and decreases for sterol regulatory element binding protein-1c (SREBP-1c) and peroxisome proliferator-activated receptorγ (PPARγ) in adipose tissue; increases for PPARα and carnitinepalmitoyltransferase-1a (CPT-1a) and decrease for SREBP-1c in the liver. Concomitantly, PV reduced increases of body weight (p = 0.048), fat mass (p = 0.033), hepatic triglycerides (p = 0.005), and plasma triglycerides (p = 0.001). Conclusions These results suggest that PV attenuates adiposity through the coordinated control of AMPK, which leads to promotion of lipolysis in adipose tissue and stimulation of fatty acid oxidation in the liver. PMID:24180378

  13. Depot- and sex-specific effects of maternal obesity in offspring's adipose tissue.

    PubMed

    Lecoutre, Simon; Deracinois, Barbara; Laborie, Christine; Eberlé, Delphine; Guinez, Céline; Panchenko, Polina E; Lesage, Jean; Vieau, Didier; Junien, Claudine; Gabory, Anne; Breton, Christophe

    2016-07-01

    According to the Developmental Origin of Health and Disease (DOHaD) concept, alterations of nutrient supply in the fetus or neonate result in long-term programming of individual body weight (BW) setpoint. In particular, maternal obesity, excessive nutrition, and accelerated growth in neonates have been shown to sensitize offspring to obesity. The white adipose tissue may represent a prime target of metabolic programming induced by maternal obesity. In order to unravel the underlying mechanisms, we have developed a rat model of maternal obesity using a high-fat (HF) diet (containing 60% lipids) before and during gestation and lactation. At birth, newborns from obese dams (called HF) were normotrophs. However, HF neonates exhibited a rapid weight gain during lactation, a key period of adipose tissue development in rodents. In males, increased BW at weaning (+30%) persists until 3months of age. Nine-month-old HF male offspring was normoglycemic but showed mild glucose intolerance, hyperinsulinemia, and hypercorticosteronemia. Despite no difference in BW and energy intake, HF adult male offspring was predisposed to fat accumulation showing increased visceral (gonadal and perirenal) depots weights and hyperleptinemia. However, only perirenal adipose tissue depot exhibited marked adipocyte hypertrophy and hyperplasia with elevated lipogenic (i.e. sterol-regulated element binding protein 1 (Srebp1), fatty acid synthase (Fas), and leptin) and diminished adipogenic (i.e. peroxisome proliferator-activated receptor gamma (Pparγ), 11β-hydroxysteroid dehydrogenase type 1 (11β-Hds1)) mRNA levels. By contrast, very few metabolic variations were observed in HF female offspring. Thus, maternal obesity and accelerated growth during lactation program offspring for higher adiposity via transcriptional alterations of visceral adipose tissue in a depot- and sex-specific manner. © 2016 Society for Endocrinology.

  14. Maternal nutrition induces gene expression changes in fetal muscle and adipose tissues in sheep.

    PubMed

    Peñagaricano, Francisco; Wang, Xin; Rosa, Guilherme Jm; Radunz, Amy E; Khatib, Hasan

    2014-11-28

    Maternal nutrition during different stages of pregnancy can induce significant changes in the structure, physiology, and metabolism of the offspring. These changes could have important implications on food animal production especially if these perturbations impact muscle and adipose tissue development. Here, we evaluated the impact of different maternal isoenergetic diets, alfalfa haylage (HY; fiber), corn (CN; starch), and dried corn distillers grains (DG; fiber plus protein plus fat), on the transcriptome of fetal muscle and adipose tissues in sheep. Prepartum diets were associated with notable gene expression changes in fetal tissues. In longissimus dorsi muscle, a total of 224 and 823 genes showed differential expression (FDR ≤0.05) in fetuses derived from DG vs. CN and HY vs. CN maternal diets, respectively. Several of these significant genes affected myogenesis and muscle differentiation. In subcutaneous and perirenal adipose tissues, 745 and 208 genes were differentially expressed (FDR ≤0.05), respectively, between CN and DG diets. Many of these genes are involved in adipogenesis, lipogenesis, and adipose tissue development. Pathway analysis revealed that several GO terms and KEGG pathways were enriched (FDR ≤0.05) with differentially expressed genes associated with tissue and organ development, chromatin biology, and different metabolic processes. These findings provide evidence that maternal nutrition during pregnancy can alter the programming of fetal muscle and fat tissues in sheep. The ramifications of the observed gene expression changes, in terms of postnatal growth, body composition, and meat quality of the offspring, warrant future investigation.

  15. Anti-Inflammatory and Anti-Obesity Properties of Food Bioactive Components: Effects on Adipose Tissue

    PubMed Central

    Jayarathne, Shasika; Koboziev, Iurii; Park, Oak-Hee; Oldewage-Theron, Wilna; Shen, Chwan-Li; Moustaid-Moussa, Naima

    2017-01-01

    Obesity is an epidemic and costly disease affecting 13% of the adult population worldwide. Obesity is associated with adipose tissue hypertrophy and hyperplasia, as well as pathologic endocrine alterations of adipose tissue including local and chronic systemic low-grade inflammation. Moreover, this inflammation is a risk factor for both metabolic syndrome (MetS) and insulin resistance. Basic and clinical studies demonstrate that foods containing bioactive compounds are capable of preventing both obesity and adipose tissue inflammation, improving obesity-associated MetS in human subjects and animal models of obesity. In this review, we discuss the anti-obesity and anti-inflammatory protective effects of some bioactive polyphenols of plant origin and omega-3 polyunsaturated fatty acids, available for the customers worldwide from commonly used foods and/or as components of commercial food supplements. We review how these bioactive compounds modulate cell signaling including through the nuclear factor-κB, adenosine monophosphate-activated protein kinase, mitogen-activated protein kinase, toll-like receptors, and G-protein coupled receptor 120 intracellular signaling pathways and improve the balance of pro- and anti-inflammatory mediators secreted by adipose tissue and subsequently lower systemic inflammation and risk for metabolic diseases. PMID:29333376

  16. Regulation of diet-induced adipose tissue and systemic inflammation by salicylates and pioglitazone.

    PubMed

    Kim, Myung-Sunny; Yamamoto, Yasuhiko; Kim, Kyungjin; Kamei, Nozomu; Shimada, Takeshi; Liu, Libin; Moore, Kristin; Woo, Ju Rang; Shoelson, Steven E; Lee, Jongsoon

    2013-01-01

    It is increasingly accepted that chronic inflammation participates in obesity-induced insulin resistance and type 2 diabetes (T2D). Salicylates and thiazolidinediones (TZDs) both have anti-inflammatory and anti-hyperglycemic properties. The present study compared the effects of these drugs on obesity-induced inflammation in adipose tissue (AT) and AT macrophages (ATMs), as well as the metabolic and immunological phenotypes of the animal models. Both drugs improved high fat diet (HFD)-induced insulin resistance. However, salicylates did not affect AT and ATM inflammation, whereas Pioglitazone improved these parameters. Interestingly, HFD and the drug treatments all modulated systemic inflammation as assessed by changes in circulating immune cell numbers and activation states. HFD increased the numbers of circulating white blood cells, neutrophils, and a pro-inflammatory monocyte subpopulation (Ly6C(hi)), whereas salicylates and Pioglitazone normalized these cell numbers. The drug treatments also decreased circulating lymphocyte numbers. These data suggest that obesity induces systemic inflammation by regulating circulating immune cell phenotypes and that anti-diabetic interventions suppress systemic inflammation by normalizing circulating immune phenotypes.

  17. Inhibitory Effect of Methyl 2-(4'-Methoxy-4'-oxobutanamide) Benzoate from Jerusalem Artichoke (Helianthus tuberosus) on the Inflammatory Paracrine Loop between Macrophages and Adipocytes.

    PubMed

    Jung, Yun Joo; Kim, Byung Oh; Kwak, Jong Hwan; Pyo, Suhkneung

    2016-12-14

    The interaction between macrophages and adipocytes is known to aggravate inflammation of the adipose tissue, leading to decreased insulin sensitivity. Hence, attenuation of the inflammatory paracrine loop between macrophages and adipocytes is deemed essential to ameliorate insulin resistance and diabetes mellitus type 2. Methyl 2-(4'-methoxy-4'-oxobutanamide) benzoate (compound 1), a newly isolated compound from Jerusalem srtichoke (JA), has not been biologically characterized yet. Here, we investigated whether JA-derived compound 1 attenuates the inflammatory cycle between RAW 264.7 macrophages and 3T3-L1 adipocytes. Compound 1 suppressed the inflammatory response of RAW 264.7 cells to lipopolysaccharide through decreased secretion of IL-1β, IL-6, and TNF-α. Moreover, the mRNA expression of TNF-α, IL-6, IL-1β, MCP-1, and Rantes and MAPK pathway activation in 3T3-L1 adipocytes, incubated in macrophage-conditioned media, were inhibited. These findings suggest an anti-inflammatory effect of a newly extracted compound against adipose tissue inflammation and insulin resistance.

  18. Controlled dexamethasone delivery via double-walled microspheres to enhance long-term adipose tissue retention

    PubMed Central

    Kelmendi-Doko, Arta; Rubin, J Peter; Klett, Katarina; Mahoney, Christopher; Wang, Sheri; Marra, Kacey G

    2017-01-01

    Current materials used for adipose tissue reconstruction have critical shortcomings such as suboptimal volume retention, donor-site morbidity, and poor biocompatibility. The aim of this study was to examine a controlled delivery system of dexamethasone to generate stable adipose tissue when mixed with disaggregated human fat in an athymic mouse model for 6 months. The hypothesis that the continued release of dexamethasone from polymeric microspheres would enhance both adipogenesis and angiogenesis more significantly when compared to the single-walled microsphere model, resulting in long-term adipose volume retention, was tested. Dexamethasone was encapsulated within single-walled poly(lactic-co-glycolic acid) microspheres (Dex SW MS) and compared to dexamethasone encapsulated in a poly(lactic-co-glycolic acid) core surrounded by a shell of poly-l-lactide. The double-walled polymer microsphere system in the second model was developed to create a more sustainable drug delivery process. Dexamethasone-loaded poly(lactic-co-glycolic acid) microspheres (Dex SW MS) and dexamethasone-loaded poly(lactic-co-glycolic acid)/poly-l-lactide double-walled microspheres (Dex DW MS) were prepared using single and double emulsion/solvent techniques. In vitro release kinetics were determined. Two doses of each type of microsphere were examined; 50 and 27 mg of Dex MS and Dex DW MS were mixed with 0.3 mL of human lipoaspirate. Additionally, 50 mg of empty MS and lipoaspirate-only controls were examined. Samples were analyzed grossly and histologically after 6 months in vivo. Mass and volume were measured; dexamethasone microsphere-containing samples demonstrated greater adipose tissue retention compared to the control group. Histological analysis, including hematoxylin and eosin and CD31 staining, indicated increased vascularization (p < 0.05) within the Dex MS-containing samples. Controlled delivery of adipogenic factors, such as dexamethasone via polymer microspheres, significantly

  19. Liver but not adipose tissue is responsive to the pattern of enteral feeding

    PubMed Central

    Otero, Yolanda F.; Lundblad, Tammy M.; Ford, Eric A.; House, Lawrence M.; McGuinness, Owen P.

    2014-01-01

    Abstract Nutritional support is an important aspect of medical care, providing calories to patients with compromised nutrient intake. Metabolism has a diurnal pattern, responding to the light cycle and food intake, which in turn can drive changes in liver and adipose tissue metabolism. In this study, we assessed the response of liver and white adipose tissue (WAT) to different feeding patterns under nutritional support (total enteral nutrition or TEN). Mice received continuous isocaloric TEN for 10 days or equal calories of chow once a day (Ch). TEN was given either at a constant (CN, same infusion rate during 24 h) or variable rate (VN, 80% of calories fed at night, 20% at day). Hepatic lipogenesis and carbohydrate‐responsive element‐binding protein (ChREBP) expression increased in parallel with the diurnal feeding pattern. Relative to Ch, both patterns of enteral feeding increased adiposity. This increase was not associated with enhanced lipogenic gene expression in WAT; moreover, lipogenesis was unaffected by the feeding pattern. Surprisingly, leptin and adiponectin expression increased. Moreover, nutritional support markedly increased hepatic and adipose FGF21 expression in CN and VN, despite being considered a fasting hormone. In summary, liver but not WAT, respond to the pattern of feeding. While hepatic lipid metabolism adapts to the pattern of nutrient availability, WAT does not. Moreover, sustained delivery of nutrients in an isocaloric diet can cause adiposity without the proinflammatory state observed in hypercaloric feeding. Thus, the liver but not adipose tissue is responsive to the pattern of feeding behavior. PMID:24744913

  20. Central Nervous System Regulation of Brown Adipose Tissue

    PubMed Central

    Morrison, Shaun F.; Madden, Christopher J.

    2015-01-01

    Thermogenesis, the production of heat energy, in brown adipose tissue is a significant component of the homeostatic repertoire to maintain body temperature during the challenge of low environmental temperature in many species from mouse to man and plays a key role in elevating body temperature during the febrile response to infection. The sympathetic neural outflow determining brown adipose tissue (BAT) thermogenesis is regulated by neural networks in the CNS which increase BAT sympathetic nerve activity in response to cutaneous and deep body thermoreceptor signals. Many behavioral states, including wakefulness, immunologic responses, and stress, are characterized by elevations in core body temperature to which central command-driven BAT activation makes a significant contribution. Since energy consumption during BAT thermogenesis involves oxidation of lipid and glucose fuel molecules, the CNS network driving cold-defensive and behavioral state-related BAT activation is strongly influenced by signals reflecting the short and long-term availability of the fuel molecules essential for BAT metabolism and, in turn, the regulation of BAT thermogenesis in response to metabolic signals can contribute to energy balance, regulation of body adipose stores and glucose utilization. This review summarizes our understanding of the functional organization and neurochemical influences within the CNS networks that modulate the level of BAT sympathetic nerve activity to produce the thermoregulatory and metabolic alterations in BAT thermogenesis and BAT energy expenditure that contribute to overall energy homeostasis and the autonomic support of behavior. PMID:25428857