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Sample records for adipose tissue insulin

  1. Natural killer T cells in adipose tissue prevent insulin resistance.

    PubMed

    Schipper, Henk S; Rakhshandehroo, Maryam; van de Graaf, Stan F J; Venken, Koen; Koppen, Arjen; Stienstra, Rinke; Prop, Serge; Meerding, Jenny; Hamers, Nicole; Besra, Gurdyal; Boon, Louis; Nieuwenhuis, Edward E S; Elewaut, Dirk; Prakken, Berent; Kersten, Sander; Boes, Marianne; Kalkhoven, Eric

    2012-09-01

    Lipid overload and adipocyte dysfunction are key to the development of insulin resistance and can be induced by a high-fat diet. CD1d-restricted invariant natural killer T (iNKT) cells have been proposed as mediators between lipid overload and insulin resistance, but recent studies found decreased iNKT cell numbers and marginal effects of iNKT cell depletion on insulin resistance under high-fat diet conditions. Here, we focused on the role of iNKT cells under normal conditions. We showed that iNKT cell-deficient mice on a low-fat diet, considered a normal diet for mice, displayed a distinctive insulin resistance phenotype without overt adipose tissue inflammation. Insulin resistance was characterized by adipocyte dysfunction, including adipocyte hypertrophy, increased leptin, and decreased adiponectin levels. The lack of liver abnormalities in CD1d-null mice together with the enrichment of CD1d-restricted iNKT cells in both mouse and human adipose tissue indicated a specific role for adipose tissue-resident iNKT cells in the development of insulin resistance. Strikingly, iNKT cell function was directly modulated by adipocytes, which acted as lipid antigen-presenting cells in a CD1d-mediated fashion. Based on these findings, we propose that, especially under low-fat diet conditions, adipose tissue-resident iNKT cells maintain healthy adipose tissue through direct interplay with adipocytes and prevent insulin resistance.

  2. Natural killer T cells in adipose tissue prevent insulin resistance

    PubMed Central

    Schipper, Henk S.; Rakhshandehroo, Maryam; van de Graaf, Stan F.J.; Venken, Koen; Koppen, Arjen; Stienstra, Rinke; Prop, Serge; Meerding, Jenny; Hamers, Nicole; Besra, Gurdyal; Boon, Louis; Nieuwenhuis, Edward E.S.; Elewaut, Dirk; Prakken, Berent; Kersten, Sander; Boes, Marianne; Kalkhoven, Eric

    2012-01-01

    Lipid overload and adipocyte dysfunction are key to the development of insulin resistance and can be induced by a high-fat diet. CD1d-restricted invariant natural killer T (iNKT) cells have been proposed as mediators between lipid overload and insulin resistance, but recent studies found decreased iNKT cell numbers and marginal effects of iNKT cell depletion on insulin resistance under high-fat diet conditions. Here, we focused on the role of iNKT cells under normal conditions. We showed that iNKT cell–deficient mice on a low-fat diet, considered a normal diet for mice, displayed a distinctive insulin resistance phenotype without overt adipose tissue inflammation. Insulin resistance was characterized by adipocyte dysfunction, including adipocyte hypertrophy, increased leptin, and decreased adiponectin levels. The lack of liver abnormalities in CD1d-null mice together with the enrichment of CD1d-restricted iNKT cells in both mouse and human adipose tissue indicated a specific role for adipose tissue–resident iNKT cells in the development of insulin resistance. Strikingly, iNKT cell function was directly modulated by adipocytes, which acted as lipid antigen-presenting cells in a CD1d-mediated fashion. Based on these findings, we propose that, especially under low-fat diet conditions, adipose tissue–resident iNKT cells maintain healthy adipose tissue through direct interplay with adipocytes and prevent insulin resistance. PMID:22863618

  3. Insulin action in adipose tissue in type 1 diabetes

    PubMed Central

    Arrieta-Blanco, Francisco; Botella-Carretero, Jose Ignacio; Iglesias, Pedro; Balsa, José Antonio; Zamarrón, Isabel; De la Puerta, Cristina; Arrieta, Juan José; Ramos, Francisco; Vázquez, Clotilde; Rovira, Adela

    2011-01-01

    Background: Insulin action has been reported to be normal in type 1 diabetic patients. However, some studies have reported an insulin resistance state in these patients. The aim of this study was to investigate insulin resistance in a group of type 1 diabetic patients. We studied the insulin action in adipose tissue and analyzed the effects of duration of disease, body mass index (BMI), and glycosylated hemoglobin on insulin action at the receptor and postreceptor levels in adipocytes. Methods: Nine female type 1 diabetic patients with different durations of disease and eight nondiabetic female patients of comparable age and BMI were studied. 125I-insulin binding and U-[14C]-D-glucose transport was measured in a sample of subcutaneous gluteus adipose tissue obtained by open surgical biopsy from each subject. Results: The duration of disease was negatively correlated with both 125I-insulin binding capacity (r = −0.70, P < 0.05) and basal and maximum insulin-stimulated glucose transport (r = −0.87, P < 0.01, and r = −0.88, P < 0.01, respectively). Maximum specific 125I-insulin binding to the receptors in adipocytes was higher in the group of patients with a shorter duration of disease (P < 0.01). Basal and maximum insulin-stimulated glucose transport was significantly higher in the group with less than 5 years of disease (P < 0.01). No correlation was found between BMI and insulin action. Conclusion: Female type 1 diabetic patients have normal insulin action. There is a high glucose uptake in the early phase of the disease, although a longer duration of disease appears to be a contributing factor to a decrease in insulin action in these patients, and involving both receptor and postreceptor mechanisms. PMID:21475629

  4. Human adipose tissue expresses intrinsic circadian rhythm in insulin sensitivity.

    PubMed

    Carrasco-Benso, Maria P; Rivero-Gutierrez, Belen; Lopez-Minguez, Jesus; Anzola, Andrea; Diez-Noguera, Antoni; Madrid, Juan A; Lujan, Juan A; Martínez-Augustin, Olga; Scheer, Frank A J L; Garaulet, Marta

    2016-09-01

    In humans, insulin sensitivity varies according to time of day, with decreased values in the evening and at night. Mechanisms responsible for the diurnal variation in insulin sensitivity are unclear. We investigated whether human adipose tissue (AT) expresses intrinsic circadian rhythms in insulin sensitivity that could contribute to this phenomenon. Subcutaneous and visceral AT biopsies were obtained from extremely obese participants (body mass index, 41.8 ± 6.3 kg/m(2); 46 ± 11 y) during gastric-bypass surgery. To assess the rhythm in insulin signaling, AKT phosphorylation was determined every 4 h over 24 h in vitro in response to different insulin concentrations (0, 1, 10, and 100 nM). Data revealed that subcutaneous AT exhibited robust circadian rhythms in insulin signaling (P < 0.00001). Insulin sensitivity reached its maximum (acrophase) around noon, being 54% higher than during midnight (P = 0.009). The amplitude of the rhythm was positively correlated with in vivo sleep duration (r = 0.53; P = 0.023) and negatively correlated with in vivo bedtime (r = -0.54; P = 0.020). No circadian rhythms were detected in visceral AT (P = 0.643). Here, we demonstrate the relevance of the time of the day for how sensitive AT is to the effects of insulin. Subcutaneous AT shows an endogenous circadian rhythm in insulin sensitivity that could provide an underlying mechanism for the daily rhythm in systemic insulin sensitivity.-Carrasco-Benso, M. P., Rivero-Gutierrez, B., Lopez-Minguez, J., Anzola, A., Diez-Noguera, A., Madrid, J. A., Lujan, J. A., Martínez-Augustin, O., Scheer, F. A. J. L., Garaulet, M. Human adipose tissue expresses intrinsic circadian rhythm in insulin sensitivity.

  5. Insulin Mediated 14C-Glucose Incorporation Into Adipose Tissue: An Undergraduate Biochemistry Experiment

    ERIC Educational Resources Information Center

    Landman, A. D.; Eskin, N. A. M.

    1975-01-01

    Describes an experiment in which rat adipose tissue samples are exposed to labeled glucose; insulin is added to one sample. Subsequent scintillation counting demonstrates the ability of insulin to facilitate the entry of glucose into the tissue. (MLH)

  6. 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

  7. Ginsenoside Rg5 Inhibits Succinate-Associated Lipolysis in Adipose Tissue and Prevents Muscle Insulin Resistance

    PubMed Central

    Xiao, Na; Yang, Le-Le; Yang, Yi-Lin; Liu, Li-Wei; Li, Jia; Liu, Baolin; Liu, Kang; Qi, Lian-Wen; Li, Ping

    2017-01-01

    Endoplasmic reticulum (ER) stress, inflammation, and lipolysis occur simultaneously in adipose dysfunction and contribute to insulin resistance. This study was designed to investigate whether ginsenoside Rg5 could ameliorate adipose dysfunction and prevent muscle insulin resistance. Short-term high-fat diet (HFD) feeding induced hypoxia with ER stress in adipose tissue, leading to succinate accumulation due to the reversal of succinate dehydrogenase (SDH) activity. Rg5 treatment reduced cellular energy charge, suppressed ER stress and then prevented succinate accumulation in adipose tissue. Succinate promoted IL-1β production through NLRP3 inflammasome activation and then increased cAMP accumulation by impairing PDE3B expression, leading to increased lipolysis. Ginsenoside Rg5 treatment suppressed NLRP3 inflammasome activation, preserved PDE3B expression and then reduced cAMP accumulation, contributing to inhibition of lipolysis. Adipose lipolysis increased FFAs trafficking from adipose tissue to muscle. Rg5 reduced diacylglycerol (DAG) and ceramides accumulation, inhibited protein kinase Cθ translocation, and prevented insulin resistance in muscle. In conclusion, succinate accumulation in hypoxic adipose tissue acts as a metabolic signaling to link ER stress, inflammation and cAMP/PKA activation, contributing to lipolysis and insulin resistance. These findings establish a previously unrecognized role of ginsenosides in the regulation of lipid and glucose homeostasis and suggest that adipose succinate-associated NLRP3 inflammasome activation might be targeted therapeutically to prevent lipolysis and insulin resistance. PMID:28261091

  8. Dietary Fructose Activates Insulin Signaling and Inflammation in Adipose Tissue: Modulatory Role of Resveratrol

    PubMed Central

    Pektas, Mehmet Bilgehan; Koca, Halit Bugra; Sadi, Gokhan; Akar, Fatma

    2016-01-01

    The effects of high-fructose diet on adipose tissue insulin signaling and inflammatory process have been poorly documented. In this study, we examined the influences of long-term fructose intake and resveratrol supplementation on the expression of genes involved in insulin signaling and the levels of inflammatory cytokines and sex hormones in the white adipose tissues of male and female rats. Consumption of high-fructose diet for 24 weeks increased the expression of genes involved in insulin signaling including IR, IRS-1, IRS-2, Akt, PI3K, eNOS, mTOR, and PPARγ, despite induction of proinflammatory markers, iNOS, TNFα, IL-1β, IL-18, MDA, and ALT, as well as anti-inflammatory factors, IL-10 and Nrf2 in adipose tissues from males and females. Total and free testosterone concentrations of adipose tissues were impaired in males but increased in females, although there were no changes in their blood levels. Resveratrol supplementation markedly restored the levels of MDA, IL6, IL-10, and IL-18, as well as iNOS, Nrf2, and PI3K mRNA, in adipose tissues of both genders. Dietary fructose activates both insulin signaling and inflammatory pathway in the adipose tissues of male and female rats proposing no correlation between the tissue insulin signaling and inflammation. Resveratrol has partly modulatory effects on fructose-induced changes. PMID:27066503

  9. Increased adipose tissue expression of Grb14 in several models of insulin resistance.

    PubMed

    Cariou, Bertrand; Capitaine, Nadège; Le Marcis, Véronique; Vega, Nathalie; Béréziat, Véronique; Kergoat, Micheline; Laville, Martine; Girard, Jean; Vidal, Hubert; Burnol, Anne-Françoise

    2004-06-01

    Grb14 is an effector of insulin signaling, which directly inhibits insulin receptor catalytic activity in vitro. Here, we investigated whether the expression of Grb14 and its binding partner ZIP (PKC zeta interacting protein) is regulated during insulin resistance in type 2 diabetic rodents and humans. Grb14 expression was increased in adipose tissue of both ob/ob mice and Goto-Kakizaki (GK) rats, whereas there was no difference in liver. An increase was also observed in subcutaneous adipose tissue of type 2 diabetic subjects when compared with controls. ZIP expression was increased in adipose tissue of ob/ob mice and type 2 diabetic patients, but it did not vary in GK rats. Hormonal regulation of Grb14 and ZIP expression was then investigated in 3T3-F442A adipocytes. In this model, insulin stimulated Grb14 expression, while TNF-alpha increased ZIP expression. Moreover, the insulin-sensitizing drugs thiazolidinediones (TZDs) decreased Grb14 expression in 3T3-F442A adipocytes. Finally, we investigated the dynamic regulation of Grb14 expression in ob/ob mice in several conditions improving their insulin sensitivity. Prolonged fasting and treatment with metformin significantly decreased Grb14 expression in peri-epidydimal adipose tissue, while there was only a trend to a diminution after TZD treatment. Taken together, these results suggest that the regulation of Grb14 expression in adipose tissue may play a physiological role in insulin sensitivity.

  10. The adaptive immune system as a fundamental regulator of adipose tissue inflammation and insulin resistance.

    PubMed

    Winer, Shawn; Winer, Daniel A

    2012-09-01

    Over the past decade, chronic inflammation in visceral adipose tissue (VAT) has gained acceptance as a lead promoter of insulin resistance in obesity. A great deal of evidence has pointed to the role of adipokines and innate immune cells, in particular, adipose tissue macrophages, in the regulation of fat inflammation and glucose homeostasis. However, more recently, cells of the adaptive immune system, specifically B and T lymphocytes, have emerged as unexpected promoters and controllers of insulin resistance. These adaptive immune cells infiltrate obesity expanded VAT and through cytokine secretion and macrophage modulation dictate the extent of the local inflammatory response, thereby directly impacting insulin resistance. The remarkable ability of our adaptive immune system to regulate insulin sensitivity and metabolism has unmasked a novel physiological function of this system, and promises new diagnostic and therapeutic strategies to manage the disease. This review highlights critical roles of adipose tissue lymphocytes in governing glucose homeostasis.

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

    Technology Transfer Automated Retrieval System (TEKTRAN)

    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...

  12. Loss of Oncostatin M Signaling in Adipocytes Induces Insulin Resistance and Adipose Tissue Inflammation in Vivo.

    PubMed

    Elks, Carrie M; Zhao, Peng; Grant, Ryan W; Hang, Hardy; Bailey, Jennifer L; Burk, David H; McNulty, Margaret A; Mynatt, Randall L; Stephens, Jacqueline M

    2016-08-12

    Oncostatin M (OSM) is a multifunctional gp130 cytokine. Although OSM is produced in adipose tissue, it is not produced by adipocytes. OSM expression is significantly induced in adipose tissue from obese mice and humans. The OSM-specific receptor, OSM receptor β (OSMR), is expressed in adipocytes, but its function remains largely unknown. To better understand the effects of OSM in adipose tissue, we knocked down Osmr expression in adipocytes in vitro using siRNA. In vivo, we generated a mouse line lacking Osmr in adiponectin-expressing cells (OSMR(FKO) mice). The effects of OSM on gene expression were also assessed in vitro and in vivo OSM exerts proinflammatory effects on cultured adipocytes that are partially rescued by Osmr knockdown. Osm expression is significantly increased in adipose tissue T cells of high fat-fed mice. In addition, adipocyte Osmr expression is increased following high fat feeding. OSMR(FKO) mice exhibit increased insulin resistance and adipose tissue inflammation and have increased lean mass, femoral length, and bone volume. Also, OSMR(FKO) mice exhibit increased expression of Osm, the T cell markers Cd4 and Cd8, and the macrophage markers F4/80 and Cd11c Interestingly, the same proinflammatory genes induced by OSM in adipocytes are induced in the adipose tissue of the OSMR(FKO) mouse, suggesting that increased expression of proinflammatory genes in adipose tissue arises both from adipocytes and other cell types. These findings suggest that adipocyte OSMR signaling is involved in the regulation of adipose tissue homeostasis and that, in obesity, OSMR ablation may exacerbate insulin resistance by promoting adipose tissue inflammation.

  13. Human adipose tissue-derived mesenchymal stem cells differentiate into insulin, somatostatin, and glucagon expressing cells

    SciTech Connect

    Timper, Katharina; Seboek, Dalma; Eberhardt, Michael; Linscheid, Philippe; Christ-Crain, Mirjam; Keller, Ulrich; Mueller, Beat; Zulewski, Henryk . E-mail: henryk.zulewski@unibas.ch

    2006-03-24

    Mesenchymal stem cells (MSC) from mouse bone marrow were shown to adopt a pancreatic endocrine phenotype in vitro and to reverse diabetes in an animal model. MSC from human bone marrow and adipose tissue represent very similar cell populations with comparable phenotypes. Adipose tissue is abundant and easily accessible and could thus also harbor cells with the potential to differentiate in insulin producing cells. We isolated human adipose tissue-derived MSC from four healthy donors. During the proliferation period, the cells expressed the stem cell markers nestin, ABCG2, SCF, Thy-1 as well as the pancreatic endocrine transcription factor Isl-1. The cells were induced to differentiate into a pancreatic endocrine phenotype by defined culture conditions within 3 days. Using quantitative PCR a down-regulation of ABCG2 and up-regulation of pancreatic developmental transcription factors Isl-1, Ipf-1, and Ngn3 were observed together with induction of the islet hormones insulin, glucagon, and somatostatin.

  14. Adipocyte SIRT1 controls systemic insulin sensitivity by modulating macrophages in adipose tissue.

    PubMed

    Hui, Xiaoyan; Zhang, Mingliang; Gu, Ping; Li, Kuai; Gao, Yuan; Wu, Donghai; Wang, Yu; Xu, Aimin

    2017-03-07

    Adipose tissue inflammation, characterized by augmented infiltration and altered polarization of macrophages, contributes to insulin resistance and its associated metabolic diseases. The NAD(+)-dependent deacetylase SIRT1 serves as a guardian against metabolic disorders in multiple tissues. To dissect the roles of SIRT1 in adipose tissues, metabolic phenotypes of mice with selective ablation of SIRT1 in adipocytes and myeloid cells were monitored. Compared to myeloid-specific SIRT1 depletion, mice with adipocyte-selective deletion of SIRT1 are more susceptible to diet-induced insulin resistance. The phenotypic changes in adipocyte-selective SIRT1 knockout mice are associated with an increased number of adipose-resident macrophages and their polarization toward the pro-inflammatory M1 subtype. Mechanistically, SIRT1 in adipocytes modulates expression and secretion of several adipokines, including adiponectin, MCP-1, and interleukin 4, which in turn alters recruitment and polarization of the macrophages in adipose tissues. In adipocytes, SIRT1 deacetylates the transcription factor NFATc1 and thereby enhances the binding of NFATc1 to the Il4 gene promoter. These findings suggest that adipocyte SIRT1 controls systemic glucose homeostasis and insulin sensitivity via the cross talk with adipose-resident macrophages.

  15. Adipose tissue α-linolenic acid is inversely associated with insulin resistance in adults1

    PubMed Central

    Sabaté, Joan

    2016-01-01

    Background: There is emerging evidence of the beneficial effects of n–3 (ω-3) fatty acids (FAs) on cardiometabolic risk factors. Nevertheless, not much is known about the association between adipose tissue α-linolenic acid (ALA), eicosapentaenoic acid (EPA), and docosahexaenoic acid (DHA) and insulin resistance. Objective: We determined the association between adipose tissue n–3 FAs (total n–3 FAs, ALA, and EPA plus DHA) and insulin resistance in healthy adults. Design: In this cross-sectional study, multivariable analyses were used to assess the association between adipose tissue FAs (ALA, EPA plus DHA, and total n–3 FAs) and the homeostasis model assessment of insulin resistance (HOMA-IR) in a subset of adult participants (n = 716; mean age: 58 y) from the Adventist Health Study-2 (AHS-2) cohort. Results: Compared with the lowest tertile, the third tertile (β = −0.13; 95% CI: −0.24, −0.01) of adipose tissue ALA was inversely associated with the HOMA-IR. When stratified by waist circumference, ALA continued to be inversely associated [third tertile: β = −0.17 (95% CI: −0.31, −0.02)] with the HOMA-IR in subjects with a waist circumference ≤88 cm in women or ≤102 cm in men but not in those with a larger waist circumference. No significant association was noted between adipose tissue EPA plus DHA and HOMA-IR. Conclusions: Higher adipose tissue ALA was inversely associated with insulin resistance in this cohort of healthy adult men and women. This finding appears to be more pronounced in individuals with a normal waist circumference. PMID:26912497

  16. (n-3) Fatty acids alleviate adipose tissue inflammation and insulin resistance: Mechanistic insights

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Obesity is associated with the metabolic syndrome, a significant risk factor for developing type-2 diabetes and cardiovascular diseases. A chronic low-grade inflammation occurring in the adipose tissue of obese individuals is causally linked to the pathogenesis of insulin resistance and the metaboli...

  17. Insulin Resistance in Adipose Tissue but Not in Liver Is Associated with Aortic Valve Calcification.

    PubMed

    Jorge-Galarza, Esteban; Posadas-Romero, Carlos; Torres-Tamayo, Margarita; Medina-Urrutia, Aida X; Rodas-Díaz, Marco A; Posadas-Sánchez, Rosalinda; Vargas-Alarcón, Gilberto; González-Salazar, María Del Carmen; Cardoso-Saldaña, Guillermo C; Juárez-Rojas, Juan G

    2016-01-01

    Background. Insulin resistance is involved in the pathogenesis of cardiovascular disease, but its relationship with cardiovascular calcification has yielded conflicting results. The purpose of the present study was to investigate the role of hepatic and adipose tissue insulin resistance on the presence of coronary artery (CAC > 0) and aortic valve calcification (AVC > 0). Methods. In 1201 subjects (52% women, 53.6 ± 9.3 years old) without familiar and personal history of coronary heart disease, CAC and AVC were assessed by multidetector-computed tomography. Cardiovascular risk factors were documented and lipid profile, inflammation markers, glucose, insulin, and free fatty acids were measured. Hepatic insulin resistance (HOMA-IR) and adipose tissue insulin resistance (Adipo-IR) indices were calculated. Results. There was a significant relationship between HOMA-IR and Adipo-IR indices (r = 0.758, p < 0.001). Participants in the highest quartiles of HOMA-IR and Adipo-IR indices had a more adverse cardiovascular profile and higher prevalence of CAC > 0 and AVC > 0. After full adjustment, subjects in the highest quartile of Adipo-IR index had higher odds of AVC > 0 (OR: 2.40; 95% CI: 1.30-4.43), as compared to those in the lowest quartile. Conclusions. Adipo-IR was independently associated with AVC > 0. This suggests that abnormal adipose tissue function favors insulin resistance that may promote the development and progression of AVC.

  18. Insulin Resistance in Adipose Tissue but Not in Liver Is Associated with Aortic Valve Calcification

    PubMed Central

    Jorge-Galarza, Esteban; Torres-Tamayo, Margarita; Rodas-Díaz, Marco A.; Posadas-Sánchez, Rosalinda; González-Salazar, María del Carmen; Cardoso-Saldaña, Guillermo C.

    2016-01-01

    Background. Insulin resistance is involved in the pathogenesis of cardiovascular disease, but its relationship with cardiovascular calcification has yielded conflicting results. The purpose of the present study was to investigate the role of hepatic and adipose tissue insulin resistance on the presence of coronary artery (CAC > 0) and aortic valve calcification (AVC > 0). Methods. In 1201 subjects (52% women, 53.6 ± 9.3 years old) without familiar and personal history of coronary heart disease, CAC and AVC were assessed by multidetector-computed tomography. Cardiovascular risk factors were documented and lipid profile, inflammation markers, glucose, insulin, and free fatty acids were measured. Hepatic insulin resistance (HOMA-IR) and adipose tissue insulin resistance (Adipo-IR) indices were calculated. Results. There was a significant relationship between HOMA-IR and Adipo-IR indices (r = 0.758, p < 0.001). Participants in the highest quartiles of HOMA-IR and Adipo-IR indices had a more adverse cardiovascular profile and higher prevalence of CAC > 0 and AVC > 0. After full adjustment, subjects in the highest quartile of Adipo-IR index had higher odds of AVC > 0 (OR: 2.40; 95% CI: 1.30–4.43), as compared to those in the lowest quartile. Conclusions. Adipo-IR was independently associated with AVC > 0. This suggests that abnormal adipose tissue function favors insulin resistance that may promote the development and progression of AVC. PMID:28127113

  19. Brown Adipose Tissue Improves Whole-Body Glucose Homeostasis and Insulin Sensitivity in Humans

    PubMed Central

    Chondronikola, Maria; Volpi, Elena; Børsheim, Elisabet; Porter, Craig; Annamalai, Palam; Enerbäck, Sven; Lidell, Martin E.; Saraf, Manish K.; Labbe, Sebastien M.; Hurren, Nicholas M.; Yfanti, Christina; Chao, Tony; Andersen, Clark R.; Cesani, Fernando; Hawkins, Hal

    2014-01-01

    Brown adipose tissue (BAT) has attracted scientific interest as an antidiabetic tissue owing to its ability to dissipate energy as heat. Despite a plethora of data concerning the role of BAT in glucose metabolism in rodents, the role of BAT (if any) in glucose metabolism in humans remains unclear. To investigate whether BAT activation alters whole-body glucose homeostasis and insulin sensitivity in humans, we studied seven BAT-positive (BAT+) men and five BAT-negative (BAT−) men under thermoneutral conditions and after prolonged (5–8 h) cold exposure (CE). The two groups were similar in age, BMI, and adiposity. CE significantly increased resting energy expenditure, whole-body glucose disposal, plasma glucose oxidation, and insulin sensitivity in the BAT+ group only. These results demonstrate a physiologically significant role of BAT in whole-body energy expenditure, glucose homeostasis, and insulin sensitivity in humans, and support the notion that BAT may function as an antidiabetic tissue in humans. PMID:25056438

  20. Insulin resistance is associated with altered amino acid metabolism and adipose tissue dysfunction in normoglycemic women

    PubMed Central

    Wiklund, Petri; Zhang, Xiaobo; Pekkala, Satu; Autio, Reija; Kong, Lingjia; Yang, Yifan; Keinänen-Kiukaanniemi, Sirkka; Alen, Markku; Cheng, Sulin

    2016-01-01

    Insulin resistance is associated adiposity, but the mechanisms are not fully understood. In this study, we aimed to identify early metabolic alterations associated with insulin resistance in normoglycemic women with varying degree of adiposity. One-hundred and ten young and middle-aged women were divided into low and high IR groups based on their median HOMA-IR (0.9 ± 0.4 vs. 2.8 ± 1.2). Body composition was assessed using DXA, skeletal muscle and liver fat by proton magnetic resonance spectroscopy, serum metabolites by nuclear magnetic resonance spectroscopy and adipose tissue and skeletal muscle gene expression by microarrays. High HOMA-IR subjects had higher serum branched-chain amino acid concentrations (BCAA) (p < 0.05 for both). Gene expression analysis of subcutaneous adipose tissue revealed significant down-regulation of genes related to BCAA catabolism and mitochondrial energy metabolism and up-regulation of several inflammation-related pathways in high HOMA-IR subjects (p < 0.05 for all), but no differentially expressed genes in skeletal muscle were found. In conclusion, in normoglycemic women insulin resistance was associated with increased serum BCAA concentrations, down-regulation of mitochondrial energy metabolism and increased expression of inflammation-related genes in the adipose tissue. PMID:27080554

  1. Adipose tissue insulin receptor knockdown via a new primate-derived hybrid recombinant AAV serotype

    PubMed Central

    Liu, Xianglan; Magee, Daniel; Wang, Chuansong; McMurphy, Travis; Slater, Andrew; During, Matthew; Cao, Lei

    2014-01-01

    Adipose tissue plays an essential role in metabolic homeostasis and holds promise as an alternative depot organ in gene therapy. However, efficient methods of gene transfer into adipose tissue in vivo have yet to be established. Here, we assessed the transduction efficiency to fat depots by a family of novel engineered hybrid capsid serotypes (Rec1~4) recombinant adeno-associated viral (AAV) vectors in comparison with natural serotypes AAV1, AAV8, and AAV9. Rec2 serotype led to widespread transduction in both brown fat and white fat with the highest efficiency among the seven serotypes tested. As a proof-of-efficacy, Rec2 serotype was used to deliver Cre recombinase to adipose tissues of insulin receptor floxed animals. Insulin receptor knockdown led to decreased fat pad mass and morphological and molecular changes in the targeted depot. These novel hybrid AAV vectors can serve as powerful tools to genetically manipulate adipose tissue and provide valuable vehicles to gene therapy targeting adipose tissue. PMID:25383359

  2. Alteration of local adipose tissue trace element homeostasis as a possible mechanism of obesity-related insulin resistance.

    PubMed

    Tinkov, Alexey A; Sinitskii, Anton I; Popova, Elizaveta V; Nemereshina, Olga N; Gatiatulina, Evgenia R; Skalnaya, Margarita G; Skalny, Anatoly V; Nikonorov, Alexandr A

    2015-09-01

    The mechanisms of association between obesity and the related metabolic disturbances in general and insulin resistance in particular are extensively studied. Taking into account a key role of adipose tissue insulin resistance in the development of systemic obesity-related insulin resistance, the estimation of mechanisms linking increased adiposity and impaired insulin signaling in adipocytes will allow to develop novel prophylactic and therapeutic approaches to treatment of these states. A number of trace elements like chromium, zinc, and vanadium have been shown to take part in insulin signaling via various mechanisms. Taking into account a key role of adipocyte in systemic carbohydrate homeostasis it can be asked if trace element homeostasis in adipose tissue may influence regulatory mechanisms of glucose metabolism. We hypothesize that caloric excess through currently unknown mechanisms results in decreased chromium, vanadium, and zinc content in adipocytes. Decreased content of trace elements in the adipose tissue causes impairment of intra-adipocyte insulin signaling subsequently leading to adipose tissue insulin resistance. The latter significantly contributes to systemic insulin resistance and further metabolic disruption in obesity. It is also possible that decreased adipose tissue trace element content is associated with dysregulation of insulin-sensitizing and proinflammatory adipokines also leading to insulin resistance. We hypothesize that insulin resistance and adipokine dysbalance increase the severity of obesity subsequently aggravating alteration of adipose tissue trace element balance. Single indications of high relative adipose tissue trace element content, decreased Cr, V, and Zn content in obese adipose tissue, and tight association between fat tissue chromium, vanadium, and zinc levels and metabolic parameters in obesity may be useful for hypothesis validation. If our hypothesis will be confirmed by later studies, adipose tissue chromium

  3. Myostatin inhibition in muscle, but not adipose tissue, decreases fat mass and improves insulin sensitivity.

    PubMed

    Guo, Tingqing; Jou, William; Chanturiya, Tatyana; Portas, Jennifer; Gavrilova, Oksana; McPherron, Alexandra C

    2009-01-01

    Myostatin (Mstn) is a secreted growth factor expressed in skeletal muscle and adipose tissue that negatively regulates skeletal muscle mass. Mstn(-/-) mice have a dramatic increase in muscle mass, reduction in fat mass, and resistance to diet-induced and genetic obesity. To determine how Mstn deletion causes reduced adiposity and resistance to obesity, we analyzed substrate utilization and insulin sensitivity in Mstn(-/-) mice fed a standard chow. Despite reduced lipid oxidation in skeletal muscle, Mstn(-/-) mice had no change in the rate of whole body lipid oxidation. In contrast, Mstn(-/-) mice had increased glucose utilization and insulin sensitivity as measured by indirect calorimetry, glucose and insulin tolerance tests, and hyperinsulinemic-euglycemic clamp. To determine whether these metabolic effects were due primarily to the loss of myostatin signaling in muscle or adipose tissue, we compared two transgenic mouse lines carrying a dominant negative activin IIB receptor expressed specifically in adipocytes or skeletal muscle. We found that inhibition of myostatin signaling in adipose tissue had no effect on body composition, weight gain, or glucose and insulin tolerance in mice fed a standard diet or a high-fat diet. In contrast, inhibition of myostatin signaling in skeletal muscle, like Mstn deletion, resulted in increased lean mass, decreased fat mass, improved glucose metabolism on standard and high-fat diets, and resistance to diet-induced obesity. Our results demonstrate that Mstn(-/-) mice have an increase in insulin sensitivity and glucose uptake, and that the reduction in adipose tissue mass in Mstn(-/-) mice is an indirect result of metabolic changes in skeletal muscle. These data suggest that increasing muscle mass by administration of myostatin antagonists may be a promising therapeutic target for treating patients with obesity or diabetes.

  4. Phosphatidic acid and phosphatidylinositol labelling in adipose tissue. Relationship to the metabolic effects of insulin and insulin-like agents.

    PubMed Central

    Honeyman, T W; Strohsnitter, W; Scheid, C R; Schimmel, R J

    1983-01-01

    Exposure to phospholipase C increased the incorporation of [32P]Pi into phosphatidate, CMP-phosphatidate and phosphatidylinositol in rat adipose tissue and isolated adipocytes. A similar effect was observed in response to insulin and oxytocin. Theophylline, 3-isobutyl-1-methylxanthine and adenosine deaminase decreased [32P]Pi incorporation, and adenosine and N6-phenylisopropyladenosine reversed these effects. As with insulin, exposure of adipose tissue to phospholipase C stimulated oxidation of glucose, pyruvate and leucine and activated pyruvate dehydrogenase. Oxytocin and adenosine also mimicked the effects of insulin on leucine oxidation and pyruvate dehydrogenase. However, only insulin stimulated glycogen synthase activity, indicating that the regulation of synthase may be achieved by intracellular events distinct from those regulating changes in phospholipid metabolism, sugar transport and mitochondrial enzyme activities. It is postulated that exposure to phospholipase C forms diacylglycerol, which is phosphorylated to yield phosphatidate. The increased labelling of CMP-phosphatidate and phosphatidylinositol results from the conversion of phosphatidate into these lipids. The correlation between the effects of phospholipase C on phosphatidate synthesis and changes in adipose-tissue metabolism suggests the possibility that increased phosphatidate may directly or indirectly produce changes in membrane transport and enzyme activities. The pattern of phospholipid labelling produced by insulin, adenosine and oxytocin suggests that these stimuli may also increase phosphatidate synthesis, and, if so, changes in phospholipid metabolism could account for some of the metabolic actions of these stimuli. PMID:6411068

  5. Modulation of age-related insulin sensitivity by VEGF-dependent vascular plasticity in adipose tissues

    PubMed Central

    Honek, Jennifer; Seki, Takahiro; Iwamoto, Hideki; Fischer, Carina; Li, Jingrong; Lim, Sharon; Samani, Nilesh J.; Zang, Jingwu; Cao, Yihai

    2014-01-01

    Mechanisms underlying age-related obesity and insulin resistance are generally unknown. Here, we report age-related adipose vascular changes markedly modulated fat mass, adipocyte functions, blood lipid composition, and insulin sensitivity. Notably, VEGF expression levels in various white adipose tissues (WATs) underwent changes uninterruptedly in different age populations. Anti-VEGF and anti- VEGF receptor 2 treatment in different age populations showed marked variations of vascular regression, with midaged mice exhibiting modest sensitivity. Interestingly, anti-VEGF treatment produced opposing effects on WAT adipocyte sizes in different age populations and affected vascular density and adipocyte sizes in brown adipose tissue. Consistent with changes of vasculatures and adipocyte sizes, anti-VEGF treatment increased insulin sensitivity in young and old mice but had no effects in the midaged group. Surprisingly, anti-VEGF treatment significantly improved insulin sensitivity in midaged obese mice fed a high-fat diet. Our findings demonstrate that adipose vasculatures show differential responses to anti-VEGF treatment in various age populations and have therapeutic implications for treatment of obesity and diabetes with anti-VEGF-based antiangiogenic drugs. PMID:25271320

  6. B Lymphocytes in obesity related adipose tissue inflammation and insulin resistance

    PubMed Central

    Winer, Daniel A.; Winer, Shawn; Chng, Melissa H. Y.; Shen, Lei; Engleman, Edgar G.

    2013-01-01

    Obesity related insulin resistance is a chronic inflammatory condition that often gives rise to type 2 diabetes (T2D). Much evidence supports a role for pro-inflammatory T cells and macrophages in promoting local inflammation in tissues such as visceral adipose tissue (VAT) leading to insulin resistance. More recently, B cells have emerged as an additional critical player in orchestrating these processes. B cells infiltrate VAT and display functional and phenotypic changes in response to diet induced obesity. B cells contribute to insulin resistance by presenting antigens to T cells, secreting inflammatory cytokines and producing pathogenic antibodies. B cell manipulation represents a novel approach to the treatment of obesity related insulin resistance and potentially to the prevention of T2D. This review summarizes the roles of B cells in governing VAT inflammation and the mechanisms by which these cells contribute to altered glucose homeostasis in insulin resistance. PMID:24127133

  7. Nutrition, insulin resistance and dysfunctional adipose tissue determine the different components of metabolic syndrome

    PubMed Central

    Paniagua, Juan Antonio

    2016-01-01

    Obesity is an excessive accumulation of body fat that may be harmful to health. Today, obesity is a major public health problem, affecting in greater or lesser proportion all demographic groups. Obesity is estimated by body mass index (BMI) in a clinical setting, but BMI reports neither body composition nor the location of excess body fat. Deaths from cardiovascular diseases, cancer and diabetes accounted for approximately 65% of all deaths, and adiposity and mainly abdominal adiposity are associated with all these disorders. Adipose tissue could expand to inflexibility levels. Then, adiposity is associated with a state of low-grade chronic inflammation, with increased tumor necrosis factor-α and interleukin-6 release, which interfere with adipose cell differentiation, and the action pattern of adiponectin and leptin until the adipose tissue begins to be dysfunctional. In this state the subject presents insulin resistance and hyperinsulinemia, probably the first step of a dysfunctional metabolic system. Subsequent to central obesity, insulin resistance, hyperglycemia, hypertriglyceridemia, hypoalphalipoproteinemia, hypertension and fatty liver are grouped in the so-called metabolic syndrome (MetS). In subjects with MetS an energy balance is critical to maintain a healthy body weight, mainly limiting the intake of high energy density foods (fat). However, high-carbohydrate rich (CHO) diets increase postprandial peaks of insulin and glucose. Triglyceride-rich lipoproteins are also increased, which interferes with reverse cholesterol transport lowering high-density lipoprotein cholesterol. In addition, CHO-rich diets could move fat from peripheral to central deposits and reduce adiponectin activity in peripheral adipose tissue. All these are improved with monounsaturated fatty acid-rich diets. Lastly, increased portions of ω-3 and ω-6 fatty acids also decrease triglyceride levels, and complement the healthy diet that is recommended in patients with MetS. PMID

  8. Interaction between heat acclimation and exogenous insulin in brown adipose tissue of rats

    NASA Astrophysics Data System (ADS)

    Ohno, H.; Yamashita, H.; Sato, N.; Habara, Y.; Gasa, S.; Nagasawa, J.; Sato, Y.; Ishikawa, M.; Segawa, M.; Yamamoto, M.

    1992-09-01

    Seventy-one male Wistar strain rats (7 weeks old) were kept at 5, 25, or 34° C, respectively, for 2 weeks with or without insulin administration. Insulin (Novo Lente MC) was given subcutaneously in a dose of 3.62 nmol/125 µl saline per 100 g body weight. An apparent effect of insulin treatment was noted only in heat-exposed rats, resulting in a remarkable gain in inter-scapular brown adipose tissue (BAT) mass of heat-acclimated, insulin-treated rats in terms of weight or weight per unit body weight. The BAT from heat-acclimated, insulin-treated rats had significantly higher levels of protein, DNA, RNA, and triglyceride than BAT from heat-acclimated, saline-treated rats. Therefore, it seems likely that the growth of BAT in heat-acclimated, insulin-treated rats was mostly due to the anabolic effects of insulin. The uncoupling protein mRNA was, however, present in BAT of heat-acclimated, insulin-treated rats at rather a depressed level, explaining a corresponding decrease in cold tolerance. On the other hand, the expression of insulin receptor mRNA was attenuated in BAT of rats from all the insulin-treated groups, possibly due to the down-regulation of insulin. Thus, there appeared to be some linkage among BAT, heat acclimation, and insulin.

  9. Native and recombinant bovine growth hormone antagonize insulin action in cultured bovine adipose tissue.

    PubMed

    Etherton, T D; Evock, C M; Kensinger, R S

    1987-08-01

    The current study was undertaken to determine if pituitary bovine GH (pbGH) and recombinant bGH (rbGH) antagonized insulin action in bovine adipose tissue after acute (2-h) and chronic (48-h) exposure and whether this was an intrinsic property of bGH. Insulin action (measured as the effect on incorporation of acetate-carbon into long-chain fatty acids) was unaffected by bGH in short term incubations regardless of whether hydrocortisone (HC) was present. After 48 h of culture, however, both pbGH and rbGH similarly antagonized the ability of insulin to maintain lipogenic capacity. This antagonism was dependent upon the presence of HC and was dose dependent, with half-maximal inhibition of insulin action occurring at about 0.5 ng/ml bGH. Bovine PRL did not mimic the effects of bGH on insulin action. These results establish that bGH antagonizes insulin action in bovine adipose tissue and that this effect is dependent upon long term exposure and the inclusion of HC in the culture medium. The fact that both rbGH and pbGH acted similarly indicates that this is an intrinsic property of bGH. The effect of bGH on insulin-dependent maintenance of lipogenic capacity may play an important role in redirecting nutrients away from adipose tissue to other tissues, such as muscle or mammary tissue. It is speculated that this metabolic effect of bGH plays an important role in the adaptive response to chronic bGH treatment, which increases milk yield of dairy cows and growth performance of beef cattle.

  10. Adipose tissue hormones and appetite and body weight regulators in insulin resistance.

    PubMed

    Koleva, Daniela Iv; Orbetzova, Maria M; Atanassova, Pepa K

    2013-01-01

    Impaired sensitivity to insulin (the so called insulin resistance, IR) occurs in a number of genetic and acquired conditions, including obesity, non-insulin dependent diabetes mellitus, polycystic ovary syndrome (PCOS) and metabolic syndrome (MS). In this review we discuss the correlation between IR, the adipose tissue hormones and appetite and body weight regulators. Leptin acts as a major adipostat: it suppresses food intake and activates catabolic pathways associated with increased energy production. It improves the peripheral insulin sensitivity and affects beta-cell function. Adiponectin is the only adipocytokine discovered so far that has anti-atherogenic properties. There is a reverse correlation between the serum adiponectin levels and the degree of obesity, IR, impaired glucose tolerance, dyslipidemia and atherosclerosis. Ghrelin stimulates food intake; of all circulating orexigenic hormones ghrelin is the most thoroughly studied. Ghrelin levels are decreased in MS and PCOS patients as this hormone is negatively correlated with body mass. Resistin is a hormone secreted by adipose tissues; a growing body of evidence suggests that it might be implicated in the link between obesity and diabetes. It has been found that the hormone's levels are significantly higher in obese people than those in normal body mass people. The recently discovered adipose tissue hormones, vaspin, visfatin, omentin-1 and their effect on IR development, have been increasingly researched.

  11. Irisin and Myonectin Regulation in the Insulin Resistant Muscle: Implications to Adipose Tissue: Muscle Crosstalk

    PubMed Central

    Gamas, Luis; Seiça, Raquel

    2015-01-01

    Myokines are peptides produced and secreted by the skeletal muscle, with autocrine, paracrine, and endocrine actions. Many of them are overexpressed during physical exercise and appear to contribute to the benefits of exercise to metabolic homeostasis. Irisin, resulting from the cleavage of the membrane protein FNDC5, was shown to induce adipocyte browning, with increased lipid oxidation and thermogenesis. Myonectin was only recently discovered and initial studies revealed a role in fatty acid uptake and oxidation in adipose tissue and liver. However, the mechanisms of their regulation by exercise are not entirely established. Impaired secretion and action of myokines, such as irisin and myonectin, may have a role in the establishment of insulin resistance. On the other hand, several studies have shown that insulin resistance in the skeletal muscle may change myokines expression and secretion. This may have consequences on lipid and glucose metabolism in adipose tissue and lead to a vicious cycle between impaired myokines production and insulin resistance. This review summarizes the current knowledge about the influence of skeletal muscle insulin resistance on the secretion of irisin and myonectin, as well as its impact on adipose tissue metabolism. PMID:26075283

  12. The Role of Adipose Tissue in Insulin Resistance in Women of African Ancestry

    PubMed Central

    Goedecke, Julia H.; Levitt, Naomi S.; Evans, Juliet; Ellman, Nicole; Hume, David John; Kotze, Liske; Tootla, Mehreen; Victor, Hendriena; Keswell, Dheshnie

    2013-01-01

    Women of African ancestry, particularly those living in industrialized countries, experience a disproportionately higher prevalence of type 2 diabetes (T2D) compared to their white counterparts. Similarly, obesity and insulin resistance, which are major risk factors for T2D, are greater in black compared to white women. The exact mechanisms underlying these phenomena are not known. This paper will focus on the role of adipose tissue biology. Firstly, the characteristic body fat distribution of women of African ancestry will be discussed, followed by the depot-specific associations with insulin resistance. Factors involved in adipose tissue biology and their relation to insulin sensitivity will then be explored, including the role of sex hormones, glucocorticoid metabolism, lipolysis and adipogenesis, and their consequent effects on adipose tissue hypoxia, oxidative stress, and inflammation. Finally the role of ectopic fat deposition will be discussed. The paper proposes directions for future research, in particular highlighting the need for longitudinal and/or intervention studies to better understand the mechanisms underlying the high prevalence of insulin resistance and T2D in women of African ancestry. PMID:23401754

  13. Disruption of inducible 6-phosphofructo-2-kinase ameliorates diet-induced adiposity but exacerbates systemic insulin resistance and adipose tissue inflammatory response.

    PubMed

    Huo, Yuqing; Guo, Xin; Li, Honggui; Wang, Huan; Zhang, Weiyu; Wang, Ying; Zhou, Huaijun; Gao, Zhanguo; Telang, Sucheta; Chesney, Jason; Chen, Y Eugene; Ye, Jianping; Chapkin, Robert S; Wu, Chaodong

    2010-02-05

    Adiposity is commonly associated with adipose tissue dysfunction and many overnutrition-related metabolic diseases including type 2 diabetes. Much attention has been paid to reducing adiposity as a way to improve adipose tissue function and systemic insulin sensitivity. PFKFB3/iPFK2 is a master regulator of adipocyte nutrient metabolism. Using PFKFB3(+/-) mice, the present study investigated the role of PFKFB3/iPFK2 in regulating diet-induced adiposity and systemic insulin resistance. On a high-fat diet (HFD), PFKFB3(+/-) mice gained much less body weight than did wild-type littermates. This was attributed to a smaller increase in adiposity in PFKFB3(+/-) mice than in wild-type controls. However, HFD-induced systemic insulin resistance was more severe in PFKFB3(+/-) mice than in wild-type littermates. Compared with wild-type littermates, PFKFB3(+/-) mice exhibited increased severity of HFD-induced adipose tissue dysfunction, as evidenced by increased adipose tissue lipolysis, inappropriate adipokine expression, and decreased insulin signaling, as well as increased levels of proinflammatory cytokines in both isolated adipose tissue macrophages and adipocytes. In an in vitro system, knockdown of PFKFB3/iPFK2 in 3T3-L1 adipocytes caused a decrease in the rate of glucose incorporation into lipid but an increase in the production of reactive oxygen species. Furthermore, knockdown of PFKFB3/iPFK2 in 3T3-L1 adipocytes inappropriately altered the expression of adipokines, decreased insulin signaling, increased the phosphorylation states of JNK and NFkappaB p65, and enhanced the production of proinflammatory cytokines. Together, these data suggest that PFKFB3/iPFK2, although contributing to adiposity, protects against diet-induced insulin resistance and adipose tissue inflammatory response.

  14. PPARγ Antagonist Gleevec Improves Insulin Sensitivity and Promotes the Browning of White Adipose Tissue

    PubMed Central

    Choi, Sun-Sil; Kim, Eun-Sun; Jung, Ji-Eun; Marciano, David P.; Jo, Ala; Koo, Ja Young; Choi, Soo Youn; Yang, Yong Ryoul; Jang, Hyun-Jun; Kim, Eung-Kyun; Park, Jiyoung; Kwon, Hyug Moo; Lee, In Hee; Park, Seung Bum; Myung, Kyung-Jae; Suh, Pann-Ghill; Griffin, Patrick R.

    2016-01-01

    Blocking phosphorylation of peroxisome proliferator–activated receptor (PPAR)γ at Ser273 is one of the key mechanisms for antidiabetes drugs to target PPARγ. Using high-throughput phosphorylation screening, we here describe that Gleevec blocks cyclin-dependent kinase 5–mediated PPARγ phosphorylation devoid of classical agonism as a PPARγ antagonist ligand. In high fat–fed mice, Gleevec improved insulin sensitivity without causing severe side effects associated with other PPARγ-targeting drugs. Furthermore, Gleevec reduces lipogenic and gluconeogenic gene expression in liver and ameliorates inflammation in adipose tissues. Interestingly, Gleevec increases browning of white adipose tissue and energy expenditure. Taken together, the results indicate that Gleevec exhibits greater beneficial effects on both glucose/lipid metabolism and energy homeostasis by blocking PPARγ phosphorylation. These data illustrate that Gleevec could be a novel therapeutic agent for use in insulin resistance and type 2 diabetes. PMID:26740599

  15. Adiponectin: a biomarker of obesity-induced insulin resistance in adipose tissue and beyond.

    PubMed

    Lu, Jin-Ying; Huang, Kuo-Chin; Chang, Lin-Chau; Huang, Ying-Shing; Chi, Yu-Chiao; Su, Ta-Chan; Chen, Chi-Ling; Yang, Wei-Shiung

    2008-09-01

    Adiponectin is one of the most thoroughly studied adipocytokines. Low plasma levels of adiponectin are found to associate with obesity, metabolic syndrome, diabetes and many other human diseases. From animal experiments and human studies, adiponectin has been shown to be a key regulator of insulin sensitivity. In this article, we review the evidence and propose that hypo-adiponectinemia is not a major cause of obesity. Instead, it is the result of obesity-induced insulin resistance in the adipose tissue. Hypo-adiponectinemia then mediates the metabolic effects of obesity on the other peripheral tissues, such as liver and skeletal muscle and may also exert some direct effects on end-organ damage. We propose that deciphering the molecular details governing the adiponectin gene expression and protein secretion will lead us to more comprehensive understanding of the mechanisms of insulin resistance in the adipose tissue and provide us new avenues for the therapeutic intervention of obesity and insulin resistance-related human disorders.

  16. TUSC5 regulates insulin-mediated adipose tissue glucose uptake by modulation of GLUT4 recycling

    PubMed Central

    Beaton, Nigel; Rudigier, Carla; Moest, Hansjörg; Müller, Sebastian; Mrosek, Nadja; Röder, Eva; Rudofsky, Gottfried; Rülicke, Thomas; Ukropec, Jozef; Ukropcova, Barbara; Augustin, Robert; Neubauer, Heike; Wolfrum, Christian

    2015-01-01

    Objective Failure to properly dispose of glucose in response to insulin is a serious health problem, occurring during obesity and is associated with type 2 diabetes development. Insulin-stimulated glucose uptake is facilitated by the translocation and plasma membrane fusion of vesicles containing glucose transporter 4 (GLUT4), the rate-limiting step of post-prandial glucose disposal. Methods We analyzed the role of Tusc5 in the regulation of insulin-stimulated Glut4-mediated glucose uptake in vitro and in vivo. Furthermore, we measured Tusc5 expression in two patient cohorts. Results Herein, we report that TUSC5 controls insulin-stimulated glucose uptake in adipocytes, in vitro and in vivo. TUSC5 facilitates the proper recycling of GLUT4 and other key trafficking proteins during prolonged insulin stimulation, thereby enabling proper protein localization and complete vesicle formation, processes that ultimately enable insulin-stimulated glucose uptake. Tusc5 knockout mice exhibit impaired glucose disposal and TUSC5 expression is predictive of glucose tolerance in obese individuals, independent of body weight. Furthermore, we show that TUSC5 is a PPARγ target and in its absence the anti-diabetic effects of TZDs are significantly blunted. Conclusions Collectively, these findings establish TUSC5 as an adipose tissue-specific protein that enables proper protein recycling, linking the ubiquitous vesicle traffic machinery with tissue-specific insulin-mediated glucose uptake into adipose tissue and the maintenance of a healthy metabolic phenotype in mice and humans. PMID:26629404

  17. CXCL5 is an adipose tissue derived factor that links obesity to insulin resistance

    PubMed Central

    Chavey, Carine; Lazennec, Gwendal; Lagarrigue, Sylviane; Clapé, Cyrielle; Iankova, Irena; Teyssier, Jacques; Annicotte, Jean-Sébastien; Schmidt, Julien; Mataki, Chikage; Yamamoto, Hiroyasu; Sanches, Rosario; Guma, Anna; Stich, Vladimir; Vitkova, Michaela; Jardin-Watelet, Bénédicte; Renard, Eric; Strieter, Robert; Tuthill, Antoinette; Hotamisligil, Gôkhan S.; Vidal-Puig, Toni; Zorzano, Antonio; Langin, Dominique; Fajas, Lluis

    2009-01-01

    We show here high levels of expression and secretion of the chemokine CXCL5 in the macrophage fraction of white adipose tissue (WAT). Moreover, we find that CXCL5 is dramatically increased in serum of human obese compared to lean subjects. Conversely, CXCL5 concentration is decreased in obese subjects after a weight reduction program, or in obese non-insulin resistant, compared to insulin resistant obese subjects. Most importantly we demonstrate that treatment with recombinant CXCL5 blocks insulin-stimulated glucose uptake in muscle in mice. CXCL5 blocks insulin signaling by activating the Jak2/STAT5/SOCS2 pathway. Finally, by treating obese, insulin resistant mice with either anti-CXCL5 neutralizing antibodies or antagonists of CXCR2, which is the CXCL5 receptor we demonstrate that CXCL5 mediates insulin resistance. Furthermore CXCR2−/− mice are protected against obesity-induced insulin resistance. Taken together, these results show that secretion of CXCL5 by WAT resident macrophages represents a link between obesity, inflammation, and insulin resistance. PMID:19356715

  18. Tofogliflozin Improves Insulin Resistance in Skeletal Muscle and Accelerates Lipolysis in Adipose Tissue in Male Mice.

    PubMed

    Obata, Atsushi; Kubota, Naoto; Kubota, Tetsuya; Iwamoto, Masahiko; Sato, Hiroyuki; Sakurai, Yoshitaka; Takamoto, Iseki; Katsuyama, Hisayuki; Suzuki, Yoshiyuki; Fukazawa, Masanori; Ikeda, Sachiya; Iwayama, Kaito; Tokuyama, Kumpei; Ueki, Kohjiro; Kadowaki, Takashi

    2016-03-01

    Sodium glucose cotransporter 2 inhibitors have attracted attention as they exert antidiabetic and antiobesity effects. In this study, we investigated the effects of tofogliflozin on glucose homeostasis and its metabolic consequences and clarified the underlying molecular mechanisms. C57BL/6 mice were fed normal chow containing tofogliflozin (0.005%) for 20 weeks or a high-fat diet containing tofogliflozin (0.005%) for 8 weeks ad libitum. In addition, the animals were pair-fed in relation to controls to exclude the influence of increased food intake. Tofogliflozin reduced the body weight gain, mainly because of fat mass reduction associated with a diminished adipocyte size. Glucose tolerance and insulin sensitivity were ameliorated. The serum levels of nonesterified fatty acid and ketone bodies were increased and the respiratory quotient was decreased in the tofogliflozin-treated mice, suggesting the acceleration of lipolysis in the white adipose tissue and hepatic β-oxidation. In fact, the phosphorylation of hormone-sensitive lipase and the adipose triglyceride lipase protein levels in the white adipose tissue as well as the gene expressions related to β-oxidation, such as Cpt1α in the liver, were significantly increased. The hepatic triglyceride contents and the expression levels of lipogenic genes were decreased. Pair-fed mice exhibited almost the same results as mice fed an high-fat diet ad libitum. Moreover, a hyperinsulinemic-euglycemic clamp revealed that tofogliflozin improved insulin resistance by increasing glucose uptake, especially in the skeletal muscle, in pair-fed mice. Taken together, these results suggest tofogliflozin ameliorates insulin resistance and obesity by increasing glucose uptake in skeletal muscle and lipolysis in adipose tissue.

  19. Inverse regulation of inflammation and mitochondrial function in adipose tissue defines extreme insulin sensitivity in morbidly obese patients.

    PubMed

    Qatanani, Mohammed; Tan, Yejun; Dobrin, Radu; Greenawalt, Danielle M; Hu, Guanghui; Zhao, Wenqing; Olefsky, Jerrold M; Sears, Dorothy D; Kaplan, Lee M; Kemp, Daniel M

    2013-03-01

    Obesity is associated with insulin resistance, a major risk factor for type 2 diabetes and cardiovascular disease. However, not all obese individuals are insulin resistant, which confounds our understanding of the mechanistic link between these conditions. We conducted transcriptome analyses on 835 obese subjects with mean BMI of 48.8, on which we have previously reported genetic associations of gene expression. Here, we selected ~320 nondiabetic (HbA(1c) <7.0) subjects and further stratified the cohort into insulin-resistant versus insulin-sensitive subgroups based on homeostasis model assessment-insulin resistance. An unsupervised informatics analysis revealed that immune response and inflammation-related genes were significantly downregulated in the omental adipose tissue of obese individuals with extreme insulin sensitivity and, to a much lesser extent, in subcutaneous adipose tissue. In contrast, genes related to β-oxidation and the citric acid cycle were relatively overexpressed in adipose of insulin-sensitive patients. These observations were verified by querying an independent cohort of our published dataset of 37 subjects whose subcutaneous adipose tissue was sampled before and after treatment with thiazolidinediones. Whereas the immune response and inflammation pathway genes were downregulated by thiazolidinedione treatment, β-oxidation and citric acid cycle genes were upregulated. This work highlights the critical role that omental adipose inflammatory pathways might play in the pathophysiology of insulin resistance, independent of body weight.

  20. Caloric restriction increases adiponectin expression by adipose tissue and prevents the inhibitory effect of insulin on circulating adiponectin in rats.

    PubMed

    Ding, Qi; Ash, Catherine; Mracek, Tomas; Merry, Brian; Bing, Chen

    2012-08-01

    Aging is associated with redistribution of body fat and the development of insulin resistance. White adipose tissue emerges as an important organ in controlling life span. Caloric restriction (CR) delays the rate of aging possibly modulated partly by altering the amount and function of adipose tissue. Adiponectin is a major adipose-derived adipokine that has anti-inflammatory and insulin-sensitizing properties. This study examined the effects of CR on adiposity and gene expression of adiponectin, its receptors (AdipoR1 and AdipoR2) in adipose tissue and in isolated adipocytes of Brown Norway rats that had undergone CR for 4 months or fed ad libitum. The study also determined plasma concentrations of adiponectin and insulin in these animals and whether insulin infusion for 7 days affects adiponectin expression and its circulating concentrations under CR conditions. CR markedly reduced body weight as anticipated, epididymal fat mass and adipocyte size. CR led to an increase in plasma free fatty acid and glycerol (both twofold), and adipose triglyceride lipase messenger RNA (mRNA) in adipose tissue and isolated adipocytes (both >2-fold). Adiponectin mRNA levels were elevated in adipose tissue and adipocytes (both >2-fold) as was plasma adiponectin concentration (2.8-fold) in CR rats. However, CR did not alter tissue or cellular AdipoR1 and AdipoR2 expression. Seven days of insulin infusion decreased adiponectin mRNA in adipose tissue but did not reverse the CR-induced up-regulation of circulating adiponectin levels. Our results suggest that the benefits of CR could be, at least in part, dependent on enhanced expression and secretion of adiponectin by adipocytes.

  1. AgRP Neurons Control Systemic Insulin Sensitivity via Myostatin Expression in Brown Adipose Tissue.

    PubMed

    Steculorum, Sophie M; Ruud, Johan; Karakasilioti, Ismene; Backes, Heiko; Engström Ruud, Linda; Timper, Katharina; Hess, Martin E; Tsaousidou, Eva; Mauer, Jan; Vogt, Merly C; Paeger, Lars; Bremser, Stephan; Klein, Andreas C; Morgan, Donald A; Frommolt, Peter; Brinkkötter, Paul T; Hammerschmidt, Philipp; Benzing, Thomas; Rahmouni, Kamal; Wunderlich, F Thomas; Kloppenburg, Peter; Brüning, Jens C

    2016-03-24

    Activation of Agouti-related peptide (AgRP) neurons potently promotes feeding, and chronically altering their activity also affects peripheral glucose homeostasis. We demonstrate that acute activation of AgRP neurons causes insulin resistance through impairment of insulin-stimulated glucose uptake into brown adipose tissue (BAT). AgRP neuron activation acutely reprograms gene expression in BAT toward a myogenic signature, including increased expression of myostatin. Interference with myostatin activity improves insulin sensitivity that was impaired by AgRP neurons activation. Optogenetic circuitry mapping reveals that feeding and insulin sensitivity are controlled by both distinct and overlapping projections. Stimulation of AgRP → LHA projections impairs insulin sensitivity and promotes feeding while activation of AgRP → anterior bed nucleus of the stria terminalis (aBNST)vl projections, distinct from AgRP → aBNSTdm projections controlling feeding, mediate the effect of AgRP neuron activation on BAT-myostatin expression and insulin sensitivity. Collectively, our results suggest that AgRP neurons in mice induce not only eating, but also insulin resistance by stimulating expression of muscle-related genes in BAT, revealing a mechanism by which these neurons rapidly coordinate hunger states with glucose homeostasis.

  2. Artemisia extracts activate PPARγ, promote adipogenesis, and enhance insulin sensitivity in adipose tissue of obese mice

    PubMed Central

    Richard, Allison J.; Burris, Thomas P.; Sanchez-Infantes, David; Wang, Yongjun; Ribnicky, David M.; Stephens, Jacqueline M.

    2014-01-01

    Objective Studies have shown that the inability of adipose tissue to properly expand during the obese state or respond to insulin can lead to metabolic dysfunction. Artemisia is a diverse group of plants that has a history of medicinal use. This study examines the ability of ethanolic extracts of Artemisia scoparia (SCO) and Artemisia santolinifolia (SAN) to modulate adipocyte development in cultured adipocytes and white adipose tissue (WAT) function in vivo using a mouse model of diet-induced obesity. Research Design & Procedures Adipogenesis was assessed using Oil Red O staining and immunoblotting. A nuclear receptor specificity assay was used to examine the specificity of SCO- and SAN-induced PPARγ activation. C57BL/6J mice, fed a high-fat diet, were gavaged with saline, SCO, or SAN for 2 weeks. Whole-body insulin sensitivity was examined using insulin tolerance tests. WAT depots were assessed via immunoblotting for markers of insulin action and adipokine production. Results We established that SCO and SAN were highly specific activators of PPARγ and did not activate other nuclear receptors. After a one-week daily gavage, SCO- and SAN-treated mice had lower insulin-induced glucose disposal rates than control mice. At the end of the 2-week treatment period, SCO- and SAN-treated mice had enhanced insulin-responsive Akt serine-473 phosphorylation and significantly decreased MCP-1 levels in visceral WAT relative to control mice; these differences were depot specific. Moreover, plasma adiponectin levels were increased following SCO treatment. Conclusion Overall, these studies demonstrate that extracts from two Artemisia species can have metabolically favorable effects on adipocytes and WAT. PMID:24985103

  3. Adipose Tissue Overexpression of Vascular Endothelial Growth Factor Protects Against Diet-Induced Obesity and Insulin Resistance

    PubMed Central

    Elias, Ivet; Franckhauser, Sylvie; Ferré, Tura; Vilà, Laia; Tafuro, Sabrina; Muñoz, Sergio; Roca, Carles; Ramos, David; Pujol, Anna; Riu, Efren; Ruberte, Jesús; Bosch, Fatima

    2012-01-01

    During the expansion of fat mass in obesity, vascularization of adipose tissue is insufficient to maintain tissue normoxia. Local hypoxia develops and may result in altered adipokine expression, proinflammatory macrophage recruitment, and insulin resistance. We investigated whether an increase in adipose tissue angiogenesis could protect against obesity-induced hypoxia and, consequently, insulin resistance. Transgenic mice overexpressing vascular endothelial growth factor (VEGF) in brown adipose tissue (BAT) and white adipose tissue (WAT) were generated. Vessel formation, metabolism, and inflammation were studied in VEGF transgenic mice and wild-type littermates fed chow or a high-fat diet. Overexpression of VEGF resulted in increased blood vessel number and size in both WAT and BAT and protection against high-fat diet–induced hypoxia and obesity, with no differences in food intake. This was associated with increased thermogenesis and energy expenditure. Moreover, whole-body insulin sensitivity and glucose tolerance were improved. Transgenic mice presented increased macrophage infiltration, with a higher number of M2 anti-inflammatory and fewer M1 proinflammatory macrophages than wild-type littermates, thus maintaining an anti-inflammatory milieu that could avoid insulin resistance. These studies suggest that overexpression of VEGF in adipose tissue is a potential therapeutic strategy for the prevention of obesity and insulin resistance. PMID:22522611

  4. Brown adipose tissue activity as a target for the treatment of obesity/insulin resistance

    PubMed Central

    Poher, Anne-Laure; Altirriba, Jordi; Veyrat-Durebex, Christelle; Rohner-Jeanrenaud, Françoise

    2015-01-01

    Presence of brown adipose tissue (BAT), characterized by the expression of the thermogenic uncoupling protein 1 (UCP1), has recently been described in adult humans. UCP1 is expressed in classical brown adipocytes, as well as in “beige cells” in white adipose tissue (WAT). The thermogenic activity of BAT is mainly controlled by the sympathetic nervous system. Endocrine factors, such as fibroblast growth factor 21 (FGF21) and bone morphogenic protein factor-9 (BMP-9), predominantly produced in the liver, were shown to lead to activation of BAT thermogenesis, as well as to “browning” of WAT. This was also observed in response to irisin, a hormone secreted by skeletal muscles. Different approaches were used to delineate the impact of UCP1 on insulin sensitivity. When studied under thermoneutral conditions, UCP1 knockout mice exhibited markedly increased metabolic efficiency due to impaired thermogenesis. The impact of UCP1 deletion on insulin sensitivity in these mice was not reported. Conversely, several studies in both rodents and humans have shown that BAT activation (by cold exposure, β3-agonist treatment, transplantation and others) improves glucose tolerance and insulin sensitivity. Interestingly, similar results were obtained by adipose tissue-specific overexpression of PR-domain-containing 16 (PRDM16) or BMP4 in mice. The mediators of such beneficial effects seem to include FGF21, interleukin-6, BMP8B and prostaglandin D2 synthase. Interestingly, some of these molecules can be secreted by BAT itself, indicating the occurrence of autocrine effects. Stimulation of BAT activity and/or recruitment of UCP1-positive cells are therefore relevant targets for the treatment of obesity/type 2 diabetes in humans. PMID:25688211

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

    SciTech Connect

    Fujii, Masakazu; Inoguchi, Toyoshi; Batchuluun, Battsetseg; Sugiyama, Naonobu; Kobayashi, Kunihisa; Sonoda, Noriyuki; Takayanagi, Ryoichi

    2013-08-16

    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 macrophage 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.

  6. Adipose tissue IL-6 content correlates with resistance to insulin activation of glucose uptake both in vivo and in vitro.

    PubMed

    Bastard, Jean-Philippe; Maachi, Mustapha; Van Nhieu, Jeanne Tran; Jardel, Claude; Bruckert, Eric; Grimaldi, André; Robert, Jean-Jacques; Capeau, Jacqueline; Hainque, Bernard

    2002-05-01

    Obesity and type 2 diabetes are associated with insulin resistance, the mechanisms of which remain poorly understood. A significant correlation between circulating IL-6 level and insulin sensitivity has recently been found in humans. Because adipose tissue could be a significant source of IL-6, we analyzed the relationship between the levels of adipose tissue IL-6 and insulin action in vivo, during a hyperinsulinemic normoglycemic clamp, and in vitro by measuring glucose transport in adipocytes from 12 obese subjects with (n = 7) or without (n = 5) diabetes. We observed an inverse correlation between adipose tissue IL-6 content and maximal insulin-responsiveness measured in vivo (P < 0.02) and in vitro (P < 0.02). Conversely, there was no significant correlation between these two later parameters and adipose tissue leptin or tumor necrosis factor-alpha protein contents. Furthermore, we showed, for the first time, the presence of immunoreactive IL-6 receptors in the plasma membrane of human abdominal sc adipocytes. This suggests that locally secreted IL-6 could act on adipocytes by an autocrine/paracrine mechanism. In conclusion, increased IL-6 production by sc adipose cells might participate to the insulin-resistant state observed in human obesity.

  7. Signalling pathways of an insulin-mimetic phosphoinositolglycan-peptide in muscle and adipose tissue.

    PubMed Central

    Kessler, A; Müller, G; Wied, S; Crecelius, A; Eckel, J

    1998-01-01

    A novel phosphoinositolglycan-peptide (PIG-P) from the yeast Saccharomyces cerevisiae potently mimicks insulin action on glucose transport and metabolism in rat muscle and adipose tissue. The aim of the present study was to elucidate the cellular signalling pathways of this insulin-mimetic compound. Rapid onset and reversibility of PIG-P action on glucose transport were observed in isolated adipocytes with a half-time of transport stimulation of 6-8 min (insulin less than 5 min). Combined treatment with PIG-P and insulin indicated additive stimulation of glucose transport at submaximal concentrations and non-additive action of both agents at maximal doses. The tyrosine phosphorylation of insulin receptor substrate-1 (IRS-1) was markedly increased in response to PIG-P in rat cardiomyocytes without any effect on the tyrosine phosphorylation of the insulin receptor beta-subunit. PIG-P action in these cells was accompanied by phosphorylation/dephosphorylation of several proteins with molecular masses of 15-30 kDa, a response not detected with insulin. Downstream signalling of IRS-1 was then analysed by monitoring IRS-1-associated phosphatidylinositol 3-kinase (PI 3-kinase) activity in cardiomyocytes. A stable (2 and 15 min incubation with PIG-P) 7-fold stimulation corresponding to about 50% of insulin action could be detected. Increased tyrosine phosphorylation of IRS-1 and enhanced PI 3-kinase activity in response to PIG-P independent of the insulin receptor was also observed in isolated adipocytes. Involvement of PI 3-kinase in PIG-P action was subsequently confirmed by the dose-dependent inhibition of PIG-P-activated glucose transport in rat diaphragm and adipocytes by the PI 3-kinase inhibitors wortmannin and LY294002. These data suggest divergent upstream signalling by insulin and PIG-P involving phosphoproteins not affected by insulin. However, PIG-P and insulin action converge at the level of IRS-1 inducing insulin-independent PI 3-kinase-mediated signalling to

  8. Insulin Signaling in Liver and Adipose Tissues in Periparturient Dairy Cows Supplemented with Dietary Nicotinic Acid

    PubMed Central

    Kinoshita, Asako; Kenéz, Ákos; Locher, Lena; Meyer, Ulrich; Dänicke, Sven; Rehage, Jürgen; Huber, Korinna

    2016-01-01

    The glucose homeostasis in dairy cattle is very well controlled, in line with the metabolic adaptation during the periparturient period. Former studies showed that nicotinic acid (NA) lowered plasma non-esterified fatty acids (NEFA) concentrations and increased insulin sensitivity in dairy cows. Thus, the purpose of this study was to investigate whether the expression of proteins involved in hepatic and adipose insulin signaling and protein expression of hepatic glucose transporter 2 (GLUT2) were affected by dietary NA and dietary concentrate intake in periparturient dairy cows. Twenty pluriparous German Holstein cows were fed with the same diet from about 21 days before the expected calving date (d-21) to calving. After calving, cows were randomly assigned in 4 groups and fed with diets different in concentrate proportion (“HC” with 60:40% or “LC” with 30:70% concentrate-to-roughage ratio) and supplemented with NA (24 g/day) (NA) or without (CON) until d21. Biopsy samples were taken from the liver, subcutaneous (SCAT) and retroperitoneal (RPAT) adipose tissues at d-21 and d21. Protein expression of insulin signaling molecules (insulin receptor (INSR), phosphatidylinositol-3-kinase (PI3K), protein kinase Cζ (PKCζ)) and hepatic GLUT2 was measured by Western Blotting. The ratio of protein expression at d21/at d-21 was calculated and statistically evaluated for the effects of time and diet. Cows in HC had significantly higher dietary energy intake than cows in LC. In RPAT a decrease in PI3K and PKCζ expression was found in all groups, irrespectively of diet. In the liver, the GLUT2 expression was significantly lower in cows in NA compared with cows in CON. In conclusion, insulin signaling might be decreased in RPAT over time without any effect of diet. NA was able to modulate hepatic GLUT2 expression, but its physiological role is unclear. PMID:26766039

  9. PEDF expression is inhibited by insulin treatment in adipose tissue via suppressing 11β-HSD1.

    PubMed

    Zhou, Yinli; Xu, Fen; Deng, Hongrong; Bi, Yan; Sun, Weiping; Zhao, Yi; Chen, Zonglan; Weng, Jianping

    2013-01-01

    Early intensive insulin therapy improves insulin sensitivity in type 2 diabetic patients; while the underlying mechanism remains largely unknown. Pigment epithelium-derived factor (PEDF), an anti-angiogenic factor, is believed to be involved in the pathogenesis of insulin resistance. Here, we hypothesize that PEDF might be down regulated by insulin and then lead to the improved insulin resistance in type 2 diabetic patients during insulin therapy. We addressed this issue by investigating insulin regulation of PEDF expression in diabetic conditions. The results showed that serum PEDF was reduced by 15% in newly diagnosed type 2 diabetic patients after insulin therapy. In adipose tissue of diabetic Sprague-Dawley rats, PEDF expression was associated with TNF-α elevation and it could be decreased both in serum and in adipose tissue by insulin treatment. In adipocytes, PEDF was induced by TNF-α through activation of NF-κB. The response was inhibited by knockdown and enhanced by over expression of NF-κB p65. However, PEDF expression was indirectly, not directly, induced by NF-κB which promoted 11β-hydroxysteroid dehydrogenase 1 (11β-HSD1) expression in adipocytes. 11β-HSD1 is likely to stimulate PEDF expression through production of active form of glucocorticoids as dexamethasone induced PEDF expression in adipose tissue. Insulin inhibited PEDF by down-regulating 11β-HSD1 expression. The results suggest that PEDF activity is induced by inflammation and decreased by insulin through targeting 11β-HSD1/glucocorticoid pathway in adipose tissue of diabetic patients.

  10. Brown adipose tissue triglyceride content is associated with decreased insulin sensitivity, independently of age and obesity.

    PubMed

    Raiko, J; Holstila, M; Virtanen, K A; Orava, J; Saunavaara, V; Niemi, T; Laine, J; Taittonen, M; Borra, R J H; Nuutila, P; Parkkola, R

    2015-05-01

    The aim of the present study was to determine whether single-voxel proton magnetic resonance spectroscopy ((1)H-MRS) can non-invasively assess triglyceride content in both supraclavicular fat depots and subcutaneous white adipose tissue (WAT) to determine whether these measurements correlate to metabolic variables. A total of 25 healthy volunteers were studied using (18)F-fluorodeoxyglucose positron emission tomography (PET) and (15)O-H2O PET perfusion during cold exposure, and (1)H-MRS at ambient temperature. Image-guided biopsies were collected from nine volunteers. The supraclavicular triglyceride content determined by (1)H-MRS varied between 60 and 91% [mean ± standard deviation (s.d.) 77 ± 10%]. It correlated positively with body mass index, waist circumference, subcutaneous and visceral fat masses and 8-year diabetes risk based on the Framingham risk score and inversely with HDL cholesterol and insulin sensitivity (M-value; euglycaemic-hyperinsulinaemic clamp). Subcutaneous WAT had a significantly higher triglyceride content, 76-95% (mean ± s.d. 87 ± 5%; p = 0.0002). In conclusion, the triglyceride content in supraclavicular fat deposits measured by (1)H-MRS may be an independent marker of whole-body insulin sensitivity, independent of brown adipose tissue metabolic activation.

  11. Combined effects of insulin treatment and adipose tissue-specific agouti expression on the development of obesity.

    PubMed

    Mynatt, R L; Miltenberger, R J; Klebig, M L; Zemel, M B; Wilkinson, J E; Wilkinson, W O; Woychik, R P

    1997-02-04

    The agouti gene product is a secreted protein that acts in a paracrine manner to regulate coat color in mammals. Several dominant mutations at the agouti locus in mice cause the ectopic, ubiquitous expression of agouti, resulting in a condition similar to adult-onset obesity and non-insulin-dependent diabetes mellitus. The human agouti protein is 85% homologous to mouse agouti; however, unlike the mouse agouti gene, human agouti is normally expressed in adipose tissue. To address whether expression of agouti in human adipose tissue is physiologically relevant, transgenic mice were generated that express agouti in adipose tissue. Similar to most humans, these mice do not become obese or diabetic. However, we found that daily insulin injections significantly increased weight gain in the transgenic lines expressing agouti in adipose tissue, but not in nontransgenic mice. These results suggest that insulin triggers the onset of obesity and that agouti expression in adipose tissue potentiates this effect. Accordingly, the investigation of agouti's role in obesity and non-insulin-dependent diabetes mellitus in mice holds significant promise for understanding the pathophysiology of human obesity.

  12. Differential Development of Inflammation and Insulin Resistance in Different Adipose Tissue Depots Along Aging in Wistar Rats: Effects of Caloric Restriction.

    PubMed

    Sierra Rojas, Johanna X; García-San Frutos, Miriam; Horrillo, Daniel; Lauzurica, Nuria; Oliveros, Eva; Carrascosa, Jose María; Fernández-Agulló, Teresa; Ros, Manuel

    2016-03-01

    The prevalence of insulin resistance and type 2 diabetes increases with aging and these disorders are associated with inflammation. Insulin resistance and inflammation do not develop at the same time in all tissues. Adipose tissue is one of the tissues where inflammation and insulin resistance are established earlier during aging. Nevertheless, the existence of different fat depots states the possibility of differential roles for these depots in the development of age-associated inflammation and insulin resistance. To explore this, we analyzed insulin signaling and inflammation in epididymal, perirenal, subcutaneous, and brown adipose tissues during aging in Wistar rats. Although all tissues showed signs of inflammation and insulin resistance with aging, epididymal fat was the first to develop signs of inflammation and insulin resistance along aging among white fat tissues. Subcutaneous adipose tissue presented the lowest degree of inflammation and insulin resistance that developed latter with age. Brown adipose tissue also presented latter insulin resistance and inflammation but with lower signs of macrophage infiltration. Caloric restriction ameliorated insulin resistance and inflammation in all tissues, being more effective in subcutaneous and brown adipose tissues. These data demonstrate differential susceptibility of the different adipose depots to the development of age-associated insulin resistance and inflammation.

  13. Adipose Tissue Promotes a Serum Cytokine Profile Related to Lower Insulin Sensitivity after Chronic Central Leptin Infusion

    PubMed Central

    Burgos-Ramos, Emma; Canelles, Sandra; Perianes-Cachero, Arancha; Arilla-Ferreiro, Eduardo; Argente, Jesús; Barrios, Vicente

    2012-01-01

    Obesity is an inflammatory state characterized by an augment in circulating inflammatory factors. Leptin may modulate the synthesis of these factors by white adipose tissue decreasing insulin sensitivity. We have examined the effect of chronic central administration of leptin on circulating levels of cytokines and the possible relationship with cytokine expression and protein content as well as with leptin and insulin signaling in subcutaneous and visceral adipose tissues. In addition, we analyzed the possible correlation between circulating levels of cytokines and peripheral insulin resistance. We studied 18 male Wistar rats divided into controls (C), those treated icv for 14 days with a daily dose of 12 μg of leptin (L) and a pair-fed group (PF) that received the same food amount consumed by the leptin group. Serum leptin and insulin were measured by ELISA, mRNA levels of interferon-γ (IFN-γ), interleukin-2 (IL-2), IL-4, IL-6, IL-10 and tumor necrosis factor-α (TNF-α) by real time PCR and serum and adipose tissue levels of these cytokines by multiplexed bead immunoassay. Serum leptin, IL-2, IL-4, IFN-γ and HOMA-IR were increased in L and TNF-α was decreased in PF and L. Serum leptin and IL-2 levels correlate positively with HOMA-IR index and negatively with serum glucose levels during an ip insulin tolerance test. In L, an increase in mRNA levels of IL-2 was found in both adipose depots and IFN-γ only in visceral tissue. Activation of leptin signaling was increased and insulin signaling decreased in subcutaneous fat of L. In conclusion, leptin mediates the production of inflammatory cytokines by adipose tissue independent of its effects on food intake, decreasing insulin sensitivity. PMID:23056516

  14. Associations of Different Adipose Tissue Depots with Insulin Resistance: A Systematic Review and Meta-analysis of Observational Studies.

    PubMed

    Zhang, Mingzhi; Hu, Tian; Zhang, Shaoyan; Zhou, Li

    2015-12-21

    Fat distribution is strongly associated with insulin resistance, a risk factor for type 2 diabetes and cardiovascular diseases. However, associations of different adipose tissue depots or/and obesity indices with insulin resistance have not been systematically evaluated. In this study we examined associations of different adipose tissue depots/obesity indices with insulin resistance, as measured by homeostatic model assessment of insulin resistance (HOMA-IR) in observational studies. A total of 40 studies with 56 populations and 29 adipose tissue depots/obesity indices were included in the meta-analysis. There were strong correlation between HOMA-IR and visceral fat mass (r = 0.570, 95% confidence interval(CI): 0.424~0.687), total fat mass (r = 0.492, 95%CI: 0.407~0.570), body mass index (r = 0.482, 95%CI: 0.445~0.518) and waist circumference (r = 0.466, 95%CI: 0.432~0.500), except lower extremity fat (r = 0.088, 95%CI: -0.116~0.285). Sample size, diabetic status, gender, mean of body mass index, and race contributed to heterogeneity of these associations. This study showed a positive correlation between insulin resistance and most adipose tissue depots/obesity indices, and the strongest association is for visceral fat mass.

  15. Adipose tissue macrophages in insulin-resistant subjects are associated with collagen VI and fibrosis and demonstrate alternative activation.

    PubMed

    Spencer, Michael; Yao-Borengasser, Aiwei; Unal, Resat; Rasouli, Neda; Gurley, Catherine M; Zhu, Beibei; Peterson, Charlotte A; Kern, Philip A

    2010-12-01

    Adipose tissue macrophages are associated with insulin resistance and are linked to changes in the extracellular matrix. To better characterize adipose macrophages, the extracellular matrix, and adipocyte-macrophage interactions, gene expression from adipose tissue and the stromal vascular fraction was assessed for markers of inflammation and fibrosis, and macrophages from obese and lean subjects were counted and characterized immunohistochemically. Coculture experiments examined the effects of adipocyte-macrophage interaction. Collagen VI gene expression was associated with insulin sensitivity and CD68 (r = -0.56 and 0.60, P < 0.0001) and with other markers of inflammation and fibrosis. Compared with adipose tissue from lean subjects, adipose tissue from obese subjects contained increased areas of fibrosis, which correlated inversely with insulin sensitivity (r = -0.58, P < 0.02) and positively with macrophage number (r = 0.70, P < 0.01). Although macrophages in crownlike structures (CLS) were more abundant in obese adipose tissue, the majority of macrophages were associated with fibrosis and were not organized in CLS. Macrophages in CLS were predominantly M1, but most other macrophages, particularly those in fibrotic areas, were M2 and also expressed CD150, a marker of M2c macrophages. Coculture of THP-1 macrophages with adipocytes promoted the M2 phenotype, with a lower level of IL-1 expression and a higher ratio of IL-10 to IL-12. Transforming growth factor-β (TGF-β) was more abundant in M2 macrophages and was further increased by coculture with adipocytes. Downstream effectors of TGF-β, such as plasminogen activator inhibitor-1, collagen VI, and phosphorylated Smad, were increased in macrophages and adipocytes. Thus adipose tissue of insulin-resistant humans demonstrated increased fibrosis, M2 macrophage abundance, and TGF-β activity.

  16. Primary Hyperparathyroidism: The Influence of Bone Marrow Adipose Tissue on Bone Loss and of Osteocalcin on Insulin Resistance

    PubMed Central

    Mendonça, Maira L.; Batista, Sérgio L.; Nogueira-Barbosa, Marcello H.; Salmon, Carlos E.G.; de Paula, Francisco J.A.

    2016-01-01

    OBJECTIVES: Bone marrow adipose tissue has been associated with low bone mineral density. However, no data exist regarding marrow adipose tissue in primary hyperparathyroidism, a disorder associated with bone loss in conditions of high bone turnover. The objective of the present study was to investigate the relationship between marrow adipose tissue, bone mass and parathyroid hormone. The influence of osteocalcin on the homeostasis model assessment of insulin resistance was also evaluated. METHODS: This was a cross-sectional study conducted at a university hospital, involving 18 patients with primary hyperparathyroidism (PHPT) and 21 controls (CG). Bone mass was assessed by dual-energy x-ray absorptiometry and marrow adipose tissue was assessed by 1H magnetic resonance spectroscopy. The biochemical evaluation included the determination of parathyroid hormone, osteocalcin, glucose and insulin levels. RESULTS: A negative association was found between the bone mass at the 1/3 radius and parathyroid hormone levels (r = -0.69; p<0.01). Marrow adipose tissue was not significantly increased in patients (CG = 32.8±11.2% vs PHPT = 38.6±12%). The serum levels of osteocalcin were higher in patients (CG = 8.6±3.6 ng/mL vs PHPT = 36.5±38.4 ng/mL; p<0.005), but no associations were observed between osteocalcin and insulin or between insulin and both marrow adipose tissue and bone mass. CONCLUSION: These results suggest that the increment of adipogenesis in the bone marrow microenvironment under conditions of high bone turnover due to primary hyperparathyroidism is limited. Despite the increased serum levels of osteocalcin due to primary hyperparathyroidism, these patients tend to have impaired insulin sensitivity. PMID:27626477

  17. Insulin-resistant subjects have normal angiogenic response to aerobic exercise training in skeletal muscle, but not in adipose tissue.

    PubMed

    Walton, R Grace; Finlin, Brian S; Mula, Jyothi; Long, Douglas E; Zhu, Beibei; Fry, Christopher S; Westgate, Philip M; Lee, Jonah D; Bennett, Tamara; Kern, Philip A; Peterson, Charlotte A

    2015-06-01

    Reduced vessel density in adipose tissue and skeletal muscle is associated with obesity and may result in decreased perfusion, decreased oxygen consumption, and insulin resistance. In the presence of VEGFA, Angiopoietin-2 (Angpt2) and Angiopoietin-1 (Angpt1) are central determinants of angiogenesis, with greater Angpt2:Angpt1 ratios promoting angiogenesis. In skeletal muscle, exercise training stimulates angiogenesis and modulates transcription of VEGFA, Angpt1, and Angpt2. However, it remains unknown whether exercise training stimulates vessel growth in human adipose tissue, and it remains unknown whether adipose angiogenesis is mediated by angiopoietin signaling. We sought to determine whether insulin-resistant subjects would display an impaired angiogenic response to aerobic exercise training. Insulin-sensitive (IS, N = 12) and insulin-resistant (IR, N = 14) subjects had subcutaneous adipose and muscle (vastus lateralis) biopsies before and after 12 weeks of cycle ergometer training. In both tissues, we measured vessels and expression of pro-angiogenic genes. Exercise training did not increase insulin sensitivity in IR Subjects. In skeletal muscle, training resulted in increased vessels/muscle fiber and increased Angpt2:Angpt1 ratio in both IR and IS subjects. However, in adipose, exercise training only induced angiogenesis in IS subjects, likely due to chronic suppression of VEGFA expression in IR subjects. These results indicate that skeletal muscle of IR subjects exhibits a normal angiogenic response to exercise training. However, the same training regimen is insufficient to induce angiogenesis in adipose tissue of IR subjects, which may help to explain why we did not observe improved insulin sensitivity following aerobic training.

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

    SciTech Connect

    Wang, Zhiquan; Xue, Liqiong; Guo, Cuicui; Han, Bing; Pan, Chunming; Zhao, Shuangxia; Song, Huaidong; Ma, Qinyun

    2012-01-27

    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 of 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.

  19. Metabolic responses to dietary leucine restriction involve remodeling of adipose tissue and enhanced hepatic insulin signaling.

    PubMed

    Wanders, Desiree; Stone, Kirsten P; Dille, Kelly; Simon, Jacob; Pierse, Alicia; Gettys, Thomas W

    2015-01-01

    Dietary leucine was incrementally restricted to test whether limiting this essential amino acid (EAA) would fully reproduce the beneficial responses produced by dietary methionine restriction. Restricting leucine by 85% increased energy intake and expenditure within 5 to 7 days of its introduction and reduced overall accumulation of adipose tissue. Leucine restriction (LR) also improved glucose tolerance, increased hepatic release of fibroblast growth factor 21 into the blood stream, and enhanced insulin-dependent activation of Akt in liver. However, LR had no effect on hepatic lipid levels and failed to lower lipogenic gene expression in the liver. LR did affect remodeling of white and brown adipose tissues, increasing expression of both thermogenic and lipogenic genes. These findings illustrate that dietary LR reproduces many but not all of the physiological responses of methionine restriction. The primary differences occur in the liver, where methionine and LR cause opposite effects on tissue lipid levels and expression of lipogenic genes. Altogether, these findings suggest that the sensing systems which detect and respond to dietary restriction of EAAs act through mechanisms that both leucine and methionine are able to engage, and in the case of hepatic lipid metabolism, may be unique to specific EAAs such as methionine.

  20. METABOLIC RESPONSES TO DIETARY LEUCINE RESTRICTION INVOLVE REMODELING OF ADIPOSE TISSUE AND ENHANCED HEPATIC INSULIN SIGNALING

    PubMed Central

    Wanders, Desiree; Stone, Kirsten P.; Dille, Kelly; Simon, Jacob; Pierse, Alicia; Gettys, Thomas W.

    2015-01-01

    Dietary leucine was incrementally restricted to test whether limiting this essential amino acid (EAA) would fully reproduce the beneficial responses produced by dietary methionine restriction. Restricting leucine by 85% increased energy intake and expenditure within five to seven days of its introduction and reduced overall accumulation of adipose tissue. Leucine restriction (LR) also improved glucose tolerance, increased hepatic release of FGF21 into the blood stream, and enhanced insulin-dependent activation of Akt in liver. However, LR had no effect on hepatic lipid levels and failed to lower lipogenic gene expression in the liver. LR did affect remodeling of white and brown adipose tissue, increasing expression of both thermogenic and lipogenic genes. These findings illustrate that dietary LR reproduces many but not all of the physiological responses of methionine restriction. The primary differences occur in the liver, where methionine and leucine restriction cause opposite effects on tissue lipid levels and expression of lipogenic genes. Together these findings suggest that the sensing systems which detect and respond to dietary restriction of EAAs act through mechanisms that both leucine and methionine are able to engage, and in the case of hepatic lipid metabolism, may be unique to specific EAAs such as methionine. PMID:26643647

  1. Adipose Tissue Free Fatty Acid Storage In Vivo: Effects of Insulin Versus Niacin as a Control for Suppression of Lipolysis.

    PubMed

    Ali, Asem H; Mundi, Manpreet; Koutsari, Christina; Bernlohr, David A; Jensen, Michael D

    2015-08-01

    Insulin stimulates the translocation fatty acid transport protein 1 (FATP1) to plasma membrane, and thus greater free fatty acid (FFA) uptake, in adipocyte cell models. Whether insulin stimulates greater FFA clearance into adipose tissue in vivo is unknown. We tested this hypothesis by comparing direct FFA storage in subcutaneous adipose tissue during insulin versus niacin-medicated suppression of lipolysis. We measured direct FFA storage in abdominal and femoral subcutaneous fat in 10 and 11 adults, respectively, during euglycemic hyperinsulinemia or after oral niacin to suppress FFA compared with 11 saline control experiments. Direct palmitate storage was assessed using a [U-(13)C]palmitate infusion to measure palmitate kinetics and an intravenous palmitate radiotracer bolus/timed biopsy. Plasma palmitate concentrations and flux were suppressed to 23 ± 3 and 26 ± 5 µmol ⋅ L(-1) (P = 0.91) and 44 ± 4 and 39 ± 5 µmol ⋅ min(-1) (P = 0.41) in the insulin and niacin groups, respectively, much less (P < 0.001) than the saline control group (102 ± 8 and 104 ± 12 µmol ⋅ min(-1), respectively). In the insulin, niacin, and saline groups, abdominal palmitate storage rates were 0.25 ± 0.05 vs. 0.25 ± 0.07 vs. 0.32 ± 0.05 µmol ⋅ kg adipose lipid(-1) ⋅ min(-1), respectively (P = NS), and femoral adipose storage rates were 0.19 ± 0.06 vs. 0.20 ± 0.05 vs. 0.31 ± 0.05 µmol ⋅ kg adipose lipid(-1) ⋅ min(-1), respectively (P = NS). In conclusion, insulin does not increase FFA storage in adipose tissue compared with niacin, which suppresses lipolysis via a different pathway.

  2. Adipose Tissue Free Fatty Acid Storage In Vivo: Effects of Insulin Versus Niacin as a Control for Suppression of Lipolysis

    PubMed Central

    Ali, Asem H.; Mundi, Manpreet; Koutsari, Christina; Bernlohr, David A.

    2015-01-01

    Insulin stimulates the translocation fatty acid transport protein 1 (FATP1) to plasma membrane, and thus greater free fatty acid (FFA) uptake, in adipocyte cell models. Whether insulin stimulates greater FFA clearance into adipose tissue in vivo is unknown. We tested this hypothesis by comparing direct FFA storage in subcutaneous adipose tissue during insulin versus niacin-medicated suppression of lipolysis. We measured direct FFA storage in abdominal and femoral subcutaneous fat in 10 and 11 adults, respectively, during euglycemic hyperinsulinemia or after oral niacin to suppress FFA compared with 11 saline control experiments. Direct palmitate storage was assessed using a [U-13C]palmitate infusion to measure palmitate kinetics and an intravenous palmitate radiotracer bolus/timed biopsy. Plasma palmitate concentrations and flux were suppressed to 23 ± 3 and 26 ± 5 µmol ⋅ L−1 (P = 0.91) and 44 ± 4 and 39 ± 5 µmol ⋅ min−1 (P = 0.41) in the insulin and niacin groups, respectively, much less (P < 0.001) than the saline control group (102 ± 8 and 104 ± 12 µmol ⋅ min−1, respectively). In the insulin, niacin, and saline groups, abdominal palmitate storage rates were 0.25 ± 0.05 vs. 0.25 ± 0.07 vs. 0.32 ± 0.05 µmol ⋅ kg adipose lipid−1 ⋅ min−1, respectively (P = NS), and femoral adipose storage rates were 0.19 ± 0.06 vs. 0.20 ± 0.05 vs. 0.31 ± 0.05 µmol ⋅ kg adipose lipid−1 ⋅ min−1, respectively (P = NS). In conclusion, insulin does not increase FFA storage in adipose tissue compared with niacin, which suppresses lipolysis via a different pathway. PMID:25883112

  3. Fatty acid binding protein expression in different human adipose tissue depots in relation to rates of lipolysis and insulin concentration in obese individuals.

    PubMed

    Fisher, R M; Thörne, A; Hamsten, A; Arner, P

    2002-10-01

    Two fatty acid binding proteins (FABPs) are expressed in adipose tissue, adipocyte lipid binding protein (ALBP) and keratinocyte lipid binding protein (KLBP). This study investigated FABP expression in visceral and subcutaneous human adipose tissue depots and associations with lipolytic differences between the depots and circulating insulin concentrations. ALBP and KLBP (protein and RNA) were quantified in subcutaneous and omental adipose tissue from obese individuals and expressed relative to actin. ALBP RNA and protein expression was significantly higher in subcutaneous compared to omental adipose tissue (both p < 0.05), whereas KLBP RNA and protein expression was no different between the two sites. There were significant inverse correlations between serum insulin concentrations and the ALBP/KLBP RNA ratio in both subcutaneous and omental adipose tissue (both p < 0.02). Basal rates of glycerol and fatty acid release measured in adipocytes isolated from subcutaneous and omental adipose tissue were significantly higher in the former (p < or = 0.02). Therefore the relative ALBP/KLBP content of human adipose tissue is different in different adipose tissue depots and at the RNA level is related to the circulating insulin concentration, at least in obese subjects. The higher rates of basal lipolysis in adipocytes isolated from subcutaneous compared to omental adipose tissue might be related to the increased ALBP content of the former. Therefore adipose tissue FABPs are interesting candidates for investigation to further our understanding of the insulin resistance syndrome and regulation of lipolysis.

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

    PubMed

    Lin, Ligen; Saha, Pradip K; Ma, Xiaojun; Henshaw, Iyabo O; Shao, Longjiang; Chang, Benny H J; Buras, Eric D; Tong, Qiang; Chan, Lawrence; McGuinness, Owen P; Sun, Yuxiang

    2011-12-01

    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 that ablation of the ghrelin receptor (growth hormone secretagogue receptor, GHS-R) improves insulin sensitivity during aging. Compared to wild-type (WT) mice, old Ghsr(-/-) mice have reduced fat and preserve a healthier lipid profile. Old Ghsr(-/-) mice also exhibit elevated energy expenditure and resting metabolic rate, yet have similar food intake and locomotor activity. While GHS-R expression in white and brown adipose tissues was below the detectable level in the young mice, GHS-R expression was readily detectable in visceral white fat and interscapular brown fat of the old mice. Gene expression profiles reveal that Ghsr ablation reduced glucose/lipid uptake and lipogenesis in white adipose tissues but increased thermogenic capacity in brown adipose tissues. Ghsr ablation prevents age-associated decline in thermogenic gene expression of uncoupling protein 1 (UCP1). Cell culture studies in brown adipocytes further demonstrate that ghrelin suppresses the expression of adipogenic and thermogenic genes, while GHS-R antagonist abolishes ghrelin's effects and increases UCP1 expression. Hence, GHS-R plays an important role in thermogenic impairment during aging. Ghsr ablation improves aging-associated obesity and insulin resistance by reducing adiposity and increasing thermogenesis. Growth hormone secretagogue receptor antagonists may be a new means of combating obesity by shifting the energy balance from obesogenesis to thermogenesis.

  5. Dietary glucose increases plasma insulin and decreases brown adipose tissue thermogenic activity in adrenalectomized ob/ob mice.

    PubMed

    Nei, Y M; Romsos, D R

    1991-09-01

    The purpose of this study was to determine whether consumption of a high glucose diet would increase plasma insulin concentrations and decrease brown adipose tissue metabolism in adrenalectomized ob/ob mice previously fed a high starch diet. Male sham-operated and adrenalectomized ob/ob and lean mice were fed a high starch diet for 12 d, then switched to a high glucose diet for the last 2 or 4 d of the 14- or 16-d feeding trials. Adrenalectomized ob/ob mice consumed 16% more energy and gained 50% more weight without an increase in oxygen consumption when switched from a high starch diet to a high glucose diet. Within 2 d after the switch to the high glucose diet, plasma insulin concentrations increased by 70% without any change in plasma glucose concentrations; brown adipose tissue metabolism, as assessed by GDP binding to brown adipose tissue mitochondria, was decreased by 26% 4 d after the diet switch. Sham-operated ob/ob and lean mice and adrenalectomized lean mice were minimally affected by the switch to the high glucose diet. The increase in plasma insulin concentrations in adrenalectomized ob/ob mice induced by the high glucose diet may contribute to the observed depression in brown adipose tissue metabolism.

  6. Insulin-independent reversal of type 1 diabetes in nonobese diabetic mice with brown adipose tissue transplant.

    PubMed

    Gunawardana, Subhadra C; Piston, David W

    2015-06-15

    Traditional therapies for type 1 diabetes (T1D) involve insulin replacement or islet/pancreas transplantation and have numerous limitations. Our previous work demonstrated the ability of embryonic brown adipose tissue (BAT) transplants to establish normoglycemia without insulin in chemically induced models of insulin-deficient diabetes. The current study sought to extend the technique to an autoimmune-mediated T1D model and document the underlying mechanisms. In nonobese diabetic (NOD) mice, BAT transplants result in complete reversal of T1D associated with rapid and long-lasting euglycemia. In addition, BAT transplants placed prior to the onset of diabetes on NOD mice can prevent or significantly delay the onset of diabetes. As with streptozotocin (STZ)-diabetic models, euglycemia is independent of insulin and strongly correlates with decrease of inflammation and increase of adipokines. Plasma insulin-like growth factor-I (IGF-I) is the first hormone to increase following BAT transplants. Adipose tissue of transplant recipients consistently express IGF-I compared with little or no expression in controls, and plasma IGF-I levels show a direct negative correlation with glucose, glucagon, and inflammatory cytokines. Adipogenic and anti-inflammatory properties of IGF-I may stimulate regeneration of new healthy white adipose tissue, which in turn secretes hypoglycemic adipokines that substitute for insulin. IGF-I can also directly decrease blood glucose through activating insulin receptor. These data demonstrate the potential for insulin-independent reversal of autoimmune-induced T1D with BAT transplants and implicate IGF-I as a likely mediator in the resulting equilibrium.

  7. Resveratrol ameliorates the chemical and microbial induction of inflammation and insulin resistance in human placenta, adipose tissue and skeletal muscle

    PubMed Central

    Tran, Ha T.; Liong, Stella; Lim, Ratana; Barker, Gillian

    2017-01-01

    Gestational diabetes mellitus (GDM), which complicates up to 20% of all pregnancies, is associated with low-grade maternal inflammation and peripheral insulin resistance. Sterile inflammation and infection are key mediators of this inflammation and peripheral insulin resistance. Resveratrol, a stilbene-type phytophenol, has been implicated to exert beneficial properties including potent anti-inflammatory and antidiabetic effects in non-pregnant humans and experimental animal models of GDM. However, studies showing the effects of resveratrol on inflammation and insulin resistance associated with GDM in human tissues have been limited. In this study, human placenta, adipose (omental and subcutaneous) tissue and skeletal muscle were stimulated with pro-inflammatory cytokines TNF-α and IL-1β, the bacterial product lipopolysaccharide (LPS) and the synthetic viral dsRNA analogue polyinosinic:polycytidylic acid (poly(I:C)) to induce a GDM-like model. Treatment with resveratrol significantly reduced the expression and secretion of pro-inflammatory cytokines IL-6, IL-1α, IL-1β and pro-inflammatory chemokines IL-8 and MCP-1 in human placenta and omental and subcutaneous adipose tissue. Resveratrol also significantly restored the defects in the insulin signalling pathway and glucose uptake induced by TNF-α, LPS and poly(I:C). Collectively, these findings suggest that resveratrol reduces inflammation and insulin resistance induced by chemical and microbial products. Resveratrol may be a useful preventative therapeutic for pregnancies complicated by inflammation and insulin resistance, like GDM. PMID:28278187

  8. New insights into adipose tissue VEGF-A actions in the control of obesity and insulin resistance

    PubMed Central

    Elias, Ivet; Franckhauser, Sylvie; Bosch, Fatima

    2013-01-01

    Vascular endothelial growth factor A (VEGF-A) is classically viewed as a key factor in angiogenesis and tissue remodeling. However, recent evidence suggests a potential role of this growth factor in the control of energy metabolism and adipose tissue function. In this regard, we and others have described the effects of the up and downregulation of VEGF-A in adipose tissue on the control of energy homeostasis. VEGF-A overexpression protects against diet-induced obesity and insulin resistance. The observation that VEGF-A overexpression leads to an increase in brown adipose tissue (BAT) thermogenesis and also promotes a “BAT-like” phenotype in white adipose tissue depots is of particular relevance for the understanding of the mechanisms underlying obesity development. In addition, VEGF-A may not only have pro-inflammatory but also anti-inflammatory properties, with a chemotactic activity specific for M2 anti-inflammatory macrophages. This new scientific evidence highlights the importance that VEGF-A actions on metabolism could have on the design of new treatments for obesity, insulin resistance and obesity-related disorders. PMID:23805408

  9. Seipin deficiency alters brown adipose tissue thermogenesis and insulin sensitivity in a non-cell autonomous mode

    PubMed Central

    Dollet, L.; Magré, J.; Joubert, M.; Le May, C.; Ayer, A.; Arnaud, L.; Pecqueur, C.; Blouin, V.; Cariou, B.; Prieur, X.

    2016-01-01

    Loss-of-function mutations in BSCL2 are responsible for Berardinelli-Seip congenital lipodystrophy, a rare disorder characterized by near absence of adipose tissue associated with insulin resistance. Seipin-deficient (Bscl2−/−) mice display an almost total loss of white adipose tissue (WAT) with residual brown adipose tissue (BAT). Previous cellular studies have shown that seipin deficiency alters white adipocyte differentiation. In this study, we aimed to decipher the consequences of seipin deficiency in BAT. Using a brown adipocyte cell-line, we show that seipin knockdown had very little effect on adipocyte differentiation without affecting insulin sensitivity and oxygen consumption. However, when submitted to cold acclimation or chronic β3 agonist treatment, Bscl2−/− mice displayed altered thermogenic capacity, despite several signs of BAT remodeling. Under cold activation, Bscl2−/− mice were able to maintain their body temperature when fed ad libitum, but not under short fasting. At control temperature (i.e. 21 °C), fasting worsened Bscl2−/− BAT properties. Finally, Bscl2−/− BAT displayed obvious signs of insulin resistance. Our results in these lipodystrophic mice strongly suggest that BAT activity relies on WAT as an energetic substrate provider and adipokine-producing organ. Therefore, the WAT/BAT dialogue is a key component of BAT integrity in guaranteeing its response to insulin and cold-activated adrenergic signals. PMID:27748422

  10. Angiopoietin Like Protein 2 (ANGPTL2) Promotes Adipose Tissue Macrophage and T lymphocyte Accumulation and Leads to Insulin Resistance

    PubMed Central

    Sasaki, Yusuke; Ohta, Masayuki; Desai, Dhruv; Figueiredo, Jose-Luiz; Whelan, Mary C.; Sugano, Tomohiro; Yamabi, Masaki; Yano, Wataru; Faits, Tyler; Yabusaki, Katsumi; Zhang, Hengmin; Mlynarchik, Andrew K.; Inoue, Keisuke; Mizuno, Ken; Aikawa, Masanori

    2015-01-01

    Objectives Angiopoietin-like protein 2 (ANGPTL2), a recently identified pro-inflammatory cytokine, is mainly secreted from the adipose tissue. This study aimed to explore the role of ANGPTL2 in adipose tissue inflammation and macrophage activation in a mouse model of diabetes. Methodology/Principal Findings Adenovirus mediated lacZ (Ad-LacZ) or human ANGPTL2 (Ad-ANGPTL2) was delivered via tail vein in diabetic db/db mice. Ad-ANGPTL2 treatment for 2 weeks impaired both glucose tolerance and insulin sensitivity as compared to Ad-LacZ treatment. Ad-ANGPTL2 treatment significantly induced pro-inflammatory gene expression in white adipose tissue. We also isolated stromal vascular fraction from epididymal fat pad and analyzed adipose tissue macrophage and T lymphocyte populations by flow cytometry. Ad-ANGPTL2 treated mice had more adipose tissue macrophages (F4/80+CD11b+) and a larger M1 macrophage subpopulation (F4/80+CD11b+CD11c+). Moreover, Ad-ANGPTL2 treatment increased a CD8-positive T cell population in adipose tissue, which preceded increased macrophage accumulation. Consistent with our in vivo results, recombinant human ANGPTL2 protein treatment increased mRNA levels of pro-inflammatory gene products and production of TNF-α protein in the human macrophage-like cell line THP-1. Furthermore, Ad-ANGPTL2 treatment induced lipid accumulation and increased fatty acid synthesis, lipid metabolism related gene expression in mouse liver. Conclusion ANGPTL2 treatment promotes macrophage accumulation and activation. These results suggest potential mechanisms for insulin resistance. PMID:26132105

  11. Effect of dietary energy source on in vitro substrate utilization and insulin sensitivity of muscle and adipose tissues of Angus and Wagyu steers.

    PubMed

    Rhoades, R D; Sawyer, J E; Chung, K Y; Schell, M L; Lunt, D K; Smith, S B

    2007-07-01

    Angus (n = 8; 210 kg of BW) and 7/8 Wagyu (n = 8; 174 kg of BW) steers were used to evaluate the effects of dietary energy source on muscle and adipose tissue metabolism and insulin sensitivity. Steers were assigned to either a grain-based (corn) or hay-based (hay) diet and fed to similar final BW. At slaughter, LM and s.c. and i.m. adipose tissue samples were collected. Portions of the LM and adipose tissues were placed immediately in liquid N for later measurement of glycolytic intermediates. Fresh LM and s.c. and i.m. adipose tissues were incubated with [U-(14)C]glucose to assess glucose metabolism in vitro. All in vitro measures were in the presence of 0 or 500 ng/mL of insulin. Also, s.c. and i.m. adipose tissues were incubated with [1-(14)C]acetate to quantify lipid synthesis in vitro. Glucose-6-phosphate and fructose-6-phosphate concentrations were 12.6- and 2.4-fold greater in muscle than in s.c. and i.m. adipose tissues, respectively. Diet did not affect acetate incorporation into fatty acids (P = 0.86). Insulin did not increase conversion of glucose to CO(2), lactate, or total lipid in steers fed hay but caused an increase (per cell) of 97 to 110% in glucose conversion to CO(2), 46 to 54% in glucose conversion to lactate, and 65 to 160% in glucose conversion to total lipid content in adipose tissue from steers fed corn. On a per-cell basis, s.c. adipose tissue had 37% greater glucose oxidation than i.m. adipose (P = 0.04) and 290% greater acetate incorporation into fatty acids than i.m. adipose (P = 0.04). Insulin addition to s.c. adipose tissue from corn-fed steers failed to stimulate glucose incorporation into fatty acids, but exposing i.m. adipose tissue from corn-fed steers to insulin resulted in a 165% increase in glucose incorporation into fatty acids. These results suggest that feeding hay limited both glucose supply and tissue capacity to increase glucose utilization in response to insulin without altering acetate conversion to fatty acids

  12. Insulin differentially modulates the peripheral endocannabinoid system in human subcutaneous abdominal adipose tissue from lean and obese individuals.

    PubMed

    Murdolo, G; Kempf, K; Hammarstedt, A; Herder, C; Smith, U; Jansson, P-A

    2007-09-01

    Human obesity has been associated with a dysregulation of the peripheral and adipose tissue (AT) endocannabinoid system (ES). The aim of this study was to elucidate the acute in vivo effects of insulin on gene expression of the cannabinoid type 1 (CB-1) and type 2 (CB-2) receptors, as well as of the fatty acid amide hydrolase (FAAH) in the sc abdominal adipose tissue (SCAAT). Nine lean (L) and 9 obese (OB), but otherwise healthy males were studied in the fasting state and during a euglycemic hyperinsulinemic clamp (40 mU/m2 * min(-1)). SCAAT biopsies were obtained at baseline and after 270 min of i.v. maintained hyperinsulinemia. The basal SCAAT gene expression pattern revealed an upregulation of the FAAH in the OB (p=0.03 vs L), whereas similar CB-1 and CB-2 mRNA levels were seen. Following hyperinsulinemia, the FAAH mRNA levels significantly increased approximately 2-fold in the L (p=0.01 vs baseline) but not in the OB. In contrast, insulin failed to significantly change both the adipose CB-1 and CB-2 gene expression. Finally, the FAAH gene expression positively correlated with the fasting serum insulin concentration (r 0.66; p=0.01), whereas an inverse association with the whole-body glucose disposal (r -0.58; p<0.05) was seen. Taken together, these first time observations demonstrate that the ES-related genes in the SCAAT differentially respond to hyperinsulinemia in lean/insulin-sensitive and in obese/insulin-resistant individuals. We suggest that insulin may play a key role in the obesity-linked dysregulation of the adipose ES at the gene level.

  13. Activation of AMPK improves inflammation and insulin resistance in adipose tissue and skeletal muscle from pregnant women.

    PubMed

    Liong, Stella; Lappas, Martha

    2015-12-01

    Gestational diabetes mellitus (GDM) is characterised by maternal peripheral insulin resistance and inflammation. Sterile inflammation and bacterial infection are key mediators of this enhanced inflammatory response. Adenosine monophosphate (AMP)-activated kinase (AMPK), which is decreased in insulin resistant states, possesses potent pro-inflammatory actions. There are, however, no studies on the role of AMPK in pregnancies complicated by GDM. Thus, the aims of this study were (i) to compare the expression of AMPK in adipose tissue and skeletal muscle from women with GDM and normal glucose-tolerant (NGT) pregnant women; and (ii) to investigate the effect of AMPK activation on inflammation and insulin resistance induced by the bacterial endotoxin lipopolysaccharide (LPS) and the pro-inflammatory cytokine IL-1β. When compared to NGT pregnant women, AMPKα activity was significantly lower in women with GDM as evidenced by a decrease in threonine phosphorylation of AMPKα. Activation of AMPK, using two pharmacologically distinct compounds, AICAR or phenformin, significantly suppressed LPS- or IL-1β-induced gene expression and secretion of pro-inflammatory cytokine IL-6, the chemokines IL-8 and MCP-1, and COX-2 and subsequent prostaglandin release from adipose tissue and skeletal muscle. In addition, activators of AMPK decreased skeletal muscle insulin resistance induced by LPS or IL-1β as evidenced by increased insulin-stimulated phosphorylation of IRS-1, GLUT-4 expression and glucose uptake. These findings suggest that AMPK may play an important role in inflammation and insulin resistance.

  14. Integrative mRNA-microRNA analyses reveal novel interactions related to insulin sensitivity in human adipose tissue.

    PubMed

    Kirby, Tyler J; Walton, R Grace; Finlin, Brian; Zhu, Beibei; Unal, Resat; Rasouli, Neda; Peterson, Charlotte A; Kern, Philip A

    2016-02-01

    Adipose tissue has profound effects on whole-body insulin sensitivity. However, the underlying biological processes are quite complex and likely multifactorial. For instance, the adipose transcriptome is posttranscriptionally modulated by microRNAs, but the relationship between microRNAs and insulin sensitivity in humans remains to be determined. To this end, we utilized an integrative mRNA-microRNA microarray approach to identify putative molecular interactions that regulate the transcriptome in subcutaneous adipose tissue of insulin-sensitive (IS) and insulin-resistant (IR) individuals. Using the NanoString nCounter Human v1 microRNA Expression Assay, we show that 17 microRNAs are differentially expressed in IR vs. IS. Of these, 16 microRNAs (94%) are downregulated in IR vs. IS, including miR-26b, miR-30b, and miR-145. Using Agilent Human Whole Genome arrays, we identified genes that were predicted targets of miR-26b, miR-30b, and miR-145 and were upregulated in IR subjects. This analysis produced ADAM22, MYO5A, LOX, and GM2A as predicted gene targets of these microRNAs. We then validated that miR-145 and miR-30b regulate these mRNAs in differentiated human adipose stem cells. We suggest that use of bioinformatic integration of mRNA and microRNA arrays yields verifiable mRNA-microRNA pairs that are associated with insulin resistance and can be validated in vitro.

  15. CONTRAST-ENHANCED ULTRASOUND ASSESSMENT OF IMPAIRED ADIPOSE TISSUE AND MUSCLE PERFUSION IN INSULIN-RESISTANT MICE

    PubMed Central

    Belcik, J. Todd; Davidson, Brian P.; Foster, Ted; Qi, Yue; Zhao, Yan; Peters, Dawn; Lindner, Jonathan R.

    2015-01-01

    Background In diabetes mellitus reduced perfusion and capillary surface area in skeletal muscle, which is a major glucose storage site, contributes to abnormal glucose homeostasis. Using contrast-enhanced ultrasound (CEU) we investigated whether abdominal adipose tissue perfusion is abnormal in insulin resistance (IR) and correlates with glycemic control. Methods and Results Abdominal adipose tissue and skeletal muscle CEU perfusion imaging was performed in obese IR (db/db) mice at 11-12 or 14-16 weeks of age, and in control lean mice. Time-intensity data were analyzed to quantify microvascular blood flow (MBF) and capillary blood volume (CBV). Blood glucose response over one hour was measured after insulin challenge (1 u/Kg, I.P.). Compared to control mice, db/db mice at 11-12 and 14-16 weeks had a higher glucose concentration area-under-the-curve after insulin (11.8±2.8, 20.6±4.3, and 28.4±5.9 mg·min/dL [×1000], respectively, p=0.0002), and also had lower adipose MBF (0.094±0.038, 0.035±0.010, and 0.023±0.01 mL/min/g, p=0.0002) and CBV (1.6±0.6, 1.0±0.3, and 0.5±0.1 mL/100 g, p=0.0017). The glucose area-under-the-curve correlated in a non-linear fashion with both adipose and skeletal muscle MBF and CBV. There were significant linear correlations between adipose and muscle MBF (r=0.81) and CBV (r=0.66). Adipocyte cell volume on histology was 25-fold higher in 14-16 week db/db versus control mice. Conclusions Abnormal adipose MBF and CBV in IR can be detected by CEU and correlates with the degree of impairment in glucose storage. Abnormalities in adipose tissue and muscle appear to be coupled. Impaired adipose tissue perfusion is in part explained by an increase in adipocyte size without proportional vascular response. PMID:25855669

  16. Insulin resistance and white adipose tissue inflammation are uncoupled in energetically challenged Fsp27-deficient mice.

    PubMed

    Zhou, Linkang; Park, Shi-Young; Xu, Li; Xia, Xiayu; Ye, Jing; Su, Lu; Jeong, Kyeong-Hoon; Hur, Jang Ho; Oh, Hyunhee; Tamori, Yoshikazu; Zingaretti, Cristina M; Cinti, Saverio; Argente, Jesús; Yu, Miao; Wu, Lizhen; Ju, Shenghong; Guan, Feifei; Yang, Hongyuan; Choi, Cheol Soo; Savage, David B; Li, Peng

    2015-01-07

    Fsp27 is a lipid droplet-associated protein almost exclusively expressed in adipocytes where it facilitates unilocular lipid droplet formation. In mice, Fsp27 deficiency is associated with increased basal lipolysis, 'browning' of white fat and a healthy metabolic profile, whereas a patient with congenital CIDEC deficiency manifested an adverse lipodystrophic phenotype. Here we reconcile these data by showing that exposing Fsp27-null mice to a substantial energetic stress by crossing them with ob/ob mice or BATless mice, or feeding them a high-fat diet, results in hepatic steatosis and insulin resistance. We also observe a striking reduction in adipose inflammation and increase in adiponectin levels in all three models. This appears to reflect reduced activation of the inflammasome and less adipocyte death. These findings highlight the importance of Fsp27 in facilitating optimal energy storage in adipocytes and represent a rare example where adipose inflammation and hepatic insulin resistance are disassociated.

  17. Insulin resistance and white adipose tissue inflammation are uncoupled in energetically challenged Fsp27-deficient mice

    PubMed Central

    Zhou, Linkang; Park, Shi-Young; Xu, Li; Xia, Xiayu; Ye, Jing; Su, Lu; Jeong, Kyeong-Hoon; Hur, Jang Ho; Oh, Hyunhee; Tamori, Yoshikazu; Zingaretti, Cristina M.; Cinti, Saverio; Argente, Jesús; Yu, Miao; Wu, Lizhen; Ju, Shenghong; Guan, Feifei; Yang, Hongyuan; Choi, Cheol Soo; Savage, David B.; Li, Peng

    2015-01-01

    Fsp27 is a lipid droplet-associated protein almost exclusively expressed in adipocytes where it facilitates unilocular lipid droplet formation. In mice, Fsp27 deficiency is associated with increased basal lipolysis, ‘browning’ of white fat and a healthy metabolic profile, whereas a patient with congenital CIDEC deficiency manifested an adverse lipodystrophic phenotype. Here we reconcile these data by showing that exposing Fsp27-null mice to a substantial energetic stress by crossing them with ob/ob mice or BATless mice, or feeding them a high-fat diet, results in hepatic steatosis and insulin resistance. We also observe a striking reduction in adipose inflammation and increase in adiponectin levels in all three models. This appears to reflect reduced activation of the inflammasome and less adipocyte death. These findings highlight the importance of Fsp27 in facilitating optimal energy storage in adipocytes and represent a rare example where adipose inflammation and hepatic insulin resistance are disassociated. PMID:25565658

  18. Obesity-associated insulin resistance is correlated to adipose tissue vascular endothelial growth factors and metalloproteinase levels

    PubMed Central

    2012-01-01

    Background The expansion of adipose tissue is linked to the development of its vasculature, which appears to have the potential to regulate the onset of obesity. However, at present, there are no studies highlighting the relationship between human adipose tissue angiogenesis and obesity-associated insulin resistance (IR). Results Our aim was to analyze and compare angiogenic factor expression levels in both subcutaneous (SC) and omentum (OM) adipose tissues from morbidly obese patients (n = 26) with low (OB/L-IR) (healthy obese) and high (OB/H-IR) degrees of IR, and lean controls (n = 17). Another objective was to examine angiogenic factor correlations with obesity and IR. Here we found that VEGF-A was the isoform with higher expression in both OM and SC adipose tissues, and was up-regulated 3-fold, together with MMP9 in OB/L-IR as compared to leans. This up-regulation decreased by 23% in OB/-H-IR compared to OB/L-IR. On the contrary, VEGF-B, VEGF-C and VEGF-D, together with MMP15 was down-regulated in both OB/H-IR and OB/L-IR compared to lean patients. Moreover, MMP9 correlated positively and VEGF-C, VEGF-D and MMP15 correlated negatively with HOMA-IR, in both SC and OM. Conclusion We hereby propose that the alteration in MMP15, VEGF-B, VEGF-C and VEGF-D gene expression may be caused by one of the relevant adipose tissue processes related to the development of IR, and the up-regulation of VEGF-A in adipose tissue could have a relationship with the prevention of this pathology. PMID:22471305

  19. Adipose Tissue CIDEA Is Associated, Independently of Weight Variation, to Change in Insulin Resistance during a Longitudinal Weight Control Dietary Program in Obese Individuals

    PubMed Central

    Montastier, Emilie; Déjean, Sébastien; Le Gall, Caroline; Saris, Wim H. M.; Langin, Dominique; Viguerie, Nathalie

    2014-01-01

    Aim Weight loss reduces risk factors associated with obesity. However, long-term metabolic improvement remains a challenge. We investigated quantitative gene expression of subcutaneous adipose tissue in obese individuals and its relationship with low calorie diet and long term weight maintenance induced changes in insulin resistance. Research Design Three hundred eleven overweight and obese individuals followed a dietary protocol consisting of an 8-week low calorie diet followed by a 6-month ad libitum weight-maintenance diet. Individuals were clustered according to insulin resistance trajectories assessed using homeostasis model assessment of insulin resistance (HOMA-IR) index. Adipose tissue mRNA levels of 267 genes selected for regulation according to obesity, metabolic status and response to dieting was assessed using high throughput RT-qPCR. A combination of discriminant analyses was used to identify genes with regulation according to insulin resistance trajectories. Partial correlation was used to control for change in body mass index. Results Three different HOMA-IR profile groups were determined. HOMA-IR improved during low calorie diet in the 3 groups. At the end of the 6-month follow-up, groups A and B had reduced HOMA-IR by 50%. In group C, HOMA-IR had returned to baseline values. Genes were differentially expressed in the adipose tissue of individuals according to groups but a single gene, CIDEA, was common to all phases of the dietary intervention. Changes in adipose tissue CIDEA mRNA levels paralleled variations in insulin sensitivity independently of change in body mass index. Overall, CIDEA was up-regulated in adipose tissue of individuals with successful long term insulin resistance relapse and not in adipose tissue of unsuccessful individuals. Conclusion The concomitant change in adipose tissue CIDEA mRNA levels and insulin sensitivity suggests a beneficial role of adipose tissue CIDEA in long term glucose homeostasis, independently of weight

  20. Diethylcarbamazine citrate ameliorates insulin resistance in high-fat diet-induced obese mice via modulation of adipose tissue inflammation.

    PubMed

    Abdel-Latif, Mahmoud

    2015-12-01

    Diethylcarbamazine citrate (DEC) had been known as anti-inflammatory drug but its effect on obesity-induced insulin resistance as a result of released inflammatory mediators from adipose tissue (AT) was not known. White male albino mice were fed with high fat diet (HFD) for 18weeks to induce obesity. DEC at different three doses (12, 50 and 200mg/kg) was orally administered twice a week starting at week 6. Body, liver and adipose tissue weights were taken, while glucose tolerance, insulin resistance, blood triglycerides and levels of adipokines (leptin, TNF-α, IL-6 and MCP-1) were tested. The activity of cyclooxygenase (COX) in the liver tissue homogenate was also tested. In addition, NF-κBp65 localization in liver cell cytoplasmic and nuclear fractions was detected using Western blotting. The only effective anti-inflammatory dose was 50mg/kg to reduce (p<0.05) the high levels of glucose, insulin and triglycerides in serum. DEC was not anti-obesity drug because the weights of body, liver and adipose tissues were not changed. Hyperleptinemia was decreased (p<0.001) and associated with a reduction in serum levels of TNF-α, IL-6 and MCP-1 (p<0.001). In addition, the activity of COX in DEC treatment decreased significantly (p<0.01), while NF-κBp65 localization in nuclear extracts was obviously inhibited in 50mg/kg treated group. It could be concluded that DEC was the only effective dose against mouse insulin resistance but not lipid accumulation.

  1. Altered glucose and lipid homeostasis in liver and adipose tissue pre-dispose inducible NOS knockout mice to insulin resistance

    PubMed Central

    Kanuri, Babu Nageswararao; Kanshana, Jitendra S.; Rebello, Sanjay C.; Pathak, Priya; Gupta, Anand P.; Gayen, Jiaur R.; Jagavelu, Kumaravelu; Dikshit, Madhu

    2017-01-01

    On the basis of diet induced obesity and KO mice models, nitric oxide is implied to play an important role in the initiation of dyslipidemia induced insulin resistance. However, outcomes using iNOS KO mice have so far remained inconclusive. The present study aimed to assess IR in iNOS KO mice after 5 weeks of LFD feeding by monitoring body composition, energy homeostasis, insulin sensitivity/signaling, nitrite content and gene expressions changes in the tissues. We found that body weight and fat content in KO mice were significantly higher while the respiratory exchange ratio (RER), volume of carbon dioxide (VCO2), and heat production were lower as compared to WT mice. Furthermore, altered systemic glucose tolerance, tissue insulin signaling, hepatic gluconeogenesis, augmented hepatic lipids, adiposity, as well as gene expression regulating lipid synthesis, catabolism and efflux were evident in iNOS KO mice. Significant reduction in eNOS and nNOS gene expression, hepatic and adipose tissue nitrite content, circulatory nitrite was also observed. Oxygen consumption rate of mitochondrial respiration has remained unaltered in KO mice as measured using extracellular flux analyzer. Our findings establish a link between the NO status with systemic and tissue specific IR in iNOS KO mice at 5 weeks. PMID:28106120

  2. HMGA1 overexpression in adipose tissue impairs adipogenesis and prevents diet-induced obesity and insulin resistance.

    PubMed

    Arce-Cerezo, Altamira; García, Miquel; Rodríguez-Nuevo, Aida; Crosa-Bonell, Mireia; Enguix, Natalia; Peró, Albert; Muñoz, Sergio; Roca, Carles; Ramos, David; Franckhauser, Sylvie; Elias, Ivet; Ferre, Tura; Pujol, Anna; Ruberte, Jesús; Villena, Josep A; Bosch, Fàtima; Riu, Efrén

    2015-09-28

    High-Mobility-Group-A1 (HMGA1) proteins are non-histone proteins that regulate chromatin structure and gene expression during embryogenesis, tumourigenesis and immune responses. In vitro studies suggest that HMGA1 proteins may be required to regulate adipogenesis. To examine the role of HMGA1 in vivo, we generated transgenic mice overexpressing HMGA1 in adipose tissues. HMGA1 transgenic mice showed a marked reduction in white and brown adipose tissue mass that was associated with downregulation of genes involved in adipogenesis and concomitant upregulation of preadipocyte markers. Reduced adipogenesis and decreased fat mass were not associated with altered glucose homeostasis since HMGA1 transgenic mice fed a regular-chow diet exhibited normal glucose tolerance and insulin sensitivity. However, when fed a high-fat diet, overexpression of HMGA1 resulted in decreased body-weight gain, reduced fat mass, but improved insulin sensitivity and glucose tolerance. Although HMGA1 transgenic mice exhibited impaired glucose uptake in adipose tissue due to impaired adipogenesis, the increased glucose uptake observed in skeletal muscle may account for the improved glucose homeostasis. Our results indicate that HMGA1 plays an important function in the regulation of white and brown adipogenesis in vivo and suggests that impaired adipocyte differentiation and decreased fat mass is not always associated with impaired whole-body glucose homeostasis.

  3. AMPK Activation by Metformin Suppresses Abnormal Extracellular Matrix Remodeling in Adipose Tissue and Ameliorates Insulin Resistance in Obesity.

    PubMed

    Luo, Ting; Nocon, Allison; Fry, Jessica; Sherban, Alex; Rui, Xianliang; Jiang, Bingbing; Xu, X Julia; Han, Jingyan; Yan, Yun; Yang, Qin; Li, Qifu; Zang, Mengwei

    2016-08-01

    Fibrosis is emerging as a hallmark of metabolically dysregulated white adipose tissue (WAT) in obesity. Although adipose tissue fibrosis impairs adipocyte plasticity, little is known about how aberrant extracellular matrix (ECM) remodeling of WAT is initiated during the development of obesity. Here we show that treatment with the antidiabetic drug metformin inhibits excessive ECM deposition in WAT of ob/ob mice and mice with diet-induced obesity, as evidenced by decreased collagen deposition surrounding adipocytes and expression of fibrotic genes including the collagen cross-linking regulator LOX Inhibition of interstitial fibrosis by metformin is likely attributable to the activation of AMPK and the suppression of transforming growth factor-β1 (TGF-β1)/Smad3 signaling, leading to enhanced systemic insulin sensitivity. The ability of metformin to repress TGF-β1-induced fibrogenesis is abolished by the dominant negative AMPK in primary cells from the stromal vascular fraction. TGF-β1-induced insulin resistance is suppressed by AMPK agonists and the constitutively active AMPK in 3T3L1 adipocytes. In omental fat depots of obese humans, interstitial fibrosis is also associated with AMPK inactivation, TGF-β1/Smad3 induction, aberrant ECM production, myofibroblast activation, and adipocyte apoptosis. Collectively, integrated AMPK activation and TGF-β1/Smad3 inhibition may provide a potential therapeutic approach to maintain ECM flexibility and combat chronically uncontrolled adipose tissue expansion in obesity.

  4. Activation of the hexosamine signaling pathway in adipose tissue results in decreased serum adiponectin and skeletal muscle insulin resistance.

    PubMed

    Hazel, Mark; Cooksey, Robert C; Jones, Deborah; Parker, Glendon; Neidigh, John L; Witherbee, Bryan; Gulve, Eric A; McClain, Donald A

    2004-05-01

    Overexpression of the rate-limiting enzyme for hexosamine synthesis (glutamine:fructose-6-phosphate amidotransferase) in muscle and adipose tissue of transgenic mice was previously shown to result in insulin resistance and hyperleptinemia. Explanted muscle from transgenic mice was not insulin resistant in vitro, suggesting that muscle insulin resistance could be mediated by soluble factors from fat tissue. To dissect the relative contributions of muscle and fat to hexosamine-induced insulin resistance, we overexpressed glutamine:fructose-6-phosphate amidotransferase 2.5-fold, specifically in fat under control of the aP2 promoter. Fasting glucose, insulin, and triglycerides were unchanged in the transgenic mice; leptin and beta-hydroxybutyrate levels were 91% and 29% higher, respectively. Fasted transgenic mice have mild glucose intolerance and skeletal muscle insulin resistance in vivo. In fasting transgenic mice, glucose disposal rates with hyperinsulinemia were decreased 27% in females and 10% in males. Uptake of 2-deoxy-D-glucose into muscle was diminished by 45% in female and 21% in male transgenics. Serum adiponectin was also lower in the fasted transgenics, by 37% in females and 22% in males. TNF alpha and resistin mRNA levels in adipose tissue were not altered in the fasted transgenics; levels of mRNA for leptin were increased and peroxisome proliferator-activated receptor gamma decreased. To further explore the relationship between adiponectin and insulin sensitivity, we examined mice that have been refed for 6 h after a 24-h fast. Refeeding wild-type mice resulted in decreased serum adiponectin and increased leptin. In transgenic mice, however, the regulation of these hormones by refeeding was lost for adiponectin and diminished for leptin. Refed transgenic female and male mice no longer exhibited decreased serum adiponectin in the refed state, and they were no longer insulin resistant as by lower or unchanged insulin and glucose levels. We conclude that

  5. 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

  6. Oleanolic acid supplement attenuates liquid fructose-induced adipose tissue insulin resistance through the insulin receptor substrate-1/phosphatidylinositol 3-kinase/Akt signaling pathway in rats

    SciTech Connect

    Li, Ying; Wang, Jianwei; Gu, Tieguang; Yamahara, Johji; Li, Yuhao

    2014-06-01

    Oleanolic acid, a triterpenoid contained in more than 1620 plants including various fruits and foodstuffs, has numerous metabolic effects, such as hepatoprotection. However, its underlying mechanisms remain poorly understood. Adipose tissue insulin resistance (Adipo-IR) may contribute to the development and progress of metabolic abnormalities through release of excessive free fatty acids from adipose tissue. This study investigated the effect of oleanolic acid on Adipo-IR. The results showed that supplement with oleanolic acid (25 mg/kg, once daily, by oral gavage) over 10 weeks attenuated liquid fructose-induced increase in plasma insulin concentration and the homeostasis model assessment of insulin resistance (HOMA-IR) index in rats. Simultaneously, oleanolic acid reversed the increase in the Adipo-IR index and plasma non-esterified fatty acid concentrations during the oral glucose tolerance test assessment. In white adipose tissue, oleanolic acid enhanced mRNA expression of the genes encoding insulin receptor, insulin receptor substrate (IRS)-1 and phosphatidylinositol 3-kinase. At the protein level, oleanolic acid upregulated total IRS-1 expression, suppressed the increased phosphorylated IRS-1 at serine-307, and restored the increased phosphorylated IRS-1 to total IRS-1 ratio. In contrast, phosphorylated Akt to total Akt ratio was increased. Furthermore, oleanolic acid reversed fructose-induced decrease in phosphorylated-Akt/Akt protein to plasma insulin concentration ratio. However, oleanolic acid did not affect IRS-2 mRNA expression. Therefore, these results suggest that oleanolic acid supplement ameliorates fructose-induced Adipo-IR in rats via the IRS-1/phosphatidylinositol 3-kinase/Akt pathway. Our findings may provide new insights into the mechanisms of metabolic actions of oleanolic acid. - Highlights: • Adipose insulin resistance (Adipo-IR) contributes to metabolic abnormalities. • We investigated the effect of oleanolic acid (OA) on adipo-IR in

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

    Technology Transfer Automated Retrieval System (TEKTRAN)

    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 ...

  8. Inhibition of Gastric Inhibitory Polypeptide Receptor Signaling in Adipose Tissue Reduces Insulin Resistance and Hepatic Steatosis in High-Fat Diet-Fed Mice.

    PubMed

    Joo, Erina; Harada, Norio; Yamane, Shunsuke; Fukushima, Toru; Taura, Daisuke; Iwasaki, Kanako; Sankoda, Akiko; Shibue, Kimitaka; Harada, Takanari; Suzuki, Kazuyo; Hamasaki, Akihiro; Inagaki, Nobuya

    2017-04-01

    Gastric inhibitory polypeptide receptor (GIPR) directly induces energy accumulation in adipose tissue in vitro. However, the importance of the direct effect of GIPR signaling on adipose tissue in vivo remains unclear. In the current study, we generated adipose tissue-specific GIPR knockout (GIPR(adipo-/-)) mice and investigated the direct actions of GIP in adipose tissue. Under high-fat diet (HFD)-fed conditions, GIPR(adipo-/-) mice had significantly lower body weight and lean body mass compared with those in floxed GIPR (GIPR(fl/fl)) mice, although the fat volume was not significantly different between the two groups. Interestingly, insulin resistance, liver weight, and hepatic steatosis were reduced in HFD-fed GIPR(adipo-/-) mice. Plasma levels of interleukin-6 (IL-6), a proinflammatory cytokine that induces insulin resistance, were reduced in HFD-fed GIPR(adipo-/-) mice compared with those in HFD-fed GIPR(fl/fl) mice. Suppressor of cytokine signaling 3 (SOCS3) signaling is located downstream of the IL-6 receptor and is associated with insulin resistance and hepatic steatosis. Expression levels of SOCS3 mRNA were significantly lower in adipose and liver tissues of HFD-fed GIPR(adipo-/-) mice compared with those of HFD-fed GIPR(fl/fl) mice. Thus, GIPR signaling in adipose tissue plays a critical role in HFD-induced insulin resistance and hepatic steatosis in vivo, which may involve IL-6 signaling.

  9. Chronic Sleep Disruption Alters Gut Microbiota, Induces Systemic and Adipose Tissue Inflammation and Insulin Resistance in Mice

    PubMed Central

    Poroyko, Valeriy A.; Carreras, Alba; Khalyfa, Abdelnaby; Khalyfa, Ahamed A.; Leone, Vanessa; Peris, Eduard; Almendros, Isaac; Gileles-Hillel, Alex; Qiao, Zhuanhong; Hubert, Nathaniel; Farré, Ramon; Chang, Eugene B.; Gozal, David

    2016-01-01

    Chronic sleep fragmentation (SF) commonly occurs in human populations, and although it does not involve circadian shifts or sleep deprivation, it markedly alters feeding behaviors ultimately promoting obesity and insulin resistance. These symptoms are known to be related to the host gut microbiota. Mice were exposed to SF for 4 weeks and then allowed to recover for 2 weeks. Taxonomic profiles of fecal microbiota were obtained prospectively, and conventionalization experiments were performed in germ-free mice. Adipose tissue insulin sensitivity and inflammation, as well as circulating measures of inflammation, were assayed. Effect of fecal water on colonic epithelial permeability was also examined. Chronic SF-induced increased food intake and reversible gut microbiota changes characterized by the preferential growth of highly fermentative members of Lachnospiraceae and Ruminococcaceae and a decrease of Lactobacillaceae families. These lead to systemic and visceral white adipose tissue inflammation in addition to altered insulin sensitivity in mice, most likely via enhanced colonic epithelium barrier disruption. Conventionalization of germ-free mice with SF-derived microbiota confirmed these findings. Thus, SF-induced metabolic alterations may be mediated, in part, by concurrent changes in gut microbiota, thereby opening the way for gut microbiome-targeted therapeutics aimed at reducing the major end-organ morbidities of chronic SF. PMID:27739530

  10. 12/15-Lipoxygenase Is Required for the Early Onset of High Fat Diet-Induced Adipose Tissue Inflammation and Insulin Resistance in Mice

    PubMed Central

    Sears, Dorothy D.; Miles, Philip D.; Chapman, Justin; Ofrecio, Jachelle M.; Almazan, Felicidad; Thapar, Divya; Miller, Yury I.

    2009-01-01

    Background Recent understanding that insulin resistance is an inflammatory condition necessitates searching for genes that regulate inflammation in insulin sensitive tissues. 12/15-lipoxygenase (12/15LO) regulates the expression of proinflammatory cytokines and chemokines and is implicated in the early development of diet-induced atherosclerosis. Thus, we tested the hypothesis that 12/15LO is involved in the onset of high fat diet (HFD)-induced insulin resistance. Methodology/Principal Findings Cells over-expressing 12/15LO secreted two potent chemokines, MCP-1 and osteopontin, implicated in the development of insulin resistance. We assessed adipose tissue inflammation and whole body insulin resistance in wild type (WT) and 12/15LO knockout (KO) mice after 2–4 weeks on HFD. In adipose tissue from WT mice, HFD resulted in recruitment of CD11b+, F4/80+ macrophages and elevated protein levels of the inflammatory markers IL-1β, IL-6, IL-10, IL-12, IFNγ, Cxcl1 and TNFα. Remarkably, adipose tissue from HFD-fed 12/15LO KO mice was not infiltrated by macrophages and did not display any increase in the inflammatory markers compared to adipose tissue from normal chow-fed mice. WT mice developed severe whole body (hepatic and skeletal muscle) insulin resistance after HFD, as measured by hyperinsulinemic euglycemic clamp. In contrast, 12/15LO KO mice exhibited no HFD-induced change in insulin-stimulated glucose disposal rate or hepatic glucose output during clamp studies. Insulin-stimulated Akt phosphorylation in muscle tissue from HFD-fed mice was significantly greater in 12/15LO KO mice than in WT mice. Conclusions These results demonstrate that 12/15LO mediates early stages of adipose tissue inflammation and whole body insulin resistance induced by high fat feeding. PMID:19787041

  11. Transplantation of insulin-secreting cells differentiated from human adipose tissue-derived stem cells into type 2 diabetes mice.

    PubMed

    Nam, Ji Sun; Kang, Hyun Mi; Kim, Jiyoung; Park, Seah; Kim, Haekwon; Ahn, Chul Woo; Park, Jin Oh; Kim, Kyung Rae

    2014-01-10

    Currently, there are limited ways to preserve or recover insulin secretory capacity in human pancreas. We evaluated the efficacy of cell therapy using insulin-secreting cells differentiated from human eyelid adipose tissue-derived stem cells (hEAs) into type 2 diabetes mice. After differentiating hEAs into insulin-secreting cells (hEA-ISCs) in vitro, cells were transplanted into a type 2 diabetes mouse model. Serum levels of glucose, insulin and c-peptide were measured, and changes of metabolism and inflammation were assessed in mice that received undifferentiated hEAs (UDC group), differentiated hEA-ISCs (DC group), or sham operation (sham group). Human gene expression and immunohistochemical analysis were done. DC group mice showed improved glucose level, and survival up to 60 days compared to those of UDC and sham group. Significantly increased levels of human insulin and c-peptide were detected in sera of DC mice. RT-PCR and immunohistochemical analysis showed human gene expression and the presence of human cells in kidneys of DC mice. When compared to sham mice, DC mice exhibited lower levels of IL-6, triglyceride and free fatty acids as the control mice. Transplantation of hEA-ISCs lowered blood glucose level in type 2 diabetes mice by increasing circulating insulin level, and ameliorating metabolic parameters including IL-6.

  12. Associations of organochlorine pesticides and polychlorinated biphenyls in visceral vs. subcutaneous adipose tissue with type 2 diabetes and insulin resistance.

    PubMed

    Kim, Ki-Su; Lee, Yu-Mi; Kim, Sang Geol; Lee, In-Kyu; Lee, Hyo-Jeong; Kim, Ji-Hyun; Kim, Jeongkook; Moon, Hyo-Bang; Jacobs, David R; Lee, Duk-Hee

    2014-01-01

    Background exposure to organochlorine (OC) pesticides and polychlorinated biphenyls (PCBs) has been linked to type 2 diabetes. As OC pesticides and PCBs mainly accumulate in adipose tissue and there are physiological and clinical differences between visceral adipose tissue (VAT) and subcutaneous adipose tissue (SAT), we explored if there were associations of OC pesticides and PCBs in VAT or SAT with type 2 diabetes and insulin resistance. Participants were 50 patients with or without type 2 diabetes who underwent surgery for either cancer or benign liver or gallbladder lesions. We analyzed 14 OC pesticides and 22 PCB congeners in both VAT and SAT. Insulin resistance was estimated using homeostasis model assessment (HOMA). Although concentrations of OC pesticides and PCBs were strongly correlated between VAT and SAT, absolute concentrations differed substantially between them. In particular, concentrations of all PCBs were consistently about 5-10 times higher in VAT than SAT, but these patterns were independent of diabetes status. Some OC pesticides or PCBs, such as dichlorodiphenyltrichloroethanes (DDTs), chlordanes, and PCBs with 5 or less chlorides showed significant associations with diabetes or insulin resistance. For example, when tertiles of concentration-based summary measures were used, adjusted ORs were 1.0, 2.3, and 9.0 (P trend=0.02) for DDTs in VAT and 1.0, 2.1, and 5.7 (P trend=0.08) for PCBs with 5 or less chlorides. This study generally confirmed previous findings using serum concentrations. It would be useful to study pharmacodynamics of POPs in VAT and SAT further.

  13. Progression from high insulin resistance to type 2 diabetes does not entail additional visceral adipose tissue inflammation.

    PubMed

    Barbarroja, Nuria; Lopez-Pedrera, Chary; Garrido-Sanchez, Lourdes; Mayas, Maria Dolores; Oliva-Olivera, Wilfredo; Bernal-Lopez, Maria Rosa; El Bekay, Rajaa; Tinahones, Francisco Jose

    2012-01-01

    Obesity is associated with a low-grade chronic inflammation state. As a consequence, adipose tissue expresses pro-inflammatory cytokines that propagate inflammatory responses systemically elsewhere, promoting whole-body insulin resistance and consequential islet β-cell exhaustation. Thus, insulin resistance is considered the early stage of type 2 diabetes. However, there is evidence of obese individuals that never develop diabetes indicating that the mechanisms governing the association between the increase of inflammatory factors and type 2 diabetes are much more complex and deserve further investigation. We studied for the first time the differences in insulin signalling and inflammatory pathways in blood and visceral adipose tissue (VAT) of 20 lean healthy donors and 40 equal morbidly obese (MO) patients classified in high insulin resistance (high IR) degree and diabetes state. We studied the changes in proinflammatory markers and lipid content from serum; macrophage infiltration, mRNA expression of inflammatory cytokines and transcription factors, activation of kinases involved in inflammation and expression of insulin signalling molecules in VAT. VAT comparison of these experimental groups revealed that type 2 diabetic-MO subjects exhibit the same pro-inflammatory profile than the high IR-MO patients, characterized by elevated levels of IL-1β, IL-6, TNFα, JNK1/2, ERK1/2, STAT3 and NFκB. Our work rules out the assumption that the inflammation should be increased in obese people with type 2 diabetes compared to high IR obese. These findings indicate that some mechanisms, other than systemic and VAT inflammation must be involved in the development of type 2 diabetes in obesity.

  14. Progression from High Insulin Resistance to Type 2 Diabetes Does Not Entail Additional Visceral Adipose Tissue Inflammation

    PubMed Central

    Barbarroja, Nuria; Lopez-Pedrera, Chary; Garrido-Sanchez, Lourdes; Mayas, Maria Dolores; Oliva-Olivera, Wilfredo; Bernal-Lopez, Maria Rosa; El Bekay, Rajaa; Tinahones, Francisco Jose

    2012-01-01

    Obesity is associated with a low-grade chronic inflammation state. As a consequence, adipose tissue expresses pro-inflammatory cytokines that propagate inflammatory responses systemically elsewhere, promoting whole-body insulin resistance and consequential islet β-cell exhaustation. Thus, insulin resistance is considered the early stage of type 2 diabetes. However, there is evidence of obese individuals that never develop diabetes indicating that the mechanisms governing the association between the increase of inflammatory factors and type 2 diabetes are much more complex and deserve further investigation. We studied for the first time the differences in insulin signalling and inflammatory pathways in blood and visceral adipose tissue (VAT) of 20 lean healthy donors and 40 equal morbidly obese (MO) patients classified in high insulin resistance (high IR) degree and diabetes state. We studied the changes in proinflammatory markers and lipid content from serum; macrophage infiltration, mRNA expression of inflammatory cytokines and transcription factors, activation of kinases involved in inflammation and expression of insulin signalling molecules in VAT. VAT comparison of these experimental groups revealed that type 2 diabetic-MO subjects exhibit the same pro-inflammatory profile than the high IR-MO patients, characterized by elevated levels of IL-1β, IL-6, TNFα, JNK1/2, ERK1/2, STAT3 and NFκB. Our work rules out the assumption that the inflammation should be increased in obese people with type 2 diabetes compared to high IR obese. These findings indicate that some mechanisms, other than systemic and VAT inflammation must be involved in the development of type 2 diabetes in obesity. PMID:23110196

  15. Insulin signaling, inflammation, and lipolysis in subcutaneous adipose tissue of transition dairy cows either overfed energy during the prepartum period or fed a controlled-energy diet.

    PubMed

    Mann, S; Nydam, D V; Abuelo, A; Leal Yepes, F A; Overton, T R; Wakshlag, J J

    2016-08-01

    Adipose tissue mobilization is a hallmark of the transition period in dairy cows. Cows overfed energy during the dry period have higher concentrations of nonesterified fatty acids (NEFA) and β-hydroxybutyrate (BHB) compared with cows fed a controlled-energy diet prepartum. The reason for an increase in blood NEFA concentrations at the level of adipose tissue in cows overfed energy has not been fully elucidated. One hypothesis is that cows with high BHB concentrations suffer from adipose tissue-specific insulin resistance, leading to higher rates of adipose tissue mobilization in the postpartum period. To test this hypothesis, subcutaneous adipose tissue biopsies of cows overfed energy in excess of predicted requirements by 50% in the dry period, and that had high concentrations of blood BHB postpartum (group H; n=12), were used. Findings were compared with results of biopsies from cows fed a controlled-energy diet and with low BHB concentrations postpartum (group C; n=12) to create the biggest contrast in BHB concentrations. Subcutaneous adipose tissue biopsies were obtained before and 60 min after an intravenous glucose challenge (0.25 g/kg of glucose) at 28 and 10 d before expected calving as well as on d 4 and 21 postpartum. Phosphorylation of protein kinase B, extracellular signal-regulated kinase, and hormone-sensitive lipase was determined before and after glucose infusion by Western blot. Western blot was also used to assess the baseline protein abundance of peroxisome proliferator-activated receptor gamma and insulin receptor β-subunit. In addition, gene expression of fatty acid synthase, adiponectin, monocyte chemoattractant protein 1, and tumor necrosis factor α was determined by real-time quantitative reverse-transcription PCR. Backfat thickness was determined in the thurl area by ultrasonography. Cows in group H showed a greater degree of lipogenesis prepartum, but no differences were found in lipolytic enzyme activity postpartum compared with cows

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

    Technology Transfer Automated Retrieval System (TEKTRAN)

    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 ...

  17. The Roles of Adipokines, Proinflammatory Cytokines, and Adipose Tissue Macrophages in Obesity-Associated Insulin Resistance in Modest Obesity and Early Metabolic Dysfunction

    PubMed Central

    Kim, Ji Min; Joung, Kyong Hye; Lee, Ju Hee; You, Bo Ram; Choi, Min Jeong; Ryu, Min Jeong; Ko, Young Bok; Lee, Min A.; Lee, Junguee; Ku, Bon Jeong; Shong, Minho; Lee, Ki Hwan; Kim, Hyun Jin

    2016-01-01

    The roles of adipokines, proinflammatory cytokines, and adipose tissue macrophages in obesity-associated insulin resistance have been explored in both animal and human studies. However, our current understanding of obesity-associated insulin resistance relies on studies of artificial metabolic extremes. The purpose of this study was to explore the roles of adipokines, proinflammatory cytokines, and adipose tissue macrophages in human patients with modest obesity and early metabolic dysfunction. We obtained omental adipose tissue and fasting blood samples from 51 females undergoing gynecologic surgery. We investigated serum concentrations of proinflammatory cytokines and adipokines as well as the mRNA expression of proinflammatory and macrophage phenotype markers in visceral adipose tissue using ELISA and quantitative RT-PCR. We measured adipose tissue inflammation and macrophage infiltration using immunohistochemical analysis. Serum levels of adiponectin and leptin were significantly correlated with HOMA-IR and body mass index. The levels of expression of MCP-1 and TNF-α in visceral adipose tissue were also higher in the obese group (body mass index ≥ 25). The expression of mRNA MCP-1 in visceral adipose tissue was positively correlated with body mass index (r = 0.428, p = 0.037) but not with HOMA-IR, whereas TNF-α in visceral adipose tissue was correlated with HOMA-IR (r = 0.462, p = 0.035) but not with body mass index. There was no obvious change in macrophage phenotype or macrophage infiltration in patients with modest obesity or early metabolic dysfunction. Expression of mRNA CD163/CD68 was significantly related to mitochondrial-associated genes and serum inflammatory cytokine levels of resistin and leptin. These results suggest that changes in the production of inflammatory biomolecules precede increased immune cell infiltration and induction of a macrophage phenotype switch in visceral adipose tissue. Furthermore, serum resistin and leptin have specific

  18. Dietary soy protein improves adipose tissue dysfunction by modulating parameters related with oxidative stress in dyslipidemic insulin-resistant rats.

    PubMed

    Illesca, Paola G; Álvarez, Silvina M; Selenscig, Dante A; Ferreira, María Del R; Giménez, María S; Lombardo, Yolanda B; D'Alessandro, María E

    2017-04-01

    The present study investigates the benefits of the dietary intake of soy protein on adipose tissue dysfunction in a rat model that mimics several aspects of the human metabolic syndrome. Wistar rats were fed a sucrose-rich diet (SRD) for 4 months. After that, half of the animals continued with SRD until month 8 while in the other half, casein protein was replaced by isolated soy protein for 4 months (SRD-S). A reference group consumed a control diet all the time. In adipose tissue we determined: i) the activities of antioxidant enzymes, gene expression of Mn-superoxide dismutase (SOD) and glutathione peroxidase (GPx), and glutathione redox state ii) the activity of xanthine oxidase (XO), ROS levels and the gene expression of NAD(P)H oxidase iii) the expression of the nuclear factor erythroid-2 related factor-2 (Nrf2). Besides, adiposity visceral index, insulin sensitivity, and tumor necrosis factor-α (TNF-α) in plasma were determined. Compared with the SRD-fed rats, the animals fed a SRD-S showed: activity normalization of SOD and glutathione reductase, improvement of mRNA SOD and normalization of mRNA GPx without changes in the expression of the Nrf2, and improvement of glutathione redox state. These results were accompanied by a normalization of XO activity and improvement of both the ROS production as well as TNF-α levels in plasma. Besides, adipocyte size distribution, adiposity visceral index and insulin sensitivity improved. The results suggest that soy protein can be a complementary nutrient for treating some signs of the metabolic syndrome.

  19. Chitosan reduces plasma adipocytokines and lipid accumulation in liver and adipose tissues and ameliorates insulin resistance in diabetic rats.

    PubMed

    Hsieh, Yu-Lin; Yao, Hsien-Tsung; Cheng, Ron-Shan; Chiang, Meng-Tsan

    2012-05-01

    Chitosan is a natural product derived from chitin. To investigate the hypoglycemic and anti-obesity effects of chitosan, male Sprague-Dawley rats were divided into four groups: normal control, diabetic, and diabetic fed 5% or 7% chitosan. Diabetes was induced in rats by injecting streptozotocin/nicotinamide. After 10 weeks of feeding, the elevated plasma glucose, tumor necrosis factor-α, and interleukin-6 and lower adiponetin levels caused by diabetes were effectively reversed by chitosan treatment. In addition, 7% chitosan feeding also elevated plasma glucagon-like peptide-1 levels and lowered the insulin resistance index (homeostasis model assessment) in diabetic rats. Lower adipocyte granular intensities and higher lipolysis rates in adipose tissues were noted in the 7% chitosan group. Moreover, chitosan feeding reduced hepatic triglyceride and cholesterol contents and increased hepatic peroxisomal proliferator-activated receptor α expression in diabetic rats. Our results indicate that long-term administration of chitosan may reduce insulin resistance through suppression of lipid accumulation in liver and adipose tissues and amelioration of chronic inflammation in diabetic rats.

  20. Visceral adiposity, insulin resistance and cancer risk

    PubMed Central

    2011-01-01

    Background There is a well established link between obesity and cancer. Emerging research is characterising this relationship further and delineating the specific role of excess visceral adiposity, as opposed to simple obesity, in promoting tumorigenesis. This review summarises the evidence from an epidemiological and pathophysiological perspective. Methods Relevant medical literature was identified from searches of PubMed and references cited in appropriate articles identified. Selection of articles was based on peer review, journal and relevance. Results Numerous epidemiological studies consistently identify increased risk of developing carcinoma in the obese. Adipose tissue, particularly viscerally located fat, is metabolically active and exerts systemic endocrine effects. Putative pathophysiological mechanisms linking obesity and carcinogenesis include the paracrine effects of adipose tissue and systemic alterations associated with obesity. Systemic changes in the obese state include chronic inflammation and alterations in adipokines and sex steroids. Insulin and the insulin-like growth factor axis influence tumorigenesis and also have a complex relationship with adiposity. There is evidence to suggest that insulin and the IGF axis play an important role in mediating obesity associated malignancy. Conclusions There is much evidence to support a role for obesity in cancer progression, however further research is warranted to determine the specific effect of excess visceral adipose tissue on tumorigenesis. Investigation of the potential mechanisms underpinning the association, including the role of insulin and the IGF axis, will improve understanding of the obesity and cancer link and may uncover targets for intervention. PMID:21696633

  1. Differentiation of rapid and slower-acting effects of insulin on mitochondrial processes in brown adipose tissue from streptozotocin-diabetic rats.

    PubMed Central

    Gualberto, A; Saggerson, E D

    1989-01-01

    Insulin treatment of streptozotocin-diabetic rats restores the depressed palmitoyl-group oxidation observed in brown-adipose-tissue mitochondria from diabetic rats. A relatively rapid effect of insulin (5 h) to increase carnitine-dependent oxidation of palmitoyl-CoA and to increase overt carnitine palmitoyltransferase activity is differentiated from a slower effect of the hormone (1 day) to increase palmitoylcarnitine oxidation. PMID:2649091

  2. 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

    2017-03-15

    It has been shown that serum homocycteine (Hcy) levels are higher in women with polycystic ovary syndrome (PCOS). However, the specific role of hyperhomocycteinemia (HHcy) in the development of PCOS has never been reported. Adipose tissue inflammation is featured by the infiltration of macrophages that 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 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 polycyctic ovaries. HHcy further intensified the effects DHEA on the metabolic, endocrinal, hormonal, and morphological changes in PCOS-like mice. In addition, the HHcy attenuated the DHEA-induced increase in serum estrogen levels in mice. Furthermore, HHcy may exacerbate the insulin resistance in the PCOS-like mice, most likely through modulating the macrophage M1/M2 polarization pathways via the suppression of estrogen. Most importantly, our clinical data showed that there were increases in serum Hcy levels in PCOS patients. 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.

  3. Corepressor SMRT promotes oxidative phosphorylation in adipose tissue and protects against diet-induced obesity and insulin resistance

    PubMed Central

    Fang, Sungsoon; Suh, Jae Myoung; Atkins, Annette R.; Hong, Suk-Hyun; Leblanc, Mathias; Nofsinger, Russell R.; Yu, Ruth T.; Downes, Michael; Evans, Ronald M.

    2011-01-01

    The ligand-dependent competing actions of nuclear receptor (NR)-associated transcriptional corepressor and coactivator complexes allow for the precise regulation of NR-dependent gene expression in response to both temporal and environmental cues. Here we report the mouse model termed silencing mediator of retinoid and thyroid hormone receptors (SMRT)mRID1 in which targeted disruption of the first receptor interaction domain (RID) of the nuclear corepressor SMRT disrupts interactions with a subset of NRs and leads to diet-induced superobesity associated with a depressed respiratory exchange ratio, decreased ambulatory activity, and insulin resistance. Although apparently normal when chow fed, SMRTmRID1 mice develop multiple metabolic dysfunctions when challenged by a high-fat diet, manifested by marked lipid accumulation in white and brown adipose tissue and the liver. The increased weight gain of SMRTmRID1 mice on a high-fat diet occurs predominantly in fat with adipocyte hypertrophy evident in both visceral and s.c. depots. Importantly, increased inflammatory gene expression was detected only in the visceral depots. SMRTmRID1 mice are both insulin-insensitive and refractory to the glucose-lowering effects of TZD and AICAR. Increased serum cholesterol and triglyceride levels were observed, accompanied by increased leptin and decreased adiponectin levels. Aberrant storage of lipids in the liver occurred as triglycerides and cholesterol significantly compromised hepatic function. Lipid accumulation in brown adipose tissue was associated with reduced thermogenic capacity and mitochondrial biogenesis. Collectively, these studies highlight the essential role of NR corepressors in maintaining metabolic homeostasis and describe an essential role for SMRT in regulating the progression, severity, and therapeutic outcome of metabolic diseases. PMID:21300871

  4. Defining dermal adipose tissue.

    PubMed

    Driskell, Ryan R; Jahoda, Colin A B; Chuong, Cheng-Ming; Watt, Fiona M; Horsley, Valerie

    2014-09-01

    Here, we explore the evolution and development of skin-associated adipose tissue with the goal of establishing nomenclature for this tissue. Underlying the reticular dermis, a thick layer of adipocytes exists that encases mature hair follicles in rodents and humans. The association of lipid-filled cells with the skin is found in many invertebrate and vertebrate species. Historically, this layer of adipocytes has been termed subcutaneous adipose, hypodermis and subcutis. Recent data have revealed a common precursor for dermal fibroblasts and intradermal adipocytes during development. Furthermore, the development of adipocytes in the skin is independent from that of subcutaneous adipose tissue development. Finally, the role of adipocytes has been shown to be relevant for epidermal homoeostasis during hair follicle regeneration and wound healing. Thus, we propose a refined nomenclature for the cells and adipose tissue underlying the reticular dermis as intradermal adipocytes and dermal white adipose tissue, respectively.

  5. Adipose Tissue Insulin Resistance in Peripubertal Girls with First-Degree Family History of Polycystic Ovary Syndrome

    PubMed Central

    Trottier, Andréanne; Battista, Marie-Claude; Geller, David H; Moreau, Brigitte; Carpentier, André C; Simoneau-Roy, Judith; Baillargeon, Jean-Patrice

    2014-01-01

    Objective To assess metabolic and endocrine defects in girls genetically predisposed to polycystic ovary syndrome (PCOS). Design Controlled cross-sectional study. Setting University hospital. Patients Nine girls aged 8–14 years having a first-degree relative diagnosed with PCOS (PCOSr) and 10 age-matched girls unrelated to PCOS. Intervention None. Main outcome measure Insulin sensitivity determined by frequently sampled intravenous glucose tolerance testing (ISFSivGTT) and insulin-induced non-esterified fatty acid suppression (NEFAsupp), estimated by the log-linear slope of NEFA levels during the first 20 min of FSivGTT. Results In comparison to controls, PCOSr had higher body mass index Z-score (BMI-z), waist circumference and waist/height ratio. Levels of the androgen 17α-hydroxyprogesterone (17OHPg) were significantly increased in PCOSr, independently of adiposity, and inversely correlated with ISFSivGTT. ISFSivGTT was decreased and NEFAsupp was less steep in PCOSr as compared to controls, independently of BMI-z and 17OHPg. NEFAsupp was more pronounced with increasing ISFSivGTT, independently of adiposity. Conclusions Girls at high risk of developing PCOS display increased adiposity and 17OHPg levels, but are mainly characterized by global insulin resistance and resistance to insulin-induced suppression of lipolysis that were independent of adiposity and 17OHPg levels. Therefore, genetic predisposition to PCOS may be related to early insulin resistance and adipocyte dysfunction. PMID:22985947

  6. Obesogenic memory can confer long-term increases in adipose tissue but not liver inflammation and insulin resistance after weight loss

    PubMed Central

    Schmitz, J.; Evers, N.; Awazawa, M.; Nicholls, H.T.; Brönneke, H.S.; Dietrich, A.; Mauer, J.; Blüher, M.; Brüning, J.C.

    2016-01-01

    Objective Obesity represents a major risk factor for the development of type 2 diabetes mellitus, atherosclerosis and certain cancer entities. Treatment of obesity is hindered by the long-term maintenance of initially reduced body weight, and it remains unclear whether all pathologies associated with obesity are fully reversible even upon successfully maintained weight loss. Methods We compared high fat diet-fed, weight reduced and lean mice in terms of body weight development, adipose tissue and liver insulin sensitivity as well as inflammatory gene expression. Moreover, we assessed similar parameters in a human cohort before and after bariatric surgery. Results Compared to lean animals, mice that demonstrated successful weight reduction showed increased weight gain following exposure to ad libitum control diet. However, pair-feeding weight-reduced mice with lean controls efficiently stabilized body weight, indicating that hyperphagia was the predominant cause for the observed weight regain. Additionally, whereas glucose tolerance improved rapidly after weight loss, systemic insulin resistance was retained and ameliorated only upon prolonged pair-feeding. Weight loss enhanced insulin action and resolved pro-inflammatory gene expression exclusively in the liver, whereas visceral adipose tissue displayed no significant improvement of metabolic and inflammatory parameters compared to obese mice. Similarly, bariatric surgery in humans (n = 55) resulted in massive weight reduction, improved hepatic inflammation and systemic glucose homeostasis, while adipose tissue inflammation remained unaffected and adipocyte-autonomous insulin action only exhibit minor improvements in a subgroup of patients (42%). Conclusions These results demonstrate that although sustained weight loss improves systemic glucose homeostasis, primarily through improved inflammation and insulin action in liver, a remarkable obesogenic memory can confer long-term increases in adipose tissue

  7. Adipose Tissue Dysfunction: Clinical Relevance and Diagnostic Possibilities.

    PubMed

    Schrover, I M; Spiering, W; Leiner, T; Visseren, F L J

    2016-04-01

    Adipose tissue dysfunction is defined as an imbalance between pro- and anti-inflammatory adipokines, causing insulin resistance, systemic low-grade inflammation, hypercoagulability, and elevated blood pressure. These can lead to cardiovascular disease and diabetes mellitus type 2. Although quantity of adipose tissue is an important determinant of adipose tissue dysfunction, it can be diagnosed in both obese and lean individuals. This implies that not only quantity of adipose tissue should be used as a measure for adipose tissue dysfunction. Instead, focus should be on measuring quality of adipose tissue, which can be done with diagnostic modalities ranging from anthropometric measurements to tissue biopsies and advanced imaging techniques. In daily clinical practice, high quantity of visceral adipose tissue (reflected in high waist circumference or adipose tissue imaging), insulin resistance, or presence of the metabolic syndrome are easy and low-cost diagnostic modalities to evaluate presence or absence of adipose tissue dysfunction.

  8. Abdominal adipose tissue: early metabolic dysfunction associated to insulin resistance and oxidative stress induced by an unbalanced diet.

    PubMed

    Rebolledo, O R; Marra, C A; Raschia, A; Rodriguez, S; Gagliardino, J J

    2008-11-01

    The possible contribution of early changes in lipid composition, function, and antioxidant status of abdominal adipose tissue (AAT) induced by a fructose-rich diet (FRD) to the development of insulin resistance (IR) and oxidative stress (OS) was studied. Wistar rats were fed with a commercial diet with (FRD) or without 10% fructose in the drinking water for 3 weeks. The glucose (G), triglyceride (TG), and insulin (I) plasma levels, and the activity of antioxidant enzymes, lyposoluble antioxidants, total glutathione (GSH), lipid peroxidation as TBARS, fatty acid (FA) composition of AAT-TG as well as their release by incubated pieces of AAT were measured. Rats fed with a FRD have significantly higher plasma levels of G, TG, and I. Their AAT showed a marked increase in content and ratios of saturated to monounsaturated and polyunsaturated FAs, TBARS, and catalase, GSH-transferase and GSH-reductase, together with a decrease in superoxide dismutase and GSH-peroxidase activity, and total GSH, alpha-tocopherol, beta-carotene and lycopene content. Incubated AAT from FRD released in vitro higher amount of free fatty acids (FFAs) with higher ratios of saturated to monounsaturated and polyunsaturated FAs. Our data suggest that FRD induced an early prooxidative state and metabolic dysfunction in AAT that would favor the overall development of IR and OS and further development of pancreatic beta-cell failure; therefore, its early control would represent an appropriate strategy to prevent alterations such as the development of type 2 diabetes.

  9. A post-weaning obesogenic diet exacerbates the detrimental effects of maternal obesity on offspring insulin signaling in adipose tissue.

    PubMed

    de Almeida Faria, Juliana; Duque-Guimarães, Daniella; Carpenter, Asha A M; Loche, Elena; Ozanne, Susan E

    2017-03-24

    Previous studies have shown that maternal diet-induced obesity leads to increased risk of type 2 diabetes in offspring. The current study investigated if weaning onto an obesogenic diet exaggerated the detrimental effects of maternal diet-induced obesity in adipose tissue. Maternal obesity and offspring obesity led to reduced expression of key insulin signalling proteins, including insulin receptor substrate-1 (IRS-1). The effects of maternal obesity and offspring obesity were, generally, independent and additive. Irs1 mRNA levels were similar between all four groups of offspring, suggesting that in both cases post-transcriptional regulation was involved. Maternal diet-induced obesity increased miR-126 expression however levels of this miR were not influenced by a post-weaning obesogenic diet. In contrast, a post-weaning obesogenic diet was associated with increased levels of suppressor of cytokine signaling-1, implicating increased degradation of IRS-1 as an underlying mechanism. Our results suggest that whilst programmed reductions in IRS-1 are associated with increased levels of miR-126 and consequently reduced translation of Irs1 mRNA, the effects of a post-weaning obesogenic diet on IRS-1 are mediated by miR-126 independent mechanisms, including increased IRS-1 protein degradation. These divergent mechanisms explain why the combination of maternal obesity and offspring obesity leads to the most pronounced effects on offspring metabolism.

  10. Key Role of STAT4 Deficiency in the Hematopoietic Compartment in Insulin Resistance and Adipose Tissue Inflammation

    PubMed Central

    Ma, Kaiwen; Glenn, Lindsey M.; Hatcher, Margaret A.; Haynes, Bronson A.; Lehrer, Eric J.; Kaplan, Mark H.

    2017-01-01

    Visceral adipose tissue (AT) inflammation is linked to the complications of obesity, including insulin resistance (IR) and type 2 diabetes. Recent data from our lab showed that germline deficiency in STAT4 reduces inflammation and improves IR in obese mice. The objective of this study was to determine the contribution of selective STAT4 deficiency in subsets of hematopoietic cells to IR and AT inflammation. To determine the contribution of hematopoietic lineage, we sublethally irradiated Stat4−/−C57Bl6 mice and reconstituted them with bone marrow cells (BMC) from Stat4+/+C57Bl6 congenic donors. We also established the contribution of selective STAT4 deficiency in CD4+ or CD8+ T cells using adoptive transfer in Rag1−/− mice. All mice received a HFD for 15 weeks (n = 7–12 mice/group). BMC that expressed STAT4 induced increases in glucose intolerance and IR compared to STAT4-deficient cells. Also, AT inflammation was increased and the numbers of CD8+ cells infiltrating AT were higher in mice with STAT4 expressing BMC. Studies in Rag1−/− mice further confirmed the prominent role of CD8+ cells expressing STAT4 in insulin resistance and AT and islet inflammation. Collectively our results show specific and dominant contribution of STAT4 in the hematopoietic compartment to metabolic health and inflammation in diet-induced obesity.

  11. A post-weaning obesogenic diet exacerbates the detrimental effects of maternal obesity on offspring insulin signaling in adipose tissue

    PubMed Central

    de Almeida Faria, Juliana; Duque-Guimarães, Daniella; Carpenter, Asha A. M.; Loche, Elena; Ozanne, Susan E.

    2017-01-01

    Previous studies have shown that maternal diet-induced obesity leads to increased risk of type 2 diabetes in offspring. The current study investigated if weaning onto an obesogenic diet exaggerated the detrimental effects of maternal diet-induced obesity in adipose tissue. Maternal obesity and offspring obesity led to reduced expression of key insulin signalling proteins, including insulin receptor substrate-1 (IRS-1). The effects of maternal obesity and offspring obesity were, generally, independent and additive. Irs1 mRNA levels were similar between all four groups of offspring, suggesting that in both cases post-transcriptional regulation was involved. Maternal diet-induced obesity increased miR-126 expression however levels of this miR were not influenced by a post-weaning obesogenic diet. In contrast, a post-weaning obesogenic diet was associated with increased levels of suppressor of cytokine signaling-1, implicating increased degradation of IRS-1 as an underlying mechanism. Our results suggest that whilst programmed reductions in IRS-1 are associated with increased levels of miR-126 and consequently reduced translation of Irs1 mRNA, the effects of a post-weaning obesogenic diet on IRS-1 are mediated by miR-126 independent mechanisms, including increased IRS-1 protein degradation. These divergent mechanisms explain why the combination of maternal obesity and offspring obesity leads to the most pronounced effects on offspring metabolism. PMID:28338072

  12. The CCR2 Inhibitor Propagermanium Attenuates Diet-Induced Insulin Resistance, Adipose Tissue Inflammation and Non-Alcoholic Steatohepatitis

    PubMed Central

    van den Hoek, Anita M.; Kleemann, Robert

    2017-01-01

    Background and aim Obese patients with chronic inflammation in white adipose tissue (WAT) have an increased risk of developing non-alcoholic steatohepatitis (NASH). The C-C chemokine receptor-2 (CCR2) has a crucial role in the recruitment of immune cells to WAT and liver, thereby promoting the inflammatory component of the disease. Herein, we examined whether intervention with propagermanium, an inhibitor of CCR2, would attenuate tissue inflammation and NASH development. Methods Male C57BL/6J mice received a high-fat diet (HFD) for 0, 6, 12 and 24 weeks to characterize the development of early disease symptoms of NASH, i.e. insulin resistance and WAT inflammation (by hyperinsulinemic-euglycemic clamp and histology, respectively) and to define the optimal time point for intervention. In a separate study, mice were pretreated with HFD followed by propagermanium treatment (0.05% w/w) after 6 weeks (early intervention) or 12 weeks (late intervention). NASH was analyzed after 24 weeks of diet feeding. Results Insulin resistance in WAT developed after 6 weeks of HFD, which was paralleled by modest WAT inflammation. Insulin resistance and inflammation in WAT intensified after 12 weeks of HFD, and preceded NASH development. The subsequent CCR2 intervention experiment showed that early, but not late, propagermanium treatment attenuated insulin resistance. Only the early treatment significantly decreased Mcp-1 and CD11c gene expression in WAT, indicating reduced WAT inflammation. Histopathological analysis of liver demonstrated that propagermanium treatment decreased macrovesicular steatosis and tended to reduce lobular inflammation, with more pronounced effects in the early intervention group. Propagermanium improved the ratio between pro-inflammatory (M1) and anti-inflammatory (M2) macrophages, quantified by CD11c and Arginase-1 gene expression in both intervention groups. Conclusions Overall, early propagermanium administration was more effective to improve insulin

  13. [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.

  14. Beta-carotene is incorporated or mobilized along with triglycerides in bovine adipose tissue in response to insulin or epinephrine.

    PubMed

    Arias, E; González, A; Shimada, A; Varela-Echavarria, A; Ruiz-López, F; During, A; Mora, O

    2009-02-01

    Pasture fed cattle ingest substantial amounts of beta-carotene (beta-C). Not all of the carotenoid compound is transformed into vitamin A, but the surplus is deposited in adipose tissue (AT). The mechanisms of beta-C incorporation and mobilization are unknown. Two experiments were conducted using explants from bovine AT cultured in vitro. First, beta-C incorporation by explants from three animals was examined with different beta-C concentrations (0, 1, 5 and 20 microm) and different times of incubation (every 5 h up to 25 h). The data showed a significant increase of beta-C concentration in explants only for 20 microm beta-C. Secondly, effects of insulin and epinephrine on beta-C and triglyceride (TG) contents of explants were studied. Explants from six animals were incubated with either hormone and 0 or 20 microm beta-C for 20 h. Both TG and beta-C contents were affected positively by insulin and negatively by epinephrine. Interestingly, changes in ratios of beta-C/TG (hormone vs. control) were similar (1.7 x 10(-3) and 1.8 x 10(-3)), respectively, for insulin and epinephrine, indicating that beta-C level is directly related to TG content. We also report the presence of mRNA for beta-C 15, 15' oxygenase in bovine AT. The in vitro culture system using explants from bovine AT is a promising model to investigate factors that might affect the accumulation and metabolism of beta-C.

  15. Adipose proteome analysis: focus on mediators of insulin resistance

    PubMed Central

    Chen, Xiaoli; Hess, Sonja

    2009-01-01

    As is well known, adipose tissue is an important site for lipid metabolism and insulin-responsive glucose uptake. The recent discovery of the endocrine function of adipose tissue and the association of obesity with chronic low-grade inflammation in adipose tissue has reinforced the concept of the central role of adipose tissue in mediating obesity-linked insulin resistance and metabolic dysregulation. The study of adipose cells has provided new insights into the mechanism underlying insulin resistance as well as the therapeutic strategies for diabetes. Numerous efforts have been made in identifying key molecular regulators of insulin action and metabolism, including the utilization of advanced proteomics technology. Various proteomic approaches have been applied to identify the adipose secretome, protein-expression profiling and post-translational modifications in adipose cells in the pathological state. In this review, we summarize the recent advances in the proteomics of adipose tissue, and discuss the identified proteins that potentially play important roles in insulin resistance and diabetes. PMID:19086862

  16. Ageing, adipose tissue, fatty acids and inflammation.

    PubMed

    Pararasa, Chathyan; Bailey, Clifford J; Griffiths, Helen R

    2015-04-01

    A common feature of ageing is the alteration in tissue distribution and composition, with a shift in fat away from lower body and subcutaneous depots to visceral and ectopic sites. Redistribution of adipose tissue towards an ectopic site can have dramatic effects on metabolic function. In skeletal muscle, increased ectopic adiposity is linked to insulin resistance through lipid mediators such as ceramide or DAG, inhibiting the insulin receptor signalling pathway. Additionally, the risk of developing cardiovascular disease is increased with elevated visceral adipose distribution. In ageing, adipose tissue becomes dysfunctional, with the pathway of differentiation of preadipocytes to mature adipocytes becoming impaired; this results in dysfunctional adipocytes less able to store fat and subsequent fat redistribution to ectopic sites. Low grade systemic inflammation is commonly observed in ageing, and may drive the adipose tissue dysfunction, as proinflammatory cytokines are capable of inhibiting adipocyte differentiation. Beyond increased ectopic adiposity, the effect of impaired adipose tissue function is an elevation in systemic free fatty acids (FFA), a common feature of many metabolic disorders. Saturated fatty acids can be regarded as the most detrimental of FFA, being capable of inducing insulin resistance and inflammation through lipid mediators such as ceramide, which can increase risk of developing atherosclerosis. Elevated FFA, in particular saturated fatty acids, maybe a driving factor for both the increased insulin resistance, cardiovascular disease risk and inflammation in older adults.

  17. Biochemistry of adipose tissue: an endocrine organ.

    PubMed

    Coelho, Marisa; Oliveira, Teresa; Fernandes, Ruben

    2013-04-20

    Adipose tissue is no longer considered to be an inert tissue that stores fat. This tissue is capable of expanding to accommodate increased lipids through hypertrophy of existing adipocytes and by initiating differentiation of pre-adipocytes. Adipose tissue metabolism exerts an impact on whole-body metabolism. As an endocrine organ, adipose tissue is responsible for the synthesis and secretion of several hormones. These are active in a range of processes, such as control of nutritional intake (leptin, angiotensin), control of sensitivity to insulin and inflammatory process mediators (tumor necrosis factor α (TNF-α), interleukin-6 (IL-6), resistin, visfatin, adiponectin, among others) and pathways (plasminogen activator inhibitor 1 (PAI-1) and acylation stimulating protein (ASP) for example). This paper reviews some of the biochemical and metabolic aspects of adipose tissue and its relationship to inflammatory disease and insulin resistance.

  18. Biochemistry of adipose tissue: an endocrine organ

    PubMed Central

    Coelho, Marisa; Oliveira, Teresa

    2013-01-01

    Adipose tissue is no longer considered to be an inert tissue that stores fat. This tissue is capable of expanding to accommodate increased lipids through hypertrophy of existing adipocytes and by initiating differentiation of pre-adipocytes. Adipose tissue metabolism exerts an impact on whole-body metabolism. As an endocrine organ, adipose tissue is responsible for the synthesis and secretion of several hormones. These are active in a range of processes, such as control of nutritional intake (leptin, angiotensin), control of sensitivity to insulin and inflammatory process mediators (tumor necrosis factor α (TNF-α), interleukin-6 (IL-6), resistin, visfatin, adiponectin, among others) and pathways (plasminogen activator inhibitor 1 (PAI-1) and acylation stimulating protein (ASP) for example). This paper reviews some of the biochemical and metabolic aspects of adipose tissue and its relationship to inflammatory disease and insulin resistance. PMID:23671428

  19. Overexpressing the novel autocrine/endocrine adipokine WISP2 induces hyperplasia of the heart, white and brown adipose tissues and prevents insulin resistance

    PubMed Central

    Grünberg, John R.; Hoffmann, Jenny M.; Hedjazifar, Shahram; Nerstedt, Annika; Jenndahl, Lachmi; Elvin, Johannes; Castellot, John; Wei, Lan; Movérare-Skrtic, Sofia; Ohlsson, Claes; Holm, Louise Mannerås; Bäckhed, Fredrik; Syed, Ismail; Bosch, Fatima; Saghatelian, Alan; Kahn, Barbara B.; Hammarstedt, Ann; Smith, Ulf

    2017-01-01

    WISP2 is a novel adipokine, most highly expressed in the adipose tissue and primarily in undifferentiated mesenchymal cells. As a secreted protein, it is an autocrine/paracrine activator of canonical WNT signaling and, as an intracellular protein, it helps to maintain precursor cells undifferentiated. To examine effects of increased WISP2 in vivo, we generated an aP2-WISP2 transgenic (Tg) mouse. These mice had increased serum levels of WISP2, increased lean body mass and whole body energy expenditure, hyperplastic brown/white adipose tissues and larger hyperplastic hearts. Obese Tg mice remained insulin sensitive, had increased glucose uptake by adipose cells and skeletal muscle in vivo and ex vivo, increased GLUT4, increased ChREBP and markers of adipose tissue lipogenesis. Serum levels of the novel fatty acid esters of hydroxy fatty acids (FAHFAs) were increased and transplantation of Tg adipose tissue improved glucose tolerance in recipient mice supporting a role of secreted FAHFAs. The growth-promoting effect of WISP2 was shown by increased BrdU incorporation in vivo and Tg serum increased mesenchymal precursor cell proliferation in vitro. In contrast to conventional canonical WNT ligands, WISP2 expression was inhibited by BMP4 thereby allowing normal induction of adipogenesis. WISP2 is a novel secreted regulator of mesenchymal tissue cellularity. PMID:28240264

  20. Overexpressing the novel autocrine/endocrine adipokine WISP2 induces hyperplasia of the heart, white and brown adipose tissues and prevents insulin resistance.

    PubMed

    Grünberg, John R; Hoffmann, Jenny M; Hedjazifar, Shahram; Nerstedt, Annika; Jenndahl, Lachmi; Elvin, Johannes; Castellot, John; Wei, Lan; Movérare-Skrtic, Sofia; Ohlsson, Claes; Holm, Louise Mannerås; Bäckhed, Fredrik; Syed, Ismail; Bosch, Fatima; Saghatelian, Alan; Kahn, Barbara B; Hammarstedt, Ann; Smith, Ulf

    2017-02-27

    WISP2 is a novel adipokine, most highly expressed in the adipose tissue and primarily in undifferentiated mesenchymal cells. As a secreted protein, it is an autocrine/paracrine activator of canonical WNT signaling and, as an intracellular protein, it helps to maintain precursor cells undifferentiated. To examine effects of increased WISP2 in vivo, we generated an aP2-WISP2 transgenic (Tg) mouse. These mice had increased serum levels of WISP2, increased lean body mass and whole body energy expenditure, hyperplastic brown/white adipose tissues and larger hyperplastic hearts. Obese Tg mice remained insulin sensitive, had increased glucose uptake by adipose cells and skeletal muscle in vivo and ex vivo, increased GLUT4, increased ChREBP and markers of adipose tissue lipogenesis. Serum levels of the novel fatty acid esters of hydroxy fatty acids (FAHFAs) were increased and transplantation of Tg adipose tissue improved glucose tolerance in recipient mice supporting a role of secreted FAHFAs. The growth-promoting effect of WISP2 was shown by increased BrdU incorporation in vivo and Tg serum increased mesenchymal precursor cell proliferation in vitro. In contrast to conventional canonical WNT ligands, WISP2 expression was inhibited by BMP4 thereby allowing normal induction of adipogenesis. WISP2 is a novel secreted regulator of mesenchymal tissue cellularity.

  1. Construction of engineering adipose-like tissue in vivo utilizing human insulin gene-modified umbilical cord mesenchymal stromal cells with silk fibroin 3D scaffolds.

    PubMed

    Li, Shi-Long; Liu, Yi; Hui, Ling

    2015-12-01

    We evaluated the use of a combination of human insulin gene-modified umbilical cord mesenchymal stromal cells (hUMSCs) with silk fibroin 3D scaffolds for adipose tissue engineering. In this study hUMSCs were isolated and cultured. HUMSCs infected with Ade-insulin-EGFP were seeded in fibroin 3D scaffolds with uniform 50-60 µm pore size. Silk fibroin scaffolds with untransfected hUMSCs were used as control. They were cultured for 4 days in adipogenic medium and transplanted under the dorsal skins of female Wistar rats after the hUMSCs had been labelled with chloromethylbenzamido-1,1'-dioctadecyl-3,3,3',3'-tetramethylindocarbocyanine perchlorate (CM-Dil). Macroscopical impression, fluorescence observation, histology and SEM were used for assessment after transplantation at 8 and 12 weeks. Macroscopically, newly formed adipose tissue was observed in the experimental group and control group after 8 and 12 weeks. Fluorescence observation supported that the formed adipose tissue originated from seeded hUMSCs rather than from possible infiltrating perivascular tissue. Oil red O staining of newly formed tissue showed that there was substantially more tissue regeneration in the experimental group than in the control group. SEM showed that experimental group cells had more fat-like cells, whose volume was larger than that of the control group, and degradation of the silk fibroin scaffold was greater under SEM observation. This study provides significant evidence that hUMSCs transfected by adenovirus vector have good compatibility with silk fibroin scaffold, and adenoviral transfection of the human insulin gene can be used for the construction of tissue-engineered adipose.

  2. Mitochondria and endocrine function of adipose tissue.

    PubMed

    Medina-Gómez, Gema

    2012-12-01

    Excess of adipose tissue is accompanied by an increase in the risk of developing insulin resistance, type 2 diabetes (T2D) and other complications. Nevertheless, total or partial absence of fat or its accumulation in other tissues (lipotoxicity) is also associated to these complications. White adipose tissue (WAT) was traditionally considered a metabolically active storage tissue for lipids while brown adipose tissue (BAT) was considered as a thermogenic adipose tissue with higher oxidative capacity. Nowadays, WAT is also considered an endocrine organ that contributes to energy homeostasis. Experimental evidence tends to link the malfunction of adipose mitochondria with the development of obesity and T2D. This review discusses the importance of mitochondrial function in adipocyte biology and the increased evidences of mitochondria dysfunction in these epidemics. New strategies targeting adipocyte mitochondria from WAT and BAT are also discussed as therapies against obesity and its complications in the near future.

  3. ALOX5AP Overexpression in Adipose Tissue Leads to LXA4 Production and Protection Against Diet-Induced Obesity and Insulin Resistance.

    PubMed

    Elias, Ivet; Ferré, Tura; Vilà, Laia; Muñoz, Sergio; Casellas, Alba; Garcia, Miquel; Molas, Maria; Agudo, Judith; Roca, Carles; Ruberte, Jesús; Bosch, Fatima; Franckhauser, Sylvie

    2016-08-01

    Eicosanoids, such as leukotriene B4 (LTB4) and lipoxin A4 (LXA4), may play a key role during obesity. While LTB4 is involved in adipose tissue inflammation and insulin resistance, LXA4 may exert anti-inflammatory effects and alleviate hepatic steatosis. Both lipid mediators derive from the same pathway, in which arachidonate 5-lipoxygenase (ALOX5) and its partner, arachidonate 5-lipoxygenase-activating protein (ALOX5AP), are involved. ALOX5 and ALOX5AP expression is increased in humans and rodents with obesity and insulin resistance. We found that transgenic mice overexpressing ALOX5AP in adipose tissue had higher LXA4 rather than higher LTB4 levels, were leaner, and showed increased energy expenditure, partly due to browning of white adipose tissue (WAT). Upregulation of hepatic LXR and Cyp7a1 led to higher bile acid synthesis, which may have contributed to increased thermogenesis. In addition, transgenic mice were protected against diet-induced obesity, insulin resistance, and inflammation. Finally, treatment of C57BL/6J mice with LXA4, which showed browning of WAT, strongly suggests that LXA4 is responsible for the transgenic mice phenotype. Thus, our data support that LXA4 may hold great potential for the future development of therapeutic strategies for obesity and related diseases.

  4. 5'AMP-activated protein kinase activity is increased in adipose tissue of northern elephant seal pups during prolonged fasting-induced insulin resistance.

    PubMed

    Viscarra, Jose A; Champagne, Cory D; Crocker, Daniel E; Ortiz, Rudy M

    2011-06-01

    Northern elephant seals endure a 2- to 3-month fast characterized by sustained hyperglycemia, hypoinsulinemia, and increased plasma cortisol and free fatty acids, conditions often seen in insulin-resistant humans. We had previously shown that adipose Glut4 expression and 5'AMP-activated protein kinase (AMPK) activity increase and plasma glucose decreases in fasting seals suggesting that AMPK activity contributes to glucose regulation during insulin-resistant conditions. To address the hypothesis that AMPK activity increases during fasting-induced insulin resistance, we performed glucose tolerance tests (GTT) on early (n=5) and late (n=8)-fasted seal pups and compared adipose tissue expression of insulin signaling proteins, peroxisome proliferator-activated receptor γ (PPARγ), and AMPK, in addition to plasma adiponectin, leptin, cortisol, insulin, and non-esterified fatty acid (NEFA) levels. Fasting was associated with decreased glucose clearance, plasma insulin and adiponectin, and intracellular insulin signaling, as well as increased plasma cortisol and NEFAs, supporting the suggestion that seals develop insulin resistance late in the fast. The expression of Glut4 and VAMP2 increased (52 and 63% respectively) with fasting but did not change significantly during the GTT. PPARγ and phosphorylated AMPK did not change in the early fasted seals, but increased significantly (73 and 50% respectively) in the late-fasted seals during the GTT. Increased AMPK activity along with the reduction in the activity of insulin-signaling proteins supports our hypothesis that AMPK activity is increased following the onset of insulin resistance. The association between increased AMPK activity and Glut4 expression suggests that AMPK plays a greater role in regulating glucose metabolism in mammals adapted to prolonged fasting than in non-fasting mammals.

  5. Site-specific differences of insulin action in adipose tissue derived from normal prepubertal children

    SciTech Connect

    Grohmann, Malcolm; Stewart, Claire; Welsh, Gavin; Hunt, Linda; Tavare, Jeremy; Holly, Jeff; Shield, Julian; Sabin, Matt; Crowne, Elizabeth . E-mail: Liz.Crowne@ubht.swest.nhs.uk

    2005-08-15

    Body fat distribution determines obesity-related morbidity in adults but little is known of the aetiology or pathophysiology in children. This study investigates differences in insulin-mediated metabolism in primary cell cultures of subcutaneous and visceral preadipocytes derived from prepubertal children. The impact of differentiation and responses to TNF{alpha} exposure was also investigated. Proliferation rates were greater in subcutaneous versus visceral preadipocytes (41 h(3) versus 69 h(4); P = 0.008). Insulin caused a dose-dependent increase in GSK-3 phosphorylation and an increase in MAPK phosphorylation over time, with increased sensitivity in subcutaneous preadipocytes. Post-differentiation, dose-dependent increases in GSK-3 phosphorylation were maintained, while MAPK phosphorylation was identical in both subtypes. No changes were observed in insulin receptor abundance pre-/post-differentiation. GLUT4 abundance was significantly increased in visceral versus subcutaneous adipocytes by 76(4)%; P = 0.03), coincidental with increased insulin-stimulated 2-deoxy-glucose transport (+150(26)% versus +79(10)%; P = 0.014) and further elevated by acute exposure to TNF{alpha} (+230(52)%; P = 0.019 versus +123(24)%; P = 0.025, respectively). TNF{alpha} also significantly increased basal glucose transport rates (+44(14)%; P = 0.006 versus +34(11)%; P = 0.007) and GLUT1 localisation to the plasma membrane. These data establish site-specific differences in subcutaneous and visceral fat cells from children. Responses to insulin varied with differentiation and TNF{alpha} exposure in the two depots, consistent with parallel changes in GLUT1/4 abundance and localisation.

  6. Site-specific differences of insulin action in adipose tissue derived from normal prepubertal children.

    PubMed

    Grohmann, Malcolm; Stewart, Claire; Welsh, Gavin; Hunt, Linda; Tavaré, Jeremy; Holly, Jeff; Shield, Julian; Sabin, Matt; Crowne, Elizabeth

    2005-08-15

    Body fat distribution determines obesity-related morbidity in adults but little is known of the aetiology or pathophysiology in children. This study investigates differences in insulin-mediated metabolism in primary cell cultures of subcutaneous and visceral preadipocytes derived from prepubertal children. The impact of differentiation and responses to TNFalpha exposure was also investigated. Proliferation rates were greater in subcutaneous versus visceral preadipocytes (41 h3 versus 69 h4; P=0.008). Insulin caused a dose-dependent increase in GSK-3 phosphorylation and an increase in MAPK phosphorylation over time, with increased sensitivity in subcutaneous preadipocytes. Post-differentiation, dose-dependent increases in GSK-3 phosphorylation were maintained, while MAPK phosphorylation was identical in both subtypes. No changes were observed in insulin receptor abundance pre-/post-differentiation. GLUT4 abundance was significantly increased in visceral versus subcutaneous adipocytes by 76(4)%; P=0.03), coincidental with increased insulin-stimulated 2-deoxy-glucose transport (+150(26)% versus +79(10)%; P=0.014) and further elevated by acute exposure to TNFalpha (+230(52)%; P=0.019 versus +123(24)%; P=0.025, respectively). TNFalpha also significantly increased basal glucose transport rates (+44(14)%; P=0.006 versus +34(11)%; P=0.007) and GLUT1 localisation to the plasma membrane. These data establish site-specific differences in subcutaneous and visceral fat cells from children. Responses to insulin varied with differentiation and TNFalpha exposure in the two depots, consistent with parallel changes in GLUT1/4 abundance and localisation.

  7. Knockout of Vasohibin-1 Gene in Mice Results in Healthy Longevity with Reduced Expression of Insulin Receptor, Insulin Receptor Substrate 1, and Insulin Receptor Substrate 2 in Their White Adipose Tissue

    PubMed Central

    Takeda, Eichi; Suzuki, Yasuhiro; Yamada, Tetsuya; Katagiri, Hideki

    2017-01-01

    Vasohibin-1 (Vash1), originally isolated as an endothelium-derived angiogenesis inhibitor, has a characteristic of promoting stress tolerance in endothelial cells (ECs). We therefore speculated that the lack of the vash1 gene would result in a short lifespan. However, to our surprise, vash1−/− mice lived significantly longer with a milder senescence phenotype than wild-type (WT) mice. We sought the cause of this healthy longevity and found that vash1−/− mice exhibited mild insulin resistance along with reduced expression of the insulin receptor (insr), insulin receptor substrate 1 (irs-1), and insulin receptor substrate 2 (irs-2) in their white adipose tissue (WAT) but not in their liver or skeletal muscle. The expression of vash1 dominated in the WAT among those 3 organs. Importantly, vash1−/− mice did not develop diabetes even when fed a high-fat diet. These results indicate that the expression of vash1 was required for the normal insulin sensitivity of the WAT and that the target molecules for this activity were insr, irs1, and irs2. The lack of vash1 caused mild insulin resistance without the outbreak of overt diabetes and might contribute to healthy longevity. PMID:28367331

  8. Adipogenic miR-27a in adipose tissue upregulates macrophage activation via inhibiting PPARγ of insulin resistance induced by high-fat diet-associated obesity.

    PubMed

    Yao, Fan; Yu, Yang; Feng, Linjing; Li, Junnan; Zhang, Meishuang; Lan, Xiaoxin; Yan, Xin; Liu, Yilun; Guan, Fengying; Zhang, Ming; Chen, Li

    2017-03-30

    Chronic low degree inflammation caused by macrophage activation is a crucial factor underlying insulin resistance induced by obesity. To illustrate the mechanism of regulating of macrophage activation in adipose tissue, the role of adipogenic miR-27a activating M1 macrophage polarization via blocking PPARγ was evaluated. Obese mice model and miR-27a overexpression or knockdown mice model were established and related biochemical index were examined. Raw264.7 and 3T3-L1 were cultured and co-cultured for mimicking the microenvironment of local inflammation. Macrophage infiltration was observed. MiR-27a and cytokines levels in serum and adipose tissue were measured. Macrophage polarization markers and protein expression in insulin or inflammatory signaling pathways were observed. Impaired glucose tolerance and insulin tolerance was observed in 4w, 8w and 12w of high fat diet and miR-27a overexpression mice. Concurrently, miR-27a was increased in serum in a time-dependent manner, along with M1 cytokines and M1 macrophages increasing in adipose tissue clearly. Insulin signaling pathway was blocked, and PPARγ was suppressed. However, NF-κB was activated. On the other hand, activated macrophages and hypertrophic adipocytes induced by miR-27a could increase the ratio of Raw264.7 migration, including improving cytokines generation, and blocking PPARγ expression markedly. The present studies are conducted to clarify that miR-27a has increased along with up-regulation in the process of proinflammatory cytokines generation, macrophage influx and M1 macrophage polarization in obesity. These indicate that miR-27a gives the novel target of intervention for inflammation and insulin resistance in obesity.

  9. Chitosan-assisted differentiation of porcine adipose tissue-derived stem cells into glucose-responsive insulin-secreting clusters

    PubMed Central

    Lin, Yuan-Yu; Chen, Yu-Jen; Liu, Bing-Hsien; Wong, Shiu-Chung; Wu, Cheng-Yu; Chang, Yun-Tsui; Chou, Han-Yi E.

    2017-01-01

    The unique advantage of easy access and abundance make the adipose-derived stem cells (ADSCs) a promising system of multipotent cells for transplantation and regenerative medicine. Among the available sources, porcine ADSCs (pADSCs) deserve especial attention due to the close resemblance of human and porcine physiology, as well as for the upcoming availability of humanized porcine models. Here, we report on the isolation and conversion of pADSCs into glucose-responsive insulin-secreting cells. We used the stromal-vascular fraction of the dorsal subcutaneous adipose from 9-day-old male piglets to isolate pADSCs, and subjected the cells to an induction scheme for differentiation on chitosan-coated plates. This one-step procedure promoted differentiation of pADSCs into pancreatic islet-like clusters (PILC) that are characterized by the expression of a repertoire of pancreatic proteins, including pancreatic and duodenal homeobox (Pdx-1), insulin gene enhancer protein (ISL-1) and insulin. Upon glucose challenge, these PILC secreted high amounts of insulin in a dose-dependent manner. Our data also suggest that chitosan plays roles not only to enhance the differentiation potential of pADSCs, but also to increase the glucose responsiveness of PILCs. Our novel approach is, therefore, of great potential for transplantation-based amelioration of type 1 diabetes. PMID:28253305

  10. Moderate doses of conjugated linoleic acid isomers mix contribute to lowering body fat content maintaining insulin sensitivity and a noninflammatory pattern in adipose tissue in mice.

    PubMed

    Parra, Pilar; Serra, Francisca; Palou, Andreu

    2010-02-01

    Conjugated linoleic acid (CLA) modulates body composition, especially by reducing adipose tissue. However, despite the increasing knowledge about CLA's beneficial effects on obesity management, the mechanism of action is not yet fully understood. Furthermore, in some human studies fat loss is accompanied by impairment in insulin sensitivity, especially when using the trans-10,cis-12 isomer. The aim of this work was to study the effects of moderate doses of CLA on body fat deposition, cytokine profile and inflammatory markers in mice. Mice were orally treated with a mixture of CLA isomers, cis-9,trans-11 and trans-10,cis-12 (50:50), for 35 days with doses of CLA1 (0.15 g CLA/kg body weight) and CLA2 (0.5 g CLA/kg body weight). CLA had discrete effects on body weight but caused a clear reduction in fat mass (retroperitoneal and mesenteric as the most sensitive depots), although no other tissue weights were affected. Glucose and insulin were not altered by CLA treatment, and maintenance of glucose homeostasis was observed even under insulin overload. The study of gene expression (Emr1, MCP-1, IL-6, TNFalpha, PPARgamma2 and iNOS) either in adipocytes and/or in the stromal vascular fraction indicated that CLA does not lead to the infiltration of macrophages in adipose tissue or to the induction of expression of pro-inflammatory cytokines. The use of a mixture of both isomers, as well as moderate doses of CLA, is able to induce a reduction of fat gain without an impairment of adipose tissue function while preserving insulin sensitivity.

  11. Osteochondral tissue formation through adipose-derived stromal cell differentiation on biomimetic polycaprolactone nanofibrous scaffolds with graded insulin and Beta-glycerophosphate concentrations.

    PubMed

    Erisken, Cevat; Kalyon, Dilhan M; Wang, Hongjun; Ornek-Ballanco, Ceren; Xu, Jiahua

    2011-05-01

    The ability to fabricate tissue engineering scaffolds containing systematic gradients in the distributions of stimulators provides additional means for the mimicking of the important gradients observed in native tissues. Here the concentration distributions of two bioactive agents were varied concomitantly for the first time (one increasing, whereas the other decreasing monotonically) in between the two sides of a nanofibrous scaffold. This was achieved via the application of a new processing method, that is, the twin-screw extrusion and electrospinning method, to generate gradients of insulin, a stimulator of chondrogenic differentiation, and β-glycerophosphate (β-GP), for mineralization. The graded poly(ɛ-caprolactone) mesh was seeded with human adipose-derived stromal cells and cultured over 8 weeks. The resulting tissue constructs were analyzed for and revealed indications of selective differentiation of human adipose-derived stromal cells toward chondrogenic lineage and mineralization as functions of position as a result of the corresponding concentrations of insulin and β-GP. Chondrogenic differentiation of the stem cells increased at insulin-rich locations and mineralization increased at β-GP-rich locations.

  12. Obesity increases the production of proinflammatory mediators from adipose tissue T cells and compromises TCR repertoire diversity: implications for systemic inflammation and insulin resistance.

    PubMed

    Yang, Hyunwon; Youm, Yun-Hee; Vandanmagsar, Bolormaa; Ravussin, Anthony; Gimble, Jeffrey M; Greenway, Frank; Stephens, Jacqueline M; Mynatt, Randall L; Dixit, Vishwa Deep

    2010-08-01

    Emerging evidence suggests that increases in activated T cell populations in adipose tissue may contribute toward obesity-associated metabolic syndrome. The present study investigates three unanswered questions: 1) Do adipose-resident T cells (ARTs) from lean and obese mice have altered cytokine production in response to TCR ligation?; 2) Do the extralymphoid ARTs possess a unique TCR repertoire compared with lymphoid-resident T cells and whether obesity alters the TCR diversity in specific adipose depots?; and 3) Does short-term elimination of T cells in epididymal fat pad without disturbing the systemic T cell homeostasis regulate inflammation and insulin-action during obesity? We found that obesity reduced the frequency of naive ART cells in s.c. fat and increased the effector-memory populations in visceral fat. The ARTs from diet-induced obese (DIO) mice had a higher frequency of IFN-gamma(+), granzyme B(+) cells, and upon TCR ligation, the ARTs from DIO mice produced increased levels of proinflammatory mediators. Importantly, compared with splenic T cells, ARTs exhibited markedly restricted TCR diversity, which was further compromised by obesity. Acute depletion of T cells from epididymal fat pads improved insulin action in young DIO mice but did not reverse obesity-associated feed forward cascade of chronic systemic inflammation and insulin resistance in middle-aged DIO mice. Collectively, these data establish that ARTs have a restricted TCR-Vbeta repertoire, and T cells contribute toward the complex proinflammatory microenvironment of adipose tissue in obesity. Development of future long-term T cell depletion protocols specific to visceral fat may represent an additional strategy to manage obesity-associated comorbidities.

  13. Obesity Increases the Production of Proinflammatory Mediators from Adipose Tissue T Cells and Compromises TCR Repertoire Diversity: Implications for Systemic Inflammation and Insulin Resistance

    PubMed Central

    Yang, Hyunwon; Youm, Yun-Hee; Vandanmagsar, Bolormaa; Ravussin, Anthony; Gimble, Jeffrey M.; Greenway, Frank; Stephens, Jacqueline M.; Mynatt, Randall L.; Dixit, Vishwa Deep

    2016-01-01

    Emerging evidence suggests that increases in activated T cell populations in adipose tissue may contribute toward obesity-associated metabolic syndrome. The present study investigates three unanswered questions: 1) Do adipose-resident T cells (ARTs) from lean and obese mice have altered cytokine production in response to TCR ligation?; 2) Do the extralymphoid ARTs possess a unique TCR repertoire compared with lymphoid-resident T cells and whether obesity alters the TCR diversity in specific adipose depots?; and 3) Does short-term elimination of T cells in epididymal fat pad without disturbing the systemic T cell homeostasis regulate inflammation and insulin-action during obesity? We found that obesity reduced the frequency of naive ART cells in s.c. fat and increased the effector-memory populations in visceral fat. The ARTs from diet-induced obese (DIO) mice had a higher frequency of IFN-γ+, granzyme B+ cells, and upon TCR ligation, the ARTs from DIO mice produced increased levels of proinflammatory mediators. Importantly, compared with splenic T cells, ARTs exhibited markedly restricted TCR diversity, which was further compromised by obesity. Acute depletion of T cells from epididymal fat pads improved insulin action in young DIO mice but did not reverse obesity-associated feed forward cascade of chronic systemic inflammation and insulin resistance in middle-aged DIO mice. Collectively, these data establish that ARTs have a restricted TCR-Vβ repertoire, and T cells contribute toward the complex proinflammatory microenvironment of adipose tissue in obesity. Development of future long-term T cell depletion protocols specific to visceral fat may represent an additional strategy to manage obesity-associated comorbidities. PMID:20581149

  14. Effect of high fat and high carbohydrate diets on adipose tissue pyruvate dehydrogenase and its activation by a plasma membrane-enriched fraction and insulin.

    PubMed

    Begum, N; Tepperman, H M; Tepperman, J

    1982-06-01

    Rats were fed a high lard diet or a high glucose diet for 5--7 days. Basal and insulin-stimulated epididymal fat pad pyruvate dehydrogenase (PDH) activities were decreased in fat diet-adapted rats compared to those fed the glucose diet. When adipocyte plasma membranes and mitochondria were incubated together with and without insulin, it was found that the insulin stimulation of PDH activity was lower in preparations from fat-fed rats on both an absolute and percentage basis. Supernatant fractions from insulin-stimulated glucose-fed rat plasma membranes activated mitochondrial PDH to a greater extent than those from lard-fed rat preparations. There was no difference in the response of mitochondria from the two groups when they were stimulated by insulin-treated plasma membranes from stock diet-fed rat adipose tissue. These experiments suggest that fat feeding results in adaptive changes in adipocyte plasma membranes which are involved in the generation of the insulin-stimulated chemical activator of PDH. This adaptive change is in addition to those described earlier.

  15. Flow Cytometry Analyses of Adipose Tissue Macrophages

    PubMed Central

    Cho, Kae Won; Morris, David L.; Lumeng, Carey N.

    2014-01-01

    Within adipose tissue, multiple leukocyte interactions contribute to metabolic homeostasis in health as well as to the pathogenesis of insulin resistance with obesity. Adipose tissue macrophages (ATMs) are the predominant leukocyte population in fat and contribute to obesity-induced inflammation. Characterization of ATMs and other leukocytes in the stromal vascular fraction from fat has benefited from the use of flow cytometry and flow-assisted cell sorting techniques. These methods permit the immunophenotyping, quantification, and purification of these unique cell populations from multiple adipose tissue depots in rodents and humans. Proper isolation, quantification, and characterization of ATM phenotypes are critical for understanding their role in adipose tissue function and obesity-induced metabolic diseases. Here, we present the flow cytometry protocols for phenotyping ATMs in lean and obese mice employed by our laboratory. PMID:24480353

  16. Berberine-improved visceral white adipose tissue insulin resistance associated with altered sterol regulatory element-binding proteins, liver x receptors, and peroxisome proliferator-activated receptors transcriptional programs in diabetic hamsters.

    PubMed

    Li, Guo-Sheng; Liu, Xu-Han; Zhu, Hua; Huang, Lan; Liu, Ya-Li; Ma, Chun-Mei; Qin, Chuan

    2011-01-01

    The diabetic "lipotoxicity" hypothesis presents that fat-induced visceral white adipose tissue insulin resistance plays a central role in the pathogenesis of type 2 diabetes. Berberine, a hypolipidemic agent, has been reported to have antidiabetic activities. The molecular mechanisms for this property are, however, not well clarified. Therefore in this study type 2 diabetic hamsters were induced by high-fat diet with low-dose streptozotocin. Then, we investigated the gene expression alterations and explored the molecular mechanisms underlying the therapeutic effect of berberine on fat-induced visceral white adipose tissue insulin resistance in diabetic hamsters by microarray analysis followed by real-time reverse transcription-polymerase chain reaction (RT-PCR) confirmation. Type 2 diabetic hamsters exhibited hyperglycemia and relative hyperinsulinemia, glucose intolerance, insulin resistance, intra-adipocyte lipid accumulation, significant increase in body weight and visceral white adipose tissue weight, abnormal serum adipokines levels, and deleterious dyslipidemia. Furthermore, they had increased sterol regulatory element-binding proteins (SREBPs) expression and decreased liver X receptors (LXRs) and peroxisome proliferator-activated receptors (PPARs) expression in visceral white adipose tissue. After 9-week berberine treatment, fat-induced insulin resistance and diabetic phenotype in type 2 diabetic hamsters were significantly improved. Compared with diabetic hamsters, expression of LXRs and PPARs significantly increased and SREBPs significantly decreased in visceral white adipose tissue from berberine-treated diabetic hamsters. These results suggest that altered visceral white adipose tissue LXRs, PPARs, and SREBPs transcriptional programs are involved in the therapeutic mechanisms of berberine on fat-induced visceral white adipose tissue insulin resistance in type 2 diabetic hamsters.

  17. Plerocercoid growth factor (PGF), a human growth hormone (hGH) analogue produced by the tapeworm Spirometra mansonoides, has direct insulin-like action in adipose tissue of normal rats in vitro

    SciTech Connect

    Salem, M.A.M.; Phares, C.K.

    1986-03-01

    The metabolic actions of GH can be divided into acute (insulin-like) and chronic (lipolytic/anti-insulin). The insulin-like actions of GH are most readily elicited in GH-deficient animals as GH induces resistance to its own insulin-like action. Like GH, PGF stimulates growth and cross-reacts with anti-hGH antibodies. Independent experiments were conducted comparing the direct actions of PGF to insulin or hGH in vitro. Insulin-like effects were determined by the ability of PGF, insulin or hGH to stimulate (U-/sup 14/C)glucose metabolism in epidydimal fat pads from normal rats and by inhibition of epinephrine-stimulated lipolysis. Direct stimulation of lipolysis was used as anti-insulin activity. To determine if PGF competes for insulin or GH receptors, adipocytes (3 x 10/sup 5/ cells/ml) were incubated with either (/sup 125/I)insulin or (/sup 125/I)hGH +/- PGF, +/- insulin or +/- hGH. PGF stimulated glucose oxidation and /sup 14/C-incorporation into lipids. Insulin, hGH and PGF inhibited lipolysis (33%, 29% and 34%, respectively). Adipose tissue was very sensitive to the lipolytic effect of hGH but PGF was neither lipolytic nor did it confer refractoriness to its insulin-like action. PGF bound to GH but not to insulin receptors. Therefore, PGF had direct insulin-like effects but did not stimulate lipolysis in tissue from normal rats in vitro.

  18. Associations of Vitamin D with Inter- and Intra-Muscular Adipose Tissue and Insulin Resistance in Women with and without Polycystic Ovary Syndrome.

    PubMed

    Scott, David; Joham, Anju; Teede, Helena; Gibson-Helm, Melanie; Harrison, Cheryce; Cassar, Samantha; Hutchison, Samantha; Ebeling, Peter R; Stepto, Nigel; de Courten, Barbora

    2016-11-30

    Low vitamin D and insulin resistance are common in polycystic ovary syndrome (PCOS) and associated with higher inter- and intra-muscular adipose tissue (IMAT). We investigated associations between vitamin D, IMAT and insulin resistance in a cross-sectional study of 40 women with PCOS and 30 women without PCOS, and pre- and post-exercise in a 12-week intervention in 16 overweight participants (10 with PCOS and six without PCOS). A non-classical body mass index (BMI) threshold was used to differentiate lean and overweight women (BMI ≥ 27 kg/m²). Measurements included plasma 25-hydroxyvitamin D (25OHD), insulin resistance (glucose infusion rate (GIR; mg/m²/min), fasting glucose and insulin, and glycated haemoglobin), visceral fat, mid-thigh IMAT (computed tomography) and total body fat (dual-energy X-ray absorptiometry). Women with both PCOS and low 25OHD levels had the lowest GIR (all p < 0.05). Higher IMAT was associated with lower 25OHD (B = -3.95; 95% CI -6.86, -1.05) and GIR (B = -21.3; 95% CI -37.16, -5.44) in women with PCOS. Overweight women with pre-exercise 25OHD ≥30 nmol/L had significant increases in GIR, and decreases in total and visceral fat (all p < 0.044), but no associations were observed when stratified by PCOS status. Women with PCOS and low 25OHD levels have increased insulin resistance which may be partly explained by higher IMAT. Higher pre-training 25OHD levels may enhance exercise-induced changes in body composition and insulin resistance in overweight women.

  19. Associations of Vitamin D with Inter- and Intra-Muscular Adipose Tissue and Insulin Resistance in Women with and without Polycystic Ovary Syndrome

    PubMed Central

    Scott, David; Joham, Anju; Teede, Helena; Gibson-Helm, Melanie; Harrison, Cheryce; Cassar, Samantha; Hutchison, Samantha; Ebeling, Peter R.; Stepto, Nigel; de Courten, Barbora

    2016-01-01

    Low vitamin D and insulin resistance are common in polycystic ovary syndrome (PCOS) and associated with higher inter- and intra-muscular adipose tissue (IMAT). We investigated associations between vitamin D, IMAT and insulin resistance in a cross-sectional study of 40 women with PCOS and 30 women without PCOS, and pre- and post-exercise in a 12-week intervention in 16 overweight participants (10 with PCOS and six without PCOS). A non-classical body mass index (BMI) threshold was used to differentiate lean and overweight women (BMI ≥ 27 kg/m2). Measurements included plasma 25-hydroxyvitamin D (25OHD), insulin resistance (glucose infusion rate (GIR; mg/m2/min), fasting glucose and insulin, and glycated haemoglobin), visceral fat, mid-thigh IMAT (computed tomography) and total body fat (dual-energy X-ray absorptiometry). Women with both PCOS and low 25OHD levels had the lowest GIR (all p < 0.05). Higher IMAT was associated with lower 25OHD (B = −3.95; 95% CI −6.86, −1.05) and GIR (B = −21.3; 95% CI −37.16, −5.44) in women with PCOS. Overweight women with pre-exercise 25OHD ≥30 nmol/L had significant increases in GIR, and decreases in total and visceral fat (all p < 0.044), but no associations were observed when stratified by PCOS status. Women with PCOS and low 25OHD levels have increased insulin resistance which may be partly explained by higher IMAT. Higher pre-training 25OHD levels may enhance exercise-induced changes in body composition and insulin resistance in overweight women. PMID:27916865

  20. Metabolic syndrome pathophysiology: the role of adipose tissue

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Several physiopathological explanations for the metabolic syndrome have been proposed involving insulin resistance, chronic inflammation and ectopic fat accumulation following adipose tissue saturation. However, current concepts create several paradoxes, including limited cardiovascular risk reducti...

  1. The development and endocrine functions of adipose tissue.

    PubMed

    Poulos, Sylvia P; Hausman, Dorothy B; Hausman, Gary J

    2010-07-08

    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 immune systems and play major roles in metabolism. Numerous studies have shown nutrient or hormonal manipulations can greatly influence adipose tissue development. In addition, the associations between various disease states, such as insulin resistance and cardiovascular disease, and disregulation of adipose tissue seen in epidemiological and intervention studies are great. Evaluation of known adipokines suggests these factors secreted from adipose tissue play roles in several pathologies. As the identification of more adipokines and determination of their role in biological systems, and the interactions between adipocytes and other cells types continues, there is little doubt that we will gain a greater appreciation for a tissue once thought to simply store excess energy.

  2. Nutritional regulation of lipid metabolism in human adipose tissue.

    PubMed

    Coppack, S W; Patel, J N; Lawrence, V J

    2001-01-01

    Pfeiffer and colleagues years ago pointed out that different distributions and amounts of adipose tissue are associated with abnormalities of lipolysis and lipoprotein metabolism. Adipose tissue has several crucial roles including (i) mobilization from stores of fatty acids as an energy source, (ii) catabolism of lipoproteins such as very-low-density lipoprotein and (iii) synthesis and release of hormonal signals such as leptin and interleukin-6. These adipose tissue actions are crucially regulated by nutrition. The review considers the existence of metabolic pathways and modes of regulation within adipose tissue, and how such metabolic activity can be quantitated in humans. Nutrition can influence adipose tissue at several 'levels'. Firstly the level of obesity or malnutrition has important effects on many aspects of adipose tissue metabolism. Secondly short-term overfeeding, underfeeding and exercise have major impacts on adipose tissue behaviour. Lastly, specific nutrients are capable of regulating adipose tissue metabolism. Recently there have been considerable advances in understanding adipose tissue metabolism and in particular its regulation. This review discusses the behaviour of adipose tissue under various nutritional conditions. There is then a review of recent work examining the ways in which nutritional influences act via intra-cellular mechanisms, insulin and the sympathetic innervation of adipose tissue.

  3. The Relationship Between Brown Adipose Tissue Content in Supraclavicular Fat Depots and Insulin Sensitivity in Patients with Type 2 Diabetes Mellitus and Prediabetes

    PubMed Central

    Ustyuzhanin, Dmitry; Philippov, Yury; Mayorov, Alexander; Shestakova, Marina; Shariya, Merab; Ternovoy, Sergey; Dedov, Ivan

    2017-01-01

    Abstract Background: The evaluation of brown adipose tissue (BAT) and its role in metabolism and obesity remains an important topic in the recent literature. This study evaluated the influence of the BAT triglyceride content measured by proton magnetic resonance (MR) spectroscopy in patients with type 2 diabetes mellitus (DM2) and prediabetes on insulin sensitivity. Methods: A total of 25 patients with DM2 and prediabetes (45.9 ± 10.1 years old, body mass index [BMI] of 31.6 ± 5.4 kg/m2) underwent anthropometric measurements (BMI), insulin sensitivity analysis (M value during euglycemic hyperinsulinemic clamp and homeostasis model assessment of insulin resistance), proton MR spectroscopy, and blood tests (total cholesterol, low-density lipoproteins, high-density lipoproteins, and triglycerides). The relationship between the triglyceride content in the supraclavicular fat depot and insulin sensitivity, anthropometric measurements, and blood test results was assessed. Results: The triglyceride content in the supraclavicular fat depot varied between 79.2% and 97.1% (mean: 92.6% ± 4.2%). The triglyceride content in the subcutaneous white adipose tissue of the neck was significantly higher (85.3%–99.3%; mean: 95.5% ± 2.9%; P = 0.0007). The triglyceride content in the supraclavicular fat depot exhibited a significantly moderate correlation with the BMI (r = 0.64; P = 0.0009). A significant weak negative correlation between the supraclavicular fat content and M value was revealed (r = −0.44; P = 0.002). Patients with high insulin resistance (IR) had a higher triglyceride content in the supraclavicular fat depot than patients with normal and lower IR (94.3% ± 2.0% vs. 90.4% ± 5.2%; P = 0.02). Conclusions: Reducing the BAT content in the supraclavicular fat depot can influence the development of IR in patients with DM2 and prediabetes. PMID:28118051

  4. Leptin selectively decreases visceral adiposity and enhances insulin action.

    PubMed Central

    Barzilai, N; Wang, J; Massilon, D; Vuguin, P; Hawkins, M; Rossetti, L

    1997-01-01

    Intraabdominal adiposity and insulin resistance are risk factors for diabetes mellitus, dyslipidemia, arteriosclerosis, and mortality. Leptin, a fat-derived protein encoded by the ob gene, has been postulated to be a sensor of energy storage in adipose tissue capable of mediating a feedback signal to sites involved in the regulation of energy homeostasis. Here, we provide evidence for specific effects of leptin on fat distribution and in vivo insulin action. Leptin (LEP) or vehicle (CON) was administered by osmotic minipumps for 8 d to pair-fed adult rats. During the 8 d of the study, body weight and total fat mass decreased similarly in LEP and in CON. However, while moderate calorie restriction (CON) resulted in similar decreases in whole body (by 20%) and visceral (by 21%) fat, leptin administration led to a specific and marked decrease (by 62%) in visceral adiposity. During physiologic hyperinsulinemia (insulin clamp), leptin markedly enhanced insulin action on both inhibition of hepatic glucose production and stimulation of glucose uptake. Finally, leptin exerted complex effects on the hepatic gene expression of key metabolic enzymes and on the intrahepatic partitioning of metabolic fluxes, which are likely to represent a defense against excessive storage of energy in adipose depots. These studies demonstrate novel actions of circulating leptin in the regulation of fat distribution, insulin action, and hepatic gene expression and suggest that it may play a role in the pathophysiology of abdominal obesity and insulin resistance. PMID:9399957

  5. Blueberry intake alters skeletal muscle and adipose tissue peroxisome proliferator-activated receptor activity and reduces insulin resistance in obese rats.

    PubMed

    Seymour, E Mitchell; Tanone, Ignasia I; Urcuyo-Llanes, Daniel E; Lewis, Sarah K; Kirakosyan, Ara; Kondoleon, Michael G; Kaufman, Peter B; Bolling, Steven F

    2011-12-01

    Metabolic syndrome can precede the development of type 2 diabetes and cardiovascular disease and includes phenotypes such as obesity, systemic inflammation, insulin resistance, and hyperlipidemia. A recent epidemiological study indicated that blueberry intake reduced cardiovascular mortality in humans, but the possible genetic mechanisms of this effect are unknown. Blueberries are a rich source of anthocyanins, and anthocyanins can alter the activity of peroxisome proliferator-activated receptors (PPARs), which affect energy substrate metabolism. The effect of blueberry intake was assessed in obesity-prone rats. Zucker Fatty and Zucker Lean rats were fed a higher-fat diet (45% of kcal) or a lower-fat diet (10% of kcal) containing 2% (wt/wt) freeze-dried whole highbush blueberry powder or added sugars to match macronutrient and calorie content. In Zucker Fatty rats fed a high-fat diet, the addition of blueberry reduced triglycerides, fasting insulin, homeostasis model index of insulin resistance, and glucose area under the curve. Blueberry intake also reduced abdominal fat mass, increased adipose and skeletal muscle PPAR activity, and affected PPAR transcripts involved in fat oxidation and glucose uptake/oxidation. In Zucker Fatty rats fed a low-fat diet, the addition of blueberry also significantly reduced liver weight, body weight, and total fat mass. Finally, Zucker Lean rats fed blueberry had higher body weight and reduced triglycerides, but all other measures were unaffected. In conclusion, whole blueberry intake reduced phenotypes of metabolic syndrome in obesity-prone rats and affected PPAR gene transcripts in adipose and muscle tissue involved in fat and glucose metabolism.

  6. Dietary fish oil reverse epididymal tissue adiposity, cell hypertrophy and insulin resistance in dyslipemic sucrose fed rat model small star, filled.

    PubMed

    Soria, Ana; Chicco, Adriana; Eugenia D'Alessandro, María; Rossi, Andrea; Lombardo, Yolanda B.

    2002-04-01

    The present work was designed to assess the possible benefits of (7% w/w) dietary fish oil in reversing the morphological and metabolic changes present in the adipose tissue of rats fed an SRD for a long time. With this purpose, in the epididymal fat tissue, we investigated the effect of dietary fish oil upon: i) the number, size and distribution of cells, ii) the basal and stimulated lipolysis, iii) the lipoprotein lipase (LPL) and the glucose 6-phosphate dehydrogenase activities, and iv) the antilipolytic action of insulin. The study was conducted on rats fed an SRD during 120 days with fish oil being isocaloric substituted for corn oil for 90-120 days in half the animals. Permanent hypertriglyceridemia, insulin resistance and abnormal glucose homeostasis were present in the rats before the source of fat in the diet was replaced. The major new findings of this study are the following: i) Dietary fish oil markedly reduced the fat pads mass, the hypertrophy of fat cells and improved the altered cell size distribution. ii) The presence of fish oil in the diet corrected the inhibitory effect of high sucrose diet upon the antilipolytic action of insulin, reduced the "in vitro" enhanced basal lipolysis and normalized isoproterenol-stimulated lipolysis. Fat pads lipoprotein lipase activity decreased reaching values similar to those observed in age-matched controls fed a control diet (CD). These effects were not accompanied by any change in rat body weight. All these data suggest that the dyslipemic rats fed a moderate amount of dietary fish oil constitute a useful animal model to study diet-regulated insulin action.

  7. 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

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

    SciTech Connect

    Iwai, Masaru; Kanno, Harumi; Senba, Izumi; Nakaoka, Hirotomo; Moritani, Tomozo; Horiuchi, Masatsugu

    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 a 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.

  9. Adipose tissue inflammation and metabolic dysfunction: a clinical perspective.

    PubMed

    Tam, Charmaine S; Redman, Leanne M

    2013-09-01

    Obesity is characterized by a state of chronic low-grade inflammation due to increased immune cells, specifically infiltrated macrophages into adipose tissue, which in turn secrete a range of proinflammatory mediators. This nonselective low-grade inflammation of adipose tissue is systemic in nature and can impair insulin signaling pathways, thus, increasing the risk of developing insulin resistance and type 2 diabetes. The aim of this review is to provide an update on clinical studies examining the role of adipose tissue in the development of obesity-associated complications in humans. We will discuss adipose tissue inflammation during different scenarios of energy imbalance and metabolic dysfunction including obesity and overfeeding, weight loss by calorie restriction or bariatric surgery, and conditions of insulin resistance (diabetes, polycystic ovarian syndrome).

  10. Intermuscular and intramuscular adipose tissues: Bad vs. good adipose tissues

    PubMed Central

    Hausman, Gary J; Basu, Urmila; Du, Min; Fernyhough-Culver, Melinda; Dodson, Michael V

    2014-01-01

    Human studies of the influence of aging and other factors on intermuscular fat (INTMF) were reviewed. Intermuscular fat increased with weight loss, weight gain, or with no weight change with age in humans. An increase in INTMF represents a similar threat to type 2 diabetes and insulin resistance as does visceral adipose tissue (VAT). Studies of INTMF in animals covered topics such as quantitative deposition and genetic relationships with other fat depots. The relationship between leanness and higher proportions of INTMF fat in pigs was not observed in human studies and was not corroborated by other pig studies. In humans, changes in muscle mass, strength and quality are associated with INTMF accretion with aging. Gene expression profiling and intrinsic methylation differences in pigs demonstrated that INTMF and VAT are primarily associated with inflammatory and immune processes. It seems that in the pig and humans, INTMF and VAT share a similar pattern of distribution and a similar association of components dictating insulin sensitivity. Studies on intramuscular (IM) adipocyte development in meat animals were reviewed. Gene expression analysis and genetic analysis have identified candidate genes involved in IM adipocyte development. Intramuscular (IM) adipocyte development in human muscle is only seen during aging and some pathological circumstance. Several genetic links between human and meat animal adipogenesis have been identified. In pigs, the Lipin1 and Lipin 2 gene have strong genetic effects on IM accumulation. Lipin1 deficiency results in immature adipocyte development in human lipodystrophy. In humans, overexpression of Perilipin 2 (PLIN2) facilitates intramyocellular lipid accretion whereas in pigs PLIN2 gene expression is associated with IM deposition. Lipins and perilipins may influence intramuscular lipid regardless of species. PMID:26317048

  11. Evidence of early alterations in adipose tissue biology and function and its association with obesity-related inflammation and insulin resistance in children.

    PubMed

    Landgraf, Kathrin; Rockstroh, Denise; Wagner, Isabel V; Weise, Sebastian; Tauscher, Roy; Schwartze, Julian T; Löffler, Dennis; Bühligen, Ulf; Wojan, Magdalena; Till, Holger; Kratzsch, Jürgen; Kiess, Wieland; Blüher, Matthias; Körner, Antje

    2015-04-01

    Accumulation of fat mass in obesity may result from hypertrophy and/or hyperplasia and is frequently associated with adipose tissue (AT) dysfunction in adults. Here we assessed early alterations in AT biology and function by comprehensive experimental and clinical characterization of 171 AT samples from lean and obese children aged 0 to 18 years. We show an increase in adipocyte size and number in obese compared with lean children beginning in early childhood. These alterations in AT composition in obese children were accompanied by decreased basal lipolytic activity and significantly enhanced stromal vascular cell proliferation in vitro, potentially underlying the hypertrophy and hyperplasia seen in obese children, respectively. Furthermore, macrophage infiltration, including the formation of crown-like structures, was increased in AT of obese children from 6 years on and was associated with higher hs-CRP serum levels. Clinically, adipocyte hypertrophy was not only associated with leptin serum levels but was highly and independently correlated with HOMA-IR as a marker of insulin resistance in children. In summary, we show that adipocyte hypertrophy is linked to increased inflammation in AT in obese children, thereby providing evidence that obesity-associated AT dysfunction develops in early childhood and is related to insulin resistance.

  12. Adipose tissues and thyroid hormones

    PubMed Central

    Obregon, Maria-Jesus

    2014-01-01

    The maintenance of energy balance is regulated by complex homeostatic mechanisms, including those emanating from adipose tissue. The main function of the adipose tissue is to store the excess of metabolic energy in the form of fat. The energy stored as fat can be mobilized during periods of energy deprivation (hunger, fasting, diseases). The adipose tissue has also a homeostatic role regulating energy balance and functioning as endocrine organ that secretes substances that control body homeostasis. Two adipose tissues have been identified: white and brown adipose tissues (WAT and BAT) with different phenotype, function and regulation. WAT stores energy, while BAT dissipates energy as heat. Brown and white adipocytes have different ontogenetic origin and lineage and specific markers of WAT and BAT have been identified. “Brite” or beige adipose tissue has been identified in WAT with some properties of BAT. Thyroid hormones exert pleiotropic actions, regulating the differentiation process in many tissues including the adipose tissue. Adipogenesis gives raise to mature adipocytes and is regulated by several transcription factors (c/EBPs, PPARs) that coordinately activate specific genes, resulting in the adipocyte phenotype. T3 regulates several genes involved in lipid mobilization and storage and in thermogenesis. Both WAT and BAT are targets of thyroid hormones, which regulate genes crucial for their proper function: lipogenesis, lipolysis, thermogenesis, mitochondrial function, transcription factors, the availability of nutrients. T3 acts directly through specific TREs in the gene promoters, regulating transcription factors. The deiodinases D3, D2, and D1 regulate the availability of T3. D3 is activated during proliferation, while D2 is linked to the adipocyte differentiation program, providing T3 needed for lipogenesis and thermogenesis. We examine the differences between BAT, WAT and brite/beige adipocytes and the process that lead to activation of UCP1 in WAT

  13. Estimation of ellagic acid and/or repaglinide effects on insulin signaling, oxidative stress, and inflammatory mediators of liver, pancreas, adipose tissue, and brain in insulin resistant/type 2 diabetic rats.

    PubMed

    Amin, Mohamed M; Arbid, Mahmoud S

    2017-02-01

    Even though ellagic acid has previously been valued in many models of cancer, so far its full mechanistic effect as a natural antiapoptotic agent in the prevention of type 2 diabetes complications has not been completely elucidated, which was the goal of this study. We fed albino rats a high-fat fructose diet (HFFD) for 2 months to induce insulin resistance/type 2 diabetes and then treated the rats with ellagic acid (10 mg/kg body weight, orally) and/or repaglinide (0.5 mg/kg body weight, orally) for 2 weeks. At the serum level, ellagic acid challenged the consequences of HFFD, significantly improving the glucose/insulin balance, liver enzymes, lipid profile, inflammatory cytokines, redox level, adipokines, ammonia, and manganese. At the tissue level (liver, pancreas, adipose tissue, and brain), ellagic acid significantly enhanced insulin signaling, autophosphorylation, adiponectin receptors, glucose transporters, inflammatory mediators, and apoptotic markers. Remarkably, combined treatment with both ellagic acid and repaglinide had a more pronounced effect than treatment with either alone. These outcomes give new insight into the promising molecular mechanisms by which ellagic acid modulates numerous factors induced in the progression of diabetes.

  14. Additional effect of metformin and celecoxib against lipid dysregulation and adipose tissue inflammation in high-fat fed rats with insulin resistance and fatty liver.

    PubMed

    Lu, Chieh-Hua; Hung, Yi-Jen; Hsieh, Po-Shiuan

    2016-10-15

    We investigated the effects of metformin and celecoxib on obesity-induced adipose tissue inflammation, insulin resistance (IR), fatty liver, and high blood pressure in high-fat (HF) fed rats. Male Sprague-Dawley rats were fed with either regular or HF diet for 8 weeks. Rats fed with regular diet were treated with vehicle for further 4 weeks. HF fed rats were divided into 6 groups, namely, vehicle, celecoxib (30mg/kg/day), metformin (300mg/kg/day), metformin (150mg/kg/day), metformin (300mg/kg/day) with celecoxib (30mg/kg/day), and metformin (150mg/kg/day) with celecoxib (15mg/kg/day) for additional 4 weeks. Increased body weight in HF fed rats was significantly reduced by metformin alone and metformin combined with celecoxib. The increases in the HOMA-IR value and the area under the curve of glucose following an oral glucose tolerance test, systolic blood pressure, and adipocyte size were significantly diminished in treated rats, especially rats undergoing combined treatment. Treatments with either celecoxib or in combination with metformin resulted in a reduction in AT macrophage infiltration and decreases in levels of adipose tissue TNF-α, MCP-1, and leptin levels in high-fat (HF) fed rats. Furthermore, the elevated hepatic triglycerides content was significantly decreased in the combined treatment group compared to that of groups of celecoxib or metformin alone. Celecoxib exerts a synergistic beneficial effect with metformin on and obesity-associated metabolic and cardiovascular disorders in high-fat fed rats.

  15. miRNA-93 inhibits GLUT4 and is overexpressed in adipose tissue of polycystic ovary syndrome patients and women with insulin resistance.

    PubMed

    Chen, Yen-Hao; Heneidi, Saleh; Lee, Jung-Min; Layman, Lawrence C; Stepp, David W; Gamboa, Gloria Mabel; Chen, Bo-Shiun; Chazenbalk, Gregorio; Azziz, Ricardo

    2013-07-01

    Approximately 70% of women with polycystic ovary syndrome (PCOS) have intrinsic insulin resistance (IR) above and beyond that associated with body mass, including dysfunctional glucose metabolism in adipose tissue (AT). In AT, analysis of the IRS/PI3-K/AKT pathway signaling components identified only GLUT4 expression to be significantly lower in PCOS patients and in control subjects with IR. We examined the role of miRNAs, particularly in the regulation of GLUT4, the insulin-sensitive glucose transporter, in the AT of PCOS and matched control subjects. PCOS AT was determined to have a differentially expressed miRNA profile, including upregulated miR-93, -133, and -223. GLUT4 is a highly predicted target for miR-93, while miR-133 and miR-223 have been demonstrated to regulate GLUT4 expression in cardiomyocytes. Expression of miR-93 revealed a strong correlation between the homeostasis model assessment of IR in vivo values and GLUT4 and miR-93 but not miR-133 and -223 expression in human AT. Overexpression of miR-93 resulted in downregulation of GLUT4 gene expression in adipocytes through direct targeting of the GLUT4 3'UTR, while inhibition of miR-93 activity led to increased GLUT4 expression. These results point to a novel mechanism for regulating insulin-stimulated glucose uptake via miR-93 and demonstrate upregulated miR-93 expression in all PCOS, and in non-PCOS women with IR, possibly accounting for the IR of the syndrome. In contrast, miR-133 and miR-223 may have a different, although yet to be defined, role in the IR of PCOS.

  16. Insulin Sensitivity in Adipose and Skeletal Muscle Tissue of Dairy Cows in Response to Dietary Energy Level and 2,4-Thiazolidinedione (TZD)

    PubMed Central

    Hosseini, Afshin; Tariq, Muhammad Rizwan; Trindade da Rosa, Fernanda; Kesser, Julia; Iqbal, Zeeshan; Mora, Ofelia; Sauerwein, Helga; Drackley, James K.; Trevisi, Erminio; Loor, Juan J.

    2015-01-01

    The effects of dietary energy level and 2,4-thiazolidinedione (TZD) injection on feed intake, body fatness, blood biomarkers and TZD concentrations, genes related to insulin sensitivity in adipose tissue (AT) and skeletal muscle, and peroxisome proliferator-activated receptor gamma (PPARG) protein in subcutaneous AT (SAT) were evaluated in Holstein cows. Fourteen nonpregnant nonlactating cows were fed a control low-energy (CON, 1.30 Mcal/kg) diet to meet 100% of estimated nutrient requirements for 3 weeks, after which half of the cows were assigned to a higher-energy diet (OVE, 1.60 Mcal/kg) and half of the cows continued on CON for 6 weeks. All cows received an intravenous injection of TZD starting 2 weeks after initiation of dietary treatments and for an additional 2 weeks, which served as the washout period. Cows fed OVE had greater energy intake and body mass than CON, and TZD had no effect during the administration period. The OVE cows had greater TZD clearance rate than CON cows. The lower concentration of nonesterified fatty acids (NEFA) and greater concentration of insulin in blood of OVE cows before TZD injection indicated positive energy balance and higher insulin sensitivity. Administration of TZD increased blood concentrations of glucose, insulin, and beta-hydroxybutyrate (BHBA) at 2 to 4 weeks after diet initiation, while the concentration of NEFA and adiponectin (ADIPOQ) remained unchanged during TZD. The TZD upregulated the mRNA expression of PPARG and its targets FASN and SREBF1 in SAT, but also SUMO1 and UBC9 which encode sumoylation proteins known to down-regulate PPARG expression and curtail adipogenesis. Therefore, a post-translational response to control PPARG gene expression in SAT could be a counteregulatory mechanism to restrain adipogenesis. The OVE cows had greater expression of the insulin sensitivity-related genes IRS1, SLC2A4, INSR, SCD, INSIG1, DGAT2, and ADIPOQ in SAT. In skeletal muscle, where PPARA and its targets orchestrate

  17. 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

  18. 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.

  19. Development of thermogenic adipose tissue.

    PubMed

    Loncar, D

    1991-09-01

    Besides having a metabolic and insulatory-supporting function, adipose tissue in endotherms also performs a thermogenic function. Thermogenic adipocytes contain specific UC-mitochondria with uncoupling protein (UCP) and produce heat. Thermogenic adipose tissue has two forms: brown adipose tissue (BAT) and convertible adipose tissue (CAT). Brown adipocytes have UC-mitochondria and express UCP throughout the entire life of small rodents, chiropterans, and insectivores. However, in other endotherms and in humans CAT participates as thermogenic tissue only during early postnatal period. Both BAT and CAT start to develop in utero, although in some animals (hamsters, marsupials) or in some particular areas (thoraco-periaortal and medio-perirenal areas in rats) development of thermogenic adipose tissue starts after birth. Postnatal development of BAT in small endotherms is characterized by quantitative changes (the amount of UC-mitochondria, UCP, and lipids). Postnatal development of CAT causes qualitative changes during which UC-mitochondria in convertible adipocytes are replaced by common, nonthermogenic C-mitochondria; vascularization of adipocytes drops to a low level and, with lipid accumulation, convertible adipocytes appear as lipid-store cells. Postnatal development of CAT can be modulated or reversed by the environmental temperature. The duration of postnatal changes varies between species; i.e., cats, rabbits and sheep, change their thermogenic form of CAT into the lipid-store form within the first postnatal month, while in humans the same process takes up to 15-20 years. In maturity all these large endotherms have CAT in lipid-store form. In light of these results, the question of participation of thermogenic adipose tissue in the regulation of human obesity needs to be answered.

  20. Adipose Tissue Oxygenation in Obesity: A Matter of Cardiovascular Risk?

    PubMed

    Landini, Linda; Honka, Miikka-Juhani; Ferrannini, Ele; Nuutila, Pirjo

    2016-01-01

    Obesity, a chronic low-grade inflammation disorder characterized by an expansion in adipose tissue mass, is rapidly expanding worldwide leading to an increase in the incidence of comorbidities such as insulin resistance, type 2 diabetes and cardiovascular diseases. This has led to a renewed interest in the adipose tissue function, historically considered as a passive fat storage. It is now well established that adipose tissue is an organ with an active role in production and release of a variety of molecules called adipocytokines. Dysregulated production of adipocytokines seems to be responsible for the pathogenesis of insulin resistance and type 2 diabetes; however, the mechanisms are still unclear. Hypoxia, that occurs when adipocytes expand in obesity, has been proposed as a possible cause of adipose tissue inflammation. On the other hand, recent studies have shown that adipose tissue oxygen tension was actually higher (hyperoxia) than normal and associated with insulin resistance in obesity, despite a reduction in blood flow. This might be explained by the role of mitochondrial oxygen consumption. Hence, further studies are needed to understand the role of adipose tissue oxygenation and perfusion in obesity to assess pathophysiology and novel opportunities for treating the diseases.

  1. Different adipose tissue depots: Metabolic implications and effects of surgical removal.

    PubMed

    Marcadenti, Aline; de Abreu-Silva, Erlon Oliveira

    2015-11-01

    Increased adiposity has been associated to worse metabolic profile, cardiovascular disease, and mortality. There are two main adipose tissue depots in the body, subcutaneous and visceral adipose tissue, which differ in anatomical location. A large body of evidence has shown the metabolic activity of adipose tissue; lipectomy and/or liposuction therefore appear to be alternatives for improving metabolic profile through rapid loss of adipose tissue. However, surgical removal of adipose tissue may be detrimental for metabolism, because subcutaneous adipose tissue has not been associated to metabolic disorders such as insulin resistance and type 2 diabetes mellitus. In addition, animal studies have shown a compensatory growth of adipose tissue in response to lipectomy. This review summarizes the implications of obesity-induced metabolic dysfunction, its relationship with the different adipose tissue depots, and the effects of lipectomy on cardiometabolic risk factors.

  2. Eicosapentaenoic acid reduces high-fat diet-induced insulin resistance by altering adipose tissue glycolytic and inflammatory function

    Technology Transfer Automated Retrieval System (TEKTRAN)

    We previously reported Eicosapentaenoic Acid (EPA)'s ability to prevent high-fat (HF) diet-induced obesity, insulin resistance, and inflammation. In this study, we dissected mechanisms mediating anti-inflammatory and anti-lipogenic actions of EPA, using histology/ immunohistochemistry, transcriptomi...

  3. The Shc locus regulates insulin signaling and adiposity in mammals

    PubMed Central

    Tomilov, Alexey A.; Ramsey, Jon J.; Hagopian, Kevork; Giorgio, Marco; Kim, Kyoungmi M.; Lam, Adam; Migliaccio, Enrica; Lloyd, Kent C.; Berniakovich, Ina; Prolla, Tomas A.; Pelicci, PierGiuseppe; Cortopassi, Gino A.

    2014-01-01

    Summary Longevity of a p66Shc knockout strain (ShcP) was previously attributed to increased stress resistance and altered mitochondria. Microarrays of ShcP tissues indicated alterations in insulin signaling. Consistent with this observation, ShcP mice were more insulin sensitive and glucose tolerant at organismal and tissue levels, as was a novel p66Shc knockout (ShcL). Increasing and decreasing Shc expression in cell lines decreased and increased insulin sensitivity, respectively – consistent with p66Shc's function as a repressor of insulin signaling. However, differences between the two p66Shc knockout strains were also observed. ShcL mice were fatter and susceptible to fatty diets, and their fat was more insulin sensitive than controls. On the other hand, ShcP mice were leaner and resisted fatty diets, and their adipose was less insulin sensitive than controls. ShcL and ShcP strains are both highly inbred on the C57Bl/6 background, so we investigated gene expression at the Shc locus, which encodes three isoforms, p66, p52, and p46. Isoform p66 is absent in both strains; thus, the remaining difference to which to attribute the ‘lean’ phenotype is expression of the other two isoforms. ShcL mice have a precise deletion of p66Shc and normal expression of p52 and p46Shc isoforms in all tissues; thus, a simple deletion of p66Shc results in a ‘fat’ phenotype. However, ShcP mice in addition to p66Shc deletion have a fourfold increase in p46Shc expression in white fat. Thus, p46Shc overexpression in fat, rather than p66Shc deletion, is the likely cause of decreased adiposity and reduced insulin sensitivity in the fat of ShcP mice, which has implications for the longevity of the strain. PMID:21040401

  4. Timed-daily ingestion of whey protein and exercise training reduces visceral adipose tissue mass and improves insulin resistance: the PRISE study.

    PubMed

    Arciero, Paul J; Baur, Daniel; Connelly, Scott; Ormsbee, Michael J

    2014-07-01

    The present study examined the effects of timed ingestion of supplemental protein (20-g servings of whey protein, 3×/day), added to the habitual diet of free-living overweight/obese adults and subsequently randomized to either whey protein only (P; n = 24), whey protein and resistance exercise (P + RT; n = 27), or a whey protein and multimode exercise training program [protein and resistance exercise, intervals, stretching/yoga/Pilates, endurance exercise (PRISE); n = 28]. Total and regional body composition and visceral adipose tissue (VAT) mass (dual-energy X-ray absorptiometry), insulin sensitivity [homeostasis model assessment-estimated insulin resistance (HOMA-IR)], plasma lipids and adipokines, and feelings of hunger and satiety (visual analog scales) were measured before and after the 16-wk intervention. All groups lost body weight, fat mass (FM), and abdominal fat; however, PRISE lost significantly (P < 0.01) more body weight (3.3 ± 0.7 vs. 1.1 ± 0.7 kg, P + RT) and FM (2.8 ± 0.7 vs. 0.9 ± 0.5 kg, P + RT) and gained (P < 0.05) a greater percentage of lean body mass (2 ± 0.5 vs. 0.9 ± 0.3 and 0.6 ± 0.4%, P + RT and P, respectively). Only P + RT (0.1 ± 0.04 kg) and PRISE (0.21 ± 0.07 kg) lost VAT mass (P < 0.05). Fasting glucose decreased only in P + RT (5.1 ± 2.5 mg/dl) and PRISE (15.3 ± 2.1 mg/dl), with the greatest decline occurring in PRISE (P < 0.05). Similarly, HOMA-IR improved (0.6 ± 0.3, 0.6 ± 0.4 units), and leptin decreased (4.7 ± 2.2, 4.7 ± 3.1 ng/dl), and adiponectin increased (3.8 ± 1.1, 2.4 ± 1.1 μg/ml) only in P + RT and PRISE, respectively, with no change in P. In conclusion, we find evidence to support exercise training and timed ingestion of whey protein added to the habitual diet of free-living overweight/obese adults, independent of caloric restriction on total and regional body fat distribution, insulin resistance, and adipokines.

  5. Subcutaneous Adipose Cell Size and Distribution: Relationship to Insulin Resistance and Body Fat

    PubMed Central

    McLaughlin, T; Lamendola, C; Coghlan, N; Liu, TC; Lerner, K; Sherman, A; Cushman, SW

    2015-01-01

    Metabolic heterogeneity among obese individuals may be attributable to differences in adipose cell size. We sought to clarify this by quantifying adipose cell-size distribution, body fat, and insulin-mediated glucose uptake in overweight/moderately-obese individuals. 148 healthy nondiabetic subjects with BMI 25–38 kg/m2 underwent subcutaneous adipose tissue biopsies and quantification of insulin-mediated glucose uptake with steady-state plasma glucose concentrations (SSPG) during the modified insulin suppression test. Cell-size distributions were obtained with Beckman Coulter Multisizer. Primary endpoints included % small adipose cells and diameter of large adipose cells. Cell-size and metabolic parameters were compared by regression for the whole group; according to IR and IS subgroups; and by body fat quintile. Both large and small adipose cells were present in nearly equal proportions. Percent small cells was associated with SSPG (r=0.26, p=0.003). Compared to BMI-matched IS individuals, IR counterparts demonstrated fewer, but larger large adipose cells, and a greater proportion of small-to-large adipose cells. Diameter of the large adipose cells was associated with %body fat (r=0.26, p=0.014), female sex (r=0.21, p=0.036), and SSPG (r=0.20, p=0.012). In the highest vs lowest % body fat quintile, adipose cell size increased by only 7% whereas adipose cell number increased by 74%. Recruitment of adipose cells is required for expansion of body fat mass beyond BMI of 25 kg/m2. Insulin resistance is associated with accumulation of small adipose cells and enlargement of large adipose cells. These data support the notion that impaired adipogenesis may underlie insulin resistance. PMID:23666871

  6. Dietary modulation of erythrocyte insulin receptor interaction and the regulation of adipose tissue pyruvate dehydrogenase enzyme activity in growing rats; a mechanism of action of dietary fiber in metabolism

    SciTech Connect

    Ogunwole, J.O.A.

    1984-01-01

    The metabolic effects of graded cellulose (a dietary fiber) intake were studied at minimal (10%) and maximal (20%) protein levels in male weanling Sprague Dawley rats. The hypothesis was tested that the hypoglycemic effect of high fiber diets is partly mediated through increased tissue sensitivity to insulin at the cell receptor level. Erythrocyte insulin receptor interaction (IRI) and percent insulin stimulation of adipose tissue pyruvate dehydrogenase (PDH) activity (PDS) were used as indices of tissue sensitivity to insulin. IRI was determined by a standardized radioceptor assay PDS by the rate of oxidation of 1-/sup 14/C-pyruvate to /sup 14/CO/sub 2/ in epidymal fat pads and serum insulin levels by radioimmunoassay. In both protein groups, the addition of fiber in the diet resulted in a significant (P < 0.05) increase in food intake (FI) for calorie compensation. Fiber and protein intake had a significant (P < 0.01) effect on IRI and both basal (PDB) and PDS activities of PDH. At all fiber levels, specific percent /sup 125/I-insulin binding (SIB) was higher in the 20% protein groups while in the fiber-free group, a higher SIB was observed in the 10% protein group.

  7. Ginkgo biloba Extract Improves Insulin Signaling and Attenuates Inflammation in Retroperitoneal Adipose Tissue Depot of Obese Rats

    PubMed Central

    Hirata, Bruna Kelly Sousa; Banin, Renata Mancini; Dornellas, Ana Paula Segantine; de Andrade, Iracema Senna; Zemdegs, Juliane Costa Silva; Caperuto, Luciana Chagas; Oyama, Lila Missae; Ribeiro, Eliane Beraldi; Telles, Monica Marques

    2015-01-01

    Due to the high incidence and severity of obesity and its related disorders, it is highly desirable to develop new strategies to treat or even to prevent its development. We have previously described that Ginkgo biloba extract (GbE) improved insulin resistance and reduced body weight gain of obese rats. In the present study we aimed to evaluate the effect of GbE on both inflammatory cascade and insulin signaling in retroperitoneal fat depot of diet-induced obese rats. Rats were fed with high fat diet for 2 months and thereafter treated for 14 days with 500 mg/kg of GbE. Rats were then euthanized and samples from retroperitoneal fat depot were used for western blotting, RT-PCR, and ELISA experiments. The GbE treatment promoted a significant reduction on both food/energy intake and body weight gain in comparison to the nontreated obese rats. In addition, a significant increase of both Adipo R1 and IL-10 gene expressions and IR and Akt phosphorylation was also observed, while NF-κB p65 phosphorylation and TNF-α levels were significantly reduced. Our data suggest that GbE might have potential as a therapy to treat obesity-related metabolic diseases, with special interest to treat obese subjects resistant to adhere to a nutritional education program. PMID:25960614

  8. Caspase Induction and BCL2 Inhibition in Human Adipose Tissue

    PubMed Central

    Tinahones, Francisco José; Coín Aragüez, Leticia; Murri, Mora; Oliva Olivera, Wilfredo; Mayas Torres, María Dolores; Barbarroja, Nuria; Gomez Huelgas, Ricardo; Malagón, Maria M.; El Bekay, Rajaa

    2013-01-01

    OBJECTIVE Cell death determines the onset of obesity and associated insulin resistance. Here, we analyze the relationship among obesity, adipose tissue apoptosis, and insulin signaling. RESEARCH DESIGN AND METHODS The expression levels of initiator (CASP8/9) and effector (CASP3/7) caspases as well as antiapoptotic B-cell lymphoma (BCL)2 and inflammatory markers were assessed in visceral (VAT) and subcutaneous (SAT) adipose tissue from patients with different degrees of obesity and without insulin resistance or diabetes. Adipose tissue explants from lean subjects were cultured with TNF-α or IL-6, and the expression of apoptotic and insulin signaling components was analyzed and compared with basal expression levels in morbidly obese subjects. RESULTS SAT and VAT exhibited increased CASP3/7 and CASP8/9 expression levels and decreased BCL2 expression with BMI increase. These changes were accompanied by increased inflammatory cytokine mRNA levels and macrophage infiltration markers. In obese subjects, CASP3/7 activation and BCL2 downregulation correlated with the IRS-1/2–expression levels. Expression levels of caspases, BCL2, p21, p53, IRS-1/2, GLUT4, protein tyrosine phosphatase 1B, and leukocyte antigen-related phosphatase in TNF-α– or IL-6–treated explants from lean subjects were comparable with those found in adipose tissue samples from morbidly obese subjects. These insulin component expression levels were reverted with CASP3/7 inhibition in these TNF-α– or IL-6–treated explants. CONCLUSIONS Body fat mass increase is associated with CASP3/7 and BCL2 expression in adipose tissue. Moreover, this proapoptotic state correlated with insulin signaling, suggesting its potential contribution to the development of insulin resistance. PMID:23193206

  9. 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

  10. Gene Expression Signature in Adipose Tissue of Acromegaly Patients.

    PubMed

    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.

  11. Assessment of brown adipose tissue function.

    PubMed

    Virtue, Sam; Vidal-Puig, Antonio

    2013-01-01

    In this review we discuss practical considerations for the assessment of brown adipose tissue in rodent models, focusing on mice. The central aim of the review is to provide a critical appraisal of the utility of specialized techniques for assessing brown adipose tissue function in vivo. We cover several of the most common specialized methods for analysing brown adipose tissue function in vivo, including assessment of maximal thermogenic capacity by indirect calorimetry and the measurement of sympathetic tone to brown adipose tissue. While these techniques are powerful, they are not readily available to all laboratories; therefore we also cover several simple measurements that, particularly in combination, can be used to determine if a mouse model is likely to have alterations in brown adipose tissue function. Such techniques include: pair feeding, analysis of brown adipose tissue lipid content and mRNA and protein markers of brown adipose tissue activation.

  12. Assessment of brown adipose tissue function

    PubMed Central

    Virtue, Sam; Vidal-Puig, Antonio

    2013-01-01

    In this review we discuss practical considerations for the assessment of brown adipose tissue in rodent models, focusing on mice. The central aim of the review is to provide a critical appraisal of the utility of specialized techniques for assessing brown adipose tissue function in vivo. We cover several of the most common specialized methods for analysing brown adipose tissue function in vivo, including assessment of maximal thermogenic capacity by indirect calorimetry and the measurement of sympathetic tone to brown adipose tissue. While these techniques are powerful, they are not readily available to all laboratories; therefore we also cover several simple measurements that, particularly in combination, can be used to determine if a mouse model is likely to have alterations in brown adipose tissue function. Such techniques include: pair feeding, analysis of brown adipose tissue lipid content and mRNA and protein markers of brown adipose tissue activation. PMID:23760815

  13. Transcriptomic identification of ADH1B as a novel candidate gene for obesity and insulin resistance in human adipose tissue in Mexican Americans from the Veterans Administration Genetic Epidemiology Study (VAGES).

    PubMed

    Winnier, Deidre A; Fourcaudot, Marcel; Norton, Luke; Abdul-Ghani, Muhammad A; Hu, Shirley L; Farook, Vidya S; Coletta, Dawn K; Kumar, Satish; Puppala, Sobha; Chittoor, Geetha; Dyer, Thomas D; Arya, Rector; Carless, Melanie; Lehman, Donna M; Curran, Joanne E; Cromack, Douglas T; Tripathy, Devjit; Blangero, John; Duggirala, Ravindranath; Göring, Harald H H; DeFronzo, Ralph A; Jenkinson, Christopher P

    2015-01-01

    Type 2 diabetes (T2D) is a complex metabolic disease that is more prevalent in ethnic groups such as Mexican Americans, and is strongly associated with the risk factors obesity and insulin resistance. The goal of this study was to perform whole genome gene expression profiling in adipose tissue to detect common patterns of gene regulation associated with obesity and insulin resistance. We used phenotypic and genotypic data from 308 Mexican American participants from the Veterans Administration Genetic Epidemiology Study (VAGES). Basal fasting RNA was extracted from adipose tissue biopsies from a subset of 75 unrelated individuals, and gene expression data generated on the Illumina BeadArray platform. The number of gene probes with significant expression above baseline was approximately 31,000. We performed multiple regression analysis of all probes with 15 metabolic traits. Adipose tissue had 3,012 genes significantly associated with the traits of interest (false discovery rate, FDR ≤ 0.05). The significance of gene expression changes was used to select 52 genes with significant (FDR ≤ 10(-4)) gene expression changes across multiple traits. Gene sets/Pathways analysis identified one gene, alcohol dehydrogenase 1B (ADH1B) that was significantly enriched (P < 10(-60)) as a prime candidate for involvement in multiple relevant metabolic pathways. Illumina BeadChip derived ADH1B expression data was consistent with quantitative real time PCR data. We observed significant inverse correlations with waist circumference (2.8 x 10(-9)), BMI (5.4 x 10(-6)), and fasting plasma insulin (P < 0.001). These findings are consistent with a central role for ADH1B in obesity and insulin resistance and provide evidence for a novel genetic regulatory mechanism for human metabolic diseases related to these traits.

  14. Transcriptomic Identification of ADH1B as a Novel Candidate Gene for Obesity and Insulin Resistance in Human Adipose Tissue in Mexican Americans from the Veterans Administration Genetic Epidemiology Study (VAGES)

    PubMed Central

    Winnier, Deidre A.; Fourcaudot, Marcel; Norton, Luke; Abdul-Ghani, Muhammad A.; Hu, Shirley L.; Farook, Vidya S.; Coletta, Dawn K.; Kumar, Satish; Puppala, Sobha; Chittoor, Geetha; Dyer, Thomas D.; Arya, Rector; Carless, Melanie; Lehman, Donna M.; Curran, Joanne E.; Cromack, Douglas T.; Tripathy, Devjit; Blangero, John; Duggirala, Ravindranath; Göring, Harald H. H.; DeFronzo, Ralph A.; Jenkinson, Christopher P.

    2015-01-01

    Type 2 diabetes (T2D) is a complex metabolic disease that is more prevalent in ethnic groups such as Mexican Americans, and is strongly associated with the risk factors obesity and insulin resistance. The goal of this study was to perform whole genome gene expression profiling in adipose tissue to detect common patterns of gene regulation associated with obesity and insulin resistance. We used phenotypic and genotypic data from 308 Mexican American participants from the Veterans Administration Genetic Epidemiology Study (VAGES). Basal fasting RNA was extracted from adipose tissue biopsies from a subset of 75 unrelated individuals, and gene expression data generated on the Illumina BeadArray platform. The number of gene probes with significant expression above baseline was approximately 31,000. We performed multiple regression analysis of all probes with 15 metabolic traits. Adipose tissue had 3,012 genes significantly associated with the traits of interest (false discovery rate, FDR ≤ 0.05). The significance of gene expression changes was used to select 52 genes with significant (FDR ≤ 10-4) gene expression changes across multiple traits. Gene sets/Pathways analysis identified one gene, alcohol dehydrogenase 1B (ADH1B) that was significantly enriched (P < 10-60) as a prime candidate for involvement in multiple relevant metabolic pathways. Illumina BeadChip derived ADH1B expression data was consistent with quantitative real time PCR data. We observed significant inverse correlations with waist circumference (2.8 x 10-9), BMI (5.4 x 10-6), and fasting plasma insulin (P < 0.001). These findings are consistent with a central role for ADH1B in obesity and insulin resistance and provide evidence for a novel genetic regulatory mechanism for human metabolic diseases related to these traits. PMID:25830378

  15. Adipose tissue immunity and cancer.

    PubMed

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

    2013-10-02

    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.

  16. Brown adipose tissue and thermogenesis.

    PubMed

    Fenzl, Anna; Kiefer, Florian W

    2014-07-01

    The growing understanding of adipose tissue as an important endocrine organ with multiple metabolic functions has directed the attention to the (patho)physiology of distinct fat depots. Brown adipose tissue (BAT), in contrast to bona fide white fat, can dissipate significant amounts of chemical energy through uncoupled respiration and heat production (thermogenesis). This process is mediated by the major thermogenic factor uncoupling protein-1 and can be activated by certain stimuli, such as cold exposure, adrenergic compounds or genetic alterations. White adipose tissue (WAT) depots, however, also possess the capacity to acquire brown fat characteristics in response to thermogenic stimuli. The induction of a BAT-like cellular and molecular program in WAT has recently been termed "browning" or "beiging". Promotion of BAT activity or the browning of WAT is associated with in vivo cold tolerance, increased energy expenditure, and protection against obesity and type 2 diabetes. These preclinical observations have gained additional significance with the recent discovery that active BAT is present in adult humans and can be detected by 18fluor-deoxy-glucose positron emission tomography coupled with computed tomography. As in rodents, human BAT can be activated by cold exposure and is associated with increased energy turnover and lower body fat mass. Despite the tremendous progress in brown fat research in recent years, pharmacological concepts to harness BAT function therapeutically are currently still lacking.

  17. Dietary Salba (Salvia hispanica L) seed rich in α-linolenic acid improves adipose tissue dysfunction and the altered skeletal muscle glucose and lipid metabolism in dyslipidemic insulin-resistant rats.

    PubMed

    Oliva, M E; Ferreira, M R; Chicco, A; Lombardo, Y B

    2013-10-01

    This work reports the effect of dietary Salba (chia) seed rich in n-3 α-linolenic acid on the morphological and metabolic aspects involved in adipose tissue dysfunction and the mechanisms underlying the impaired glucose and lipid metabolism in the skeletal muscle of rats fed a sucrose-rich diet (SRD). Rats were fed a SRD for 3 months. Thereafter, half the rats continued with SRD while in the other half, corn oil (CO) was replaced by chia seed for 3 months (SRD+chia). In control group, corn starch replaced sucrose. The replacement of CO by chia seed in the SRD reduced adipocyte hypertrophy, cell volume and size distribution, improved lipogenic enzyme activities, lipolysis and the anti-lipolytic action of insulin. In the skeletal muscle lipid storage, glucose phosphorylation and oxidation were normalized. Chia seed reversed the impaired insulin stimulated glycogen synthase activity, glycogen, glucose-6-phosphate and GLUT-4 protein levels as well as insulin resistance and dyslipidemia.

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

    PubMed Central

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

    2016-01-01

    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. PMID:26975571

  19. Regulation of glucose homoeostasis by brown adipose tissue.

    PubMed

    Peirce, Vivian; Vidal-Puig, Antonio

    2013-12-01

    Brown adipose tissue (BAT) has emerged as a therapeutic target for the treatment of obesity. Activation of BAT in human beings could also have beneficial metabolic effects that might resolve common complications of obesity, such as type 2 diabetes, by ameliorating the glucolipotoxic pathological changes that underlie the development of peripheral insulin resistance and impaired insulin secretion due to pancreatic β-cell failure. Evidence from rodent models suggests that BAT activation improves glucose homoeostasis through several mechanisms, which could point to new strategies to optimise stimulation of BAT in human beings and reverse insulin resistance in peripheral tissues.

  20. Sex differences in adipose tissue

    PubMed Central

    Fuente-Martín, Esther; Argente-Arizón, Pilar; Ros, Purificación; Argente, Jesús; Chowen, Julie A

    2013-01-01

    Obesity and its associated secondary complications are active areas of investigation in search of effective treatments. As a result of this intensified research numerous differences between males and females at all levels of metabolic control have come to the forefront. These differences include not only the amount and distribution of adipose tissue, but also differences in its metabolic capacity and functions between the sexes. Here, we review some of the recent advances in our understanding of these dimorphisms and emphasize the fact that these differences between males and females must be taken into consideration in hopes of obtaining successful treatments for both sexes. PMID:23991358

  1. Lipokines and oxysterols: novel adipose-derived lipid hormones linking adipose dysfunction and insulin resistance.

    PubMed

    Murdolo, Giuseppe; Bartolini, Desirée; Tortoioli, Cristina; Piroddi, Marta; Iuliano, Luigi; Galli, Francesco

    2013-12-01

    The expansion of adipose tissue (AT) is, by definition, a hallmark of obesity. However, not all increases in fat mass are associated with pathophysiological cues. Indeed, whereas a "healthy" fat mass accrual, mainly in the subcutaneous depots, preserves metabolic homeostasis, explaining the occurrence of the metabolically healthy obese phenotype, "unhealthy" AT expansion is importantly associated with insulin resistance/type 2 diabetes and the metabolic syndrome. The development of a dysfunctional adipose organ may find mechanistic explanation in a reduced ability to recruit new and functional (pre)adipocytes from undifferentiated precursor cells. Such a failure of the adipogenic process underlies the "AT expandability" paradigm. The inability of AT to expand further to store excess nutrients, rather than obesity per se, induces a diabetogenic milieu by promoting the overflow and the ectopic deposition of fatty acids in insulin-dependent organs (i.e., lipotoxicity), the secretion of various metabolically detrimental adipose-derived hormones (i.e., adipokines and lipokines), and the occurrence of local and systemic inflammation and oxidative stress. Hitherto, fatty acids (i.e., lipokines) and the oxidation by-products of cholesterol and polyunsaturated fatty acids, such as nonenzymatic oxysterols and reactive aldehyde species, respectively, emerge as key modulators of (pre)adipocyte signaling through Wnt/β-catenin and MAPK pathways and potential regulators of glucose homeostasis. These and other mechanistic insights linking adipose dysfunction, oxidative stress, and impairment of glucose homeostasis are discussed in this review article, which focuses on adipose peroxidation as a potential instigator of, and a putative therapeutic target for, obesity-associated metabolic dysfunctions.

  2. Short-term in vivo inhibition of insulin receptor substrate-1 expression leads to insulin resistance, hyperinsulinemia, and increased adiposity.

    PubMed

    Araújo, Eliana P; De Souza, Cláudio T; Gasparetti, Alessandra L; Ueno, Mirian; Boschero, Antonio C; Saad, Mário J A; Velloso, Lício A

    2005-03-01

    Insulin receptor substrate-1 (IRS-1) has an important role as an early intermediary between the insulin and IGF receptors and downstream molecules that participate in insulin and IGF-I signal transduction. Here we employed an antisense oligonucleotide (IRS-1AS) to inhibit whole-body expression of IRS-1 in vivo and evaluate the consequences of short-term inhibition of IRS-1 in Wistar rats. Four days of treatment with IRS-1AS reduced the expression of IRS-1 by 80, 75, and 65% (P < 0.05) in liver, skeletal muscle, and adipose tissue, respectively. This was accompanied by a 40% (P < 0.05) reduction in the constant of glucose decay during an insulin tolerance test, a 78% (P < 0.05) reduction in glucose consumption during a hyperinsulinemic-euglycemic clamp, and a 90% (P < 0.05) increase in basal plasma insulin level. The metabolic effects produced by IRS-1AS were accompanied by a significant reduction in insulin-induced [Ser (473)] Akt phosphorylation in liver (85%, P < 0.05), skeletal muscle (40%, P < 0.05), and adipose tissue (85%, P < 0.05) and a significant reduction in insulin-induced tyrosine phosphorylation of ERK in liver (20%, P < 0.05) and skeletal muscle (30%, P < 0.05). However, insulin-induced tyrosine phosphorylation of ERK was significantly increased (60%, P < 0.05) in adipose tissue of IRS-1AS-treated rats. In rats treated with IRS-1AS for 8 d, a 100% increase (P < 0.05) in relative epididymal fat weight and a 120% (P < 0.05) increase in nuclear expression of peroxisome proliferator-activated receptor-gamma were observed. Thus, acute inhibition of IRS-1 expression in rats leads to insulin resistance accompanied by activation of a growth-related pathway exclusively in white adipose tissue.

  3. Amelioration of insulin resistance by rosiglitazone is associated with increased adipose cell size in obese type 2 diabetic patients

    PubMed Central

    Eliasson, Bjorn; Smith, Ulf; Mullen, Shawn; Cushman, Samuel W; Sherman, Arthur S; Yang, Jian

    2014-01-01

    Early studies reported that the size of adipose cells positively correlates with insulin resistance, but recent evidence suggests that the relationship between adipose cell size and insulin resistance is more complex. We previously reported that among BMI-matched moderately obese subjects who were either insulin sensitive or resistant insulin resistance correlated with the proportion of small adipose cells, rather than the size of the large adipose cells, whereas the size of large adipose cells was found to be a predictor of insulin resistance in the first-degree relatives of type 2 diabetic (T2D) patients. The relationship between adipose cellularity and insulin resistance thus appears to depend on the metabolic state of the individual. We did a longitudinal study with T2D patients treated with the insulin-sensitizer rosiglitazone to test the hypothesis that improved insulin sensitivity is associated with increased adipocyte size. Eleven T2D patients were recruited and treated with rosiglitazone for 90 days. Blood samples and needle biopsies of abdominal subcutaneous fat were taken at six time points and analyzed for cell size distributions. Rosiglitazone treatment ameliorated insulin resistance as evidenced by significantly decreased fasting plasma glucose and increased index of insulin sensitivity, QUICKI. In association with this, we found significantly increased size of the large adipose cells and, with a weaker effect, increased proportion of small adipose cells. We conclude rosiglitazone treatment both enlarges existing large adipose cells and recruits new small adipose cells in T2D patients, improving fat storage capacity in adipose tissue and thus systemic insulin sensitivity. PMID:26317056

  4. Obesity induces a phenotypic switch in adipose tissue macrophage polarization.

    PubMed

    Lumeng, Carey N; Bodzin, Jennifer L; Saltiel, Alan R

    2007-01-01

    Adipose tissue macrophages (ATMs) infiltrate adipose tissue during obesity and contribute to insulin resistance. We hypothesized that macrophages migrating to adipose tissue upon high-fat feeding may differ from those that reside there under normal diet conditions. To this end, we found a novel F4/80(+)CD11c(+) population of ATMs in adipose tissue of obese mice that was not seen in lean mice. ATMs from lean mice expressed many genes characteristic of M2 or "alternatively activated" macrophages, including Ym1, arginase 1, and Il10. Diet-induced obesity decreased expression of these genes in ATMs while increasing expression of genes such as those encoding TNF-alpha and iNOS that are characteristic of M1 or "classically activated" macrophages. Interestingly, ATMs from obese C-C motif chemokine receptor 2-KO (Ccr2-KO) mice express M2 markers at levels similar to those from lean mice. The antiinflammatory cytokine IL-10, which was overexpressed in ATMs from lean mice, protected adipocytes from TNF-alpha-induced insulin resistance. Thus, diet-induced obesity leads to a shift in the activation state of ATMs from an M2-polarized state in lean animals that may protect adipocytes from inflammation to an M1 proinflammatory state that contributes to insulin resistance.

  5. Obesity induces a phenotypic switch in adipose tissue macrophage polarization

    PubMed Central

    Lumeng, Carey N.; Bodzin, Jennifer L.; Saltiel, Alan R.

    2007-01-01

    Adipose tissue macrophages (ATMs) infiltrate adipose tissue during obesity and contribute to insulin resistance. We hypothesized that macrophages migrating to adipose tissue upon high-fat feeding may differ from those that reside there under normal diet conditions. To this end, we found a novel F4/80+CD11c+ population of ATMs in adipose tissue of obese mice that was not seen in lean mice. ATMs from lean mice expressed many genes characteristic of M2 or “alternatively activated” macrophages, including Ym1, arginase 1, and Il10. Diet-induced obesity decreased expression of these genes in ATMs while increasing expression of genes such as those encoding TNF-α and iNOS that are characteristic of M1 or “classically activated” macrophages. Interestingly, ATMs from obese C-C motif chemokine receptor 2–KO (Ccr2-KO) mice express M2 markers at levels similar to those from lean mice. The antiinflammatory cytokine IL-10, which was overexpressed in ATMs from lean mice, protected adipocytes from TNF-α–induced insulin resistance. Thus, diet-induced obesity leads to a shift in the activation state of ATMs from an M2-polarized state in lean animals that may protect adipocytes from inflammation to an M1 proinflammatory state that contributes to insulin resistance. PMID:17200717

  6. Targeting adipose tissue via systemic gene therapy.

    PubMed

    O'Neill, S M; Hinkle, C; Chen, S-J; Sandhu, A; Hovhannisyan, R; Stephan, S; Lagor, W R; Ahima, R S; Johnston, J C; Reilly, M P

    2014-07-01

    Adipose tissue has a critical role in energy and metabolic homeostasis, but it is challenging to adapt techniques to modulate adipose function in vivo. Here we develop an in vivo, systemic method of gene transfer specifically targeting adipose tissue using adeno-associated virus (AAV) vectors. We constructed AAV vectors containing cytomegalovirus promoter-regulated reporter genes, intravenously injected adult mice with vectors using multiple AAV serotypes, and determined that AAV2/8 best targeted adipose tissue. Altering vectors to contain adiponectin promoter/enhancer elements and liver-specific microRNA-122 target sites restricted reporter gene expression to adipose tissue. As proof of efficacy, the leptin gene was incorporated into the adipose-targeted expression vector, package into AAV2/8 and administered intravenously to 9- to 10-week-old ob/ob mice. Phenotypic changes were measured over an 8-week period. Leptin mRNA and protein were expressed in adipose and leptin protein was secreted into plasma. Mice responded with reversal of weight gain, decreased hyperinsulinemia and improved glucose tolerance. AAV2/8-mediated systemic delivery of an adipose-targeted expression vector can replace a gene lacking in adipose tissue and correct a mouse model of human disease, demonstrating experimental application and therapeutic potential in disorders of adipose.

  7. Brown adipose tissue and bone

    PubMed Central

    Lidell, M E; Enerbäck, S

    2015-01-01

    Brown adipose tissue (BAT) is capable of transforming chemically stored energy, in the form of triglycerides, into heat. Recent studies have shown that metabolically active BAT is present in a large proportion of adult humans, where its activity correlates with a favorable metabolic status. Hence, the tissue is now regarded as an interesting target for therapies against obesity and associated diseases such as type 2 diabetes, the hypothesis being that an induction of BAT would be beneficial for these disease states. Apart from the association between BAT activity and a healthier metabolic status, later studies have also shown a positive correlation between BAT volume and both bone cross-sectional area and bone mineral density, suggesting that BAT might stimulate bone anabolism. The aim of this review is to give the reader a brief overview of the BAT research field and to summarize and discuss recent findings regarding BAT being a potential player in bone metabolism. PMID:27152171

  8. 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

  9. 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.

  10. A novel ChREBP isoform in adipose tissue regulates systemic glucose metabolism.

    PubMed

    Herman, Mark A; Peroni, Odile D; Villoria, Jorge; Schön, Michael R; Abumrad, Nada A; Blüher, Matthias; Klein, Samuel; Kahn, Barbara B

    2012-04-19

    The prevalence of obesity and type 2 diabetes is increasing worldwide and threatens to shorten lifespan. Impaired insulin action in peripheral tissues is a major pathogenic factor. Insulin stimulates glucose uptake in adipose tissue through the GLUT4 (also known as SLC2A4) glucose transporter, and alterations in adipose tissue GLUT4 expression or function regulate systemic insulin sensitivity. Downregulation of human and mouse adipose tissue GLUT4 occurs early in diabetes development. Here we report that adipose tissue GLUT4 regulates the expression of carbohydrate-responsive-element-binding protein (ChREBP; also known as MLXIPL), a transcriptional regulator of lipogenic and glycolytic genes. Furthermore, adipose ChREBP is a major determinant of adipose tissue fatty acid synthesis and systemic insulin sensitivity. We find a new mechanism for glucose regulation of ChREBP: glucose-mediated activation of the canonical ChREBP isoform (ChREBP-α) induces expression of a novel, potent isoform (ChREBP-β) that is transcribed from an alternative promoter. ChREBP-β expression in human adipose tissue predicts insulin sensitivity, indicating that it may be an effective target for treating diabetes.

  11. Renin dynamics in adipose tissue: adipose tissue control of local renin concentrations.

    PubMed

    Fowler, Jason D; Krueth, Stacy B; Bernlohr, David A; Katz, Stephen A

    2009-02-01

    The renin-angiotensin system (RAS) has been implicated in a variety of adipose tissue functions, including tissue growth, differentiation, metabolism, and inflammation. Although expression of all components necessary for a locally derived adipose tissue RAS has been demonstrated within adipose tissue, independence of local adipose RAS component concentrations from corresponding plasma RAS fluctuations has not been addressed. To analyze this, we varied in vivo rat plasma concentrations of two RAS components, renin and angiotensinogen (AGT), to determine the influence of their plasma concentrations on adipose and cardiac tissue levels in both perfused (plasma removed) and nonperfused samples. Variation of plasma RAS components was accomplished by four treatment groups: normal, DOCA salt, bilateral nephrectomy, and losartan. Adipose and cardiac tissue AGT concentrations correlated positively with plasma values. Perfusion of adipose tissue decreased AGT concentrations by 11.1%, indicating that adipose tissue AGT was in equilibrium with plasma. Cardiac tissue renin levels positively correlated with plasma renin concentration for all treatments. In contrast, adipose tissue renin levels did not correlate with plasma renin, with the exception of extremely high plasma renin concentrations achieved in the losartan-treated group. These results suggest that adipose tissue may control its own local renin concentration independently of plasma renin as a potential mechanism for maintaining a functional local adipose RAS.

  12. Insulin-Mediated FFA Suppression Is Associated with Triglyceridemia and Insulin Sensitivity Independent of Adiposity

    PubMed Central

    Bush, Nikki C.; Basu, Rita; Rizza, Robert A.; Nair, K. Sreekumaran; Khosla, Sundeep

    2012-01-01

    Context: A central/visceral fat distribution and excess free fatty acid (FFA) availability are associated with dyslipidemia and insulin resistance. However, these two characteristics often coexist, making it difficult to detect the independent contributions of each. Whether FFA suppression is more closely linked to metabolic abnormalities is not clear. Objective: The aim of the study was to examine the relationship between FFA suppression, body fat distribution, and fitness as contributors toward insulin resistance and hypertriglyceridemia. Design: We measured systemic palmitate turnover using an iv infusion of [9,10-3H]palmitate; upper body sc adipose tissue (UBSQ) and visceral adipose tissue (VAT) with dual-energy x-ray absorptiometry and a single-slice abdominal computed tomography scan; fitness with a graded exercise treadmill test; and insulin sensitivity with both the iv glucose tolerance test (IVGTT) (SIIVGTT) and mixed meal tolerance test (SIMeal). Setting: The study was conducted at a General Clinical Research Center. Participants: Baseline data were obtained from 140 elderly adults (age, 60–88 yr; 83 males) and 60 young adults (age, 18–31 yr; 31 males) who participated in a previously published trial assessing the effects of 2-yr supplementation of dehydroepiandrosterone or testosterone on body composition, glucose metabolism, and bone density. Interventions: There were no interventions. Main Outcome Measures: We measured fasting plasma triglyceride (TG) concentrations, SIIVGTT, and SIMeal. Results: Using multivariate regression analysis, the strongest combined predictors of TG concentrations were VAT, postmeal nadir FFA concentrations, sex, and age. The best predictors of SIIVGTT were IVGTT nadir palmitate concentration, VAT, UBSQ fat, fitness, and age, whereas the best predictors of SIMeal were meal nadir palmitate concentration, UBSQ fat, fitness, and sex. Conclusions: FFA suppression is associated with both fasting TG concentrations and insulin

  13. 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.

  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. Regulation of cholesteryl ester transfer activity in adipose tissue: comparison between hamster and rat species.

    PubMed

    Shen, G X; Angel, A

    1995-07-01

    The present study demonstrates cholesteryl ester transfer activity (CETA) in cultured hamster and rat adipose tissue. Cultured hamster and rat adipose tissue fragments released CETA into the conditioned medium, and this was associated with a reciprocal decrease in adipose tissue CETA. Regional variations in adipose CETA were observed. The levels of CETA released from cultured hamster and rat adipocytes were higher than those from adipose tissue fragments. In hamsters but not in rats, the secretion of CETA from cultured adipose tissue was increased by insulin and inhibited by EDTA in a dose-dependent fashion. Monoclonal antibodies against human cholesteryl ester transfer protein inhibited the CETA secreted from hamster adipose tissue but not that from rat adipose tissue. Fasting for 24 h and a high-cholesterol saturated fat-rich diet increased adipose CETA in hamsters and rats, and this was associated with an elevation of plasma CETA only in hamsters. This supports the view that, in hamsters, adipose CETA has in situ and intravascular functions, whereas in rats the role of adipose CETA is restricted to tissue-specific functions. Hamster cholesteryl ester transfer protein may differ from rat adipose-associated CETA in the structure of the active site and the regulatory mechanism for its secretion.

  16. Cellularity of adipose tissue in fetal pig.

    PubMed

    Desnoyers, F; Pascal, G; Etienne, M; Vodovar, N

    1980-03-01

    Adipose tissue cellularity was studied in the 85-day-old Large-White pig fetus. The aim of this work was to count the adipose cells of forming tissue in an animal species which could be a possible model for studying adipose tissue in humans. Using a morphometric method with electron microscopy, mean triglyceride volume per cell was determined independently of mean cell volume. This method is suitable for counting adipose cells in the early stage of differentiation whatever their size and lipid inclusion volume. Site-by-site dissection of adipose tissue was not feasible in the 85-day old fetus and adipose cell number was computed by dividing total carcass triglyceride volume by mean triglyceride volume per cell. The carcass triglyceride seemed to originate only from adipose cells. The mean total carcass triglyceride volume per fetus (1.84 g) was low but, owing to the low mean triglyceride volume per cell (180.28 microns3), the adipose cell number (11.15 X 10(9)) was relatively important, as it represented about 27% of the extramuscular adipose cell number in the Large-White adult pig (41 X 10(9)).

  17. Adipose tissue macrophages impair preadipocyte differentiation in humans

    PubMed Central

    Liu, Li Fen; Craig, Colleen M.; Tolentino, Lorna L.; Choi, Okmi; Morton, John; Rivas, Homero; Cushman, Samuel W.; Engleman, Edgar G.; McLaughlin, Tracey

    2017-01-01

    Aim The physiologic mechanisms underlying the relationship between obesity and insulin resistance are not fully understood. Impaired adipocyte differentiation and localized inflammation characterize adipose tissue from obese, insulin-resistant humans. The directionality of this relationship is not known, however. The aim of the current study was to investigate whether adipose tissue inflammation is causally-related to impaired adipocyte differentiation. Methods Abdominal subcutaneous(SAT) and visceral(VAT) adipose tissue was obtained from 20 human participants undergoing bariatric surgery. Preadipocytes were isolated, and cultured in the presence or absence of CD14+ macrophages obtained from the same adipose tissue sample. Adipocyte differentiation was quantified after 14 days via immunofluorescence, Oil-Red O, and adipogenic gene expression. Cytokine secretion by mature adipocytes cultured with or without CD14+macrophages was quantified. Results Adipocyte differentiation was significantly lower in VAT than SAT by all measures (p<0.001). With macrophage removal, SAT preadipocyte differentiation increased significantly as measured by immunofluorescence and gene expression, whereas VAT preadipocyte differentiation was unchanged. Adipocyte-secreted proinflammatory cytokines were higher and adiponectin lower in media from VAT vs SAT: macrophage removal reduced inflammatory cytokine and increased adiponectin secretion from both SAT and VAT adipocytes. Differentiation of preadipocytes from SAT but not VAT correlated inversely with systemic insulin resistance. Conclusions The current results reveal that proinflammatory immune cells in human SAT are causally-related to impaired preadipocyte differentiation, which in turn is associated with systemic insulin resistance. In VAT, preadipocyte differentiation is poor even in the absence of tissue macrophages, pointing to inherent differences in fat storage potential between the two depots. PMID:28151993

  18. Adipose tissue chromium and vanadium disbalance in high-fat fed Wistar rats.

    PubMed

    Tinkov, Alexey A; Popova, Elizaveta V; Polyakova, Valentina S; Kwan, Olga V; Skalny, Anatoly V; Nikonorov, Alexandr A

    2015-01-01

    The primary objective of the current study is to investigate the relationship between adipose tissue chromium and vanadium content and adipose tissue dysfunction in a model of diet-induced obesity. A total of 26 female Wistar rats were fed either standard or high-fat diet (31.6% of fat from total caloric content) for 3 months. High-fat-feeding resulted in 21 and 33% decrease in adipose tissue chromium and vanadium content, respectively. No change was seen in hair chromium or vanadium levels. Statistical analysis revealed a significant inverse correlation of adipose tissue Cr and V with animal morphometric parameters and adipocyte size. Significant inverse dependence was observed between adipose tissue Cr and V and serum leptin and proinflammatory cytokines' levels. At the same time, adipose tissue Cr and V levels were characterized by positive correlation between serum adiponectin and adiponectin/leptin ratio. Adipose tissue Cr and V were inversely correlated (p<0.05) with insulin and homeostatic model assessment insulin resistance index (HOMA-IR) levels. Cr and V concentrations were not correlated with serum glucose in either high-fat fed or control rats; however, both serum glucose and HOMA-IR levels were significantly higher in high-fat fed, compared to control, rats. The results allow to hypothesize that impairment of adipose tissue Cr and V content plays a certain role in the development of adipose tissue endocrine dysfunction in obesity.

  19. 11-Beta hydroxysteroid dehydrogenase type 2 expression in white adipose tissue is strongly correlated with adiposity.

    PubMed

    Milagro, Fermin I; Campión, Javier; Martínez, J Alfredo

    2007-04-01

    Glucocorticoid action within the cells is regulated by the levels of glucocorticoid receptor (GR) expression and two enzymes, 11-beta hydroxysteroid dehydrogenase type 1 (11betaHSD1), which converts inactive to active glucocorticoids, and 11-beta hydroxysteroid dehydrogenase type 2 (11betaHSD2), which regulates the access of active glucocorticoids to the receptor by converting cortisol/corticosterone to the glucocorticoid-inactive form cortisone/dehydrocorticosterone. Male Wistar rats developed obesity by being fed a high-fat diet for 56 days, and GR, 11betaHSD1 and 11betaHSD2 gene expression were compared with control-diet fed animals. Gene expression analysis of 11betaHSD1, 11betaHSD2 and GR were performed by RT-PCR in subcutaneous and retroperitoneal adipose tissue. High-fat fed animals overexpressed 11betaHSD2 in subcutaneous but not in retroperitoneal fat. Interestingly, mRNA levels strongly correlated in both tissues with different parameters related to obesity, such as body weight, adiposity and insulin resistance, suggesting that this gene is a reliable marker of adiposity in this rat model of obesity. Thus, 11betaHSD2 is expressed in adipose tissue by both adipocytes and stromal-vascular cells, which suggests that this enzyme may play an important role in preventing fat accumulation in adipose tissue.

  20. Cardiac adipose tissue and atrial fibrillation: the perils of adiposity.

    PubMed

    Hatem, Stéphane N; Redheuil, Alban; Gandjbakhch, Estelle

    2016-04-01

    The amount of adipose tissue that accumulates around the atria is associated with the risk, persistence, and severity of atrial fibrillation (AF). A strong body of clinical and experimental evidence indicates that this relationship is not an epiphenomenon but is the result of complex crosstalk between the adipose tissue and the neighbouring atrial myocardium. For instance, epicardial adipose tissue is a major source of adipokines, inflammatory cytokines, or reactive oxidative species, which can contribute to the fibrotic remodelling of the atrial myocardium. Fibro-fatty infiltrations of the subepicardium could also contribute to the functional disorganization of the atrial myocardium. The observation that obesity is associated with distinct structural and functional remodelling of the atria has opened new perspectives of treating AF substrate with aggressive risk factor management. Advances in cardiac imaging should lead to an improved ability to visualize myocardial fat depositions and to localize AF substrates.

  1. Brown adipose tissue, thermogenesis, angiogenesis: pathophysiological aspects.

    PubMed

    Honek, Jennifer; Lim, Sharon; Fischer, Carina; Iwamoto, Hideki; Seki, Takahiro; Cao, Yihai

    2014-07-01

    The number of obese and overweight individuals is globally rising, and obesity-associated disorders such as type 2 diabetes, cardiovascular disease and certain types of cancer are among the most common causes of death. While white adipose tissue is the key player in the storage of energy, active brown adipose tissue expends energy due to its thermogenic capacity. Expanding and activating brown adipose tissue using pharmacological approaches therefore might offer an attractive possibility for therapeutic intervention to counteract obesity and its consequences for metabolic health.

  2. New Physiological Aspects of Brown Adipose Tissue.

    PubMed

    Trayhurn, Paul; Arch, Jonathan R S

    2014-12-01

    Brown adipose tissue is specialised for the generation of heat by non-shivering mechanisms. In rodents, the tissue plays a role in energy balance and the development of obesity, as well as in thermoregulation. Studies using fluorodeoxyglucose positron emission tomography (FDG-PET), together with the identification of uncoupling protein-1, have provided definitive evidence that brown adipose tissue is present in adult humans. Brown fat activity is stimulated by cold exposure, declines with age and is inversely proportional to BMI. This has led to renewed interest in the tissue as a therapeutic target for the treatment of obesity. Brown adipose tissue also plays a role in glucose disposal and triglyceride clearance, implicating it in the metabolic syndrome. A potential mechanism for increasing thermogenesis is by the 'browning' of white adipose depots through the recruitment of the recently identified third type of adipocyte - the brite (or beige) fat cell.

  3. Insulin response in individual tissues of control and gold thioglucose-obese mice in vivo with (1-/sup 14/C)2-deoxyglucose

    SciTech Connect

    Cooney, G.J.; Astbury, L.D.; Williams, P.F.; Caterson, I.D.

    1987-02-01

    The dose-response characteristics of several glucose-utilizing tissues (brain, heart, white adipose tissue, brown adipose tissue, and quadriceps muscle) to a single injection of insulin have been compared in control mice and mice made obese with a single injection of gold thioglucose (GTG). Tissue content of (1-/sup 14/C)2-deoxyglucose 6-phosphate and blood disappearance rate of (1-/sup 14/C)2-deoxyglucose (2-DG) were measured at nine different insulin doses and used to calculate rates of 2-DG uptake and phosphorylation in tissues from control and obese mice. The insulin sensitivity of tissues reflected in the ED50 of insulin response varied widely, and brown adipose tissue was the most insulin-sensitive tissue studied. In GTG-obese mice, heart, quadriceps, and brown adipose tissue were insulin resistant (demonstrated by increased ED50), whereas in white adipose tissue, 2-DG phosphorylation was more sensitive to insulin. Brain 2-DG phosphorylation was insulin independent in control and obese animals. The largest decrease in insulin sensitivity in GTG-obese mice was observed in brown adipose tissue. The loss of diet-induced thermogenesis in brown adipose tissue as a result of the hypothalamic lesion in GTG-obese mice could be a major cause of insulin resistance in brown adipose tissue. Because brown adipose tissue can make a major contribution to whole-body glucose utilization, insulin resistance in this tissue may have a significant effect on whole-animal glucose homeostasis in GTG-obese mice.

  4. Brown adipose tissue and its therapeutic potential.

    PubMed

    Lidell, M E; Betz, M J; Enerbäck, S

    2014-10-01

    Obesity and related diseases are a major cause of human morbidity and mortality and constitute a substantial economic burden for society. Effective treatment regimens are scarce, and new therapeutic targets are needed. Brown adipose tissue, an energy-expending tissue that produces heat, represents a potential therapeutic target. Its presence is associated with low body mass index, low total adipose tissue content and a lower risk of type 2 diabetes mellitus. Knowledge about the development and function of thermogenic adipocytes in brown adipose tissue has increased substantially in the last decade. Important transcriptional regulators have been identified, and hormones able to modulate the thermogenic capacity of the tissue have been recognized. Intriguingly, it is now clear that humans, like rodents, possess two types of thermogenic adipocytes: the classical brown adipocytes found in the interscapular brown adipose organ and the so-called beige adipocytes primarily found in subcutaneous white adipose tissue after adrenergic stimulation. The presence of two distinct types of energy-expending adipocytes in humans is conceptually important because these cells might be stimulated and recruited by different signals, raising the possibility that they might be separate potential targets for therapeutic intervention. In this review, we will discuss important features of the energy-expending brown adipose tissue and highlight those that may serve as potential targets for pharmacological intervention aimed at expanding the tissue and/or enhancing its function to counteract obesity.

  5. Glucose transporter isoform-3-null heterozygous mutation causes sexually dimorphic adiposity with insulin resistance.

    PubMed

    Ganguly, Amit; Devaskar, Sherin U

    2008-06-01

    We examined male and female glucose transporter isoform-3 (GLUT3; placenta)-null heterozygous(+/-) mutation-carrying mice and compared them with age- and sex-matched wild-type(+/+) littermates. No difference in postnatal (1-2 days, 6-7 days, 12-13 days, 20-21 days), postsuckling (1-2 mo), and adult (3-6 mo) growth pattern was seen except for an increase in body weight of 9- to 11-mo-old male but not female GLUT3(+/-) mice. This change in male mutant mice was associated with increased total body fat mass, perirenal and epididymal white adipose tissue weight, and hepatic lipid infiltration. These minimally glucose-intolerant male mutant mice demonstrated no change in caloric intake but a decline in basal metabolic rate and insulin resistance. No perturbation in basal circulating glucose concentrations but an increase in insulin concentrations, triglycerides, and total cholesterol was observed in GLUT3(+/-) male mice. Tissue analysis in males and females demonstrated diminished GLUT3 protein in GLUT3(+/-) brain and skeletal muscle with no change in brain and adipose tissue GLUT1 protein concentrations. Furthermore, the male GLUT3(+/-) mice expressed decreased insulin-responsive GLUT4 in white adipose tissue and skeletal muscle sarcolemma. We conclude that the GLUT3(+/-) male mice develop adult-onset adiposity with insulin resistance.

  6. The Ubiquitin Ligase Siah2 Regulates Obesity-induced Adipose Tissue Inflammation

    PubMed Central

    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

    2015-01-01

    Objective 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, we examined the effect of the ubiquitin ligase Siah2 on obesity-related adipose tissue inflammation. Methods Wild-type and Siah2KO mice were fed a low or high fat diet for 16 weeks. Indirect calorimetry, body composition, 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. Results Enlarged adipocytes in obese Siah2KO mice are not associated with obesity-induced insulin resistance. Proinflammatory gene expression, stress kinase signaling, fibrosis and crown-like structures are reduced in the Siah2KO adipose tissue and Siah2KO adipocytes are more responsive to insulin-dependent inhibition of lipolysis. Loss of Siah2 increases expression of PPARγ target genes involved in lipid metabolism and decreases expression of proinflammatory adipokines regulated by PPARγ. Conclusions 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. PMID:26380945

  7. Influencing Factors of Thermogenic Adipose Tissue Activity

    PubMed Central

    Zhang, Guoqing; Sun, Qinghua; Liu, Cuiqing

    2016-01-01

    Obesity is an escalating public health challenge and contributes tremendously to the disease burden globally. New therapeutic strategies are required to alleviate the health impact of obesity-related metabolic dysfunction. Brown adipose tissue (BAT) is specialized for dissipating chemical energy for thermogenesis as a defense against cold environment. Intriguingly, the brown-fat like adipocytes that dispersed throughout white adipose tissue (WAT) in rodents and humans, called “brite” or “beige” adipocytes, share similar thermogenic characteristics to brown adipocytes. Recently, researchers have focused on cognition of these thermogenic adipose tissues. Some factors have been identified to regulate the development and function of thermogenic adipose tissues. Cold exposure, pharmacological conditions, and lifestyle can enhance non-shivering thermogenesis and metabolism via some mechanisms. However, environmental pollutants, such as ambient fine particulates and ozone, may impair the function of these thermogenic adipose tissues and thereby induce metabolic dysfunction. In this review, the origin, function and influencing factors of thermogenic adipose tissues were summarized and it will provide insights into identifying new therapeutic strategies for the treatment of obesity and obesity-related diseases. PMID:26903879

  8. A peptide probe for targeted brown adipose tissue imaging.

    PubMed

    Azhdarinia, Ali; Daquinag, Alexes C; Tseng, Chieh; Ghosh, Sukhen C; Ghosh, Pradip; Amaya-Manzanares, Felipe; Sevick-Muraca, Eva; Kolonin, Mikhail G

    2013-01-01

    The presence of brown adipose tissue responsible for thermogenic energy dissipation has been revealed in adult humans and has high clinical importance. Owing to limitations of current methods for brown adipose tissue detection, analysing the abundance and localization of brown adipose tissue in the body has remained challenging. Here we screen a combinatorial peptide library in mice and characterize a peptide (with the sequence CPATAERPC) that selectively binds to the vascular endothelium of brown adipose tissue, but not of intraperitoneal white adipose tissue. We show that in addition to brown adipose tissue, this peptide probe also recognizes the vasculature of brown adipose tissue-like depots of subcutaneous white adipose tissue. Our results indicate that the CPATAERPC peptide localizes to brown adipose tissue even in the absence of sympathetic nervous system stimulation. Finally, we demonstrate that this probe can be used to identify brown adipose tissue depots in mice by whole-body near-infrared fluorescence imaging.

  9. Maternal nutritional manipulations program adipose tissue dysfunction in offspring

    PubMed Central

    Lecoutre, Simon; Breton, Christophe

    2015-01-01

    Based on the concept of Developmental Origin of Health and Disease, both human and animal studies have demonstrated a close link between nutrient supply perturbations in the fetus or neonate (i.e., maternal undernutrition, obesity, gestational diabetes and/or rapid catch-up growth) and increased risk of adult-onset obesity. Indeed, the adipose tissue has been recognized as a key target of developmental programming in a sex-and depot-specific manner. Despite different developmental time windows, similar mechanisms of adipose tissue programming have been described in rodents and in bigger mammals (sheep, primates). Maternal nutritional manipulations reprogram offspring's adipose tissue resulting in series of alterations: enhanced adipogenesis and lipogenesis, impaired sympathetic activity with reduced noradrenergic innervations and thermogenesis as well as low-grade inflammation. These changes affect adipose tissue development, distribution and composition predisposing offspring to fat accumulation. Modifications of hormonal tissue sensitivity (i.e., leptin, insulin, glucocorticoids) and/or epigenetic mechanisms leading to persistent changes in gene expression may account for long-lasting programming across generations. PMID:26029119

  10. Visceral adipose tissue but not subcutaneous adipose tissue is associated with urine and serum metabolites.

    PubMed

    Schlecht, Inga; Gronwald, Wolfram; Behrens, Gundula; Baumeister, Sebastian E; Hertel, Johannes; Hochrein, Jochen; Zacharias, Helena U; Fischer, Beate; Oefner, Peter J; Leitzmann, Michael F

    2017-01-01

    Obesity is a complex multifactorial phenotype that influences several metabolic pathways. Yet, few studies have examined the relations of different body fat compartments to urinary and serum metabolites. Anthropometric phenotypes (visceral adipose tissue (VAT), subcutaneous adipose tissue (SAT), the ratio between VAT and SAT (VSR), body mass index (BMI), waist circumference (WC)) and urinary and serum metabolite concentrations measured by nuclear magnetic resonance spectroscopy were measured in a population-based sample of 228 healthy adults. Multivariable linear and logistic regression models, corrected for multiple testing using the false discovery rate, were used to associate anthropometric phenotypes with metabolites. We adjusted for potential confounding variables: age, sex, smoking, physical activity, menopausal status, estimated glomerular filtration rate (eGFR), urinary glucose, and fasting status. In a fully adjusted logistic regression model dichotomized for the absence or presence of quantifiable metabolite amounts, VAT, BMI and WC were inversely related to urinary choline (ß = -0.18, p = 2.73*10-3), glycolic acid (ß = -0.20, 0.02), and guanidinoacetic acid (ß = -0.12, p = 0.04), and positively related to ethanolamine (ß = 0.18, p = 0.02) and dimethylamine (ß = 0.32, p = 0.02). BMI and WC were additionally inversely related to urinary glutamine and lactic acid. Moreover, WC was inversely associated with the detection of serine. VAT, but none of the other anthropometric parameters, was related to serum essential amino acids, such as valine, isoleucine, and phenylalanine among men. Compared to other adiposity measures, VAT demonstrated the strongest and most significant relations to urinary and serum metabolites. The distinct relations of VAT, SAT, VSR, BMI, and WC to metabolites emphasize the importance of accurately differentiating between body fat compartments when evaluating the potential role of metabolic regulation in the development of obesity

  11. Human omental and subcutaneous adipose tissue exhibit specific lipidomic signatures.

    PubMed

    Jové, Mariona; Moreno-Navarrete, José María; Pamplona, Reinald; Ricart, Wifredo; Portero-Otín, Manuel; Fernández-Real, José Manuel

    2014-03-01

    Despite their differential effects on human metabolic pathophysiology, the differences in omental and subcutaneous lipidomes are largely unknown. To explore this field, liquid chromatography coupled with mass spectrometry was used for lipidome analyses of adipose tissue samples (visceral and subcutaneous) selected from a group of obese subjects (n=38). Transcriptomics and in vitro studies in adipocytes were used to confirm the pathways affected by location. The analyses revealed the existence of obesity-related specific lipidome signatures in each of these locations, attributed to selective enrichment of specific triglycerides, glycerophospholipids, and sphingolipids, because these were not observed in adipose tissues from nonobese individuals. The changes were compatible with subcutaneous enrichment in pathways involved in adipogenesis, triacylglyceride synthesis, and lipid droplet formation, as well as increased α-oxidation. Marked differences between omental and subcutaneous depots in obese individuals were seen in the association of lipid species with metabolic traits (body mass index and insulin sensitivity). Targeted studies also revealed increased cholesterol (Δ56%) and cholesterol epoxide (Δ34%) concentrations in omental adipose tissue. In view of the effects of cholesterol epoxide, which induced enhanced expression of adipocyte differentiation and α-oxidation genes in human omental adipocytes, a novel role for cholesterol epoxide as a signaling molecule for differentiation is proposed. In summary, in obesity, adipose tissue exhibits a location-specific differential lipid profile that may contribute to explaining part of its distinct pathogenic role.

  12. In vitro glucose and 2-aminoisobutyric acid uptake by rat interscapular brown adipose tissue.

    PubMed

    Zamora, F; Arola, L; Alemany, M

    1988-03-11

    The dependence upon substrate and insulin concentrations, as well as on sodium and potassium concentrations in the medium of the uptake of glucose and 2-aminoisobutyric acid, was determined for fragments of brown and white adipose tissues incubated in vitro. Brown adipose tissue showed a high capacity for glucose uptake at high glucose concentrations, this uptake being dependent on both glucose and insulin concentration. White adipose tissue showed much more limited uptake capabilities. The presence of Na+ and K+ had little effect on the uptake. The uptake of 2-aminoisobutyric acid was similar in both adipose tissues, being enhanced by physiological levels of insulin and depressed by ouabain. This amino acid transport was dependent on Na+ and K+ concentrations, and the overall transporting capability was two to three orders of magnitude lower than that for glucose. It was concluded that amino acids could not play a significant role as bulk thermogenic substrates for brown adipose tissue, as their transporters lack the plasticity of response to high substrate and insulin concentrations which characterize brown adipose tissue uptake of glucose.

  13. Predictors of Whole-Body Insulin Sensitivity Across Ages and Adiposity in Adult Humans

    PubMed Central

    Lalia, Antigoni Z.; Dasari, Surendra; Johnson, Matthew L.; Robinson, Matthew M.; Konopka, Adam R.; Distelmaier, Klaus; Port, John D.; Glavin, Maria T.; Esponda, Raul Ruiz; Nair, K. Sreekumaran

    2016-01-01

    (P = .01) as independent predictors. Conclusion: The reduction in insulin sensitivity observed with aging is driven primarily by age-related changes in the content and distribution of adipose tissue and is independent of muscle mitochondrial function or chronological age. PMID:26709968

  14. [New anatomo clinic approach of adipose tissue].

    PubMed

    Dardour, J-C

    2012-10-01

    For a long time, adipose tissue was supposed to be inert with only a function of long-term energetic reserve. The obesity, abnormal accumulation of fat, for its part has always been considered the sole result of hyperphagia, itself secondary to a lack of willingness of the subject. This article focuses on the multiple aspects and functions of the different fatty tissues. One must distinguish brown adipose tissue (AT) and the white AT. This includes visceral fat and subcutaneous AT, which itself is divided into two sectors, a genetic fat and grease that we called ecological. The brown adipose tissue has essentially a function of thermogenesis. Visceral adipose tissue (VAT), from a certain volume, behaves as true endocrine gland acting on glycemic and lipid function. In addition to its role of energy reserve, the sub cutaneous AT has a mechanical role of shock absorber and fabric slip. We will emphasize finally the genetic aspect still too misunderstood and underestimated that regulates the different functions of the adipose tissue.

  15. Brown adipose tissue growth and development.

    PubMed

    Symonds, Michael E

    2013-01-01

    Brown adipose tissue is uniquely able to rapidly produce large amounts of heat through activation of uncoupling protein (UCP) 1. Maximally stimulated brown fat can produce 300 watts/kg of heat compared to 1 watt/kg in all other tissues. UCP1 is only present in small amounts in the fetus and in precocious mammals, such as sheep and humans; it is rapidly activated around the time of birth following the substantial rise in endocrine stimulatory factors. Brown adipose tissue is then lost and/or replaced with white adipose tissue with age but may still contain small depots of beige adipocytes that have the potential to be reactivated. In humans brown adipose tissue is retained into adulthood, retains the capacity to have a significant role in energy balance, and is currently a primary target organ in obesity prevention strategies. Thermogenesis in brown fat humans is environmentally regulated and can be stimulated by cold exposure and diet, responses that may be further modulated by photoperiod. Increased understanding of the primary factors that regulate both the appearance and the disappearance of UCP1 in early life may therefore enable sustainable strategies in order to prevent excess white adipose tissue deposition through the life cycle.

  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. Prolactin (PRL) in adipose tissue: regulation and functions.

    PubMed

    Ben-Jonathan, Nira; Hugo, Eric

    2015-01-01

    New information concerning the effects of prolactin (PRL) on metabolic processes warrants reevaluation of its overall metabolic actions. PRL affects metabolic homeostasis by regulating key enzymes and transporters associated with glucose and lipid metabolism in several target organs. In the lactating mammary gland, PRL increases the production of milk proteins, lactose, and lipids. In adipose tissue, PRL generally suppresses lipid storage and adipokine release and affect adipogenesis. A specific case is made for PRL in the human breast and adipose tissues, where it acts as a circulating hormone and an autocrine/paracrine factor. Although its overall effects on body composition are both modest and species-specific, PRL may be involved in the manifestation of insulin resistance.

  18. The adipose renin-angiotensin system modulates sysemic markers of insulin sensitivity activates the intrarenal renin-angiotensin system

    SciTech Connect

    Kim, Suyeon; Soltani-Bejnood, Morvarid; Quignard-Boulange, Annie; Massiera, Florence; Teboul, Michele; Ailhaud, Gerard; Kim, Jung; Moustaid-Moussa, Naima; Voy, Brynn H

    2006-07-01

    BACKGROUND: A growing body of data provides increasing evidence that the adipose tissue renin-angiotensin system (RAS) contributes to regulation of fat mass. Beyond its paracrine actions within adipose tissue, adipocyte-derived angiotensin II (Ang II) may also impact systemic functions such as blood pressure and metabolism. METHODS AND RESULTS: We used a genetic approach to manipulate adipose RAS activity in mice and then study the consequences on metabolic parameters and on feedback regulation of the RAS. The models included deletion of the angiotensinogen (Agt) gene (Agt-KO), its expression solely in adipose tissue under the control of an adipocyte-specific promoter (aP2-Agt/ Agt-KO), and overexpression in adipose tissue of wild type mice (aP2-Agt). Total body weight, epididymal fat pad weight, and circulating levels of leptin, insulin and resistin were significantly decreased in Agt-KO mice, while plasma adiponectin levels were increased. Overexpression of Agt in adipose tissue resulted in increased adiposity and plasma leptin and insulin levels compared to wild type (WT) controls. Angiotensinogen and type I Ang II receptor protein levels were also markedly elevated in kidney of aP2-Agt mice, suggesting that hypertension in these animals may be in part due to stimulation of the intrarenal RAS. CONCLUSIONS: Taken together, the results from this study demonstrate that alterations in adipose RAS activity significantly alter both local and systemic physiology in a way that may contribute to the detrimental health effects of obesity.

  19. Integrated control of brown adipose tissue.

    PubMed

    Marzetti, Emanuele; D'Angelo, Emanuela; Savera, Giulia; Leeuwenburgh, Christiaan; Calvani, Riccardo

    2016-03-01

    Brown adipose tissue (BAT) has evolved as a unique thermogenic organ that allows placental mammals to withstand cold environmental temperatures through the dissipation of metabolic energy in the form of heat. Although traditionally believed to be lost shortly after birth, metabolically active BAT depots have recently been identified in a large percentage of human adults. Besides classical brown cells, a distinct type of thermogenic adipocytes named beige or brite (brown in white) cells are recruited in white adipose tissue depots under specific stimuli. Given the well-known energy-dissipating properties of thermogenic adipose tissue and its function of metabolic sink for glucose and lipids, this tissue has attracted considerable research interest as a possible target for treating obesity and metabolic disease. The complex network of interorgan connections that regulate BAT and brite tissue mass and function is a major hurdle for the development of therapeutic strategies against metabolic disorders. This review provides an overview of the current knowledge on the regulation of BAT and brite adipose tissue function. The possibility of targeting these tissues to treat obesity and other metabolic disorders is also discussed.

  20. Adipose Tissue - Adequate, Accessible Regenerative Material

    PubMed Central

    Kolaparthy, Lakshmi Kanth.; Sanivarapu, Sahitya; Moogla, Srinivas; Kutcham, Rupa Sruthi

    2015-01-01

    The potential use of stem cell based therapies for the repair and regeneration of various tissues offers a paradigm shift that may provide alternative therapeutic solutions for a number of diseases. The use of either embryonic stem cells (ESCs) or induced pluripotent stem cells in clinical situations is limited due to cell regulations and to technical and ethical considerations involved in genetic manipulation of human ESCs, even though these cells are highly beneficial. Mesenchymal stem cells seen to be an ideal population of stem cells in particular, Adipose derived stem cells (ASCs) which can be obtained in large number and easily harvested from adipose tissue. It is ubiquitously available and has several advantages compared to other sources as easily accessible in large quantities with minimal invasive harvesting procedure, and isolation of adipose derived mesenchymal stem cells yield a high amount of stem cells which is essential for stem cell based therapies and tissue engineering. Recently, periodontal tissue regeneration using ASCs has been examined in some animal models. This method has potential in the regeneration of functional periodontal tissues because various secreted growth factors from ASCs might not only promote the regeneration of periodontal tissues but also encourage neovascularization of the damaged tissues. This review summarizes the sources, isolation and characteristics of adipose derived stem cells and its potential role in periodontal regeneration is discussed. PMID:26634060

  1. Integrated control of brown adipose tissue

    PubMed Central

    Marzetti, Emanuele; D’Angelo, Emanuela; Savera, Giulia; Leeuwenburgh, Christiaan; Calvani, Riccardo

    2016-01-01

    Brown adipose tissue (BAT) has evolved as a unique thermogenic organ that allows placental mammals to withstand cold environmental temperatures through the dissipation of metabolic energy in the form of heat. Although traditionally believed to be lost shortly after birth, metabolically active BAT depots have recently been identified in a large percentage of human adults. Besides classical brown cells, a distinct type of thermogenic adipocytes named beige or brite (brown in white) cells are recruited in white adipose tissue depots under specific stimuli. Given the well-known energy-dissipating properties of thermogenic adipose tissue and its function of metabolic sink for glucose and lipids, this tissue has attracted considerable research interest as a possible target for treating obesity and metabolic disease. The complex network of interorgan connections that regulate BAT and brite tissue mass and function is a major hurdle for the development of therapeutic strategies against metabolic disorders. This review provides an overview of the current knowledge on the regulation of BAT and brite adipose tissue function. The possibility of targeting these tissues to treat obesity and other metabolic disorders is also discussed. PMID:27524955

  2. Circadian Rhythms in Adipose Tissue Physiology.

    PubMed

    Kiehn, Jana-Thabea; Tsang, Anthony H; Heyde, Isabel; Leinweber, Brinja; Kolbe, Isa; Leliavski, Alexei; Oster, Henrik

    2017-03-16

    The different types of adipose tissues fulfill a wide range of biological functions-from energy storage to hormone secretion and thermogenesis-many of which show pronounced variations over the course of the day. Such 24-h rhythms in physiology and behavior are coordinated by endogenous circadian clocks found in all tissues and cells, including adipocytes. At the molecular level, these clocks are based on interlocked transcriptional-translational feedback loops comprised of a set of clock genes/proteins. Tissue-specific clock-controlled transcriptional programs translate time-of-day information into physiologically relevant signals. In adipose tissues, clock gene control has been documented for adipocyte proliferation and differentiation, lipid metabolism as well as endocrine function and other adipose oscillations are under control of systemic signals tied to endocrine, neuronal, or behavioral rhythms. Circadian rhythm disruption, for example, by night shift work or through genetic alterations, is associated with changes in adipocyte metabolism and hormone secretion. At the same time, adipose metabolic state feeds back to central and peripheral clocks, adjusting behavioral and physiological rhythms. In this overview article, we summarize our current knowledge about the crosstalk between circadian clocks and energy metabolism with a focus on adipose physiology. © 2017 American Physiological Society. Compr Physiol 7:383-427, 2017.

  3. Protein turnover in adipose tissue from fasted or diabetic rats

    NASA Technical Reports Server (NTRS)

    Tischler, Marc E.; Ost, Alan H.; Coffman, Julia

    1986-01-01

    Protein synthesis and degradation in vitro were compared in epididymal fat pads from animals deprived of food for 48 h or treated 6 or 12 days prior with streptozotocin to induce diabetes. Although both fasting and diabetes led to depressed (-24 to -57 percent) protein synthesis, the diminution in protein degradation (-63 to -72 percent) was even greater, so that net in vitro protein balance improved dramatically. Insulin failed to inhibit protein degradation in fat pads of these rats as it does for fed animals. Although insulin stimulated protein synthesis in fat pads of fasted and 12 day diabetic rats, the absolute change was much smaller than that seen in the fed state. The inhibition of protein degradation by leucine also seems to be less in fasted animals, probably because leucine catabolism is slower in fasting. These results show that fasting and diabetes may improve protein balance in adipose tissue but diminish the regulatory effects of insulin.

  4. Enhanced insulin sensitivity mediated by adipose tissue browning perturbs islet morphology and hormone secretion in response to autonomic nervous activation in female mice.

    PubMed

    Omar, Bilal A; Kvist-Reimer, Martina; Enerbäck, Sven; Ahrén, Bo

    2016-01-01

    Insulin resistance results in a compensatory increase in insulin secretion to maintain normoglycemia. Conversely, high insulin sensitivity results in reduced insulin secretion to prevent hypoglycemia. The mechanisms for this inverse adaptation are not well understood. We utilized highly insulin-sensitive mice, due to adipocyte-specific overexpression of the FOXC2 transcription factor, to study mechanisms of the reversed islet adaptation to increased insulin sensitivity. We found that Foxc2TG mice responded to mild hyperglycemia with insulin secretion significantly lower than that of wild-type mice; however, when severe hyperglycemia was induced, Foxc2TG mice demonstrated insulin secretion equal to or greater than that of wild-type mice. In response to autonomic nervous activation by 2-deoxyglucose, the acute suppression of insulin seen in wild-type mice was absent in Foxc2TG mice, suggesting impaired sympathetic signaling to the islet. Basal glucagon was increased in Foxc2TG mice, but they displayed severely impaired glucagon responses to cholinergic and autonomic nervous stimuli. These data suggest that the autonomic nerves contribute to the islet adaptation to high insulin sensitivity, which is compatible with a neuro-adipo regulation of islet function being instrumental for maintaining glucose regulation.

  5. IRF3 promotes adipose inflammation and insulin resistance and represses browning

    PubMed Central

    Wang, Xun; Lyubetskaya, Anna; Eguchi, Jun; Kang, Sona; Tenen, Danielle; Roh, Hyun Cheol; Kong, Xingxing; Kazak, Lawrence; Ahmad, Rasheed; Rosen, Evan D.

    2016-01-01

    The chronic inflammatory state that accompanies obesity is a major contributor to insulin resistance and other dysfunctional adaptations in adipose tissue. Cellular and secreted factors promote the inflammatory milieu of obesity, but the transcriptional pathways that drive these processes are not well described. Although the canonical inflammatory transcription factor NF-κB is considered to be the major driver of adipocyte inflammation, members of the interferon regulatory factor (IRF) family may also play a role in this process. Here, we determined that IRF3 expression is upregulated in the adipocytes of obese mice and humans. Signaling through TLR3 and TLR4, which lie upstream of IRF3, induced insulin resistance in murine adipocytes, while IRF3 knockdown prevented insulin resistance. Furthermore, improved insulin sensitivity in IRF3-deficient mice was associated with reductions in intra-adipose and systemic inflammation in the high fat–fed state, enhanced browning of subcutaneous fat, and increased adipose expression of GLUT4. Taken together, the data indicate that IRF3 is a major transcriptional regulator of adipose inflammation and is involved in maintaining systemic glucose and energy homeostasis. PMID:27400129

  6. Metabolic remodeling of white adipose tissue in obesity

    PubMed Central

    Cummins, Timothy D.; Holden, Candice R.; Sansbury, Brian E.; Gibb, Andrew A.; Shah, Jasmit; Zafar, Nagma; Tang, Yunan; Hellmann, Jason; Rai, Shesh N.; Spite, Matthew; Bhatnagar, Aruni

    2014-01-01

    Adipose tissue metabolism is a critical regulator of adiposity and whole body energy expenditure; however, metabolic changes that occur in white adipose tissue (WAT) with obesity remain unclear. The purpose of this study was to understand the metabolic and bioenergetic changes occurring in WAT with obesity. Wild-type (C57BL/6J) mice fed a high-fat diet (HFD) showed significant increases in whole body adiposity, had significantly lower V̇o2, V̇co2, and respiratory exchange ratios, and demonstrated worsened glucose and insulin tolerance compared with low-fat-fed mice. Metabolomic analysis of WAT showed marked changes in lipid, amino acid, carbohydrate, nucleotide, and energy metabolism. Tissue levels of succinate and malate were elevated, and metabolites that could enter the Krebs cycle via anaplerosis were mostly diminished in high-fat-fed mice, suggesting altered mitochondrial metabolism. Despite no change in basal oxygen consumption or mitochondrial DNA abundance, citrate synthase activity was decreased by more than 50%, and responses to FCCP were increased in WAT from mice fed a high-fat diet. Moreover, Pgc1a was downregulated and Cox7a1 upregulated after 6 wk of HFD. After 12 wk of high-fat diet, the abundance of several proteins in the mitochondrial respiratory chain or matrix was diminished. These changes were accompanied by increased Parkin and Pink1, decreased p62 and LC3-I, and ultrastructural changes suggestive of autophagy and mitochondrial remodeling. These studies demonstrate coordinated restructuring of metabolism and autophagy that could contribute to the hypertrophy and whitening of adipose tissue in obesity. PMID:24918202

  7. High levels of dietary stearate promote adiposity and deteriorate hepatic insulin sensitivity

    PubMed Central

    2010-01-01

    Background Relatively little is known about the role of specific saturated fatty acids in the development of high fat diet induced obesity and insulin resistance. Here, we have studied the effect of stearate in high fat diets (45% energy as fat) on whole body energy metabolism and tissue specific insulin sensitivity. Methods C57Bl/6 mice were fed a low stearate diet based on palm oil or one of two stearate rich diets, one diet based on lard and one diet based on palm oil supplemented with tristearin (to the stearate level of the lard based diet), for a period of 5 weeks. Ad libitum fed Oxidative metabolism was assessed by indirect calorimetry at week 5. Changes in body mass and composition was assessed by DEXA scan analysis. Tissue specific insulin sensitivity was assessed by hyperinsulinemic-euglycemic clamp analysis and Western blot at the end of week 5. Results Indirect calorimetry analysis revealed that high levels of dietary stearate resulted in lower caloric energy expenditure characterized by lower oxidation of fatty acids. In agreement with this metabolic phenotype, mice on the stearate rich diets gained more adipose tissue mass. Whole body and tissue specific insulin sensitivity was assessed by hyperinsulinemic-euglycemic clamp and analysis of insulin induced PKBser473 phosphorylation. Whole body insulin sensitivity was decreased by all high fat diets. However, while insulin-stimulated glucose uptake by peripheral tissues was impaired by all high fat diets, hepatic insulin sensitivity was affected only by the stearate rich diets. This tissue-specific pattern of reduced insulin sensitivity was confirmed by similar impairment in insulin-induced phosphorylation of PKBser473 in both liver and skeletal muscle. Conclusion In C57Bl/6 mice, 5 weeks of a high fat diet rich in stearate induces a metabolic state favoring low oxidative metabolism, increased adiposity and whole body insulin resistance characterized by severe hepatic insulin resistance. These results

  8. Central Administration of Galanin Receptor 1 Agonist Boosted Insulin Sensitivity in Adipose Cells of Diabetic Rats

    PubMed Central

    Zhang, Zhenwen; Fang, Penghua; He, Biao; Guo, Lili; Runesson, Johan; Langel, Ülo; Shi, Mingyi; Zhu, Yan; Bo, Ping

    2016-01-01

    Our previous studies testified the beneficial effect of central galanin on insulin sensitivity of type 2 diabetic rats. The aim of the study was further to investigate whether central M617, a galanin receptor 1 agonist, can benefit insulin sensitivity. The effects of intracerebroventricular administration of M617 on insulin sensitivity and insulin signaling were evaluated in adipose tissues of type 2 diabetic rats. The results showed that central injection of M617 significantly increased plasma adiponectin contents, glucose infusion rates in hyperinsulinemic-euglycemic clamp tests, GLUT4 mRNA expression levels, GLUT4 contents in plasma membranes, and total cell membranes of the adipose cells but reduced the plasma C-reactive protein concentration in nondiabetic and diabetic rats. The ratios of GLUT4 contents were higher in plasma membranes to total cell membranes in both nondiabetic and diabetic M617 groups than each control. In addition, the central administration of M617 enhanced the ratios of pAkt/Akt and pAS160/AS160, but not phosphorylative cAMP response element-binding protein (pCREB)/CREB in the adipose cells of nondiabetic and diabetic rats. These results suggest that excitation of central galanin receptor 1 facilitates insulin sensitivity via activation of the Akt/AS160 signaling pathway in the fat cells of type 2 diabetic rats. PMID:27127795

  9. KK/Ta Mice Administered Lactobacillus plantarum Strain No. 14 Have Lower Adiposity and Higher Insulin Sensitivity.

    PubMed

    Okubo, Takuma; Takemura, Naoki; Yoshida, Ayako; Sonoyama, Kei

    2013-01-01

    Excess accumulation of white adipose tissue can lead to obesity-related metabolic abnormalities such as insulin resistance. We previously reported that intragastric administration of Lactobacillus plantarum No. 14 reduced adipocyte size in diet-induced obese C57BL/6 mice. The present study tested whether L. plantarum No. 14 affects adiposity and insulin sensitivity in an animal model of type-2 diabetes mellitus. Male KK/Ta mice were fed a normal-fat diet and intragastrically given L. plantarum No. 14 (10(8) CFU/mouse) or vehicle daily for 10 weeks. Interscapular brown adipose tissue and inguinal, mesenteric, and retroperitoneal white adipose tissue weights, serum leptin and insulin concentrations, and insulin resistance index (HOMA-IR) were significantly lower in L. plantarum No. 14-fed mice than in vehicle-fed mice. The sum of the inguinal, epididymal, mesenteric and retroperitoneal white adipose tissue weights correlated with serum leptin and non-esterified fatty acid concentrations and HOMA-IR. The mesenteric adipose tissue mRNA levels of monocyte chemoattractant protein-1 and tumor necrosis factor-α were significantly lower in L. plantarum No. 14-fed mice than in vehicle-fed mice. Mesenteric adipose tissue weight correlated with interleukin-6, monocyte chemoattractant protein-1, and tumor necrosis factor-α mRNA levels. HOMA-IR correlated with monocyte chemoattractant protein-1 and tumor necrosis factor-α mRNA levels. These data suggest that L. plantarum No. 14 prevents the development of insulin resistance, which is at least partly attributable to the prevention of obesity, in KK/Ta mice.

  10. Metabolic disorders and adipose tissue insulin responsiveness in neonatally STZ-induced diabetic rats are improved by long-term melatonin treatment.

    PubMed

    de Oliveira, Ariclécio C; Andreotti, Sandra; Farias, Talita da S M; Torres-Leal, Francisco L; de Proença, André R G; Campaña, Amanda B; de Souza, Arnaldo H; Sertié, Rogério A L; Carpinelli, Angelo R; Cipolla-Neto, José; Lima, Fábio B

    2012-05-01

    Diabetes mellitus is a product of low insulin sensibility and pancreatic β-cell insufficiency. Rats with streptozotocin-induced diabetes during the neonatal period by the fifth day of age develop the classic diabetic picture of hyperglycemia, hypoinsulinemia, polyuria, and polydipsia aggravated by insulin resistance in adulthood. In this study, we investigated whether the effect of long-term treatment with melatonin can improve insulin resistance and other metabolic disorders in these animals. At the fourth week of age, diabetic animals started an 8-wk treatment with melatonin (1 mg/kg body weight) in the drinking water at night. Animals were then killing, and the sc, epididymal (EP), and retroperitoneal (RP) fat pads were excised, weighed, and processed for adipocyte isolation for morphometric analysis as well as for measuring glucose uptake, oxidation, and incorporation of glucose into lipids. Blood samples were collected for biochemical assays. Melatonin treatment reduced hyperglycemia, polydipsia, and polyphagia as well as improved insulin resistance as demonstrated by constant glucose disappearance rate and homeostasis model of assessment-insulin resistance. However, melatonin treatment was unable to recover body weight deficiency, fat mass, and adipocyte size of diabetic animals. Adiponectin and fructosamine levels were completely recovered by melatonin, whereas neither plasma insulin level nor insulin secretion capacity was improved in diabetic animals. Furthermore, melatonin caused a marked delay in the sexual development, leaving genital structures smaller than those of nontreated diabetic animals. Melatonin treatment improved the responsiveness of adipocytes to insulin in diabetic animals measured by tests of glucose uptake (sc, EP, and RP), glucose oxidation, and incorporation of glucose into lipids (EP and RP), an effect that seems partially related to an increased expression of insulin receptor substrate 1, acetyl-coenzyme A carboxylase and fatty acid

  11. 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.

  12. Tenomodulin promotes human adipocyte differentiation and beneficial visceral adipose tissue expansion

    PubMed Central

    Senol-Cosar, Ozlem; Flach, Rachel J. Roth; DiStefano, Marina; Chawla, Anil; Nicoloro, Sarah; Straubhaar, Juerg; Hardy, Olga T.; Noh, Hye Lim; Kim, Jason K.; Wabitsch, Martin; Scherer, Philipp E.; Czech, Michael P.

    2016-01-01

    Proper regulation of energy storage in adipose tissue is crucial for maintaining insulin sensitivity and molecules contributing to this process have not been fully revealed. Here we show that type II transmembrane protein tenomodulin (TNMD) is upregulated in adipose tissue of insulin-resistant versus insulin-sensitive individuals, who were matched for body mass index (BMI). TNMD expression increases in human preadipocytes during differentiation, whereas silencing TNMD blocks adipogenesis. Upon high-fat diet feeding, transgenic mice overexpressing Tnmd develop increased epididymal white adipose tissue (eWAT) mass, and preadipocytes derived from Tnmd transgenic mice display greater proliferation, consistent with elevated adipogenesis. In Tnmd transgenic mice, lipogenic genes are upregulated in eWAT, as is Ucp1 in brown fat, while liver triglyceride accumulation is attenuated. Despite expanded eWAT, transgenic animals display improved systemic insulin sensitivity, decreased collagen deposition and inflammation in eWAT, and increased insulin stimulation of Akt phosphorylation. Our data suggest that TNMD acts as a protective factor in visceral adipose tissue to alleviate insulin resistance in obesity. PMID:26880110

  13. [White adipose tissue dysfunction observed in obesity].

    PubMed

    Lewandowska, Ewa; Zieliński, Andrzej

    2016-05-01

    Obesity is a disease with continuingly increasing prevalence. It occurs worldwide independently of age group, material status or country of origin. At these times the most common reasons for obesity are bad eating habits and dramatic reduction of physical activity, which cause the energy imbalance of organism. Fundamental alteration observed in obese subjects is white adipose tissue overgrowth, which is linked to increased incidence of obesity-related comorbidities, such as: cardiovascular diseases, type 2 diabetes or digestive tract diseases. What is more, obesity is also a risk factor for some cancers. Special risk for diseases linked to excessive weight is associated with overgrowth of visceral type of adipose tissue. Adipose tissue, which is the main energy storehouse in body and acts also as an endocrine organ, undergoes both the morphological and the functional changes in obesity, having a negative impact on whole body function. In this article we summarize the most important alterations in morphology and function of white adipose tissue, observed in obese subjects.

  14. Reversal of type 1 diabetes in mice by brown adipose tissue transplant.

    PubMed

    Gunawardana, Subhadra C; Piston, David W

    2012-03-01

    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.

  15. Eicosapentaenoic acid regulates brown adipose tissue gene expression and metabolism in high fat fed mice

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Brown adipose tissue (BAT) is a thermogenic tissue, a key regulator of energy balance and a potential therapeutic target for obesity. We previously reported that eicosapentaenoic acid (EPA) reduced high fat (HF) diet-induced obesity and insulin resistance in mice, independent of energy intake. We hy...

  16. Adipose tissue mTORC2 regulates ChREBP-driven de novo lipogenesis and hepatic glucose metabolism

    PubMed Central

    Tang, Yuefeng; Wallace, Martina; Sanchez-Gurmaches, Joan; Hsiao, Wen-Yu; Li, Huawei; Lee, Peter L.; Vernia, Santiago; Metallo, Christian M.; Guertin, David A.

    2016-01-01

    Adipose tissue de novo lipogenesis (DNL) positively influences insulin sensitivity, is reduced in obesity, and predicts insulin resistance. Therefore, elucidating mechanisms controlling adipose tissue DNL could lead to therapies for type 2 diabetes. Here, we report that mechanistic target of rapamycin complex 2 (mTORC2) functions in white adipose tissue (WAT) to control expression of the lipogenic transcription factor ChREBPβ. Conditionally deleting the essential mTORC2 subunit Rictor in mature adipocytes decreases ChREBPβ expression, which reduces DNL in WAT, and impairs hepatic insulin sensitivity. Mechanistically, Rictor/mTORC2 promotes ChREBPβ expression in part by controlling glucose uptake, but without impairing pan-AKT signalling. High-fat diet also rapidly decreases adipose tissue ChREBPβ expression and insulin sensitivity in wild-type mice, and does not further exacerbate insulin resistance in adipose tissue Rictor knockout mice, implicating adipose tissue DNL as an early target in diet-induced insulin resistance. These data suggest mTORC2 functions in WAT as part of an extra-hepatic nutrient-sensing mechanism to control glucose homeostasis. PMID:27098609

  17. Adipose Expression of Tumor Necrosis Factor-α: Direct Role in Obesity-Linked Insulin Resistance

    NASA Astrophysics Data System (ADS)

    Hotamisligil, Gokhan S.; Shargill, Narinder S.; Spiegelman, Bruce M.

    1993-01-01

    Tumor necrosis factor-α (TNF-α) has been shown to have certain catabolic effects on fat cells and whole animals. An induction of TNF-α messenger RNA expression was observed in adipose tissue from four different rodent models of obesity and diabetes. TNF-α protein was also elevated locally and systemically. Neutralization of TNF-α in obese fa/fa rats caused a significant increase in the peripheral uptake of glucose in response to insulin. These results indicate a role for TNF-α in obesity and particularly in the insulin resistance and diabetes that often accompany obesity.

  18. Integrative genomic analysis implicates limited peripheral adipose storage capacity in the pathogenesis of human insulin resistance.

    PubMed

    Lotta, Luca A; Gulati, Pawan; Day, Felix R; Payne, Felicity; Ongen, Halit; van de Bunt, Martijn; Gaulton, Kyle J; Eicher, John D; Sharp, Stephen J; Luan, Jian'an; De Lucia Rolfe, Emanuella; Stewart, Isobel D; Wheeler, Eleanor; Willems, Sara M; Adams, Claire; Yaghootkar, Hanieh; Forouhi, Nita G; Khaw, Kay-Tee; Johnson, Andrew D; Semple, Robert K; Frayling, Timothy; Perry, John R B; Dermitzakis, Emmanouil; McCarthy, Mark I; Barroso, Inês; Wareham, Nicholas J; Savage, David B; Langenberg, Claudia; O'Rahilly, Stephen; Scott, Robert A

    2017-01-01

    Insulin resistance is a key mediator of obesity-related cardiometabolic disease, yet the mechanisms underlying this link remain obscure. Using an integrative genomic approach, we identify 53 genomic regions associated with insulin resistance phenotypes (higher fasting insulin levels adjusted for BMI, lower HDL cholesterol levels and higher triglyceride levels) and provide evidence that their link with higher cardiometabolic risk is underpinned by an association with lower adipose mass in peripheral compartments. Using these 53 loci, we show a polygenic contribution to familial partial lipodystrophy type 1, a severe form of insulin resistance, and highlight shared molecular mechanisms in common/mild and rare/severe insulin resistance. Population-level genetic analyses combined with experiments in cellular models implicate CCDC92, DNAH10 and L3MBTL3 as previously unrecognized molecules influencing adipocyte differentiation. Our findings support the notion that limited storage capacity of peripheral adipose tissue is an important etiological component in insulin-resistant cardiometabolic disease and highlight genes and mechanisms underpinning this link.

  19. The role of adipose tissue in mediating the beneficial effects of dietary fish oil

    PubMed Central

    Puglisi, Michael J.; Hasty, Alyssa H.; Saraswathi, Viswanathan

    2010-01-01

    Fish oil improves several features of metabolic syndrome such as dyslipidemia, insulin resistance and hepatic steatosis. Fish oil may mediate some of its beneficial effects by modulating the storage and/or secretory functions of adipose tissue. The storage of triglycerides in adipose tissue is regulated by the availability of free fatty acids as well as the degree of lipolysis in adipose tissue. Fish oil has been shown to reduce lipolysis in several studies indicating improved triglyceride storage. Importantly, adipose tissue secretes a variety of adipokines and fish oil feeding is associated with remarkable changes in the plasma levels of two key adipokines, adiponectin and leptin. Much attention has been focused on the contribution of adiponectin in fish oil mediated improvements in metabolic syndrome. However, emerging evidence also indicates a role of leptin in modulating the components of the metabolic syndrome upon fish oil feeding. In addition to improving the storage and secretory functions of adipose tissue, fish oil, and the n-3 fatty acids found in fish oil, has been shown to reduce inflammation in adipose tissue. These effects may be in part a result of activation of peroxisome proliferator-activated receptor γ or inhibition of toll-like receptor 4. Thus, there is compelling evidence that fish oil mediates its beneficial effects on metabolic syndrome by improving adipose tissue storage and secretory functions and by reducing inflammation. PMID:21145721

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

    PubMed Central

    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. PMID:27597806

  1. Oestrone sulphate, adipose tissue, and breast cancer.

    PubMed

    Hawkins, R A; Thomson, M L; Killen, E

    1985-01-01

    Oestrone sulphate, the oestrogen in highest concentration in the plasma, may play a role in the induction and growth of breast cancers. By enzymolysis and radioimmunoassay, oestrone sulphate concentrations were measured in 3 biological fluids. High concentrations of the conjugate (up to 775 nmol/l) were detected in breast cyst fluids from some premenopausal women, the concentrations in blood plasma (0.91-4.45 nmol/l) being much lower. Concentrations in the plasmas from postmenopausal women with (0.23-4.63 nmol/l) or without (0.18-1.27 nmol/l) breast cancer were still lower. Oestrone sulphate concentration in cow's milk or cream (0.49-0.67 nmol/l) was also low: dietary intake in these fluids is probably of little consequence. The capacity of breast tissues for hydrolysis of oestrone sulphate was examined in two ways: In tissue slices incubated with 85 pM (3H) oestrone sulphate solution at 37 degrees C, cancers (131-412 fmol/g tissue/hr) and adipose tissues (23-132 fmol/g tissue/hr) hydrolysed significantly more sulphate than did benign tissues (1-36 fmol/g tissue/hr). In tissue homogenates incubated with 5-25 microM [3H] oestrone sulphate at 37 degrees much higher capacities for hydrolysis (nmol/g tissue/hr) were demonstrated with a Km of 2-16.5 microM: cancers (34-394) and benign tissues (9-485) had significantly higher sulphatase activities than adipose tissues (9-39). On a protein basis, however, the sulphatase activities in the 3 tissues were comparable. It is concluded that oestrone sulphate is present in breast cysts and blood plasma and that in vitro, the conjugated hormone can be hydrolysed by breast tissues. The biological significance of these findings in vivo remains to be established.

  2. Brown adipose tissue and novel therapeutic approaches to treat metabolic disorders.

    PubMed

    Roman, Sabiniano; Agil, Ahmad; Peran, Macarena; Alvaro-Galue, Eduardo; Ruiz-Ojeda, Francisco J; Fernández-Vázquez, Gumersindo; Marchal, Juan A

    2015-04-01

    In humans, 2 functionally different types of adipose tissue coexist: white adipose tissue (WAT) and brown adipose tissue (BAT). WAT is involved in energy storage, whereas BAT is involved in energy expenditure. Increased amounts of WAT may contribute to the development of metabolic disorders, such as obesity-associated type 2 diabetes mellitus and cardiovascular diseases. In contrast, the thermogenic function of BAT allows high consumption of fatty acids because of the activity of uncoupling protein 1 in the internal mitochondrial membrane. Interestingly, obesity reduction and insulin sensitization have been achieved by BAT activation-regeneration in animal models. This review describes the origin, function, and differentiation mechanisms of BAT to identify new therapeutic strategies for the treatment of metabolic disorders related to obesity. On the basis of the animal studies, novel approaches for BAT regeneration combining stem cells from the adipose tissue with active components, such as melatonin, may have potential for the treatment of metabolic disorders in humans.

  3. Adipose tissue and skeletal muscle plasticity modulates metabolic health.

    PubMed

    Ukropec, Jozef; Ukropcova, Barbara; Kurdiova, Timea; Gasperikova, Daniela; Klimes, Iwar

    2008-12-01

    Obesity, accumulation of adipose tissue, develops when energy intake exceeds energy expenditure. Adipose tissue is essential for buffering the differences between energy intake and expenditure by accumulating lipids while skeletal muscle is the energy burning machine. Here we adopted the concept that (i) adipose tissue ability to regulate the storage capacity for lipids as well as (ii) dynamic regulation of muscle and adipose tissue secretory and metabolic activity is important for maintaining the metabolic health. This might be at least in part related to tissue plasticity, a phenomenon enabling dynamic modulation of the tissue phenotype in different physiological and pathophysiological situations. Recent advances in our understanding of the complex endocrine function of adipose tissue in regulating lipid metabolism, adipogenesis, angiogenesis, extracellular matrix remodelling, inflammation and oxidative stress prompted us to review the role of tissue plasticity--dynamic changes in adipose tissue and skeletal muscle metabolic and endocrine phenotype--in determining the difference between metabolic health and disease.

  4. Adipose tissue glycogen accumulation is associated with obesity-linked inflammation in humans

    PubMed Central

    Ceperuelo-Mallafré, Victòria; Ejarque, Miriam; Serena, Carolina; Duran, Xavier; Montori-Grau, Marta; Rodríguez, Miguel Angel; Yanes, Oscar; Núñez-Roa, Catalina; Roche, Kelly; Puthanveetil, Prasanth; Garrido-Sánchez, Lourdes; Saez, Enrique; Tinahones, Francisco J.; Garcia-Roves, Pablo M.; Gómez-Foix, Anna Ma; Saltiel, Alan R.; Vendrell, Joan; Fernández-Veledo, Sonia

    2015-01-01

    Objective Glycogen metabolism has emerged as a mediator in the control of energy homeostasis and studies in murine models reveal that adipose tissue might contain glycogen stores. Here we investigated the physio(patho)logical role of glycogen in human adipose tissue in the context of obesity and insulin resistance. Methods We studied glucose metabolic flux of hypoxic human adipoctyes by nuclear magnetic resonance and mass spectrometry-based metabolic approaches. Glycogen synthesis and glycogen content in response to hypoxia was analyzed in human adipocytes and macrophages. To explore the metabolic effects of enforced glycogen deposition in adipocytes and macrophages, we overexpressed PTG, the only glycogen-associated regulatory subunit (PP1-GTS) reported in murine adipocytes. Adipose tissue gene expression analysis was performed on wild type and homozygous PTG KO male mice. Finally, glycogen metabolism gene expression and glycogen accumulation was analyzed in adipose tissue, mature adipocytes and resident macrophages from lean and obese subjects with different degrees of insulin resistance in 2 independent cohorts. Results We show that hypoxia modulates glucose metabolic flux in human adipocytes and macrophages and promotes glycogenesis. Enforced glycogen deposition by overexpression of PTG re-orients adipocyte secretion to a pro-inflammatory response linked to insulin resistance and monocyte/lymphocyte migration. Furthermore, glycogen accumulation is associated with inhibition of mTORC1 signaling and increased basal autophagy flux, correlating with greater leptin release in glycogen-loaded adipocytes. PTG-KO mice have reduced expression of key inflammatory genes in adipose tissue and PTG overexpression in M0 macrophages induces a pro-inflammatory and glycolytic M1 phenotype. Increased glycogen synthase expression correlates with glycogen deposition in subcutaneous adipose tissue of obese patients. Glycogen content in subcutaneous mature adipocytes is associated

  5. 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

  6. Platycodon grandiflorus Root Extract Attenuates Body Fat Mass, Hepatic Steatosis and Insulin Resistance through the Interplay between the Liver and Adipose Tissue

    PubMed Central

    Kim, Ye Jin; Choi, Ji-Young; Ryu, Ri; Lee, Jeonghyeon; Cho, Su-Jung; Kwon, Eun-Young; Lee, Mi-Kyung; Liu, Kwang-Hyeon; Rina, Yu; Sung, Mi-Kyung; Choi, Myung-Sook

    2016-01-01

    The Platycodon grandiflorus root, a Korean medicinal food, is well known to have beneficial effects on obesity and diabetes. In this study, we demonstrated the metabolic effects of P. grandiflorus root ethanol extract (PGE), which is rich in platycodins, on diet-induced obesity. C57BL/6J mice (four-week-old males) were fed a normal diet (16.58% of kilocalories from fat), high-fat diet (HFD, 60% of kilocalories from fat), and HFD supplemented with 5% (w/w) PGE. In the HFD-fed mice, PGE markedly suppressed the body weight gain and white fat mass to normal control level, with simultaneous increase in the expression of thermogenic genes (such as SIRT1, PPARα, PGC1α, and UCP1), that accompanied changes in fatty acid oxidation (FAO) and energy expenditure. In addition, PGE improved insulin sensitivity through activation of the PPARγ expression, which upregulates adiponectin while decreasing leptin gene expression in adipocytes. Furthermore, PGE improved hepatic steatosis by suppressing hepatic lipogenesis while increasing expression of FAO-associated genes such as PGC1α. PGE normalized body fat and body weight, which is likely associated with the increased energy expenditure and thermogenic gene expression. PGE can protect from HFD-induced insulin resistance, and hepatic steatosis by controlling lipid and glucose metabolism. PMID:27589792

  7. Androgenic Regulation of White Adipose Tissue-Prostate Cancer Interactions

    DTIC Science & Technology

    2015-08-01

    rights reserved.1. Introduction White adipose tissue (WAT) is a loose connective tissue that is crucial in the regulation of whole-body fatty-acid...AWARD NUMBER: W81XWH-10-1-0275 TITLE: Androgenic Regulation of White Adipose Tissue -Prostate Cancer Interactions PRINCIPAL INVESTIGATOR...2010-05/31/2015 4. TITLE AND SUBTITLE 5a. CONTRACT NUMBER W81XWH-10-1-0275 Androgenic Regulation of White Adipose Tissue -Prostate Cancer

  8. Encapsulation Thermogenic Preadipocytes for Transplantation into Adipose Tissue Depots

    PubMed Central

    Xu, Lu; Shen, Qiwen; Mao, Zhongqi; Lee, L. James; Ziouzenkova, Ouliana

    2015-01-01

    Cell encapsulation was developed to entrap viable cells within semi-permeable membranes. The engrafted encapsulated cells can exchange low molecular weight metabolites in tissues of the treated host to achieve long-term survival. The semipermeable membrane allows engrafted encapsulated cells to avoid rejection by the immune system. The encapsulation procedure was designed to enable a controlled release of bioactive compounds, such as insulin, other hormones, and cytokines. Here we describe a method for encapsulation of catabolic cells, which consume lipids for heat production and energy dissipation (thermogenesis) in the intra-abdominal adipose tissue of obese mice. Encapsulation of thermogenic catabolic cells may be potentially applicable to the prevention and treatment of obesity and type 2 diabetes. Another potential application of catabolic cells may include detoxification from alcohols or other toxic metabolites and environmental pollutants. PMID:26066392

  9. Related factors of insulin resistance in Korean children: adiposity and maternal insulin resistance.

    PubMed

    Cho, Young-Gyu; Kang, Jae-Heon; Hur, Yang-Im; Song, Jihyun; Lee, Kang-Sook

    2011-12-01

    Increased adiposity and unhealthy lifestyle augment the risk for type 2 diabetes in children with familial predisposition. Insulin resistance (IR) is an excellent clinical marker for identifying children at high risk for type 2 diabetes. This study was conducted to investigate parental, physiological, behavioral and socio-economic factors related to IR in Korean children. This study is a cross-sectional study using data from 111 children aged 7 years and their parents. Homeostasis model assessment of insulin resistance (HOMA-IR) was calculated using fasting glucose and insulin level as a marker of IR. All children's adiposity indices (r = 0.309-0.318, all P-value = 0.001) and maternal levels of fasting insulin (r = 0.285, P-value = 0.003) and HOMA-IR (r = 0.290, P-value = 0.002) were positively correlated with children's HOMA-IR level. There was no statistical difference of children's HOMA-IR level according to children's lifestyle habits and socioeconomic status of families. An increase of 1 percentage point in body fat was related to 2.7% increase in children's HOMA-IR (P-value < 0.001) and an increase of 1% of maternal level of HOMA-IR was related to 0.2% increase in children's HOMA-IR (P-value = 0.002). This study shows that children's adiposity and maternal IR are positively associated with children's IR.

  10. Ghrelin receptor regulates adipose tissue inflammation in aging

    Technology Transfer Automated Retrieval System (TEKTRAN)

    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 ho...

  11. Characterization of adipose tissue macrophages and adipose-derived stem cells in critical wounds

    PubMed Central

    Tilstam, Pathricia V.; Springenberg-Jung, Katrin; Boecker, Arne Hendrick; Schmitz, Corinna; Heinrichs, Daniel; Hwang, Soo Seok; Stromps, Jan Philipp; Ganse, Bergita; Kopp, Ruedger; Knobe, Matthias; Bernhagen, Juergen

    2017-01-01

    Background Subcutaneous adipose tissue is a rich source of adipose tissue macrophages and adipose-derived stem cells which both play a key role in wound repair. While macrophages can be divided into the classically-activated M1 and the alternatively-activated M2 phenotype, ASCs are characterized by the expression of specific stem cell markers. Methods In the present study, we have investigated the expression of common macrophage polarization and stem cell markers in acutely inflamed adipose tissue. Subcutaneous adipose tissue adjacent to acutely inflamed wounds of 20 patients and 20 healthy subjects were harvested and underwent qPCR and flow cytometry analysis. Results Expression levels of the M1-specific markers CD80, iNOS, and IL-1b were significantly elevated in inflammatory adipose tissue when compared to healthy adipose tissue, whereas the M2-specific markers CD163 and TGF-β were decreased. By flow cytometry, a significant shift of adipose tissue macrophage populations towards the M1 phenotype was confirmed. Furthermore, a decrease in the mesenchymal stem cell markers CD29, CD34, and CD105 was observed whereas CD73 and CD90 remained unchanged. Discussion This is the first report describing the predominance of M1 adipose tissue macrophages and the reduction of stem cell marker expression in acutely inflamed, non-healing wounds. PMID:28070458

  12. Omega-3 fatty acids and adipose tissue function in obesity and metabolic syndrome.

    PubMed

    Martínez-Fernández, Leyre; Laiglesia, Laura M; Huerta, Ana E; Martínez, J Alfredo; Moreno-Aliaga, María J

    2015-09-01

    The n-3 long-chain polyunsaturated fatty acids (n-3 PUFAs) such as eicosapentaenoic (EPA) and docosahexaenoic (DHA) have been reported to improve obesity-associated metabolic disorders including chronic inflammation, insulin resistance and dyslipidaemia. Growing evidence exits about adipose tissue as a target in mediating the beneficial effects of these marine n-3 PUFAs in adverse metabolic syndrome manifestations. Therefore, in this manuscript we focus in reviewing the current knowledge about effects of marine n-3 PUFAs on adipose tissue metabolism and secretory functions. This scope includes n-3 PUFAs actions on adipogenesis, lipogenesis and lipolysis as well as on fatty acid oxidation and mitochondrial biogenesis. The effects of n-3 PUFAs on adipose tissue glucose uptake and insulin signaling are also summarized. Moreover, the roles of peroxisome proliferator-activated receptor γ (PPARγ) and AMPK activation in mediating n-3 PUFAs actions on adipose tissue functions are discussed. Finally, the mechanisms underlying the ability of n-3 PUFAs to prevent and/or ameliorate adipose tissue inflammation are also revised, focusing on the role of n-3 PUFAs-derived specialized proresolving lipid mediators such as resolvins, protectins and maresins.

  13. Adrenal gland volume, intra-abdominal and pericardial adipose tissue in major depressive disorder.

    PubMed

    Kahl, Kai G; Schweiger, Ulrich; Pars, Kaweh; Kunikowska, Alicja; Deuschle, Michael; Gutberlet, Marcel; Lichtinghagen, Ralf; Bleich, Stefan; Hüper, Katja; Hartung, Dagmar

    2015-08-01

    Major depressive disorder (MDD) is associated with an increased risk for the development of cardio-metabolic diseases. Increased intra-abdominal (IAT) and pericardial adipose tissue (PAT) have been found in depression, and are discussed as potential mediating factors. IAT and PAT are thought to be the result of a dysregulation of the hypothalamus-pituitary-adrenal axis (HPAA) with subsequent hypercortisolism. Therefore we examined adrenal gland volume as proxy marker for HPAA activation, and IAT and PAT in depressed patients. Twenty-seven depressed patients and 19 comparison subjects were included in this case-control study. Adrenal gland volume, pericardial, intraabdominal and subcutaneous adipose tissue were measured by magnetic resonance imaging. Further parameters included factors of the metabolic syndrome, fasting cortisol, fasting insulin, and proinflammatory cytokines. Adrenal gland and pericardial adipose tissue volumes, serum concentrations of cortisol and insulin, and serum concentrations tumor-necrosis factor-α were increased in depressed patients. Adrenal gland volume was positively correlated with intra-abdominal and pericardial adipose tissue, but not with subcutaneous adipose tissue. Our findings point to the role of HPAA dysregulation and hypercortisolism as potential mediators of IAT and PAT enlargement. Further studies are warranted to examine whether certain subtypes of depression are more prone to cardio-metabolic diseases.

  14. Early B cell factor 1 regulates adipocyte morphology and lipolysis in white adipose tissue.

    PubMed

    Gao, Hui; Mejhert, Niklas; Fretz, Jackie A; Arner, Erik; Lorente-Cebrián, Silvia; Ehrlund, Anna; Dahlman-Wright, Karin; Gong, Xiaowei; Strömblad, Staffan; Douagi, Iyadh; Laurencikiene, Jurga; Dahlman, Ingrid; Daub, Carsten O; Rydén, Mikael; Horowitz, Mark C; Arner, Peter

    2014-06-03

    White adipose tissue (WAT) morphology characterized by hypertrophy (i.e., fewer but larger adipocytes) associates with increased adipose inflammation, lipolysis, insulin resistance, and risk of diabetes. However, the causal relationships and the mechanisms controlling WAT morphology are unclear. Herein, we identified EBF1 as an adipocyte-expressed transcription factor with decreased expression/activity in WAT hypertrophy. In human adipocytes, the regulatory targets of EBF1 were enriched for genes controlling lipolysis and adipocyte morphology/differentiation, and in both humans and murine models, reduced EBF1 levels associated with increased lipolysis and adipose hypertrophy. Although EBF1 did not affect adipose inflammation, TNFα reduced EBF1 gene expression. High-fat diet intervention in Ebf1(+/-) mice resulted in more pronounced WAT hypertrophy and attenuated insulin sensitivity compared with wild-type littermate controls. We conclude that EBF1 is an important regulator of adipose morphology and fat cell lipolysis and may constitute a link between WAT inflammation, altered lipid metabolism, adipose hypertrophy, and insulin resistance.

  15. Early B-cell Factor 1 Regulates Adipocyte Morphology and Lipolysis in White Adipose Tissue

    PubMed Central

    Gao, Hui; Mejhert, Niklas; Fretz, Jackie A.; Arner, Erik; Lorente-Cebrián, Silvia; Ehrlund, Anna; Dahlman-Wright, Karin; Gong, Xiaowei; Strömblad, Staffan; Douagi, Iyadh; Laurencikiene, Jurga; Dahlman, Ingrid; Daub, Carsten O.; Rydén, Mikael; Horowitz, Mark C.; Arner, Peter

    2014-01-01

    Summary White adipose tissue (WAT) morphology characterized by hypertrophy (i.e. fewer but larger adipocytes) associates with increased adipose inflammation, lipolysis, insulin resistance and risk of diabetes. However, the causal relationships and the mechanisms controlling WAT morphology are unclear. Herein, we identified EBF1 as an adipocyte-expressed transcription factor with decreased expression/activity in WAT hypertrophy. In human adipocytes, the regulatory targets of EBF1 were enriched for genes controlling lipolysis and adipocyte morphology/differentiation and in both humans and murine models, reduced EBF1 levels associated with increased lipolysis and adipose hypertrophy. Although EBF1 did not affect adipose inflammation, TNFα reduced EBF1 gene expression. High fat diet-intervention in Ebf1+/− mice resulted in more pronounced WAT hypertrophy and attenuated insulin sensitivity compared with wild-type littermate controls. We conclude that EBF1 is an important regulator of adipose morphology and fat cell lipolysis and may constitute a link between WAT inflammation, altered lipid metabolism, adipose hypertrophy and insulin resistance. PMID:24856929

  16. Divergent phenotype of rat thoracic and abdominal perivascular adipose tissues

    PubMed Central

    Jenkins, Nathan T.; Vieira-Potter, Victoria J.; Laughlin, M. Harold

    2013-01-01

    Perivascular adipose tissue (PVAT) is implicated as a source of proatherogenic cytokines. Phenotypic differences in local PVAT depots may contribute to differences in disease susceptibility among arteries and even regions within an artery. It has been proposed that PVAT around the abdominal and thoracic aorta shares characteristics of white and brown adipose tissue (BAT), respectively; however, a detailed comparison of the phenotype of these PVAT depots has not been performed. Using young and older adult rats, we compared the phenotype of PVATs surrounding the abdominal and thoracic aorta to each other and also to epididymal white and subscapular BAT. Compared with young rats, older rats exhibited greater percent body fat (34.5 ± 3.1 vs. 10.4 ± 0.9%), total cholesterol (112.2 ± 7.5 vs. 58.7 ± 6.3 mg/dl), HOMA-insulin resistance (1.7 ± 0.1 vs. 0.9 ± 0.1 a.u.), as well as reduced ACh-induced relaxation of the aorta (maximal relaxation: 54 ± 10 vs. 77 ± 6%) (all P < 0.05). Expression of inflammatory genes and markers of immune cell infiltration were greater in abdominal PVAT than in thoracic PVAT, and overall, abdominal and thoracic PVATs resembled the phenotype of white adipose tissue (WAT) and BAT, respectively. Histology and electron microscopy indicated structural similarity between visceral WAT and abdominal PVAT and between BAT and thoracic PVAT. Our data provide evidence that abdominal PVAT is more inflamed than thoracic PVAT, a difference that was by and large independent of sedentary aging. Phenotypic differences in PVAT between regions of the aorta may be relevant in light of the evidence in large animals and humans that the abdominal aorta is more vulnerable to atherosclerosis than the thoracic aorta. PMID:23389108

  17. Physiological functions of Vitamin D in adipose tissue.

    PubMed

    Abbas, Manal A

    2017-01-01

    Adipose tissue has long been identified as the major site of vitamin D storage. Recent studies have demonstrated that VDR and vitamin D metabolizing enzymes are expressed in adipocytes. Furthermore, it has been shown that vitamin D regulates adipogenic gene expression as well as adipocyte apoptosis. Vitamin D is active in adipocytes at all levels. It interacts with membrane receptors, adaptor molecules, and nuclear coregulator proteins. Several functions of unliganded nVDR were discovered by studying human samples from patients having hereditary vitamin D resistant rickets, transgenic mice overexpressing the VDR and VDR knockout mice. Through its genomic action, vitamin D participates in the regulation of energy metabolism by controlling the expression of uncoupling proteins. In vitro, vitamin D stimulates lipogenesis and inhibits lipolysis by interacting with mVDR. mVDR is present in caveolae of the plasma membrane and is the same as the classic nVDR. In addition, vitamin D affects directly the expression of the appetite regulating hormone, leptin. Some researchers reported also that vitamin D regulates the expression of the insulin sensitizing hormone, adiponectin. Vitamin D reduced cytokine release and adipose tissue inflammation through the inhibition of NF-κB signaling. Scientific research investigating the role of adipose tissue resident immune cells in the pathogenesis of obesity-associated inflammation is scarce. Obesity is associated with vitamin D deficiency. However there is no scientific evidence to prove that vitamin D deficiency predispose to obesity. Vitamin D supplementation may prevent obesity but it does not lead to weight loss in obese subjects.

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

    PubMed Central

    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

    2016-01-01

    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 18F-FDG PET/MRI was performed to determine the effects of hypo- and hyperthyroidism on BAT mass and BAT activity. Ex-vivo14C-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. 18F-FDG PET/MRI revealed a lack of brown adipose tissue activity in hypothyroid mice, whereas hyperthyroid mice displayed increased BAT mass alongside enhanced 18F-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. PMID:27941950

  19. 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.

  20. 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.

  1. Cidea controls lipid droplet fusion and lipid storage in brown and white adipose tissue.

    PubMed

    Wu, Lizhen; Zhou, Linkang; Chen, Cheng; Gong, Jingyi; Xu, Li; Ye, Jing; Li, De; Li, Peng

    2014-01-01

    Excess lipid storage in adipose tissue results in the development of obesity and other metabolic disorders including diabetes, fatty liver and cardiovascular diseases. The lipid droplet (LD) is an important subcellular organelle responsible for lipid storage. We previously observed that Fsp27, a member of the CIDE family proteins, is localized to LD-contact sites and promotes atypical LD fusion and growth. Cidea, a close homolog of Fsp27, is expressed at high levels in brown adipose tissue. However, the exact role of Cidea in promoting LD fusion and lipid storage in adipose tissue remains unknown. Here, we expressed Cidea in Fsp27-knockdown adipocytes and observed that Cidea has similar activity to Fsp27 in promoting lipid storage and LD fusion and growth. Next, we generated Cidea and Fsp27 double-deficient mice and observed that these animals had drastically reduced adipose tissue mass and a strong lean phenotype. In addition, Cidea/Fsp27 double-deficient mice had improved insulin sensitivity and were intolerant to cold. Furthermore, we observed that the brown and white adipose tissues of Cidea/Fsp27 double-deficient mice had significantly reduced lipid storage and contained smaller LDs compared to those of Cidea or Fsp27 single deficient mice. Overall, these data reveal an important role of Cidea in controlling lipid droplet fusion, lipid storage in brown and white adipose tissue, and the development of obesity.

  2. Prolactin suppresses malonyl-CoA concentration in human adipose tissue.

    PubMed

    Nilsson, L A; Roepstorff, C; Kiens, B; Billig, H; Ling, C

    2009-10-01

    Prolactin is best known for its involvement in lactation, where it regulates mechanisms that supply nutrients for milk production. In individuals with pathological hyperprolactinemia, glucose and fat homeostasis have been reported to be negatively influenced. It is not previously known, however, whether prolactin regulates lipogenesis in human adipose tissue. The aim of this study was to investigate the effect of prolactin on lipogenesis in human adipose tissue in vitro. Prolactin decreased the concentration of malonyl-CoA, the product of the first committed step in lipogenesis, to 77+/-6% compared to control 100+/-5% (p=0.022) in cultured human adipose tissue. In addition, prolactin was found to decrease glucose transporter 4 ( GLUT4) mRNA expression, which may cause decreased glucose uptake. In conclusion, we propose that prolactin decreases lipogenesis in human adipose tissue as a consequence of suppressed malonyl-CoA concentration in parallel with decreased GLUT-4 expression. In the lactating woman, this regulation in adipose tissue may enhance the provision of nutrients for the infant instead of nutrients being stored in adipose tissue. In hyperprolactinemic individuals, a suppressed lipogenesis could contribute to an insulin resistant state with consequences for the health.

  3. Nutritional manipulations in the perinatal period program adipose tissue in offspring.

    PubMed

    Lukaszewski, Marie-Amélie; Eberlé, Delphine; Vieau, Didier; Breton, Christophe

    2013-11-15

    Epidemiological studies demonstrated initially that maternal undernutrition results in low birth weight with increased risk for long-lasting energy balance disorders. Maternal obesity and diabetes associated with high birth weight, excessive nutrition in neonates, and rapid catchup growth also increase the risk of adult-onset obesity. As stated by the Developmental Origin of Health and Disease concept, nutrient supply perturbations in the fetus or neonate result in long-term programming of individual body weight set point. Adipose tissue is a key fuel storage unit involved mainly in the maintenance of energy homeostasis. Studies in numerous animal models have demonstrated that the adipose tissue is the focus of developmental programming events in a sex- and depot-specific manner. In rodents, adipose tissue development is particularly active during the perinatal period, especially during the last week of gestation and during early postnatal life. In contrast to rodents, this process essentially takes place before birth in bigger mammals. Despite these different developmental time windows, altricial and precocial species share several mechanisms of adipose tissue programming. Offspring from malnourished dams present adipose tissue with a series of alterations: impaired glucose uptake, insulin and leptin resistance, low-grade inflammation, modified sympathetic activity with reduced noradrenergic innervations, and thermogenesis. These modifications reprogram adipose tissue metabolism by changing fat distribution and composition and by enhancing adipogenesis, predisposing the offspring to fat accumulation. Subtle adipose tissue circadian rhythm changes are also observed. Inappropriate hormone levels, modified tissue sensitivity (especially glucocorticoid system), and epigenetic mechanisms are key factors for adipose tissue programming during the perinatal period.

  4. Adipose Tissue Deficiency and Chronic Inflammation in Diabetic Goto-Kakizaki Rats

    PubMed Central

    Xue, Bai; Sukumaran, Siddharth; Nie, Jing; Jusko, William J.; DuBois, Debra C.; Almon, Richard R.

    2011-01-01

    Type 2 diabetes (T2DM) is a heterogeneous group of diseases that is progressive and involves multiple tissues. Goto-Kakizaki (GK) rats are a polygenic model with elevated blood glucose, peripheral insulin resistance, a non-obese phenotype, and exhibit many degenerative changes observed in human T2DM. As part of a systems analysis of disease progression in this animal model, this study characterized the contribution of adipose tissue to pathophysiology of the disease. We sacrificed subgroups of GK rats and appropriate controls at 4, 8, 12, 16 and 20 weeks of age and carried out a gene array analysis of white adipose tissue. We expanded our physiological analysis of the animals that accompanied our initial gene array study on the livers from these animals. The expanded analysis included adipose tissue weights, HbA1c, additional hormonal profiles, lipid profiles, differential blood cell counts, and food consumption. HbA1c progressively increased in the GK animals. Altered corticosterone, leptin, and adiponectin profiles were also documented in GK animals. Gene array analysis identified 412 genes that were differentially expressed in adipose tissue of GKs relative to controls. The GK animals exhibited an age-specific failure to accumulate body fat despite their relatively higher calorie consumption which was well supported by the altered expression of genes involved in adipogenesis and lipogenesis in the white adipose tissue of these animals, including Fasn, Acly, Kklf9, and Stat3. Systemic inflammation was reflected by chronically elevated white blood cell counts. Furthermore, chronic inflammation in adipose tissue was evident from the differential expression of genes involved in inflammatory responses and activation of natural immunity, including two interferon regulated genes, Ifit and Iipg, as well as MHC class II genes. This study demonstrates an age specific failure to accumulate adipose tissue in the GK rat and the presence of chronic inflammation in adipose

  5. 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

  6. Brown adipose tissue in cetacean blubber.

    PubMed

    Hashimoto, Osamu; Ohtsuki, Hirofumi; Kakizaki, Takehiko; Amou, Kento; Sato, Ryo; Doi, Satoru; Kobayashi, Sara; Matsuda, Ayaka; Sugiyama, Makoto; Funaba, Masayuki; Matsuishi, Takashi; Terasawa, Fumio; Shindo, Junji; Endo, Hideki

    2015-01-01

    Brown adipose tissue (BAT) plays an important role in thermoregulation in species living in cold environments, given heat can be generated from its chemical energy reserves. Here we investigate the existence of BAT in blubber in four species of delphinoid cetacean, the Pacific white-sided and bottlenose dolphins, Lagenorhynchus obliquidens and Tursiops truncates, and Dall's and harbour porpoises, Phocoenoides dalli and Phocoena phocoena. Histology revealed adipocytes with small unilocular fat droplets and a large eosinophilic cytoplasm intermingled with connective tissue in the innermost layers of blubber. Chemistry revealed a brown adipocyte-specific mitochondrial protein, uncoupling protein 1 (UCP1), within these same adipocytes, but not those distributed elsewhere throughout the blubber. Western blot analysis of extracts from the inner blubber layer confirmed that the immunohistochemical positive reaction was specific to UCP1 and that this adipose tissue was BAT. To better understand the distribution of BAT throughout the entire cetacean body, cadavers were subjected to computed tomography (CT) scanning. Resulting imagery, coupled with histological corroboration of fine tissue structure, revealed adipocytes intermingled with connective tissue in the lowest layer of blubber were distributed within a thin, highly dense layer that extended the length of the body, with the exception of the rostrum, fin and fluke regions. As such, we describe BAT effectively enveloping the cetacean body. Our results suggest that delphinoid blubber could serve a role additional to those frequently attributed to it: simple insulation blanket, energy storage, hydrodynamic streamlining or contributor to positive buoyancy. We believe delphinoid BAT might also function like an electric blanket, enabling animals to frequent waters cooler than blubber as an insulator alone might otherwise allow an animal to withstand, or allow animals to maintain body temperature in cool waters during

  7. Brown Adipose Tissue in Cetacean Blubber

    PubMed Central

    Hashimoto, Osamu; Ohtsuki, Hirofumi; Kakizaki, Takehiko; Amou, Kento; Sato, Ryo; Doi, Satoru; Kobayashi, Sara; Matsuda, Ayaka; Sugiyama, Makoto; Funaba, Masayuki; Matsuishi, Takashi; Terasawa, Fumio; Shindo, Junji; Endo, Hideki

    2015-01-01

    Brown adipose tissue (BAT) plays an important role in thermoregulation in species living in cold environments, given heat can be generated from its chemical energy reserves. Here we investigate the existence of BAT in blubber in four species of delphinoid cetacean, the Pacific white-sided and bottlenose dolphins, Lagenorhynchus obliquidens and Tursiops truncates, and Dall’s and harbour porpoises, Phocoenoides dalli and Phocoena phocoena. Histology revealed adipocytes with small unilocular fat droplets and a large eosinophilic cytoplasm intermingled with connective tissue in the innermost layers of blubber. Chemistry revealed a brown adipocyte-specific mitochondrial protein, uncoupling protein 1 (UCP1), within these same adipocytes, but not those distributed elsewhere throughout the blubber. Western blot analysis of extracts from the inner blubber layer confirmed that the immunohistochemical positive reaction was specific to UCP1 and that this adipose tissue was BAT. To better understand the distribution of BAT throughout the entire cetacean body, cadavers were subjected to computed tomography (CT) scanning. Resulting imagery, coupled with histological corroboration of fine tissue structure, revealed adipocytes intermingled with connective tissue in the lowest layer of blubber were distributed within a thin, highly dense layer that extended the length of the body, with the exception of the rostrum, fin and fluke regions. As such, we describe BAT effectively enveloping the cetacean body. Our results suggest that delphinoid blubber could serve a role additional to those frequently attributed to it: simple insulation blanket, energy storage, hydrodynamic streamlining or contributor to positive buoyancy. We believe delphinoid BAT might also function like an electric blanket, enabling animals to frequent waters cooler than blubber as an insulator alone might otherwise allow an animal to withstand, or allow animals to maintain body temperature in cool waters during

  8. Innate lymphoid type 2 cells sustain visceral adipose tissue eosinophils and alternatively activated macrophages

    PubMed Central

    Molofsky, Ari B.; Nussbaum, Jesse C.; Liang, Hong-Erh; Van Dyken, Steven J.; Cheng, Laurence E.; Mohapatra, Alexander; Chawla, Ajay

    2013-01-01

    Eosinophils in visceral adipose tissue (VAT) have been implicated in metabolic homeostasis and the maintenance of alternatively activated macrophages (AAMs). The absence of eosinophils can lead to adiposity and systemic insulin resistance in experimental animals, but what maintains eosinophils in adipose tissue is unknown. We show that interleukin-5 (IL-5) deficiency profoundly impairs VAT eosinophil accumulation and results in increased adiposity and insulin resistance when animals are placed on a high-fat diet. Innate lymphoid type 2 cells (ILC2s) are resident in VAT and are the major source of IL-5 and IL-13, which promote the accumulation of eosinophils and AAM. Deletion of ILC2s causes significant reductions in VAT eosinophils and AAMs, and also impairs the expansion of VAT eosinophils after infection with Nippostrongylus brasiliensis, an intestinal parasite associated with increased adipose ILC2 cytokine production and enhanced insulin sensitivity. Further, IL-33, a cytokine previously shown to promote cytokine production by ILC2s, leads to rapid ILC2-dependent increases in VAT eosinophils and AAMs. Thus, ILC2s are resident in VAT and promote eosinophils and AAM implicated in metabolic homeostasis, and this axis is enhanced during Th2-associated immune stimulation. PMID:23420878

  9. cGMP and Brown Adipose Tissue.

    PubMed

    Hoffmann, Linda S; Larson, Christopher J; Pfeifer, Alexander

    2016-01-01

    The second messenger cyclic guanosine monophosphate (cGMP) is a key mediator in physiological processes such as vascular tone, and its essential involvement in pathways regulating metabolism has been recognized in recent years. Here, we focus on the fundamental role of cGMP in brown adipose tissue (BAT) differentiation and function. In contrast to white adipose tissue (WAT), which stores energy in the form of lipids, BAT consumes energy stored in lipids to generate heat. This so-called non-shivering thermogenesis takes place in BAT mitochondria, which express the specific uncoupling protein 1 (UCP1). The energy combusting properties of BAT render it a promising target in antiobesity strategies in which BAT could burn the surplus energy that has accumulated in obese and overweight individuals. cGMP is generated by guanylyl cyclases upon activation by nitric oxide or natriuretic peptides. It affects several downstream molecules including cGMP-receptor proteins such as cGMP-dependent protein kinase and is degraded by phosphodiesterases. The cGMP pathway contains several signaling molecules that can increase cGMP signaling, resulting in activation and recruitment of brown adipocytes, and hence can enhance the energy combusting features of BAT. In this review we highlight recent results showing the physiological significance of cGMP signaling in BAT, as well as pharmacological options targeting cGMP signaling that bear a high potential to become BAT-centered therapies for the treatment of obesity.

  10. Hormonal effects on partitioning of nutrients for tissue growth: role of insulin.

    PubMed

    Prior, R L; Smith, S B

    1982-07-01

    Understanding factors that potentially regulate pathways of nutrient utilization is essential to the development of means of manipulating tissue growth to optimize the type and quality of product produced. Insulin is one hormone that has pronounced effects on carbohydrate and protein metabolism. Relative to most monogastric animals, ruminants absorb little glucose directly from the gastrointestinal tract. Therefore, it might be expected that insulin would have a less important role in regulating glucose and carbohydrate metabolism in the ruminant animal. Effects of insulin on lipogenesis and lipolysis both in vitro and in vivo in the ruminant appear to be small. Insulin may promote lipid deposition by increasing adipocyte membrane permeability to glucose with subsequent metabolism to alpha-glycerolphosphoric acid and thereby stimulating fatty acid esterification. Insulin also stimulates adipose lipoprotein lipase, which would increase the supply of fatty acids for esterification in adipose tissue. Insulin appears to indirectly alter hepatic glucose production by decreasing the release of gluconeogenic precursors from peripheral tissues. The known effects of insulin on lipid and carbohydrate metabolism have tended to direct attention away from protein metabolism, a process on which insulin may have a more significant role in the ruminant. Insulin or insulin and glucose have marked effects on regulating plasma levels of branched-chain amino acids, presumably by promoting their uptake or by decreasing their catabolism by muscle tissue. More information is needed to fully understand the role of insulin in regulating muscle protein metabolism.

  11. 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

  12. Visceral adipose tissue is an independent correlate of glucose disposal in older obese postmenopausal women.

    PubMed

    Brochu, M; Starling, R D; Tchernof, A; Matthews, D E; Garcia-Rubi, E; Poehlman, E T

    2000-07-01

    Older obese postmenopausal women have an increased risk for type 2 diabetes and cardiovascular disease. Increased abdominal obesity may contribute to these comorbidities. There is considerable controversy, however, regarding the effects of visceral adipose tissue as a singular predictor of insulin resistance compared to the other constituents of adiposity. To address this issue, we examined the independent association of regional adiposity and total fat mass with glucose disposal in obese older postmenopausal women. A secondary objective examined the association between glucose disposal with markers of skeletal muscle fat content (muscle attenuation) and physical activity levels. We studied 44 healthy obese postmenopausal women between 50 and 71 yr of age (mean +/- SD, 56.5 +/- 5.3 yr). The rate of glucose disposal was measured using the euglycemic/hyperinsulinemic clamp technique. Visceral and sc adipose tissue areas and midthigh muscle attenuation were measured from computed tomography. Fat mass and lean body mass were estimated from dual energy x-ray absorptiometry. Peak VO2 was measured from a treadmill test to volitional fatigue. Physical activity energy expenditure was measured from indirect calorimetry and doubly labeled water. Pearson correlations indicated that glucose disposal was inversely related to visceral adipose tissue area (r = -0.40; P < 0.01), but not to sc adipose tissue area (r = 0.17), total fat mass (r = 0.05), midthigh muscle attenuation (r = 0.01), peak VO2 (r = -0.22), or physical activity energy expenditure (r = -0.01). The significant association persisted after adjusting visceral adipose tissue for fat mass and abdominal sc adipose tissue levels (r = -0.45; P < 0.005; in both cases). Additional analyses matched two groups of women for fat mass, but with different visceral adipose tissue levels. Results showed that obese women with high visceral adipose tissue levels (283 +/- 59 vs. 137 +/- 24 cm2; P < 0.0001) had a lower glucose

  13. Effect of alloxan-diabetes on multiple forms of hexokinase in adipose tissue and lung

    PubMed Central

    McLean, Patricia; Brown, J.; Walters, Eileen; Greenslade, K.

    1967-01-01

    Comparison has been made of the effect of alloxan-diabetes on the multiple forms of hexokinase (EC 2.7.1.1) in adipose tissue and lung. Types I and II hexokinase were distinguished in adipose tissue by their different stabilities to heat treatment, which made it possible to determine the activity of each form spectrophotometrically; additional confirmatory evidence was obtained from starch-gel electrophoresis. Type II hexokinase was markedly depressed in adipose tissue from alloxan-diabetic rats. Lung contained types I, II and III hexokinase, type I predominating. There was no significant change in the pattern of these multiple forms of hexokinase in lung from alloxan-diabetic rats. These results are discussed in relation to current ideas that the insulin-sensitivity of a tissue may be correlated with the content of type II hexokinase. PMID:16742560

  14. Regulation of visceral adipose tissue-derived serine protease inhibitor by nutritional status, metformin, gender and pituitary factors in rat white adipose tissue.

    PubMed

    González, C R; Caminos, J E; Vázquez, M J; Garcés, M F; Cepeda, L A; Angel, A; González, A C; García-Rendueles, M E; Sangiao-Alvarellos, S; López, M; Bravo, S B; Nogueiras, R; Diéguez, C

    2009-07-15

    Visceral adipose tissue-derived serine protease inhibitor (vaspin) is a recently discovered adipocytokine mainly secreted from visceral adipose tissue, which plays a main role in insulin sensitivity. In this study, we have investigated the regulation of vaspin gene expression in rat white adipose tissue (WAT) in different physiological (nutritional status, pregnancy, age and gender) and pathophysiological (gonadectomy, thyroid status and growth hormone deficiency) settings known to be associated with energy homeostasis and alterations in insulin sensitivity. We have determined vaspin gene expression by real-time PCR. Vaspin was decreased after fasting and its levels were partially recovered after leptin treatment. Chronic treatment with metformin increased vaspin gene expression. Vaspin mRNA expression reached the highest peak at 45 days in both sexes after birth and its expression was higher in females than males, but its levels did not change throughout pregnancy. Finally, decreased levels of growth hormone and thyroid hormones suppressed vaspin expression. These findings suggest that WAT vaspin mRNA expression is regulated by nutritional status, and leptin seems to be the nutrient signal responsible for those changes. Vaspin is influenced by age and gender, and its expression is increased after treatment with insulin sensitizers. Finally, alterations in pituitary functions modify vaspin levels. Understanding the molecular mechanisms regulating vaspin will provide new insights into the pathogenesis of the metabolic syndrome.

  15. Adipose tissue gene expression and metabolic health of obese adults

    PubMed Central

    Das, Swapan Kumar; Ma, Lijun; Sharma, Neeraj

    2014-01-01

    Obese subjects with a similar body mass index (BMI) exhibit substantial heterogeneity in gluco- and cardio-metabolic heath phenotypes. However, defining genes that underlie the heterogeneity of metabolic features among obese individuals and determining metabolically healthy and unhealthy phenotypes remain challenging. We conducted unsupervised hierarchical clustering analysis of subcutaneous adipose tissue transcripts from 30 obese men and women ≥40 years old. Despite similar BMIs in all subjects, we found two distinct subgroups, one metabolically healthy (Group 1) and one metabolically unhealthy (Group 2). Subjects in Group 2 showed significantly higher total cholesterol (p=0.005), LDL cholesterol (p=0.006), 2h-Insulin during OGTT (p=0.015) and lower insulin sensitivity (SI, p=0.029) compared to Group 1. We identified significant up-regulation of 141 genes (e.g. MMP9 and SPP1) and down-regulation of 17 genes (e.g. NDRG4 and GINS3) in group 2 subjects. Intriguingly, these differentially expressed transcripts were enriched for genes involved in cardiovascular disease-related processes (p=2.81×10−11–3.74×10−02) and pathways involved in immune and inflammatory response (p=8.32×10−5–0.04). Two down-regulated genes, NDRG4 and GINS3, have been located in a genomic interval associated with cardiac repolarization in published GWASs and zebra fish knockout models. Our study provides evidence that perturbations in the adipose tissue gene expression network are important in defining metabolic health in obese subjects. PMID:25520251

  16. 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

    Technology Transfer Automated Retrieval System (TEKTRAN)

    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...

  17. Subcutaneous adipose tissue macropage infiltration is associated with hepatic and visceral fat deposition, hyperinsulinemia, and stimulation of NF-kB stress pathway

    Technology Transfer Automated Retrieval System (TEKTRAN)

    The goal was to examine in obese young adults the influence of ethnicity and subcutaneous adipose tissue (SAT) inflammation on hepatic fat fraction (HFF), visceral adipose tissue (VAT) deposition, insulin sensitivity (SI), Beta-cell function, and SAT gene expression. SAT biopsies were obtained from...

  18. Preventing diet-induced obesity in mice by adipose tissue transformation and angiogenesis using targeted nanoparticles

    PubMed Central

    Xue, Yuan; Xu, Xiaoyang; Zhang, Xue-Qing; Farokhzad, Omid C.; Langer, Robert

    2016-01-01

    The incidence of obesity, which is recognized by the American Medical Association as a disease, has nearly doubled since 1980, and obesity-related comorbidities have become a major threat to human health. Given that adipose tissue expansion and transformation require active growth of new blood vasculature, angiogenesis offers a potential target for the treatment of obesity-associated disorders. Here we construct two peptide-functionalized nanoparticle (NP) platforms to deliver either Peroxisome Proliferator-Activated Receptor gamma (PPARgamma) activator rosiglitazone (Rosi) or prostaglandin E2 analog (16,16-dimethyl PGE2) to adipose tissue vasculature. These NPs were engineered through self-assembly of a biodegradable triblock polymer composed of end-to-end linkages between poly(lactic-coglycolic acid)-b-poly(ethylene glycol) (PLGA-b-PEG) and an endothelial-targeted peptide. In this system, released Rosi promotes both transformation of white adipose tissue (WAT) into brown-like adipose tissue and angiogenesis, which facilitates the homing of targeted NPs to adipose angiogenic vessels, thereby amplifying their delivery. We show that i.v. administration of these NPs can target WAT vasculature, stimulate the angiogenesis that is required for the transformation of adipose tissue, and transform WAT into brown-like adipose tissue, by the up-regulation of angiogenesis and brown adipose tissue markers. In a diet-induced obese mouse model, these angiogenesis-targeted NPs have inhibited body weight gain and modulated several serological markers including cholesterol, triglyceride, and insulin, compared with the control group. These findings suggest that angiogenesis-targeting moieties with angiogenic stimulator-loaded NPs could be incorporated into effective therapeutic regimens for clinical treatment of obesity and other metabolic diseases. PMID:27140638

  19. Adipose-derived stem cells for periodontal tissue regeneration.

    PubMed

    Tobita, Morikuni; Mizuno, Hiroshi

    2011-01-01

    Mesenchymal stem cells can effectively regenerate destroyed periodontal tissue. Because periodontal tissues are complex, mesenchymal stem cells that can differentiate into many tissue types would aid periodontal tissue regeneration. Indeed, periodontal tissue regeneration using mesenchymal stem cells derived from adipose tissue or bone marrow has been performed in experimental animal models, such as rat, canine, swine, and monkey. We have shown that rat periodontal tissue can be regenerated with adipose-derived stem cells. Adipose tissue contains a large number of stromal cells and is relatively easy to obtain in large quantities, and thus constitutes a very convenient stromal cell source. In this chapter, we introduce a rat periodontal tissue regeneration model using adipose-derived stem cells.

  20. Albumin induced cytokine expression in porcine adipose tissue explants

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Albumin has historically been included in medium designed for use with adipose tissue when evaluating metabolism, gene expression or protein secretion. However, recent studies with mouse adipocytes (Ruan et al., J. Biol. Chem. 278:47585-47593, 2003) and human adipose tissue (Schlesinger et al., Ame...

  1. Altered autophagy in human adipose tissues in obesity

    Technology Transfer Automated Retrieval System (TEKTRAN)

    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...

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

    Technology Transfer Automated Retrieval System (TEKTRAN)

    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 ...

  3. Effects of salicylic acid-induced wine rich in anthocyanins on metabolic parameters and adipose insulin signaling in high-fructose fed rats.

    PubMed

    Rodriguez Lanzi, Cecilia; de Rosas, Inés; Perdicaro, Diahann J; Ponce, María Teresa; Martinez, Liliana; Miatello, Roberto M; Cavagnaro, Bruno; Vazquez Prieto, Marcela A

    2016-12-01

    We evaluated the effects of Syrah red wine treated with salicylic acid (RW SA) and its control red wine (RW) on metabolic parameters, systolic blood pressure and adipose tissue insulin signaling in high-fructose (F) fed rats. Grape treated with SA increased the anthocyanin (ANTs) levels in RW. F induced increased systolic blood pressure, dislipidemia and insulin resistance (HOMA:IR). F rats treated with RW significantly prevented these alterations while RW SA partially attenuated triglycerides levels and HOMA:IR without modifications in HDL cholesterol levels. F impaired the adipose tissue response to insulin. Supplementation with RW and RW SA partially attenuated these alterations. Rats supplemented with RW SA had lesser beneficial effects on metabolic alterations than control RW, while both RW and RW SA attenuated altered adipose response to insulin. More studies are necessary to deeply evaluate the effect on SA-induced RW rich in ANTs levels on metabolic alterations associated to MetS.

  4. Associations of Adiponectin with Adiposity, Insulin Sensitivity, and Diet in Young, Healthy, Mexican Americans and Non-Latino White Adults.

    PubMed

    Pereira, Rocio I; Low Wang, Cecilia C; Wolfe, Pamela; Havranek, Edward P; Long, Carlin S; Bessesen, Daniel H

    2015-12-22

    Low circulating adiponectin levels may contribute to higher diabetes risk among Mexican Americans (MA) compared to non-Latino whites (NLW). Our objective was to determine if among young healthy adult MAs have lower adiponectin than NLWs, independent of differences in adiposity. In addition, we explored associations between adiponectin and diet. This was an observational, cross-sectional study of healthy MA and NLW adults living in Colorado (U.S.A.). We measured plasma total adiponectin, adiposity (BMI, and visceral adipose tissue), insulin sensitivity (IVGTT), and self-reported dietary intake in 43 MA and NLW adults. Mean adiponectin levels were 40% lower among MA than NLW (5.8 ± 3.3 vs. 10.7 ± 4.2 µg/mL, p = 0.0003), and this difference persisted after controlling for age, sex, BMI, and visceral adiposity. Lower adiponectin in MA was associated with lower insulin sensitivity (R² = 0.42, p < 0.01). Lower adiponectin was also associated with higher dietary glycemic index, lower intake of vegetables, higher intake of trans fat, and higher intake of grains. Our findings confirm that ethnic differences in adiponectin reflect differences in insulin sensitivity, but suggest that these are not due to differences in adiposity. Observed associations between adiponectin and diet support the need for future studies exploring the regulation of adiponectin by diet and other environmental factors.

  5. Associations of Adiponectin with Adiposity, Insulin Sensitivity, and Diet in Young, Healthy, Mexican Americans and Non-Latino White Adults

    PubMed Central

    Pereira, Rocio I.; Low Wang, Cecilia C.; Wolfe, Pamela; Havranek, Edward P.; Long, Carlin S.; Bessesen, Daniel H.

    2015-01-01

    Low circulating adiponectin levels may contribute to higher diabetes risk among Mexican Americans (MA) compared to non-Latino whites (NLW). Our objective was to determine if among young healthy adult MAs have lower adiponectin than NLWs, independent of differences in adiposity. In addition, we explored associations between adiponectin and diet. This was an observational, cross-sectional study of healthy MA and NLW adults living in Colorado (U.S.A.). We measured plasma total adiponectin, adiposity (BMI, and visceral adipose tissue), insulin sensitivity (IVGTT), and self-reported dietary intake in 43 MA and NLW adults. Mean adiponectin levels were 40% lower among MA than NLW (5.8 ± 3.3 vs. 10.7 ± 4.2 µg/mL, p = 0.0003), and this difference persisted after controlling for age, sex, BMI, and visceral adiposity. Lower adiponectin in MA was associated with lower insulin sensitivity (R2 = 0.42, p < 0.01). Lower adiponectin was also associated with higher dietary glycemic index, lower intake of vegetables, higher intake of trans fat, and higher intake of grains. Our findings confirm that ethnic differences in adiponectin reflect differences in insulin sensitivity, but suggest that these are not due to differences in adiposity. Observed associations between adiponectin and diet support the need for future studies exploring the regulation of adiponectin by diet and other environmental factors. PMID:26703682

  6. Pharmacological inhibition of adipose triglyceride lipase corrects high-fat diet-induced insulin resistance and hepatosteatosis in mice

    PubMed Central

    Schweiger, Martina; Romauch, Matthias; Schreiber, Renate; Grabner, Gernot F.; Hütter, Sabrina; Kotzbeck, Petra; Benedikt, Pia; Eichmann, Thomas O.; Yamada, Sohsuke; Knittelfelder, Oskar; Diwoky, Clemens; Doler, Carina; Mayer, Nicole; De Cecco, Werner; Breinbauer, Rolf; Zimmermann, Robert; Zechner, Rudolf

    2017-01-01

    Elevated circulating fatty acids (FAs) contribute to the development of obesity-associated metabolic complications such as insulin resistance (IR) and non-alcoholic fatty liver disease (NAFLD). Hence, reducing adipose tissue lipolysis to diminish the mobilization of FAs and lower their respective plasma concentrations represents a potential treatment strategy to counteract obesity-associated disorders. Here we show that specific inhibition of adipose triglyceride lipase (Atgl) with the chemical inhibitor, Atglistatin, effectively reduces adipose tissue lipolysis, weight gain, IR and NAFLD in mice fed a high-fat diet. Importantly, even long-term treatment does not lead to lipid accumulation in ectopic tissues such as the skeletal muscle or heart. Thus, the severe cardiac steatosis and cardiomyopathy that is observed in genetic models of Atgl deficiency does not occur in Atglistatin-treated mice. Our data validate the pharmacological inhibition of Atgl as a potentially powerful therapeutic strategy to treat obesity and associated metabolic disorders. PMID:28327588

  7. Basal plasma levels of insulin, leptin, ghrelin, and amylin do not signal adiposity in rats recovering from forced overweight.

    PubMed

    Gloy, Viktoria L; Lutz, Thomas A; Langhans, Wolfgang; Geary, Nori; Hillebrand, Jacquelien J

    2010-09-01

    This study examined how adiposity signals are related to adiposity during recovery from forced overweight (OW). Rats were rendered OW by chronic intragastric overfeeding (OW). Overfeeding was stopped when OW rats reached 126-129% of saline-infused normal-weight (NW) rats. Adipose tissue (AT) mass was estimated by computed tomography, and blood was drawn from chronic atrial cannulas throughout. Basal levels (i.e. after 2-3 h fasts late in the diurnal phase) of the hypothesized adiposity signals insulin, leptin, ghrelin, and amylin were assayed. OW rats gained approximately 130 g more body weight (BW) and approximately 100 g more AT mass during overfeeding. Plasma levels of insulin and leptin increased, whereas those of ghrelin decreased, linearly with AT mass; amylin did not change reliably. During recovery, OW rats' BW and AT mass decreased but were still elevated vs. NW rats after 39 d. OW rats' insulin returned to NW levels on d 1 of recovery and decreased below NW levels thereafter. Leptin was no longer elevated after d 8 of recovery. Ghrelin and amylin did not change reliably during recovery. Although AT mass decreased in OW rats during each intermeasurement interval between d 0 and d 23 of recovery, insulin and leptin did so during only the first interval (d 0-5). Insulin and leptin levels were exponentially related to AT mass during recovery. These data indicate that basal insulin, leptin, ghrelin, and amylin do not encode AT mass in rats dynamically regulating BW and adiposity during recovery from OW.

  8. Regulation of systemic energy homeostasis by serotonin in adipose tissues

    PubMed Central

    Oh, Chang-Myung; Namkung, Jun; Go, Younghoon; Shong, Ko Eun; Kim, Kyuho; Kim, Hyeongseok; Park, Bo-Yoon; Lee, Ho Won; Jeon, Yong Hyun; Song, Junghan; Shong, Minho; Yadav, Vijay K.; Karsenty, Gerard; Kajimura, Shingo; Lee, In-Kyu; Park, Sangkyu; Kim, Hail

    2015-01-01

    Central serotonin (5-HT) is an anorexigenic neurotransmitter in the brain. However, accumulating evidence suggests peripheral 5-HT may affect organismal energy homeostasis. Here we show 5-HT regulates white and brown adipose tissue function. Pharmacological inhibition of 5-HT synthesis leads to inhibition of lipogenesis in epididymal white adipose tissue (WAT), induction of browning in inguinal WAT and activation of adaptive thermogenesis in brown adipose tissue (BAT). Mice with inducible Tph1 KO in adipose tissues exhibit a similar phenotype as mice in which 5-HT synthesis is inhibited pharmacologically, suggesting 5-HT has localized effects on adipose tissues. In addition, Htr3a KO mice exhibit increased energy expenditure and reduced weight gain when fed a high-fat diet. Treatment with an Htr2a antagonist reduces lipid accumulation in 3T3-L1 adipocytes. These data suggest important roles for adipocyte-derived 5-HT in controlling energy homeostasis. PMID:25864946

  9. 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

  10. FEEDING INFLUENCES ADIPOSE TISSUE RESPONSES TO EXERCISE IN OVERWEIGHT MEN.

    PubMed

    Chen, Yung-Chih; Travers, Rebecca L; Walhin, Jean-Philippe; Gonzalez, Javier T; Koumanov, Francoise; Betts, James A; Thompson, Dylan

    2017-03-14

    Feeding profoundly affects metabolic responses to exercise in various tissues but the effect of feeding status on human adipose tissue responses to exercise has never been studied. Ten healthy overweight men aged 26 ± 5 years (mean ± SD) with a waist circumference of 105 ± 10 cm walked at 60% of maximum oxygen uptake under either FASTED or FED conditions in a randomised, counterbalanced design. Feeding comprised 648 ± 115 kcal 2 h before exercise. Blood samples were collected at regular intervals to examine changes in metabolic parameters and adipokine concentrations. Adipose tissue samples were obtained at baseline and one hour post-exercise to examine changes in adipose tissue mRNA expression and secretion of selected adipokines ex-vivo. Adipose tissue mRNA expression of PDK4, ATGL, HSL, FAT/CD36, GLUT4 and IRS2 in response to exercise were lower in FED compared to FASTED conditions (all p ≤ 0.05). Post-exercise adipose IRS2 protein was affected by feeding (p ≤ 0.05), but Akt2, AMPK, IRS1, GLUT4, PDK4 and HSL protein levels were not different. Feeding status did not impact serum and ex-vivo adipose secretion of IL-6, leptin or adiponectin in response to exercise. This is the first study to show that feeding prior to acute exercise affects post-exercise adipose tissue gene expression and we propose that feeding is likely to blunt long-term adipose tissue adaptation to regular exercise.

  11. Adipose tissue transplantation may be a potential treatment for diabetes, atherosclerosis and nonalcoholic steatohepatitis.

    PubMed

    Sanal, Madhusudana Girija

    2009-03-01

    Adipose tissue is critical in energy homeostasis. Adipose tissue 'buffers' the lipids and energy rich compounds which are pumped into the blood stream soon after meals. It senses, signals other organs like liver and brain about the energy reserves via adipokines. Adiponectin, the most abundant adipokine has insulin sensitizing, anti-inflammatory antiatherogenic and antisteatotic effects. Adipose tissue dysfunction is accompanied by abnormal lipid distribution and storage which contributes to diseases like diabetes, nonalcoholic fatty liver disease and atherosclerosis. Obesity and lipodystrophy are associated with dysfunctional adipocytes. Pre-adipocytes are easy to isolate and culture. A personalized depot specific liposuction to remove the inactive adipocytes followed by adipocyte repopulation could be useful in the treatment of these diseases.

  12. Visceral adipose tissue as a source of inflammation and promoter of atherosclerosis.

    PubMed

    Alexopoulos, Nikolaos; Katritsis, Demosthenes; Raggi, Paolo

    2014-03-01

    The current epidemic of obesity with the associated increasing incidence of insulin resistance, diabetes mellitus and atherosclerosis affecting a large proportion of the North American and Western populations, has generated a strong interest in the potential role of visceral adipose tissue in the development of atherosclerosis and its complications. The intra-abdominal and epicardial space are two compartments that contain visceral adipose tissue with a similar embryological origin. These visceral fats are highly inflamed in obese patients, patients with the metabolic syndrome and in those with established coronary artery disease; additionally they are capable of secreting large quantities of pro-inflammatory cytokines and free fatty acids. There is accumulating evidence to support a direct involvement of these regional adipose tissue deposits in the development of atherosclerosis and its complicating events, as will be reviewed in this article.

  13. The Ontogeny of Brown Adipose Tissue.

    PubMed

    Symonds, Michael E; Pope, Mark; Budge, Helen

    2015-01-01

    There are three different types of adipose tissue (AT)-brown, white, and beige-that differ with stage of development, species, and anatomical location. Of these, brown AT (BAT) is the least abundant but has the greatest potential impact on energy balance. BAT is capable of rapidly producing large amounts of heat through activation of the unique uncoupling protein 1 (UCP1) located within the inner mitochondrial membrane. White AT is an endocrine organ and site of lipid storage, whereas beige AT is primarily white but contains some cells that possess UCP1. BAT first appears in the fetus around mid-gestation and is then gradually lost through childhood, adolescence, and adulthood. We focus on the interrelationships between adipocyte classification, anatomical location, and impact of diet in early life together with the extent to which fat development differs between the major species examined. Ultimately, novel dietary interventions designed to reactivate BAT could be possible.

  14. The role of sex steroids in white adipose tissue adipocyte function.

    PubMed

    Newell-Fugate, A E

    2017-04-01

    With the increasing knowledge that gender influences normal physiology, much biomedical research has begun to focus on the differential effects of sex on tissue function. Sexual dimorphism in mammals is due to the combined effects of both genetic and hormonal factors. Hormonal factors are mutable particularly in females in whom the estrous cycle dominates the hormonal milieu. Given the severity of the obesity epidemic and the fact that there are differences in the obesity rates in men and women, the role of sex in white adipose tissue function is being recognized as increasingly important. Although sex differences in white adipose tissue distribution are well established, the mechanisms affecting differential function of adipocytes within white adipose tissue in males and females remain largely understudied and poorly understood. One of the largest differences in the endocrine environment in males and females is the concentration of circulating androgens and estrogens. This review examines the effects of androgens and estrogens on lipolysis/lipogenesis, adipocyte differentiation, insulin sensitivity and adipokine production in adipocytes from white adipose tissue with a specific emphasis on the sexual dimorphism of adipocyte function in white adipose tissue during both health and disease.

  15. Differential Role of Adipose Tissues in Obesity and Related Metabolic and Vascular Complications

    PubMed Central

    Beneit, Nuria; Díaz-Castroverde, Sabela

    2016-01-01

    This review focuses on the contribution of white, brown, and perivascular adipose tissues to the pathophysiology of obesity and its associated metabolic and vascular complications. Weight gain in obesity generates excess of fat, usually visceral fat, and activates the inflammatory response in the adipocytes and then in other tissues such as liver. Therefore, low systemic inflammation responsible for insulin resistance contributes to atherosclerotic process. Furthermore, an inverse relationship between body mass index and brown adipose tissue activity has been described. For these reasons, in recent years, in order to combat obesity and its related complications, as a complement to conventional treatments, a new insight is focusing on the role of the thermogenic function of brown and perivascular adipose tissues as a promising therapy in humans. These lines of knowledge are focused on the design of new drugs, or other approaches, in order to increase the mass and/or activity of brown adipose tissue or the browning process of beige cells from white adipose tissue. These new treatments may contribute not only to reduce obesity but also to prevent highly prevalent complications such as type 2 diabetes and other vascular alterations, such as hypertension or atherosclerosis. PMID:27766104

  16. Developmental androgen excess programs sympathetic tone and adipose tissue dysfunction and predisposes to a cardiometabolic syndrome in female mice.

    PubMed

    Nohara, Kazunari; Waraich, Rizwana S; Liu, Suhuan; Ferron, Mathieu; Waget, Aurélie; Meyers, Matthew S; Karsenty, Gérard; Burcelin, Rémy; Mauvais-Jarvis, Franck

    2013-06-15

    Among women, the polycystic ovarian syndrome (PCOS) is considered a form of metabolic syndrome with reproductive abnormalities. Women with PCOS show increased sympathetic tone, visceral adiposity with enlarged adipocytes, hypoadiponectinemia, insulin resistance, glucose intolerance, increased inactive osteocalcin, and hypertension. Excess fetal exposure to androgens has been hypothesized to play a role in the pathogenesis of PCOS. Previously, we showed that neonatal exposure to the androgen testosterone (NT) programs leptin resistance in adult female mice. Here, we studied the impact of NT on lean and adipose tissues, sympathetic tone in cardiometabolic tissues, and the development of metabolic dysfunction in mice. Neonatally androgenized adult female mice (NTF) displayed masculinization of lean tissues with increased cardiac and skeletal muscle as well as kidney masses. NTF mice showed increased and dysfunctional white adipose tissue with increased sympathetic tone in both visceral and subcutaneous fat as well as increased number of enlarged and insulin-resistant adipocytes that displayed altered expression of developmental genes and hypoadiponectinemia. NTF exhibited dysfunctional brown adipose tissue with increased mass and decreased energy expenditure. They also displayed decreased undercarboxylated and active osteocalcin and were predisposed to obesity during chronic androgen excess. NTF showed increased renal sympathetic tone associated with increased blood pressure, and they developed glucose intolerance and insulin resistance. Thus, developmental exposure to testosterone in female mice programs features of cardiometabolic dysfunction, as can be observed in women with PCOS, including increased sympathetic tone, visceral adiposity, insulin resistance, prediabetes, and hypertension.

  17. Porous decellularized adipose tissue foams for soft tissue regeneration.

    PubMed

    Yu, Claire; Bianco, Juares; Brown, Cody; Fuetterer, Lydia; Watkins, John F; Samani, Abbas; Flynn, Lauren E

    2013-04-01

    To design tissue-specific bioscaffolds with well-defined properties and 3-D architecture, methods were developed for preparing porous foams from enzyme-solubilized human decellularized adipose tissue (DAT). Additionally, a technique was established for fabricating "bead foams" comprised of interconnected networks of porous DAT beads fused through a controlled freeze-thawing and lyophilization procedure. In characterization studies, the foams were stable without the need for chemical crosslinking, with properties that could be tuned by controlling the protein concentration and freezing rate during synthesis. Adipogenic differentiation studies with human adipose-derived stem cells (ASCs) suggested that stiffness influenced ASC adipogenesis on the foams. In support of our previous work with DAT scaffolds and microcarriers, the DAT foams and bead foams strongly supported adipogenesis and were also adipo-inductive, as demonstrated by glycerol-3-phosphate dehydrogenase (GPDH) enzyme activity, endpoint RT-PCR analysis of adipogenic gene expression, and intracellular lipid accumulation. Adipogenic differentiation was enhanced on the microporous DAT foams, potentially due to increased cell-cell interactions in this group. In vivo assessment in a subcutaneous Wistar rat model demonstrated that the DAT bioscaffolds were well tolerated and integrated into the host tissues, supporting angiogenesis and adipogenesis. The DAT-based foams induced a strong angiogenic response, promoted inflammatory cell migration and gradually resorbed over the course of 12 weeks, demonstrating potential as scaffolds for wound healing and soft tissue regeneration.

  18. Epicardial Adipose Tissue Is Nonlinearly Related to Anthropometric Measures and Subcutaneous Adipose Tissue.

    PubMed

    Šram, Miroslav; Vrselja, Zvonimir; Lekšan, Igor; Ćurić, Goran; Selthofer-Relatić, Kristina; Radić, Radivoje

    2015-01-01

    Introduction. Adipose tissue is the largest endocrine organ, composed of subcutaneous (SAT) and visceral adipose tissue (VAT), the latter being highly associated with coronary artery disease (CAD). Expansion of epicardial adipose tissue (EAT) is linked to CAD. One way of assessing the CAD risk is with low-cost anthropometric measures, although they are inaccurate and cannot discriminate between VAT and SAT. The aim of this study is to evaluate (1) the relationship between EAT thickness, SAT thickness and anthropometric measures in a cohort of patients assessed at the cardiology unit and (2) determine predictive power of anthropometric measures and EAT and SAT thickness in establishment of CAD. Methods. Anthropometric measures were obtained from 53 CAD and 42 non-CAD patients. Vascular and structural statuses were obtained with coronarography and echocardiography, as well as measurements of the EAT and SAT thickness. Results. Anthropometric measures showed moderate positive correlation with EAT and SAT thickness. Anthropometric measures and SAT follow nonlinear S curve relationship with EAT. Strong nonlinear power curve relationship was observed between EAT and SAT thinner than 10 mm. Anthropometric measures and EAT and SAT were poor predictors of CAD. Conclusion. Anthropometric measures and SAT have nonlinear relationship with EAT. EAT thickness and anthropometric measures have similar CAD predictive value.

  19. Adropin deficiency is associated with increased adiposity and insulin resistance.

    PubMed

    Ganesh Kumar, K; Zhang, Jingying; Gao, Su; Rossi, Jari; McGuinness, Owen P; Halem, Heather H; Culler, Michael D; Mynatt, Randall L; Butler, Andrew A

    2012-07-01

    Adropin is a secreted peptide that improves hepatic steatosis and glucose homeostasis when administered to diet-induced obese mice. It is not clear if adropin is a peptide hormone regulated by signals of metabolic state. Moreover, the significance of a decline in adropin expression with obesity with respect to metabolic disease is also not clear. We investigated the regulation of serum adropin by metabolic status and diet. Serum adropin levels were high in chow-fed conditions and were suppressed by fasting and diet-induced obesity (DIO). High adropin levels were observed in mice fed a high-fat low carbohydrate diet, whereas lower levels were observed in mice fed a low-fat high carbohydrate diet. To investigate the role of adropin deficiency in metabolic homeostasis, we generated adropin knockout mice (AdrKO) on the C57BL/6J background. AdrKO displayed a 50%-increase in increase in adiposity, although food intake and energy expenditure were normal. AdrKO also exhibited dyslipidemia and impaired suppression of endogenous glucose production (EndoR(a)) in hyperinsulinemic-euglycemic clamp conditions, suggesting insulin resistance. While homo- and heterozygous carriers of the null adropin allele exhibited normal DIO relative to controls, impaired glucose tolerance associated with weight gain was more severe in both groups. In summary, adropin is a peptide hormone regulated by fasting and feeding. In fed conditions, adropin levels are regulated dietary macronutrients, and increase with dietary fat content. Adropin is not required for regulating food intake, however, its functions impact on adiposity and are involved in preventing insulin resistance, dyslipidemia, and impaired glucose tolerance.

  20. Adropin Deficiency Is Associated With Increased Adiposity and Insulin Resistance

    PubMed Central

    Kumar, K. Ganesh; Zhang, Jingying; Gao, Su; Rossi, Jari; McGuinness, Owen P.; Halem, Heather H.; Culler, Michael D.; Mynatt, Randall L.; Butler, Andrew A.

    2014-01-01

    Adropin is a secreted peptide that improves hepatic steatosis and glucose homeostasis when administered to diet-induced obese mice. It is not clear if adropin is a peptide hormone regulated by signals of metabolic state. Moreover, the significance of a decline in adropin expression with obesity with respect to metabolic disease is also not clear. We investigated the regulation of serum adropin by metabolic status and diet. Serum adropin levels were high in chow-fed conditions and were suppressed by fasting and diet-induced obesity (DIO). High adropin levels were observed in mice fed a high-fat low carbohydrate diet, whereas lower levels were observed in mice fed a low-fat high carbohydrate diet. To investigate the role of adropin deficiency in metabolic homeostasis, we generated adropin knockout mice (AdrKO) on the C57BL/6J background. AdrKO displayed a 50%-increase in increase in adiposity, although food intake and energy expenditure were normal. AdrKO also exhibited dyslipidemia and impaired suppression of endogenous glucose production (EndoRa) in hyperinsulinemic–euglycemic clamp conditions, suggesting insulin resistance. While homo- and heterozygous carriers of the null adropin allele exhibited normal DIO relative to controls, impaired glucose tolerance associated with weight gain was more severe in both groups. In summary, adropin is a peptide hormone regulated by fasting and feeding. In fed conditions, adropin levels are regulated dietary macronutrients, and increase with dietary fat content. Adropin is not required for regulating food intake, however, its functions impact on adiposity and are involved in preventing insulin resistance, dyslipidemia, and impaired glucose tolerance. PMID:22318315

  1. Effect of insulin on in vivo glucose utilization in individual tissues of anesthetized lactating rats

    SciTech Connect

    Burnol, A.F.; Ferre, P.; Leturque, A.; Girard, J.

    1987-02-01

    Glucose utilization rate has been measured in skeletal muscles, white adipose tissue, and mammary gland of anesthetized nonlactating and lactating rats. During lactation, basal (1-TH) glucose utilization is decreased by 40% in periovarian white adipose tissue and by 65% in epitrochlearis and extensor digitorum longus but not in soleus muscle. This may be related to the lower blood glucose and plasma insulin concentrations observed during lactation. Basal glucose utilization rate in the mammary gland was, respectively, 18 +/- 2 and 350 +/- 50 g/min in nonlactating and lactating rats. During the euglycemic hyperinsulinemic clamp, a physiological increment in plasma insulin concentration induces a similar increase in glucose utilization rate in skeletal muscles and white adipose tissue in the two groups of rats. Furthermore this low increase in plasma insulin concentration does not alter mammary glucose utilization rate in nonlactating rats but induces the same increase as a maximal insulin concentration in lactating rats. These data show that the active mammary gland is the most insulin-sensitive tissue of the lactating rat that has been tested. The overall increase in insulin sensitivity and responsiveness that has been described in lactating rats can then mainly be attributed to the presence of the active mammary gland. Plasma insulin was determined by radioimmunoassay.

  2. Role of adipose tissue in the pathogenesis of cardiac arrhythmias.

    PubMed

    Samanta, Rahul; Pouliopoulos, Jim; Thiagalingam, Aravinda; Kovoor, Pramesh

    2016-01-01

    Epicardial adipose tissue is present in normal healthy individuals. It is a unique fat depot that, under physiologic conditions, plays a cardioprotective role. However, excess epicardial adipose tissue has been shown to be associated with prevalence and severity of atrial fibrillation. In arrhythmogenic right ventricular cardiomyopathy and myotonic dystrophy, fibrofatty infiltration of the myocardium is associated with ventricular arrhythmias. In the ovine model of ischemic cardiomyopathy, the presence of intramyocardial adipose or lipomatous metaplasia has been associated with increased propensity to ventricular tachycardia. These observations suggest a role of adipose tissue in the pathogenesis of cardiac arrhythmias. In this article, we review the role of cardiac adipose tissue in various cardiac arrhythmias and discuss the possible pathophysiologic mechanisms.

  3. Improved adipose tissue metabolism after 5-year growth hormone replacement therapy in growth hormone deficient adults: The role of zinc-α2-glycoprotein

    PubMed Central

    Balaž, Miroslav; Ukropcova, Barbara; Kurdiova, Timea; Vlcek, Miroslav; Surova, Martina; Krumpolec, Patrik; Vanuga, Peter; Gašperíková, Daniela; Klimeš, Iwar; Payer, Juraj; Wolfrum, Christian; Ukropec, Jozef

    2014-01-01

    Growth hormone (GH) supplementation therapy to adults with GH deficiency has beneficial effects on adipose tissue lipid metabolism, improving thus adipocyte functional morphology and insulin sensitivity. However, molecular nature of these effects remains unclear. We therefore tested the hypothesis that lipid-mobilizing adipokine zinc-α2-glycoprotein is causally linked to GH effects on adipose tissue lipid metabolism. Seventeen patients with severe GH deficiency examined before and after the 5-year GH replacement therapy were compared with age-, gender- and BMI-matched healthy controls. Euglycemic hyperinsulinemic clamp was used to assess whole-body and adipose tissue-specific insulin sensitivity. Glucose tolerance was determined by oGTT, visceral and subcutaneous abdominal adiposity by MRI, adipocyte size morphometrically after collagenase digestion, lipid accumulation and release was studied in differentiated human primary adipocytes in association with GH treatment and zinc-α2-glycoprotein gene silencing. Five-year GH replacement therapy improved glucose tolerance, adipose tissue insulin sensitivity and reduced adipocyte size without affecting adiposity and whole-body insulin sensitivity. Adipose tissue zinc-α2-glycoprotein expression was positively associated with whole-body and adipose tissue insulin sensitivity and negatively with adipocyte size. GH treatment to adipocytes in vitro increased zinc-α2-glycoprotein expression (>50%) and was paralleled by enhanced lipolysis and decreased triglyceride accumulation (>35%). Moreover, GH treatment improved antilipolytic action of insulin in cultured adipocytes. Most importantly, silencing zinc-α2-glycoprotein eliminated all of the GH effects on adipocyte lipid metabolism. Effects of 5-year GH supplementation therapy on adipose tissue lipid metabolism and insulin sensitivity are associated with zinc-α2-glycoprotein. Presence of this adipokine is required for the GH action on adipocyte lipid metabolism in vitro

  4. 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.

  5. Adipocyte Fetuin-A Contributes to Macrophage Migration into Adipose Tissue and Polarization of Macrophages*

    PubMed Central

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

    2013-01-01

    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. PMID:23943623

  6. Persistent organic pollutants meet adipose tissue hypoxia: does cross-talk contribute to inflammation during obesity?

    PubMed

    Myre, M; Imbeault, P

    2014-01-01

    Lipophilic persistent organic pollutants (POPs) accumulate in lipid-rich tissues such as human adipose tissue. This is particularly problematic in individuals with excess adiposity, a physiological state that may be additionally characterized by local adipose tissue hypoxia. Hypoxic patches occur when oxygen diffusion is insufficient to reach all hypertrophic adipocytes. POPs and hypoxia independently contribute to the development of adipose tissue-specific and systemic inflammation often associated with obesity. Inflammation is induced by increased proinflammatory mediators such as tumour necrosis factor-alpha, interleukin-6, and monocyte chemotactic protein-1, as well as reduced adiponectin release, an anti-inflammatory and insulin-sensitizing adipokine. The aryl hydrocarbon receptor (AhR) mediates the cellular response to some pollutants, while hypoxia responses occur through the oxygen-sensitive transcription factor hypoxia-inducible factor (HIF)-1. There is some overlap between the two signalling pathways since both require a common subunit called the AhR nuclear translocator. As such, it is unclear how adipocytes respond to simultaneous POP and hypoxia exposure. This brief review explores the independent contribution of POPs and adipose tissue hypoxia as factors underlying the inflammatory response from adipocytes during obesity. It also highlights that the combined effect of POPs and hypoxia through the AhR and HIF-1 signalling pathways remains to be tested.

  7. Agouti expression in human adipose tissue: functional consequences and increased expression in type 2 diabetes.

    PubMed

    Smith, Steven R; Gawronska-Kozak, Barbara; Janderová, Lenka; Nguyen, Taylor; Murrell, Angela; Stephens, Jacqueline M; Mynatt, Randall L

    2003-12-01

    It is well recognized that the agouti/melanocortin system is an important regulator of body weight homeostasis. Given that agouti is expressed in human adipose tissue and that the ectopic expression of agouti in adipose tissue results in moderately obese mice, the link between agouti expression in human adipose tissue and obesity/type 2 diabetes was investigated. Although there was no apparent relationship between agouti mRNA levels and BMI, agouti mRNA levels were significantly elevated in subjects with type 2 diabetes. The regulation of agouti in cultured human adipocytes revealed that insulin did not regulate agouti mRNA, whereas dexamethasone treatment potently increased the levels of agouti mRNA. Experiments with cultured human preadipocytes and with cells obtained from transgenic mice that overexpress agouti demonstrated that melanocortin receptor (MCR) signaling in adipose tissue can regulate both preadipocyte proliferation and differentiation. Taken together, these results reveal that agouti can regulate adipogenesis at several levels and suggest that there are functional consequences of elevated agouti levels in human adipose tissue. The influence of MCR signaling on adipogenesis combined with the well-established role of MCR signaling in the hypothalamus suggest that adipogenesis is coordinately regulated with food intake and energy expenditure.

  8. Intermittent cold exposure improves glucose homeostasis associated with brown and white adipose tissues in mice

    PubMed Central

    Wang, Tse-Yao; Liu, Cuiqing; Wang, Aixia; Sun, Qinghua

    2015-01-01

    Aims The discovery of different shades of fat has been implicated in the pathogenesis of obesity-related metabolic disorders. However, the effects of early and intermittent exposure to cold temperature on systemic metabolic changes in adult life remain unclear. Main methods To elucidate the impact of cold temperature exposure on metabolic function of adipose tissues, we investigated the glucose homeostasis, activation of brown adipose tissue (BAT) and “browning” of white adipose tissue (WAT) in mice in response to intermittent cold exposure. Mice were exposed to 4 °C, 2 hours per day and 5 days per week, for 14 weeks. Glucose homeostasis was tested via intraperitoneal glucose tolerance test and insulin tolerance test; body fat mass was evaluated using in vivo magnetic resonance imaging; BAT activity was detected primarily by positron emission tomography/computed tomography; and WAT “browning” was evaluated using immunohistochemistry. Key findings Our results showed that 14-week cold exposure improved glucose tolerance and enhanced insulin sensitivity, reduced the relative weights of epididymal and retroperitoneal WAT, increased expressions of UCP1 and PGC1α in subcutaneous adipose tissue. Significance Intermittent exposure to cold temperature in early life may improve systemic glucose homeostasis and induce WAT “browning”, suggesting that ambient cold temperature exposure may serve as a promising intervention to metabolic disorders. PMID:26281919

  9. Proline oxidase-adipose triglyceride lipase pathway restrains adipose cell death and tissue inflammation.

    PubMed

    Lettieri Barbato, D; Aquilano, K; Baldelli, S; Cannata, S M; Bernardini, S; Rotilio, G; Ciriolo, M R

    2014-01-01

    The nutrient-sensing lipolytic enzyme adipose triglyceride lipase (ATGL) has a key role in adipose tissue function, and alterations in its activity have been implicated in many age-related metabolic disorders. In adipose tissue reduced blood vessel density is related to hypoxia state, cell death and inflammation. Here we demonstrate that adipocytes of poorly vascularized enlarged visceral adipose tissue (i.e. adipose tissue of old mice) suffer from limited nutrient delivery. In particular, nutrient starvation elicits increased activity of mitochondrial proline oxidase/dehydrogenase (POX/PRODH) that is causal in triggering a ROS-dependent induction of ATGL. We demonstrate that ATGL promotes the expression of genes related to mitochondrial oxidative metabolism (peroxisome proliferator-activated receptor-α, peroxisome proliferator-activated receptor-γ coactivator-1α), thus setting a metabolic switch towards fat utilization that supplies energy to starved adipocytes and prevents cell death, as well as adipose tissue inflammation. Taken together, these results identify ATGL as a stress resistance mediator in adipocytes, restraining visceral adipose tissue dysfunction typical of age-related metabolic disorders.

  10. Adipose tissue and skeletal muscle blood flow during mental stress

    SciTech Connect

    Linde, B.; Hjemdahl, P.; Freyschuss, U.; Juhlin-Dannfelt, A.

    1989-01-01

    Mental stress (a modified Stroop color word conflict test (CWT)) increased adipose tissue blood flow (ATBF; 133Xe clearance) by 70% and reduced adipose tissue vascular resistance (ATR) by 25% in healthy male volunteers. The vasculatures of adipose tissue (abdomen as well as thigh), skeletal muscle of the calf (133Xe clearance), and the entire calf (venous occlusion plethysmography) responded similarly. Arterial epinephrine (Epi) and glycerol levels were approximately doubled by stress. Beta-Blockade by metoprolol (beta 1-selective) or propranolol (nonselective) attenuated CWT-induced tachycardia similarly. Metoprolol attenuated stress-induced vasodilation in the calf and tended to do so in adipose tissue. Propranolol abolished vasodilation in the calf and resulted in vasoconstriction during CWT in adipose tissue. Decreases in ATR, but not in skeletal muscle or calf vascular resistances, were correlated to increases in arterial plasma glycerol (r = -0.42, P less than 0.05), whereas decreases in skeletal muscle and calf vascular resistances, but not in ATR, were correlated to increases in arterial Epi levels (r = -0.69, P less than 0.01; and r = -0.43, P less than 0.05, respectively). The results suggest that mental stress increases nutritive blood flow in adipose tissue and skeletal muscle considerably, both through the elevation of perfusion pressure and via vasodilatation. Withdrawal of vasoconstrictor nerve activity, vascular beta 2-adrenoceptor stimulation by circulating Epi, and metabolic mechanisms (in adipose tissue) may contribute to the vasodilatation.

  11. Brown adipose tissue as a secretory organ.

    PubMed

    Villarroya, Francesc; Cereijo, Rubén; Villarroya, Joan; Giralt, Marta

    2017-01-01

    Brown adipose tissue (BAT) is the main site of adaptive thermogenesis and experimental studies have associated BAT activity with protection against obesity and metabolic diseases, such as type 2 diabetes mellitus and dyslipidaemia. Active BAT is present in adult humans and its activity is impaired in patients with obesity. The ability of BAT to protect against chronic metabolic disease has traditionally been attributed to its capacity to utilize glucose and lipids for thermogenesis. However, BAT might also have a secretory role, which could contribute to the systemic consequences of BAT activity. Several BAT-derived molecules that act in a paracrine or autocrine manner have been identified. Most of these factors promote hypertrophy and hyperplasia of BAT, vascularization, innervation and blood flow, processes that are all associated with BAT recruitment when thermogenic activity is enhanced. Additionally, BAT can release regulatory molecules that act on other tissues and organs. This secretory capacity of BAT is thought to be involved in the beneficial effects of BAT transplantation in rodents. Fibroblast growth factor 21, IL-6 and neuregulin 4 are among the first BAT-derived endocrine factors to be identified. In this Review, we discuss the current understanding of the regulatory molecules (the so-called brown adipokines or batokines) that are released by BAT that influence systemic metabolism and convey the beneficial metabolic effects of BAT activation. The identification of such adipokines might also direct drug discovery approaches for managing obesity and its associated chronic metabolic diseases.

  12. Cell Supermarket: Adipose Tissue as a Source of Stem Cells

    PubMed Central

    Dodson, M.V.; Wei, S.; Duarte, M.; Du, M.; Jiang, Z.; Hausman, G.J.; Bergen, W.G.

    2013-01-01

    Adipose tissue is derived from numerous sources, and in recent years this tissue 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 and scientific applications. The focus of this paper is to reflect on this area of research and to provide a list of potential (future) research areas. PMID:25031654

  13. 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.

  14. Palmitate-induced inflammatory pathways in human adipose microvascular endothelial cells promote monocyte adhesion and impair insulin transcytosis.

    PubMed

    Pillon, Nicolas J; Azizi, Paymon M; Li, Yujin E; Liu, Jun; Wang, Changsen; Chan, Kenny L; Hopperton, Kathryn E; Bazinet, Richard P; Heit, Bryan; Bilan, Philip J; Lee, Warren L; Klip, Amira

    2015-07-01

    Obesity is associated with inflammation and immune cell recruitment to adipose tissue, muscle and intima of atherosclerotic blood vessels. Obesity and hyperlipidemia are also associated with tissue insulin resistance and can compromise insulin delivery to muscle. The muscle/fat microvascular endothelium mediates insulin delivery and facilitates monocyte transmigration, yet its contribution to the consequences of hyperlipidemia is poorly understood. Using primary endothelial cells from human adipose tissue microvasculature (HAMEC), we investigated the effects of physiological levels of fatty acids on endothelial inflammation and function. Expression of cytokines and adhesion molecules was measured by RT-qPCR. Signaling pathways were evaluated by pharmacological manipulation and immunoblotting. Surface expression of adhesion molecules was determined by immunohistochemistry. THP1 monocyte interaction with HAMEC was measured by cell adhesion and migration across transwells. Insulin transcytosis was measured by total internal reflection fluorescence microscopy. Palmitate, but not palmitoleate, elevated the expression of IL-6, IL-8, TLR2 (Toll-like receptor 2), and intercellular adhesion molecule 1 (ICAM-1). HAMEC had markedly low fatty acid uptake and oxidation, and CD36 inhibition did not reverse the palmitate-induced expression of adhesion molecules, suggesting that inflammation did not arise from palmitate uptake/metabolism. Instead, inhibition of TLR4 to NF-κB signaling blunted palmitate-induced ICAM-1 expression. Importantly, palmitate-induced surface expression of ICAM-1 promoted monocyte binding and transmigration. Conversely, palmitate reduced insulin transcytosis, an effect reversed by TLR4 inhibition. In summary, palmitate activates inflammatory pathways in primary microvascular endothelial cells, impairing insulin transport and increasing monocyte transmigration. This behavior may contribute in vivo to reduced tissue insulin action and enhanced tissue

  15. Total DDT and dieldrin content of human adipose tissue

    SciTech Connect

    Ahmad, N.; Harsas, W.; Marolt, R.S.; Morton, M.; Pollack, J.K.

    1988-12-01

    As far as the authors could ascertain only 4 well-documented analytical studies have been carried out in Australia determining the total DDT and dieldrin content of human adipose tissue. The latest of these studies was published over 16 years ago. Therefore it is timely and important to re-examine the total DDT and dieldrin concentration within the adipose tissue of the Australian population. The present investigation has analyzed 290 samples of human adipose tissue obtained from Westmead Hospital situated in an outer suburb of Sydney, New South Wales for their content of total DDT and dieldrin.

  16. The Adipose Renin-Angiotensin System Modulates Systemic Markers of Insulin Sensitivity and Activates the Intrarenal Renin-Angiotensin System

    DOE PAGES

    Kim, Suyeon; Soltani-Bejnood, Morvarid; Quignard-Boulange, Annie; ...

    2006-01-01

    Background . The adipose tissue renin-angiotensin system (RAS) contributes to regulation of fat mass and may also impact systemic functions such as blood pressure and metabolism. Methods and results . A panel of mouse models including mice lacking angiotensinogen, Agt ( Agt -KO), mice expressing Agt solely in adipose tissue (aP2- Agt/Agt -KO), and mice overexpressing Agt in adipose tissue (aP2- Agt ) was studied. Total body weight, epididymal fat pad weight, and circulating levels of leptin, insulin, and resistin were significantly decreased in Agt -KO mice, while plasma adiponectin levels were increased. aP2- Agt mice exhibited increased adipositymore » and plasma leptin and insulin levels compared to wild type (WT) controls. Angiotensinogen and type I Ang II receptor protein levels were also elevated in kidney of aP2- Agt mice. Conclusion . These findings demonstrate that alterations in adipose RAS activity significantly impact both local and systemic physiology in a way that may contribute to the detrimental health effects of obesity.« less

  17. Self-synthesized extracellular matrix contributes to mature adipose tissue regeneration in a tissue engineering chamber.

    PubMed

    Zhan, Weiqing; Chang, Qiang; Xiao, Xiaolian; Dong, Ziqing; Zeng, Zhaowei; Gao, Jianhua; Lu, Feng

    2015-01-01

    The development of an engineered adipose tissue substitute capable of supporting reliable, predictable, and complete fat tissue regeneration would be of value in plastic and reconstructive surgery. For adipogenesis, a tissue engineering chamber provides an optimized microenvironment that is both efficacious and reproducible; however, for reasons that remain unclear, tissues regenerated in a tissue engineering chamber consist mostly of connective rather than adipose tissue. Here, we describe a chamber-based system for improving the yield of mature adipose tissue and discuss the potential mechanism of adipogenesis in tissue-chamber models. Adipose tissue flaps with independent vascular pedicles placed in chambers were implanted into rabbits. Adipose volume increased significantly during the observation period (week 1, 2, 3, 4, 16). Histomorphometry revealed mature adipose tissue with signs of adipose tissue remolding. The induced engineered constructs showed high-level expression of adipogenic (peroxisome proliferator-activated receptor γ), chemotactic (stromal cell-derived factor 1a), and inflammatory (interleukin 1 and 6) genes. In our system, the extracellular matrix may have served as a scaffold for cell migration and proliferation, allowing mature adipose tissue to be obtained in a chamber microenvironment without the need for an exogenous scaffold. Our results provide new insights into key elements involved in the early development of adipose tissue regeneration.

  18. Fructose, but not glucose, impairs insulin signaling in the three major insulin-sensitive tissues

    PubMed Central

    Baena, Miguel; Sangüesa, Gemma; Dávalos, Alberto; Latasa, María-Jesús; Sala-Vila, Aleix; Sánchez, Rosa María; Roglans, Núria; Laguna, Juan Carlos; Alegret, Marta

    2016-01-01

    Human studies support the relationship between high intake of fructose-sweetened beverages and type 2 diabetes, but there is a debate on whether this effect is fructose-specific or it is merely associated to an excessive caloric intake. Here we investigate the effects of 2 months’ supplementation to female rats of equicaloric 10% w/v fructose or glucose solutions on insulin sensitivity in target tissues. Fructose supplementation caused hepatic deposition of triglycerides and changed the fatty acid profile of this fraction, with an increase in monounsaturated and a decrease in polyunsaturated species, but did not cause inflammation and oxidative stress. Fructose but not glucose-supplemented rats displayed an abnormal glucose tolerance test, and did not show increased phosphorylation of V-akt murine thymoma viral oncogene homolog-2 (Akt) in white adipose tissue and liver after insulin administration. In skeletal muscle, phosphorylation of Akt and of Akt substrate of 160 kDA (AS160) was not impaired but the expression of the glucose transporter type 4 (GLUT4) in the plasma membrane was reduced only in fructose-fed rats. In conclusion, fructose but not glucose supplementation causes fatty liver without inflammation and oxidative stress and impairs insulin signaling in the three major insulin-responsive tissues independently from the increase in energy intake. PMID:27194405

  19. Fructose, but not glucose, impairs insulin signaling in the three major insulin-sensitive tissues.

    PubMed

    Baena, Miguel; Sangüesa, Gemma; Dávalos, Alberto; Latasa, María-Jesús; Sala-Vila, Aleix; Sánchez, Rosa María; Roglans, Núria; Laguna, Juan Carlos; Alegret, Marta

    2016-05-19

    Human studies support the relationship between high intake of fructose-sweetened beverages and type 2 diabetes, but there is a debate on whether this effect is fructose-specific or it is merely associated to an excessive caloric intake. Here we investigate the effects of 2 months' supplementation to female rats of equicaloric 10% w/v fructose or glucose solutions on insulin sensitivity in target tissues. Fructose supplementation caused hepatic deposition of triglycerides and changed the fatty acid profile of this fraction, with an increase in monounsaturated and a decrease in polyunsaturated species, but did not cause inflammation and oxidative stress. Fructose but not glucose-supplemented rats displayed an abnormal glucose tolerance test, and did not show increased phosphorylation of V-akt murine thymoma viral oncogene homolog-2 (Akt) in white adipose tissue and liver after insulin administration. In skeletal muscle, phosphorylation of Akt and of Akt substrate of 160 kDA (AS160) was not impaired but the expression of the glucose transporter type 4 (GLUT4) in the plasma membrane was reduced only in fructose-fed rats. In conclusion, fructose but not glucose supplementation causes fatty liver without inflammation and oxidative stress and impairs insulin signaling in the three major insulin-responsive tissues independently from the increase in energy intake.

  20. Low-frequency electro-acupuncture and physical exercise improve metabolic disturbances and modulate gene expression in adipose tissue in rats with dihydrotestosterone-induced polycystic ovary syndrome.

    PubMed

    Mannerås, Louise; Jonsdottir, Ingibjörg H; Holmäng, Agneta; Lönn, Malin; Stener-Victorin, Elisabet

    2008-07-01

    Polycystic ovary syndrome (PCOS) is a complex endocrine and metabolic disorder associated with ovulatory dysfunction, hyperandrogenism, abdominal obesity, and insulin resistance. Pharmacotherapy is often unsatisfactory. This study evaluates the effects of low-frequency electro-acupuncture (EA) and physical exercise on metabolic disturbances and adipose tissue mRNA expression of selected genes in a rat PCOS model characterized by insulin resistance and adiposity. Dihydrotestosterone (inducing PCOS) or vehicle (control) was administrated continuously, beginning before puberty. At age 10 wk, PCOS rats were randomly divided into three groups; PCOS, PCOS EA, and PCOS exercise. PCOS EA rats received 2-Hz EA (evoking muscle twitches) three times/wk during 4-5 wk. PCOS exercise rats had free access to a running wheel for 4-5 wk. EA and exercise improved insulin sensitivity, measured by clamp, in PCOS rats. Exercise also reduced adiposity, visceral adipocyte size, and plasma leptin. EA increased plasma IGF-I. Real-time RT-PCR revealed increased expression of leptin and IL-6 and decreased expression of uncoupling protein 2 in visceral adipose tissue of PCOS rats compared with controls. EA restored the expression of leptin and uncoupling protein 2, whereas exercise normalized adipose tissue leptin and IL-6 expression in PCOS rats. Thus, EA and exercise ameliorate insulin resistance in rats with PCOS. This effect may involve regulation of adipose tissue metabolism and production because EA and exercise each partly restore divergent adipose tissue gene expression associated with insulin resistance, obesity, and inflammation. In contrast to exercise, EA improves insulin sensitivity and modulates adipose tissue gene expression without influencing adipose tissue mass and cellularity.

  1. Adipose hypothermia in obesity and its association with period homolog 1, insulin sensitivity, and inflammation in fat.

    PubMed

    Yamaoka, Masaya; Maeda, Norikazu; Takayama, Yasunori; Sekimoto, Ryohei; Tsushima, Yu; Matsuda, Keisuke; Mori, Takuya; Inoue, Kana; Nishizawa, Hitoshi; Tominaga, Makoto; Funahashi, Tohru; Shimomura, Iichiro

    2014-01-01

    Visceral fat adiposity plays an important role in the development of metabolic syndrome. We reported previously the impact of human visceral fat adiposity on gene expression profile of peripheral blood cells. Genes related to circadian rhythm were highly associated with visceral fat area and period homolog 1 (PER1) showed the most significant negative correlation with visceral fat area. However, regulation of adipose Per1 remains poorly understood. The present study was designed to understand the regulation of Per1 in adipose tissues. Adipose Per1 mRNA levels of ob/ob mice were markedly low at 25 and 35 weeks of age. The levels of other core clock genes of white adipose tissues were also low in ob/ob mice at 25 and 35 weeks of age. Per1 mRNA was mainly expressed in the mature adipocyte fraction (MAF) and it was significantly low in MAF of ob/ob mice. To examine the possible mechanisms, 3T3-L1 adipocytes were treated with H2O2, tumor necrosis factor-α (TNF-α), S100A8, and lipopolysaccharide (LPS). However, no significant changes in Per1 mRNA level were observed by these agents. Exposure of cultured 3T3-L1 adipocytes to low temperature (33°C) decreased Per1 and catalase, and increased monocyte chemoattractant protein-1 (Mcp-1) mRNA levels. Hypothermia also worsened insulin-mediated Akt phosphorylation in 3T3-L1 adipocytes. Finally, telemetric analysis showed low temperature of adipose tissues in ob/ob mice. In obesity, adipose hypothermia seems to accelerate adipocyte dysfunction.

  2. Adipose Hypothermia in Obesity and Its Association with Period Homolog 1, Insulin Sensitivity, and Inflammation in Fat

    PubMed Central

    Yamaoka, Masaya; Maeda, Norikazu; Takayama, Yasunori; Sekimoto, Ryohei; Tsushima, Yu; Matsuda, Keisuke; Mori, Takuya; Inoue, Kana; Nishizawa, Hitoshi; Tominaga, Makoto; Funahashi, Tohru; Shimomura, Iichiro

    2014-01-01

    Visceral fat adiposity plays an important role in the development of metabolic syndrome. We reported previously the impact of human visceral fat adiposity on gene expression profile of peripheral blood cells. Genes related to circadian rhythm were highly associated with visceral fat area and period homolog 1 (PER1) showed the most significant negative correlation with visceral fat area. However, regulation of adipose Per1 remains poorly understood. The present study was designed to understand the regulation of Per1 in adipose tissues. Adipose Per1 mRNA levels of ob/ob mice were markedly low at 25 and 35 weeks of age. The levels of other core clock genes of white adipose tissues were also low in ob/ob mice at 25 and 35 weeks of age. Per1 mRNA was mainly expressed in the mature adipocyte fraction (MAF) and it was significantly low in MAF of ob/ob mice. To examine the possible mechanisms, 3T3-L1 adipocytes were treated with H2O2, tumor necrosis factor-α (TNF-α), S100A8, and lipopolysaccharide (LPS). However, no significant changes in Per1 mRNA level were observed by these agents. Exposure of cultured 3T3-L1 adipocytes to low temperature (33°C) decreased Per1 and catalase, and increased monocyte chemoattractant protein-1 (Mcp-1) mRNA levels. Hypothermia also worsened insulin-mediated Akt phosphorylation in 3T3-L1 adipocytes. Finally, telemetric analysis showed low temperature of adipose tissues in ob/ob mice. In obesity, adipose hypothermia seems to accelerate adipocyte dysfunction. PMID:25397888

  3. Dietary patterns, insulin sensitivity and adiposity in the multi-ethnic Insulin Resistance Atherosclerosis Study population.

    PubMed

    Liese, Angela D; Schulz, Mandy; Moore, Charity G; Mayer-Davis, Elizabeth J

    2004-12-01

    Epidemiological investigations increasingly employ dietary-pattern techniques to fully integrate dietary data. The present study evaluated the relationship of dietary patterns identified by cluster analysis with measures of insulin sensitivity (SI) and adiposity in the multi-ethnic, multi-centre Insulin Resistance Atherosclerosis Study (IRAS, 1992-94). Cross-sectional data from 980 middle-aged adults, of whom 67 % had normal and 33 % had impaired glucose tolerance, were analysed. Usual dietary intake was obtained by an interviewer-administered, validated food-frequency questionnaire. Outcomes included SI, fasting insulin (FI), BMI and waist circumference. The relationship of dietary patterns to log(SI+1), log(FI), BMI and waist circumference was modelled with multivariable linear regressions. Cluster analysis identified six distinct diet patterns--'dark bread', 'wine', 'fruits', 'low-frequency eaters', 'fries' and 'white bread'. The 'white bread' and the 'fries' patterns over-represented the Hispanic IRAS population predominantly from two centres, while the 'wine' and 'dark bread' groups were dominated by non-Hispanic whites. The dietary patterns were associated significantly with each of the outcomes first at the crude, clinical level (P<0.001). Furthermore, they were significantly associated with FI, BMI and waist circumference independent of age, sex, race or ethnicity, clinic, family history of diabetes, smoking and activity (P<0.004), whereas significance was lost for SI. Studying the total dietary behaviour via a pattern approach allowed us to focus both on the qualitative and quantitative dimensions of diet. The present study identified highly consistent associations of distinct dietary patterns with measures of insulin resistance and adiposity, which are risk factors for diabetes and heart disease.

  4. Imidacloprid Promotes High Fat Diet-Induced Adiposity and Insulin Resistance in Male C57BL/6J Mice

    PubMed Central

    2016-01-01

    Imidacloprid, a neonicotinoid insecticide widely used in agriculture worldwide, has been reported to promote adipogenesis and cause insulin resistance in vitro. The purpose of the current study was to determine the effects of imidacloprid and its interaction with dietary fat in the development of adiposity and insulin resistance using male C57BL/6J mice. Imidacloprid (0.06, 0.6, or 6 mg/kg bw/day) was mixed in a low-fat (4% w/w) or high-fat (20% w/w) diet and given to mice ad libitum for 12 weeks. Imidacloprid significantly promoted high fat diet-induced body weight gain and adiposity. In addition, imidacloprid treatment with the high fat diet resulted in impaired glucose metabolism. Consistently, there were significant effects of imidacloprid on genes regulating lipid and glucose metabolisms, including the AMP-activated protein kinase-α (AMPKα) pathway in white adipose tissue and liver. These results suggest that imidacloprid may potentiate high fat diet-induced adiposity and insulin resistance in male C57BL/6J mice. PMID:27960282

  5. Imidacloprid Promotes High Fat Diet-Induced Adiposity and Insulin Resistance in Male C57BL/6J Mice.

    PubMed

    Sun, Quancai; Xiao, Xiao; Kim, Yoo; Kim, Daeyoung; Yoon, Kyoon Sup; Clark, John M; Park, Yeonhwa

    2016-12-14

    Imidacloprid, a neonicotinoid insecticide widely used in agriculture worldwide, has been reported to promote adipogenesis and cause insulin resistance in vitro. The purpose of the current study was to determine the effects of imidacloprid and its interaction with dietary fat in the development of adiposity and insulin resistance using male C57BL/6J mice. Imidacloprid (0.06, 0.6, or 6 mg/kg bw/day) was mixed in a low-fat (4% w/w) or high-fat (20% w/w) diet and given to mice ad libitum for 12 weeks. Imidacloprid significantly promoted high fat diet-induced body weight gain and adiposity. In addition, imidacloprid treatment with the high fat diet resulted in impaired glucose metabolism. Consistently, there were significant effects of imidacloprid on genes regulating lipid and glucose metabolisms, including the AMP-activated protein kinase-α (AMPKα) pathway in white adipose tissue and liver. These results suggest that imidacloprid may potentiate high fat diet-induced adiposity and insulin resistance in male C57BL/6J mice.

  6. Hypothalamic control of brown adipose tissue thermogenesis

    PubMed Central

    Labbé, Sebastien M.; Caron, Alexandre; Lanfray, Damien; Monge-Rofarello, Boris; Bartness, Timothy J.; Richard, Denis

    2015-01-01

    It has long been known, in large part from animal studies, that the control of brown adipose tissue (BAT) thermogenesis is insured by the central nervous system (CNS), which integrates several stimuli in order to control BAT activation through the sympathetic nervous system (SNS). SNS-mediated BAT activity is governed by diverse neurons found in brain structures involved in homeostatic regulations and whose activity is modulated by various factors including oscillations of energy fluxes. The characterization of these neurons has always represented a challenging issue. The available literature suggests that the neuronal circuits controlling BAT thermogenesis are largely part of an autonomic circuitry involving the hypothalamus, brainstem and the SNS efferent neurons. In the present review, we recapitulate the latest progresses in regards to the hypothalamic regulation of BAT metabolism. We briefly addressed the role of the thermoregulatory pathway and its interactions with the energy balance systems in the control of thermogenesis. We also reviewed the involvement of the brain melanocortin and endocannabinoid systems as well as the emerging role of steroidogenic factor 1 (SF1) neurons in BAT thermogenesis. Finally, we examined the link existing between these systems and the homeostatic factors that modulate their activities. PMID:26578907

  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. Central Control of Brown Adipose Tissue Thermogenesis

    PubMed Central

    Morrison, Shaun F.; Madden, Christopher J.; Tupone, Domenico

    2011-01-01

    Thermogenesis, the production of heat energy, is an essential component of the homeostatic repertoire to maintain body temperature during the challenge of low environmental temperature and plays a key role in elevating body temperature during the febrile response to infection. Mitochondrial oxidation in brown adipose tissue (BAT) is a significant source of neurally regulated metabolic heat production in many species from mouse to man. BAT thermogenesis is regulated by neural networks in the central nervous system which responds to feedforward afferent signals from cutaneous and core body thermoreceptors and to feedback signals from brain thermosensitive neurons to activate BAT sympathetic nerve activity. This review summarizes the research leading to a model of the feedforward reflex pathway through which environmental cold stimulates BAT thermogenesis and includes the influence on this thermoregulatory network of the pyrogenic mediator, prostaglandin E2, to increase body temperature during fever. The cold thermal afferent circuit from cutaneous thermal receptors, through second-order thermosensory neurons in the dorsal horn of the spinal cord ascends to activate neurons in the lateral parabrachial nucleus which drive GABAergic interneurons in the preoptic area (POA) to inhibit warm-sensitive, inhibitory output neurons of the POA. The resulting disinhibition of BAT thermogenesis-promoting neurons in the dorsomedial hypothalamus activates BAT sympathetic premotor neurons in the rostral ventromedial medulla, including the rostral raphe pallidus, which provide excitatory, and possibly disinhibitory, inputs to spinal sympathetic circuits to drive BAT thermogenesis. Other recently recognized central sites influencing BAT thermogenesis and energy expenditure are also described. PMID:22389645

  9. The role of dietary fat in adipose tissue metabolism.

    PubMed

    Fernández-Quintela, Alfredo; Churruca, Itziar; Portillo, Maria Puy

    2007-10-01

    Energy intake and expenditure tend on average to remain adjusted to each other in order to maintain a stable body weight, which is only likely to be sustained if the fuel mix oxidised is equivalent to the nutrient content of the diet. Whereas protein and carbohydrate degradation and oxidation are closely adjusted to their intakes, fat balance regulation is less precise and that fat is more likely to be stored than oxidised. It has been demonstrated that dietary fatty acids have an influence not only on the fatty acid composition of membrane phospholipids, thus modulating several metabolic processes that take place in the adipocyte, but also on the composition and the quantity of different fatty acids in adipose tissue. Moreover, dietary fatty acids also modulate eicosanoid presence, which have hormone-like activities in lipid metabolism regulation in adipose tissue. Until recently, the adipocyte has been considered to be no more than a passive tissue for storage of excess energy. However, there is now compelling evidence that adipocytes have a role as endocrine secretory cells. Some of the adipokines produced by adipose tissue, such as leptin and adiponectin, act on adipose tissue in an autocrine/paracrine manner to regulate adipocyte metabolism. Furthermore, dietary fatty acids may influence the expression of adipokines. The nutrients are among the most influential of the environmental factors that determine the way adipose tissue genes are expressed by functioning as regulators of gene transcription. Therefore, not only dietary fat amount but also dietary fat composition influence adipose tissue metabolism.

  10. Light/dark cycle-dependent metabolic changes in adipose tissue of pinealectomized rats.

    PubMed

    Alonso-Vale, M I; Borges-Silva, C N; Anhê, G F; Andreotti, S; Machado, M A; Cipolla-Neto, J; Lima, F B

    2004-07-01

    We investigated the effects of pinealectomy on adipose tissue metabolism at different times of day. Adult male Wistar rats were divided into two groups: pinealectomized and control (sham-operated). Eight weeks after surgery, the animals were killed at three different times (at 8.00 a.m., at 4.00 p.m. and 11.00 p.m.). We collected blood samples for glucose, insulin, corticosterone, and leptin determinations, and periepididymal adipocytes for in vitro insulin-stimulated glucose uptake, oxidation, and incorporation into lipids. Pinealectomy caused insulin resistance as measured by 2-deoxyglucose uptake (a fall of approximately 40 % in the maximally insulin-stimulated rates) accompanied by hypercorticosteronemia at the three time points investigated without changes in plasma insulin an or leptin levels. Furthermore, pinealectomy increased the insulin-induced glucose incorporation into lipids (77 %) at 4.00 p.m. and insulin-induced glucose oxidation in the morning and in the afternoon, while higher rates were observed in the evening and in the morning in control rats. In conclusion, cell responsiveness to insulin was differentially affected by pineal ablation and time of day, and persistent insulin resistance was obtained in pinealectomized rats. We hypothesize that pinealectomy exposes the animal to an inadequate match between energy requirements and fuel mobilization.

  11. 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.

  12. Glucose delays the insulin-induced increase in thyroid hormone-mediated signaling in adipose of prolong-fasted elephant seal pups.

    PubMed

    Martinez, Bridget; Soñanez-Organis, José G; Viscarra, Jose A; Jaques, John T; MacKenzie, Duncan S; Crocker, Daniel E; Ortiz, Rudy M

    2016-03-15

    Prolonged food deprivation in mammals typically reduces glucose, insulin, and thyroid hormone (TH) concentrations, as well as tissue deiodinase (DI) content and activity, which, collectively, suppress metabolism. However, in elephant seal pups, prolonged fasting does not suppress TH levels; it is associated with upregulation of adipose TH-mediated cellular mechanisms and adipose-specific insulin resistance. The functional relevance of this apparent paradox and the effects of glucose and insulin on TH-mediated signaling in an insulin-resistant tissue are not well defined. To address our hypothesis that insulin increases adipose TH signaling in pups during extended fasting, we assessed the changes in TH-associated genes in response to an insulin infusion in early- and late-fasted pups. In late fasting, insulin increased DI1, DI2, and THrβ-1 mRNA expression by 566%, 44%, and 267% at 60 min postinfusion, respectively, with levels decreasing by 120 min. Additionally, we performed a glucose challenge in late-fasted pups to differentiate between insulin- and glucose-mediated effects on TH signaling. In contrast to the insulin-induced effects, glucose infusion did not increase the expressions of DI1, DI2, and THrβ-1 until 120 min, suggesting that glucose delays the onset of the insulin-induced effects. The data also suggest that fasting duration increases the sensitivity of adipose TH-mediated mechanisms to insulin, some of which may be mediated by increased glucose. These responses appear to be unique among mammals and to have evolved in elephant seals to facilitate their adaptation to tolerate an extreme physiological condition.

  13. Role of hypoxia in obesity-induced disorders of glucose and lipid metabolism in adipose tissue

    PubMed Central

    Yin, Jun; Gao, Zhanguo; He, Qing; Zhou, Dequan; Guo, ZengKui; Ye, Jianping

    2009-01-01

    Recent studies suggest that adipose tissue hypoxia (ATH) may contribute to endocrine dysfunction in adipose tissue of obese mice. In this study, we examined hypoxia's effects on metabolism in adipocytes. We determined the dynamic relationship of ATH and adiposity in ob/ob mice. The interstitial oxygen pressure (Po2) was monitored in the epididymal fat pads for ATH. During weight gain from 39.5 to 55.5 g, Po2 declined from 34.8 to 20.1 mmHg, which are 40–60% lower than those in the lean mice. Insulin receptor-β (IRβ) and insulin receptor substrate-1 (IRS-1) were decreased in the adipose tissue of obese mice, and the alteration was observed in 3T3-L1 adipocytes after hypoxia (1% oxygen) treatment. Insulin-induced glucose uptake and Akt Ser473 phosphorylation was blocked by hypoxia in the adipocytes. This effect of hypoxia exhibited cell type specificity, as it was not observed in L6 myotubes and βTC6 cells. In response to hypoxia, free fatty acid (FFA) uptake was reduced and lipolysis was increased in 3T3-L1 adipocytes. The molecular mechanism of decreased fatty acid uptake may be related to inhibition of fatty acid transporters (FATP1 and CD36) and transcription factors (PPARγ and C/EBPα) by hypoxia. The hypoxia-induced lipolysis was observed in vivo after femoral arterial clamp. Necrosis and apoptosis were induced by hypoxia in 3T3-L1 adipocytes. These data suggest that ATH may promote FFA release and inhibit glucose uptake in adipocytes by inhibition of the insulin-signaling pathway and induction of cell death. PMID:19066318

  14. THE POTENTIAL ROLES FOR ADIPOSE TISSUE IN PERIPHERAL NERVE REGENERATION

    PubMed Central

    Walocko, Frances M.; Khouri, Roger K.; Urbanchek, Melanie G.; Levi, Benjamin; Cederna, Paul S.

    2016-01-01

    Introduction This review summarizes current understanding about the role of adipose-derived tissues in peripheral nerve regeneration and discusses potential advances that would translate this approach into the clinic. Methods We searched PubMed for in vivo, experimental studies on the regenerative effects of adipose-derived tissues on peripheral nerve injuries. We summarized the methods and results for the 42 experiments. Results Adipose-derived tissues enhanced peripheral nerve regeneration in 86% of the experiments. Ninety-five percent evaluated purified, cultured, or differentiated adipose tissue. These approaches have regulatory and scaling burdens, restricting clinical usage. Only one experiment tested the ability of adipose tissue to enhance nerve regeneration in conjunction with nerve autografts, the clinical gold standard. Conclusion Scientific studies illustrate that adipose-derived tissues enhance regeneration of peripheral nerves. Before this approach achieves clinical acceptance, fat processing must become automated and regulatory approval achieved. Animal studies using whole fat grafts are greatly needed for clinical translation. PMID:26773850

  15. HOXC10 suppresses browning of white adipose tissues

    PubMed Central

    Ng, Yvonne; Tan, Shi-Xiong; Chia, Sook Yoong; Tan, Hwee Yim Angeline; Gun, Sin Yee; Sun, Lei; Hong, Wanjin; Han, Weiping

    2017-01-01

    Given that increased thermogenesis in white adipose tissue, also known as browning, promotes energy expenditure, significant efforts have been invested to determine the molecular factors involved in this process. Here we show that HOXC10, a homeobox domain-containing transcription factor expressed in subcutaneous white adipose tissue, is a suppressor of genes involved in browning white adipose tissue. Ectopic expression of HOXC10 in adipocytes suppresses brown fat genes, whereas the depletion of HOXC10 in adipocytes and myoblasts increases the expression of brown fat genes. The protein level of HOXC10 inversely correlates with brown fat genes in subcutaneous white adipose tissue of cold-exposed mice. Expression of HOXC10 in mice suppresses cold-induced browning in subcutaneous white adipose tissue and abolishes the beneficial effect of cold exposure on glucose clearance. HOXC10 exerts its effect, at least in part, by suppressing PRDM16 expression. The results support that HOXC10 is a key negative regulator of the process of browning in white adipose tissue. PMID:28186086

  16. Adipose weight gain during chronic insulin treatment of mice results from changes in lipid storage without affecting de novo synthesis of palmitate.

    PubMed

    Frikke-Schmidt, Henriette; Pedersen, Thomas Åskov; Fledelius, Christian; Olsen, Grith Skytte; Hellerstein, Marc

    2013-01-01

    Insulin treatment is associated with increased adipose mass in both humans and mice. However, the underlying dynamic basis of insulin induced lipid accumulation in adipose tissue remains elusive. To assess this, young female C57BL6/J mice were fed a low fat diet for 3 weeks, treated subsequently with 7 days of constant subcutaneous insulin infusion by osmotic minipumps and compared to mice with only buffer infused. To track changes in lipid deposition during insulin treatment, metabolic labeling was conducted with heavy water for the final 4 days. Blood glucose was significantly lowered within one hour after implantation of insulin loaded mini pumps and remained lower throughout the study. Insulin treated animals gained significantly more weight during treatment and the mean weight of the subcutaneous adipose depots was significantly higher with the highest dose of insulin. Surprisingly, de novo palmitate synthesis within the subcutaneous and the gonadal depots was not affected significantly by insulin treatment. In contrast insulin treatment caused accumulation of triglycerides in both depots due to either deposition of newly synthesised triglycerides (subcutaneous depot) or inhibition of lipolysis (gonadal depot).

  17. Polymerase I and transcript release factor (PTRF) regulates adipocyte differentiation and determines adipose tissue expandability

    PubMed Central

    Perez-Diaz, Sergio; Johnson, Lance A.; DeKroon, Robert M.; Moreno-Navarrete, Jose M.; Alzate, Oscar; Fernandez-Real, Jose M.; Maeda, Nobuyo; Arbones-Mainar, Jose M.

    2014-01-01

    Impaired adipogenesis renders an adipose tissue unable to expand, leading to lipotoxicity and conditions such as diabetes and cardiovascular disease. While factors important for adipogenesis have been studied extensively, those that set the limits of adipose tissue expansion remain undetermined. Feeding a Western-type diet to apolipoprotein E2 knock-in mice, a model of metabolic syndrome, produced 3 groups of equally obese mice: mice with normal glucose tolerance, hyperinsulinemic yet glucose-tolerant mice, and prediabetic mice with impaired glucose tolerance and reduced circulating insulin. Using proteomics, we compared subcutaneous adipose tissues from mice in these groups and found that the expression of PTRF (polymerase I and transcript release factor) associated selectively with their glucose tolerance status. Lentiviral and pharmacologically overexpressed PTRF, whose function is critical for caveola formation, compromised adipocyte differentiation of cultured 3T3-L1cells. In human adipose tissue, PTRF mRNA levels positively correlated with markers of lipolysis and cellular senescence. Furthermore, a negative relationship between telomere length and PTRF mRNA levels was observed in human subcutaneous fat. PTRF is associated with limited adipose tissue expansion underpinning the key role of caveolae in adipocyte regulation. Furthermore, PTRF may be a suitable adipocyte marker for predicting pathological obesity and inform clinical management.—Perez-Diaz, S., Johnson, L. A., DeKroon, R. M., Moreno-Navarrete, J. M., Alzate, O., Fernandez-Real, J. M., Maeda, N., Arbones-Mainar, J. M. Polymerase I and transcript release factor (PTRF) regulates adipocyte differentiation and determines adipose tissue expandability. PMID:24812087

  18. Hypertrophy and/or Hyperplasia: Dynamics of Adipose Tissue Growth.

    PubMed

    Jo, Junghyo; Gavrilova, Oksana; Pack, Stephanie; Jou, William; Mullen, Shawn; Sumner, Anne E; Cushman, Samuel W; Periwal, Vipul

    2009-03-01

    Adipose tissue grows by two mechanisms: hyperplasia (cell number increase) and hypertrophy (cell size increase). Genetics and diet affect the relative contributions of these two mechanisms to the growth of adipose tissue in obesity. In this study, the size distributions of epididymal adipose cells from two mouse strains, obesity-resistant FVB/N and obesity-prone C57BL/6, were measured after 2, 4, and 12 weeks under regular and high-fat feeding conditions. The total cell number in the epididymal fat pad was estimated from the fat pad mass and the normalized cell-size distribution. The cell number and volume-weighted mean cell size increase as a function of fat pad mass. To address adipose tissue growth precisely, we developed a mathematical model describing the evolution of the adipose cell-size distributions as a function of the increasing fat pad mass, instead of the increasing chronological time. Our model describes the recruitment of new adipose cells and their subsequent development in different strains, and with different diet regimens, with common mechanisms, but with diet- and genetics-dependent model parameters. Compared to the FVB/N strain, the C57BL/6 strain has greater recruitment of small adipose cells. Hyperplasia is enhanced by high-fat diet in a strain-dependent way, suggesting a synergistic interaction between genetics and diet. Moreover, high-fat feeding increases the rate of adipose cell size growth, independent of strain, reflecting the increase in calories requiring storage. Additionally, high-fat diet leads to a dramatic spreading of the size distribution of adipose cells in both strains; this implies an increase in size fluctuations of adipose cells through lipid turnover.

  19. FNDC5 expression and circulating irisin levels are modified by diet and hormonal conditions in hypothalamus, adipose tissue and muscle.

    PubMed

    Varela-Rodríguez, B M; Pena-Bello, L; Juiz-Valiña, P; Vidal-Bretal, B; Cordido, F; Sangiao-Alvarellos, S

    2016-07-19

    Irisin is processed from fibronectin type III domain-containing protein 5 (FNDC5). However, a controversy exists concerning irisin origin, regulation and function. To elucidate the relationship between serum irisin and FNDC5 mRNA expression levels, we evaluated plasma irisin levels and FNDC5 gene expression in the hypothalamus, gastrocnemius muscle and different depots of adipose tissue in models of altered metabolism. In normal rats, blood irisin levels diminished after 48-h fast and with leptin, insulin and alloxan treatments, and serum irisin concentrations increased in diabetic rats after insulin treatment and acute treatments of irisin increased blood insulin levels. No changes were observed during long-term experiments with different diets. We suggested that levels of circulating irisin are the result of the sum of the irisin produced by different depots of adipose tissue and skeletal muscle. This study shows for the first time that there are differences in FNDC5 expression depending on white adipose tissue depots. Moreover, a considerable decrease in visceral and epididymal adipose tissue depots correlated with increased FNDC5 mRNA expression levels, probably in an attempt to compensate the decrease that occurs in their mass. Hypothalamic FNDC5 expression did not change for any of the tested diets but increased with leptin, insulin and metformin treatments suggesting that the regulation of central and peripheral FNDC5/irisin expression and functions are different.

  20. FNDC5 expression and circulating irisin levels are modified by diet and hormonal conditions in hypothalamus, adipose tissue and muscle

    PubMed Central

    Varela-Rodríguez, B. M.; Pena-Bello, L.; Juiz-Valiña, P.; Vidal-Bretal, B.; Cordido, F.; Sangiao-Alvarellos, S.

    2016-01-01

    Irisin is processed from fibronectin type III domain-containing protein 5 (FNDC5). However, a controversy exists concerning irisin origin, regulation and function. To elucidate the relationship between serum irisin and FNDC5 mRNA expression levels, we evaluated plasma irisin levels and FNDC5 gene expression in the hypothalamus, gastrocnemius muscle and different depots of adipose tissue in models of altered metabolism. In normal rats, blood irisin levels diminished after 48-h fast and with leptin, insulin and alloxan treatments, and serum irisin concentrations increased in diabetic rats after insulin treatment and acute treatments of irisin increased blood insulin levels. No changes were observed during long-term experiments with different diets. We suggested that levels of circulating irisin are the result of the sum of the irisin produced by different depots of adipose tissue and skeletal muscle. This study shows for the first time that there are differences in FNDC5 expression depending on white adipose tissue depots. Moreover, a considerable decrease in visceral and epididymal adipose tissue depots correlated with increased FNDC5 mRNA expression levels, probably in an attempt to compensate the decrease that occurs in their mass. Hypothalamic FNDC5 expression did not change for any of the tested diets but increased with leptin, insulin and metformin treatments suggesting that the regulation of central and peripheral FNDC5/irisin expression and functions are different. PMID:27432282

  1. 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

  2. Human periprostatic adipose tissue promotes prostate cancer aggressiveness in vitro

    PubMed Central

    2012-01-01

    Background Obesity is associated with prostate cancer aggressiveness and mortality. The contribution of periprostatic adipose tissue, which is often infiltrated by malignant cells, to cancer progression is largely unknown. Thus, this study aimed to determine if periprostatic adipose tissue is linked with aggressive tumor biology in prostate cancer. Methods Supernatants of whole adipose tissue (explants) or stromal vascular fraction (SVF) from paired fat samples of periprostatic (PP) and pre-peritoneal visceral (VIS) anatomic origin from different donors were prepared and analyzed for matrix metalloproteinases (MMPs) 2 and 9 activity. The effects of those conditioned media (CM) on growth and migration of hormone-refractory (PC-3) and hormone-sensitive (LNCaP) prostate cancer cells were measured. Results We show here that PP adipose tissue of overweight men has higher MMP9 activity in comparison with normal subjects. The observed increased activities of both MMP2 and MMP9 in PP whole adipose tissue explants, likely reveal the contribution of adipocytes plus stromal-vascular fraction (SVF) as opposed to SVF alone. MMP2 activity was higher for PP when compared to VIS adipose tissue. When PC-3 cells were stimulated with CM from PP adipose tissue explants, increased proliferative and migratory capacities were observed, but not in the presence of SVF. Conversely, when LNCaP cells were stimulated with PP explants CM, we found enhanced motility despite the inhibition of proliferation, whereas CM derived from SVF increased both cell proliferation and motility. Explants culture and using adipose tissue of PP origin are most effective in promoting proliferation and migration of PC-3 cells, as respectively compared with SVF culture and using adipose tissue of VIS origin. In LNCaP cells, while explants CM cause increased migration compared to SVF, the use of PP adipose tissue to generate CM result in the increase of both cellular proliferation and migration. Conclusions Our

  3. Role of Autonomic Nervous System and Orexinergic System on Adipose Tissue

    PubMed Central

    Messina, Giovanni; Valenzano, Anna; Moscatelli, Fiorenzo; Salerno, Monica; Lonigro, Antonio; Esposito, Teresa; Monda, Vincenzo; Corso, Gaetano; Messina, Antonietta; Viggiano, Andrea; Triggiani, Antonio I.; Chieffi, Sergio; Guglielmi, Giuseppe; Monda, Marcellino; Cibelli, Giuseppe

    2017-01-01

    Adipose tissue, defined as white adipose tissue (WAT) and brown adipose tissue (BAT), is a biological caloric reservoir; in response to over-nutrition it expands and, in response to energy deficit, it releases lipids. The WAT primarily stores energy as triglycerides, whereas BAT dissipates chemical energy as heat. In mammals, the BAT is a key site for heat production and an attractive target to promote weight loss. The autonomic nervous system (ANS) exerts a direct control at the cellular and molecular levels in adiposity. The sympathetic nervous system (SNS) provides a complex homeostatic control to specifically coordinate function and crosstalk of both fat pads, as indicated by the increase of the sympathetic outflow to BAT, in response to cold and high-fat diet, but also by the increase or decrease of the sympathetic outflow to selected WAT depots, in response to different lipolytic requirements of these two conditions. More recently, a role has been attributed to the parasympathetic nervous system (PNS) in modulating both adipose tissue insulin-mediated glucose uptake and fatty free acid (FFA) metabolism in an anabolic way and its endocrine function. The regulation of adipose tissue is unlikely to be limited to the autonomic control, since a number of signaling cytokines and neuropeptides play an important role, as well. In this review, we report some experimental evidences about the role played by both the ANS and orexins into different fat pads, related to food intake and energy expenditure, with a special emphasis on body weight status and fat mass (FM) content. PMID:28344558

  4. Exercise Regulation of Marrow Adipose Tissue

    PubMed Central

    Pagnotti, Gabriel M.; Styner, Maya

    2016-01-01

    Despite association with low bone density and skeletal fractures, marrow adipose tissue (MAT) remains poorly understood. The marrow adipocyte originates from the mesenchymal stem cell (MSC) pool that also gives rise to osteoblasts, chondrocytes, and myocytes, among other cell types. To date, the presence of MAT has been attributed to preferential biasing of MSC into the adipocyte rather than osteoblast lineage, thus negatively impacting bone formation. Here, we focus on understanding the physiology of MAT in the setting of exercise, dietary interventions, and pharmacologic agents that alter fat metabolism. The beneficial effect of exercise on musculoskeletal strength is known: exercise induces bone formation, encourages growth of skeletally supportive tissues, inhibits bone resorption, and alters skeletal architecture through direct and indirect effects on a multiplicity of cells involved in skeletal adaptation. MAT is less well studied due to the lack of reproducible quantification techniques. In recent work, osmium-based 3D quantification shows a robust response of MAT to both dietary and exercise intervention in that MAT is elevated in response to high-fat diet and can be suppressed following daily exercise. Exercise-induced bone formation correlates with suppression of MAT, such that exercise effects might be due to either calorie expenditure from this depot or from mechanical biasing of MSC lineage away from fat and toward bone, or a combination thereof. Following treatment with the anti-diabetes drug rosiglitazone – a PPARγ-agonist known to increase MAT and fracture risk – mice demonstrate a fivefold higher femur MAT volume compared to the controls. In addition to preventing MAT accumulation in control mice, exercise intervention significantly lowers MAT accumulation in rosiglitazone-treated mice. Importantly, exercise induction of trabecular bone volume is unhindered by rosiglitazone. Thus, despite rosiglitazone augmentation of MAT, exercise

  5. [Interests and potentials of adipose tissue in scleroderma].

    PubMed

    Daumas, A; Eraud, J; Hautier, A; Sabatier, F; Magalon, G; Granel, B

    2013-12-01

    Systemic sclerosis is a disorder involving the connective tissue, arterioles and microvessels. It is characterized by skin and visceral fibrosis and ischemic phenomena. Currently, therapy is limited and no antifibrotic treatment has proven its efficacy. Beyond some severe organ lesions (pulmonary arterial hypertension, pulmonary fibrosis, scleroderma renal crisis), which only concern a minority of patients, the skin sclerosis of hands and face and the vasculopathy lead to physical and psychological disability in most patients. Thus, functional improvement of hand motion and face represents a priority for patient therapy. Due to its easy obtention by fat lipopaspirate and adipocytes survival, re injection of adipose tissue is a common therapy used in plastic surgery for its voluming effect. Identification and characterization of the adipose tissue-derived stroma vascular fraction, mainly including mesenchymal stem cells, have revolutionized the science showing that adipose tissue is a valuable source of multipotent stem cells, able to migrate to site of injury and to differentiate according to the receiver tissue's needs. Due to easy harvest by liposuction, its abundance in mesenchymal cells far higher that the bone marrow, and stroma vascular fraction's ability to differentiate and secrete growth angiogenic and antiapoptotic factors, the use of adipose tissue is becoming more attractive in regenerative medicine. We here present the interest of adipose tissue use in the treatment of the hands and face in scleroderma.

  6. Growth hormone and adipose tissue: beyond the adipocyte

    PubMed Central

    Berryman, Darlene E.; List, Edward O.; Sackmann-Sala, Lucila; Lubbers, Ellen; Munn, Rachel; Kopchick, John J.

    2011-01-01

    The last two decades have seen resurgence in the interest in, and research on, adipose tissue. In part, the increased interest stems from an alarming increase in obesity rates worldwide. However, an understanding that this once simple tissue is significantly more intricate and interactive than previously realized has fostered additional attention. While few would argue that growth hormone (GH) radically alters adipose tissue, a better appreciation of the newer complexities requires that GH's influence on this tissue be reexamined. Therefore, the objective of this review is to describe the more recent understanding of adipose tissue and how GH may influence and contribute to these newer complexities with special focus on the available data from mice with altered GH action. PMID:21470887

  7. Brown adipose tissue transplantation ameliorates polycystic ovary syndrome

    PubMed Central

    Yuan, Xiaoxue; Hu, Tao; Zhao, Han; Huang, Yuanyuan; Ye, Rongcai; Lin, Jun; Zhang, Chuanhai; Zhang, Hanlin; Wei, Gang; Zhou, Huiqiao; Dong, Meng; Zhao, Jun; Wang, Haibin; Liu, Qingsong; Lee, Hyuek Jong; Jin, Wanzhu; Chen, Zi-Jiang

    2016-01-01

    Polycystic ovary syndrome (PCOS), which is characterized by anovulation, hyperandrogenism, and polycystic ovaries, is a complex endocrinopathy. Because the cause of PCOS at the molecular level is largely unknown, there is no cure or specific treatment for PCOS. Here, we show that transplantation of brown adipose tissue (BAT) reversed anovulation, hyperandrogenism, and polycystic ovaries in a dehydroepiandrosterone (DHEA)-induced PCOS rat. BAT transplantation into a PCOS rat significantly stabilized menstrual irregularity and improved systemic insulin sensitivity up to a normal level, which was not shown in a sham-operated or muscle-transplanted PCOS rat. Moreover, BAT transplantation, not sham operation or muscle transplantation, surprisingly improved fertility in PCOS rats. Interestingly, BAT transplantation activated endogenous BAT and thereby increased the circulating level of adiponectin, which plays a prominent role in whole-body energy metabolism and ovarian physiology. Consistent with BAT transplantation, administration of adiponectin protein dramatically rescued DHEA-induced PCOS phenotypes. These results highlight that endogenous BAT activity is closely related to the development of PCOS phenotypes and that BAT activation might be a promising therapeutic option for the treatment of PCOS. PMID:26903641

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

    Technology Transfer Automated Retrieval System (TEKTRAN)

    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...

  9. GPR120: a critical role in adipogenesis, inflammation, and energy metabolism in adipose tissue.

    PubMed

    Song, Tongxing; Yang, Yang; Zhou, Yuanfei; Wei, Hongkui; Peng, Jian

    2017-03-11

    It is well known that adipose tissue has a critical role in the development of obesity and metabolic diseases and that adipose tissue acts as an endocrine organ to regulate lipid and glucose metabolism. Accumulating in the adipose tissue, fatty acids serve as a primary source of essential nutrients and act on intracellular and cell surface receptors to regulate biological events. G protein-coupled receptor 120 (GPR120) represents a promising target for the treatment of obesity-related metabolic disorders for its involvement in the regulation of adipogenesis, inflammation, glucose uptake, and insulin resistance. In this review, we summarize recent studies and advances regarding the systemic role of GPR120 in adipose tissue, including both white and brown adipocytes. We offer a new perspective by comparing the different roles in a variety of homeostatic processes from adipogenic development to adipocyte metabolism, and we also discuss the effects of natural and synthetic agonists that may be potential agents for the treatment of metabolic diseases.

  10. Impaired tethering and fusion of GLUT4 vesicles in insulin-resistant human adipose cells.

    PubMed

    Lizunov, Vladimir A; Lee, Jo-Ping; Skarulis, Monica C; Zimmerberg, Joshua; Cushman, Samuel W; Stenkula, Karin G

    2013-09-01

    Systemic glucose homeostasis is profoundly influenced by adipose cell function. Here we investigated GLUT4 dynamics in living adipose cells from human subjects with varying BMI and insulin sensitivity index (Si) values. Cells were transfected with hemagglutinin (HA)-GLUT4-green fluorescent protein (GFP)/mCherry (red fluorescence), and were imaged live using total internal reflection fluorescence and confocal microscopy. HA-GLUT4-GFP redistribution to the plasma membrane (PM) was quantified by surface-exposed HA epitope. In the basal state, GLUT4 storage vesicle (GSV) trafficking to and fusion with the PM were invariant with donor subject Si, as was total cell-surface GLUT4. In cells from insulin-sensitive subjects, insulin augmented GSV tethering and fusion approximately threefold, resulting in a corresponding increase in total PM GLUT4. However, with decreasing Si, these effects diminished progressively. All insulin-induced effects on GLUT4 redistribution and trafficking correlated strongly with Si and only weakly with BMI. Thus, while basal GLUT4 dynamics and total cell-surface GLUT4 are intact in human adipose cells, independent of donor Si, cells from insulin-resistant donors show markedly impaired GSV tethering and fusion responses to insulin, even after overnight culture. This altered insulin responsiveness is consistent with the hypothesis that adipose cellular dysfunction is a primary contributor to systemic metabolic dysfunction.

  11. Enzymatic intracrine regulation of white adipose tissue

    PubMed Central

    DiSilvestro, David; Petrosino, Jennifer; Aldoori, Ayat; Melgar-Bermudez, Emiliano; Wells, Alexandra; Ziouzenkova, Ouliana

    2015-01-01

    Abdominal fat formation has become a permanent risk factor for metabolic syndrome and various cancers in one-third of the world's population of obese and even lean patients. Formation of abdominal fat involves additional mechanisms beyond an imbalance in energy intake and expenditure, which explains systemic obesity. In this review, we briefly summarized autonomous regulatory circuits that locally produce hormones from inactive precursors or nutrients for intra-/auto-/paracrine signaling in white adipose depots. Enzymatic pathways activating steroid and thyroid hormones in adipose depots were compared with enzymatic production of retinoic acid from vitamin A. We discussed the role of intracrine circuits in fat-depot functions and strategies to reduce abdominal adiposity through thermogenic adipocytes with interrupted generation of retinoic acid. PMID:25390015

  12. The metabolic syndrome of omega3-depleted rats. II. Body weight, adipose tissue mass and glycemic homeostasis.

    PubMed

    Sener, Abdullah; Zhang, Ying; Bulur, Nurdan; Louchami, Karim; Malaisse, Willy J; Carpentier, Yvon A

    2009-07-01

    Exposure of 7-week-old normal rats for 3-7 months to a diet deprived of long-chain polyunsaturated omega3 fatty acids was recently reported to induce changes in the fatty acid content and pattern of liver phospholipids and triglycerides similar to those otherwise found in second generation omega3-depleted rats. In the present study, the changes in body weight, parametrial adipose tissue mass, plasma glucose and insulin concentrations and insulin resistance index were investigated in the same control and omega3-depleted rats, which were then given access for 2 to 4-5 weeks to either a flaxseed oil-enriched diet (control and omega3-depleted rats) or a soybean oil-enriched diet (control rats). The body weight failed to differ between control and omega3-depleted rats. The latter rats, however, displayed increases in adipose tissue mass, plasma glucose and insulin concentrations, and insulin resistance index. In the control rats given access to the soybean or flaxseed oil-enriched diet, body weight and adipose tissue mass were little affected, but both the plasma glucose concentration and insulin resistance index decreased. In the omega3-depleted rats given access to the flaxseed oil-enriched diet, both body weight and adipose tissue mass underwent a rapid, pronounced and sustained increase, whilst the plasma glucose concentration and insulin resistance index decreased similarly to those in the control rats. The present design of omega3 fatty acid dietary deprivation thus reproduces the visceral obesity and insulin resistance otherwise observed in second-generation omega3-depleted rats. However, the supply of exogenous omega3 fatty acids to the omega3-depleted rats failed to oppose visceral obesity, possibly as a result of the orexigenic effects of these omega3 fatty acids.

  13. Brown adipose tissue as an anti-obesity tissue in humans.

    PubMed

    Chechi, K; Nedergaard, J; Richard, D

    2014-02-01

    During the 11th Stock Conference held in Montreal, Quebec, Canada, world-leading experts came together to present and discuss recent developments made in the field of brown adipose tissue biology. Owing to the vast capacity of brown adipose tissue for burning food energy in the process of thermogenesis, and due to demonstrations of its presence in adult humans, there is tremendous interest in targeting brown adipose tissue as an anti-obesity tissue in humans. However, the future of such therapeutic approaches relies on our understanding of the origin, development, recruitment, activation and regulation of brown adipose tissue in humans. As reviewed here, the 11th Stock Conference was organized around these themes to discuss the recent progress made in each aspect, to identify gaps in our current understanding and to further provide a common groundwork that could support collaborative efforts aimed at a future therapy for obesity, based on brown adipose tissue thermogenesis.

  14. Adiponectin self-regulates its expression and multimerization in adipose tissue: an autocrine/paracrine mechanism?

    PubMed

    Lin, Huan; Li, Zhen

    2012-01-01

    Adiponectin, a 30-kDa peptide hormone discovered in the mid 1990s, is secreted abundantly and exclusively by adipose tissue. Adiponectin exists in three major forms: a low molecular weight (LMW) trimer, a medium molecular weight (MMW) hexamer, and a high molecular weight (HMW) 18-36 oligomer. The HMW oligomer has the most potent insulin-sensitizing activity therefore impaired adiponectin multimerization may lead to impaired glycemic control. Decreased ratio of HMW/total adiponectin has been observed in patients with obesity, type-2 diabetes mellitus, cardiovascular diseases and insulin resistance-related metabolic syndrome. Previous studies have indicated that berberine or aminoimidazole carboxamide ribonucleotide (AICAR)-induced activation of AMP-activated protein kinase (AMPK) suppresses the expression of adiponectin but promotes adiponectin multimerization in adipocytes. Since adiponectin activates AMPK through adiponectin receptors (AdipoRs) in the membranes of adipocytes, we speculate that adiponectin self-regulates its expression and multimerization in adipose tissue. The hypothesis suggests a potential drug target for treating insulin resistance and provides new interpretation of several clinical observations. In addition, we propose a rapid method for one-step detection of the distribution of adiponectin oligomers in approximately 30 min, based on the open sandwich immunoassay and fluorescence resonance energy transfer technology. With the development of this new method, the ratio of HMW/total adiponectin may be applied in clinical diagnosis as a novel biomarker for insulin resistance and metabolic disorders.

  15. 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

  16. Role of antigen presentation in the production of pro-inflammatory cytokines in obese adipose tissue.

    PubMed

    Majdoubi, Abdelilah; Kishta, Osama A; Thibodeau, Jacques

    2016-06-01

    Type II diabetes regroups different physiological anomalies that ultimately lead to low-grade chronic inflammation, insulin resistance and loss of pancreatic β-cells. Obesity is one of the best examples of such a condition that can develop into Metabolic Syndrome, causing serious health problems of great socio-economic consequences. The pathological outcome of obesity has a genetic basis and depends on the delicate balance between pro- and anti-inflammatory effectors of the immune system. The causal link between obesity and inflammation is well established. While innate immunity plays a key role in the development of a pro-inflammatory state in obese adipose tissues, it has now become clear that adaptive immune cells are also involved and participate in the cascade of events that lead to metabolic perturbations. The efficacy of some immunotherapeutic protocols in reducing the symptoms of obesity-driven metabolic syndrome in mice implicated all arms of the immune response. Recently, the production of pathogenic immunoglobulins and pro-inflammatory cytokines by B and T lymphocytes suggested an auto-immune basis for the establishment of a non-healthy obese state. Understanding the cellular landscape of obese adipose tissues and how immune cells sustain chronic inflammation holds the key to the development of targeted therapies. In this review, we emphasize the role of antigen-presenting cells and MHC molecules in obese adipose tissue and the general contribution of the adaptive arm of the immune system in inflammation-induced insulin resistance.

  17. Osteopontin Deletion Prevents the Development of Obesity and Hepatic Steatosis via Impaired Adipose Tissue Matrix Remodeling and Reduced Inflammation and Fibrosis in Adipose Tissue and Liver in Mice

    PubMed Central

    Lancha, Andoni; Rodríguez, Amaia; Catalán, Victoria; Becerril, Sara; Sáinz, Neira; Ramírez, Beatriz; Burrell, María A.; Salvador, Javier; Frühbeck, Gema; Gómez-Ambrosi, Javier

    2014-01-01

    Osteopontin (OPN) is a multifunctional extracellular matrix (ECM) protein involved in multiple physiological processes. OPN expression is dramatically increased in visceral adipose tissue in obesity and the lack of OPN protects against the development of insulin resistance and inflammation in mice. We sought to unravel the potential mechanisms involved in the beneficial effects of the absence of OPN. We analyzed the effect of the lack of OPN in the development of obesity and hepatic steatosis induced by a high-fat diet (HFD) using OPN-KO mice. OPN expression was upregulated in epididymal white adipose tissue (EWAT) and liver in wild type (WT) mice with HFD. OPN-KO mice had higher insulin sensitivity, lower body weight and fat mass with reduced adipose tissue ECM remodeling and reduced adipocyte size than WT mice under a HFD. Reduced MMP2 and MMP9 activity was involved in the decreased ECM remodeling. Crown-like structure number in EWAT as well as F4/80-positive cells and Emr1 expression in EWAT and liver increased with HFD, while OPN-deficiency blunted the increase. Moreover, our data show for the first time that OPN-KO under a HFD mice display reduced fibrosis in adipose tissue and liver, as well as reduced oxidative stress in adipose tissue. Gene expression of collagens Col1a1, Col6a1 and Col6a3 in EWAT and liver, as well as the profibrotic cytokine Tgfb1 in EWAT were increased with HFD, while OPN-deficiency prevented this increase. OPN deficiency prevented hepatic steatosis via reduction in the expression of molecules involved in the onset of fat accumulation such as Pparg, Srebf1, Fasn, Mogat1, Dgat2 and Cidec. Furthermore, OPN-KO mice exhibited higher body temperature and improved BAT function. The present data reveal novel mechanisms of OPN in the development of obesity, pointing out the inhibition of OPN as a promising target for the treatment of obesity and fatty liver. PMID:24871103

  18. Osteopontin deletion prevents the development of obesity and hepatic steatosis via impaired adipose tissue matrix remodeling and reduced inflammation and fibrosis in adipose tissue and liver in mice.

    PubMed

    Lancha, Andoni; Rodríguez, Amaia; Catalán, Victoria; Becerril, Sara; Sáinz, Neira; Ramírez, Beatriz; Burrell, María A; Salvador, Javier; Frühbeck, Gema; Gómez-Ambrosi, Javier

    2014-01-01

    Osteopontin (OPN) is a multifunctional extracellular matrix (ECM) protein involved in multiple physiological processes. OPN expression is dramatically increased in visceral adipose tissue in obesity and the lack of OPN protects against the development of insulin resistance and inflammation in mice. We sought to unravel the potential mechanisms involved in the beneficial effects of the absence of OPN. We analyzed the effect of the lack of OPN in the development of obesity and hepatic steatosis induced by a high-fat diet (HFD) using OPN-KO mice. OPN expression was upregulated in epididymal white adipose tissue (EWAT) and liver in wild type (WT) mice with HFD. OPN-KO mice had higher insulin sensitivity, lower body weight and fat mass with reduced adipose tissue ECM remodeling and reduced adipocyte size than WT mice under a HFD. Reduced MMP2 and MMP9 activity was involved in the decreased ECM remodeling. Crown-like structure number in EWAT as well as F4/80-positive cells and Emr1 expression in EWAT and liver increased with HFD, while OPN-deficiency blunted the increase. Moreover, our data show for the first time that OPN-KO under a HFD mice display reduced fibrosis in adipose tissue and liver, as well as reduced oxidative stress in adipose tissue. Gene expression of collagens Col1a1, Col6a1 and Col6a3 in EWAT and liver, as well as the profibrotic cytokine Tgfb1 in EWAT were increased with HFD, while OPN-deficiency prevented this increase. OPN deficiency prevented hepatic steatosis via reduction in the expression of molecules involved in the onset of fat accumulation such as Pparg, Srebf1, Fasn, Mogat1, Dgat2 and Cidec. Furthermore, OPN-KO mice exhibited higher body temperature and improved BAT function. The present data reveal novel mechanisms of OPN in the development of obesity, pointing out the inhibition of OPN as a promising target for the treatment of obesity and fatty liver.

  19. PAFR in adipose tissue macrophages is associated with anti-inflammatory phenotype and metabolic homoeostasis.

    PubMed

    Filgueiras, Luciano Ribeiro; Koga, Marianna Mainardi; Quaresma, Paula G; Ishizuka, Edson Kiyotaka; Montes, Marlise B A; Prada, Patricia O; Saad, Mario J; Jancar, Sonia; Rios, Francisco J

    2016-04-01

    Metabolic dysfunction is associated with adipose tissue inflammation and macrophage infiltration. PAFR (platelet-activating factor receptor) is expressed in several cell types and binds to PAF (platelet-activating factor) and oxidized phospholipids. Engagement of PAFR in macrophages drives them towards the anti-inflammatory phenotype. In the present study, we investigated whether genetic deficiency of PAFR affects the phenotype of ATMs (adipose tissue macrophages) and its effect on glucose and insulin metabolism. PARFKO (PAFR-knockout) and WT (wild-type) mice were fed on an SD (standard diet) or an HFD (high-fat diet). Glucose and insulin tolerance tests were performed by blood monitoring. ATMs were evaluated by FACS for phenotypic markers. Gene and protein expression was investigated by real-time reverse transcription-quantitative PCR and Western blotting respectively. Results showed that the epididymal adipose tissue of PAFRKO mice had increased gene expression of Ccr7, Nos2, Il6 and Il12, associated with pro-inflammatory mediators, and reduced expression of the anti-inflammatory Il10. Moreover, the adipose tissue of PAFRKO mice presented more pro-inflammatory macrophages, characterized by an increased frequency of F4/80(+)CD11c(+) cells. Blood monocytes of PAFRKO mice also exhibited a pro-inflammatory phenotype (increased frequency of Ly6C(+) cells) and PAFR ligands were detected in the serum of both PAFRKO and WT mice. Regarding metabolic parameters, compared with WT, PAFRKO mice had: (i) higher weight gain and serum glucose concentration levels; (ii) decreased insulin-stimulated glucose disappearance; (iii) insulin resistance in the liver; (iv) increased expression of Ldlr in the liver. In mice fed on an HFD, some of these changes were potentiated, particularly in the liver. Thus it seems that endogenous ligands of PAFR are responsible for maintaining the anti-inflammatory profile of blood monocytes and ATMs under physiological conditions. In the absence of

  20. NPY antagonism reduces adiposity and attenuates age-related imbalance of adipose tissue metabolism.

    PubMed

    Park, Seongjoon; Fujishita, Chika; Komatsu, Toshimitsu; Kim, Sang Eun; Chiba, Takuya; Mori, Ryoichi; Shimokawa, Isao

    2014-12-01

    An orexigenic hormone, neuropeptide Y (NPY), plays a role not only in the hypothalamic regulation of appetite, but also in the peripheral regulation of lipid metabolism. However, the intracellular mechanisms triggered by NPY to regulate lipid metabolism are poorly understood. Here we report that NPY deficiency reduces white adipose tissue (WAT) mass and ameliorates the age-related imbalance of adipose tissue metabolism in mice. Gene expression involved in adipogenesis/lipogenesis was found to decrease, whereas proteins involved in lipolysis increased in gonadal WAT (gWAT) of NPY-knockout mice. These changes were associated with an activated SIRT1- and PPARγ-mediated pathway. Moreover, the age-related decrease of de novo lipogenesis in gWAT and thermogenesis in inguinal WAT was inhibited by NPY deficiency. Further analysis using 3T3-L1 cells showed that NPY inhibited lipolysis through the Y1 receptor and enhanced lipogenesis following a reduction in cAMP response element-binding protein (CREB) and SIRT1 protein expression. Therefore, NPY appears to act as a key regulator of adipose tissue metabolism via the CREB-SIRT1 signaling pathway. Taken together, NPY deficiency reduces adiposity and ameliorates the age-related imbalance of adipose tissue metabolism, suggesting that antagonism of NPY may be a promising target for drug development to prevent age-related metabolic diseases.

  1. A stringent validation of mouse adipose tissue identity markers.

    PubMed

    de Jong, Jasper M A; Larsson, Ola; Cannon, Barbara; Nedergaard, Jan

    2015-06-15

    The nature of brown adipose tissue in humans is presently debated: whether it is classical brown or of brite/beige nature. The dissimilar developmental origins and proposed distinct functions of the brown and brite/beige tissues make it essential to ascertain the identity of human depots with the perspective of recruiting and activating them for the treatment of obesity and type 2 diabetes. For identification of the tissues, a number of marker genes have been proposed, but the validity of the markers has not been well documented. We used established brown (interscapular), brite (inguinal), and white (epididymal) mouse adipose tissues and corresponding primary cell cultures as validators and examined the informative value of a series of suggested markers earlier used in the discussion considering the nature of human brown adipose tissue. Most of these markers unexpectedly turned out to be noninformative concerning tissue classification (Car4, Cited1, Ebf3, Eva1, Fbxo31, Fgf21, Lhx8, Hoxc8, and Hoxc9). Only Zic1 (brown), Cd137, Epsti1, Tbx1, Tmem26 (brite), and Tcf21 (white) proved to be informative in these three tissues. However, the expression of the brite markers was not maintained in cell culture. In a more extensive set of adipose depots, these validated markers provide new information about depot identity. Principal component analysis supported our single-gene conclusions. Furthermore, Zic1, Hoxc8, Hoxc9, and Tcf21 displayed anteroposterior expression patterns, indicating a relationship between anatomic localization and adipose tissue identity (and possibly function). Together, the observed expression patterns of these validated marker genes necessitates reconsideration of adipose depot identity in mice and humans.

  2. Adipose tissue inflammation: feeding the development of type 2 diabetes mellitus.

    PubMed

    Richardson, Victoria R; Smith, Kerrie A; Carter, Angela M

    2013-12-01

    The global increase in obesity-induced type 2 diabetes (T2DM) represents a burden for healthcare systems worldwide. Of particular concern is the increased morbidity associated with T2DM, in particular cardiovascular disease (CVD), leading to premature death. Obesity initially leads to the development of insulin resistance in adipose and other tissues. Insulin resistance is initially compensated by increased insulin secretion but ultimately insufficient insulin is produced and this leads to the development of T2DM. Understanding the causal mechanisms underpinning the development of obesity-induced insulin resistance may be beneficial in improving quality of life and life expectancy, with the potential for a major global impact on healthcare systems. There is abundant evidence from animal, human studies and in vitro studies to support functional roles for a number of inflammatory factors in obesity-induced insulin resistance. In this review we provide an overview of the evidence supporting a fundamental role for the fluid phase (in particular the complement system) and the cellular components of the innate immune system in the pathogenesis of obesity-induced insulin resistance and ultimately development of T2DM.

  3. Inside out: Bone marrow adipose tissue as a source of circulating adiponectin

    PubMed Central

    Scheller, Erica L.; Burr, Aaron A.; MacDougald, Ormond A.; Cawthorn, William P.

    2016-01-01

    ABSTRACT The adipocyte-derived hormone adiponectin mediates beneficial cardiometabolic effects, and hypoadiponectinemia is a biomarker for increased metabolic and cardiovascular risk. Indeed, circulating adiponectin decreases in obesity and insulin-resistance, likely because of impaired production from white adipose tissue (WAT). Conversely, lean states such as caloric restriction (CR) are characterized by hyperadiponectinemia, even without increased adiponectin production from WAT. The reasons underlying this paradox have remained elusive, but our recent research suggests that CR-associated hyperadiponectinemia derives from an unexpected source: bone marrow adipose tissue (MAT). Herein, we elaborate on this surprising discovery, including further discussion of potential mechanisms influencing adiponectin production from MAT; additional evidence both for and against our conclusions; and observations suggesting that the relationship between MAT and adiponectin might extend beyond CR. While many questions remain, the burgeoning study of MAT promises to reveal further key insights into MAT biology, both as a source of adiponectin and beyond. PMID:27617171

  4. New genetic loci link adipose and insulin biology to body fat distribution

    PubMed Central

    Strawbridge, Rona J; Pers, Tune H; Fischer, Krista; Justice, Anne E; Workalemahu, Tsegaselassie; Wu, Joseph M.W.; Buchkovich, Martin L; Heard-Costa, Nancy L; Roman, Tamara S; Drong, Alexander W; Song, Ci; Gustafsson, Stefan; Day, Felix R; Esko, Tonu; Fall, Tove; Kutalik, Zoltán; Luan, Jian’an; Randall, Joshua C; Scherag, André; Vedantam, Sailaja; Wood, Andrew R; Chen, Jin; Fehrmann, Rudolf; Karjalainen, Juha; Kahali, Bratati; Liu, Ching-Ti; Schmidt, Ellen M; Absher, Devin; Amin, Najaf; Anderson, Denise; Beekman, Marian; Bragg-Gresham, Jennifer L; Buyske, Steven; Demirkan, Ayse; Ehret, Georg B; Feitosa, Mary F; Goel, Anuj; Jackson, Anne U; Johnson, Toby; Kleber, Marcus E; Kristiansson, Kati; Mangino, Massimo; Leach, Irene Mateo; Medina-Gomez, Carolina; Palmer, Cameron D; Pasko, Dorota; Pechlivanis, Sonali; Peters, Marjolein J; Prokopenko, Inga; Stančáková, Alena; Sung, Yun Ju; Tanaka, Toshiko; Teumer, Alexander; Van Vliet-Ostaptchouk, Jana V; Yengo, Loïc; Zhang, Weihua; Albrecht, Eva; Ärnlöv, Johan; Arscott, Gillian M; Bandinelli, Stefania; Barrett, Amy; Bellis, Claire; Bennett, Amanda J; Berne, Christian; Blüher, Matthias; Böhringer, Stefan; Bonnet, Fabrice; Böttcher, Yvonne; Bruinenberg, Marcel; Carba, Delia B; Caspersen, Ida H; Clarke, Robert; Daw, E Warwick; Deelen, Joris; Deelman, Ewa; Delgado, Graciela; Doney, Alex SF; Eklund, Niina; Erdos, Michael R; Estrada, Karol; Eury, Elodie; Friedrich, Nele; Garcia, Melissa E; Giedraitis, Vilmantas; Gigante, Bruna; Go, Alan S; Golay, Alain; Grallert, Harald; Grammer, Tanja B; Gräßler, Jürgen; Grewal, Jagvir; Groves, Christopher J; Haller, Toomas; Hallmans, Goran; Hartman, Catharina A; Hassinen, Maija; Hayward, Caroline; Heikkilä, Kauko; Herzig, Karl-Heinz; Helmer, Quinta; Hillege, Hans L; Holmen, Oddgeir; Hunt, Steven C; Isaacs, Aaron; Ittermann, Till; James, Alan L; Johansson, Ingegerd; Juliusdottir, Thorhildur; Kalafati, Ioanna-Panagiota; Kinnunen, Leena; Koenig, Wolfgang; Kooner, Ishminder K; Kratzer, Wolfgang; Lamina, Claudia; Leander, Karin; Lee, Nanette R; Lichtner, Peter; Lind, Lars; Lindström, Jaana; Lobbens, Stéphane; Lorentzon, Mattias; Mach, François; Magnusson, Patrik KE; Mahajan, Anubha; McArdle, Wendy L; Menni, Cristina; Merger, Sigrun; Mihailov, Evelin; Milani, Lili; Mills, Rebecca; Moayyeri, Alireza; Monda, Keri L; Mooijaart, Simon P; Mühleisen, Thomas W; Mulas, Antonella; Müller, Gabriele; Müller-Nurasyid, Martina; Nagaraja, Ramaiah; Nalls, Michael A; Narisu, Narisu; Glorioso, Nicola; Nolte, Ilja M; Olden, Matthias; Rayner, Nigel W; Renstrom, Frida; Ried, Janina S; Robertson, Neil R; Rose, Lynda M; Sanna, Serena; Scharnagl, Hubert; Scholtens, Salome; Sennblad, Bengt; Seufferlein, Thomas; Sitlani, Colleen M; Smith, Albert Vernon; Stirrups, Kathleen; Stringham, Heather M; Sundström, Johan; Swertz, Morris A; Swift, Amy J; Syvänen, Ann-Christine; Tayo, Bamidele O; Thorand, Barbara; Thorleifsson, Gudmar; Tomaschitz, Andreas; Troffa, Chiara; van Oort, Floor VA; Verweij, Niek; Vonk, Judith M; Waite, Lindsay L; Wennauer, Roman; Wilsgaard, Tom; Wojczynski, Mary K; Wong, Andrew; Zhang, Qunyuan; Zhao, Jing Hua; Brennan, Eoin P.; Choi, Murim; Eriksson, Per; Folkersen, Lasse; Franco-Cereceda, Anders; Gharavi, Ali G; Hedman, Åsa K; Hivert, Marie-France; Huang, Jinyan; Kanoni, Stavroula; Karpe, Fredrik; Keildson, Sarah; Kiryluk, Krzysztof; Liang, Liming; Lifton, Richard P; Ma, Baoshan; McKnight, Amy J; McPherson, Ruth; Metspalu, Andres; Min, Josine L; Moffatt, Miriam F; Montgomery, Grant W; Murabito, Joanne M; Nicholson, George; Nyholt, Dale R; Olsson, Christian; Perry, John RB; Reinmaa, Eva; Salem, Rany M; Sandholm, Niina; Schadt, Eric E; Scott, Robert A; Stolk, Lisette; Vallejo, Edgar E.; Westra, Harm-Jan; Zondervan, Krina T; Amouyel, Philippe; Arveiler, Dominique; Bakker, Stephan JL; Beilby, John; Bergman, Richard N; Blangero, John; Brown, Morris J; Burnier, Michel; Campbell, Harry; Chakravarti, Aravinda; Chines, Peter S; Claudi-Boehm, Simone; Collins, Francis S; Crawford, Dana C; Danesh, John; de Faire, Ulf; de Geus, Eco JC; Dörr, Marcus; Erbel, Raimund; Eriksson, Johan G; Farrall, Martin; Ferrannini, Ele; Ferrières, Jean; Forouhi, Nita G; Forrester, Terrence; Franco, Oscar H; Gansevoort, Ron T; Gieger, Christian; Gudnason, Vilmundur; Haiman, Christopher A; Harris, Tamara B; Hattersley, Andrew T; Heliövaara, Markku; Hicks, Andrew A; Hingorani, Aroon D; Hoffmann, Wolfgang; Hofman, Albert; Homuth, Georg; Humphries, Steve E; Hyppönen, Elina; Illig, Thomas; Jarvelin, Marjo-Riitta; Johansen, Berit; Jousilahti, Pekka; Jula, Antti M; Kaprio, Jaakko; Kee, Frank; Keinanen-Kiukaanniemi, Sirkka M; Kooner, Jaspal S; Kooperberg, Charles; Kovacs, Peter; Kraja, Aldi T; Kumari, Meena; Kuulasmaa, Kari; Kuusisto, Johanna; Lakka, Timo A; Langenberg, Claudia; Le Marchand, Loic; Lehtimäki, Terho; Lyssenko, Valeriya; Männistö, Satu; Marette, André; Matise, Tara C; McKenzie, Colin A; McKnight, Barbara; Musk, Arthur W; Möhlenkamp, Stefan; Morris, Andrew D; Nelis, Mari; Ohlsson, Claes; Oldehinkel, Albertine J; Ong, Ken K; Palmer, Lyle J; Penninx, Brenda W; Peters, Annette; Pramstaller, Peter P; Raitakari, Olli T; Rankinen, Tuomo; Rao, DC; Rice, Treva K; Ridker, Paul M; Ritchie, Marylyn D.; Rudan, Igor; Salomaa, Veikko; Samani, Nilesh J; Saramies, Jouko; Sarzynski, Mark A; Schwarz, Peter EH; Shuldiner, Alan R; Staessen, Jan A; Steinthorsdottir, Valgerdur; Stolk, Ronald P; Strauch, Konstantin; Tönjes, Anke; Tremblay, Angelo; Tremoli, Elena; Vohl, Marie-Claude; Völker, Uwe; Vollenweider, Peter; Wilson, James F; Witteman, Jacqueline C; Adair, Linda S; Bochud, Murielle; Boehm, Bernhard O; Bornstein, Stefan R; Bouchard, Claude; Cauchi, Stéphane; Caulfield, Mark J; Chambers, John C; Chasman, Daniel I; Cooper, Richard S; Dedoussis, George; Ferrucci, Luigi; Froguel, Philippe; Grabe, Hans-Jörgen; Hamsten, Anders; Hui, Jennie; Hveem, Kristian; Jöckel, Karl-Heinz; Kivimaki, Mika; Kuh, Diana; Laakso, Markku; Liu, Yongmei; März, Winfried; Munroe, Patricia B; Njølstad, Inger; Oostra, Ben A; Palmer, Colin NA; Pedersen, Nancy L; Perola, Markus; Pérusse, Louis; Peters, Ulrike; Power, Chris; Quertermous, Thomas; Rauramaa, Rainer; Rivadeneira, Fernando; Saaristo, Timo E; Saleheen, Danish; Sinisalo, Juha; Slagboom, P Eline; Snieder, Harold; Spector, Tim D; Stefansson, Kari; Stumvoll, Michael; Tuomilehto, Jaakko; Uitterlinden, André G; Uusitupa, Matti; van der Harst, Pim; Veronesi, Giovanni; Walker, Mark; Wareham, Nicholas J; Watkins, Hugh; Wichmann, H-Erich; Abecasis, Goncalo R; Assimes, Themistocles L; Berndt, Sonja I; Boehnke, Michael; Borecki, Ingrid B; Deloukas, Panos; Franke, Lude; Frayling, Timothy M; Groop, Leif C; Hunter, David J.; Kaplan, Robert C; O’Connell, Jeffrey R; Qi, Lu; Schlessinger, David; Strachan, David P; Thorsteinsdottir, Unnur; van Duijn, Cornelia M; Willer, Cristen J; Visscher, Peter M; Yang, Jian; Hirschhorn, Joel N; Zillikens, M Carola; McCarthy, Mark I; Speliotes, Elizabeth K; North, Kari E; Fox, Caroline S; Barroso, Inês; Franks, Paul W; Ingelsson, Erik; Heid, Iris M; Loos, Ruth JF; Cupples, L Adrienne; Morris, Andrew P; Lindgren, Cecilia M; Mohlke, Karen L

    2014-01-01

    Body fat distribution is a heritable trait and a well-established predictor of adverse metabolic outcomes, independent of overall adiposity. To increase our understanding of the genetic basis of body fat distribution and its molecular links to cardiometabolic traits, we conducted genome-wide association meta-analyses of waist and hip circumference-related traits in up to 224,459 individuals. We identified 49 loci (33 new) associated with waist-to-hip ratio adjusted for body mass index (WHRadjBMI) and an additional 19 loci newly associated with related waist and hip circumference measures (P<5×10−8). Twenty of the 49 WHRadjBMI loci showed significant sexual dimorphism, 19 of which displayed a stronger effect in women. The identified loci were enriched for genes expressed in adipose tissue and for putative regulatory elements in adipocytes. Pathway analyses implicated adipogenesis, angiogenesis, transcriptional regulation, and insulin resistance as processes affecting fat distribution, providing insight into potential pathophysiological mechanisms. PMID:25673412

  5. New genetic loci link adipose and insulin biology to body fat distribution.

    PubMed

    Shungin, Dmitry; Winkler, Thomas W; Croteau-Chonka, Damien C; Ferreira, Teresa; Locke, Adam E; Mägi, Reedik; Strawbridge, Rona J; Pers, Tune H; Fischer, Krista; Justice, Anne E; Workalemahu, Tsegaselassie; Wu, Joseph M W; Buchkovich, Martin L; Heard-Costa, Nancy L; Roman, Tamara S; Drong, Alexander W; Song, Ci; Gustafsson, Stefan; Day, Felix R; Esko, Tonu; Fall, Tove; Kutalik, Zoltán; Luan, Jian'an; Randall, Joshua C; Scherag, André; Vedantam, Sailaja; Wood, Andrew R; Chen, Jin; Fehrmann, Rudolf; Karjalainen, Juha; Kahali, Bratati; Liu, Ching-Ti; Schmidt, Ellen M; Absher, Devin; Amin, Najaf; Anderson, Denise; Beekman, Marian; Bragg-Gresham, Jennifer L; Buyske, Steven; Demirkan, Ayse; Ehret, Georg B; Feitosa, Mary F; Goel, Anuj; Jackson, Anne U; Johnson, Toby; Kleber, Marcus E; Kristiansson, Kati; Mangino, Massimo; Mateo Leach, Irene; Medina-Gomez, Carolina; Palmer, Cameron D; Pasko, Dorota; Pechlivanis, Sonali; Peters, Marjolein J; Prokopenko, Inga; Stančáková, Alena; Ju Sung, Yun; Tanaka, Toshiko; Teumer, Alexander; Van Vliet-Ostaptchouk, Jana V; Yengo, Loïc; Zhang, Weihua; Albrecht, Eva; Ärnlöv, Johan; Arscott, Gillian M; Bandinelli, Stefania; Barrett, Amy; Bellis, Claire; Bennett, Amanda J; Berne, Christian; Blüher, Matthias; Böhringer, Stefan; Bonnet, Fabrice; Böttcher, Yvonne; Bruinenberg, Marcel; Carba, Delia B; Caspersen, Ida H; Clarke, Robert; Daw, E Warwick; Deelen, Joris; Deelman, Ewa; Delgado, Graciela; Doney, Alex S F; Eklund, Niina; Erdos, Michael R; Estrada, Karol; Eury, Elodie; Friedrich, Nele; Garcia, Melissa E; Giedraitis, Vilmantas; Gigante, Bruna; Go, Alan S; Golay, Alain; Grallert, Harald; Grammer, Tanja B; Gräßler, Jürgen; Grewal, Jagvir; Groves, Christopher J; Haller, Toomas; Hallmans, Goran; Hartman, Catharina A; Hassinen, Maija; Hayward, Caroline; Heikkilä, Kauko; Herzig, Karl-Heinz; Helmer, Quinta; Hillege, Hans L; Holmen, Oddgeir; Hunt, Steven C; Isaacs, Aaron; Ittermann, Till; James, Alan L; Johansson, Ingegerd; Juliusdottir, Thorhildur; Kalafati, Ioanna-Panagiota; Kinnunen, Leena; Koenig, Wolfgang; Kooner, Ishminder K; Kratzer, Wolfgang; Lamina, Claudia; Leander, Karin; Lee, Nanette R; Lichtner, Peter; Lind, Lars; Lindström, Jaana; Lobbens, Stéphane; Lorentzon, Mattias; Mach, François; Magnusson, Patrik K E; Mahajan, Anubha; McArdle, Wendy L; Menni, Cristina; Merger, Sigrun; Mihailov, Evelin; Milani, Lili; Mills, Rebecca; Moayyeri, Alireza; Monda, Keri L; Mooijaart, Simon P; Mühleisen, Thomas W; Mulas, Antonella; Müller, Gabriele; Müller-Nurasyid, Martina; Nagaraja, Ramaiah; Nalls, Michael A; Narisu, Narisu; Glorioso, Nicola; Nolte, Ilja M; Olden, Matthias; Rayner, Nigel W; Renstrom, Frida; Ried, Janina S; Robertson, Neil R; Rose, Lynda M; Sanna, Serena; Scharnagl, Hubert; Scholtens, Salome; Sennblad, Bengt; Seufferlein, Thomas; Sitlani, Colleen M; Vernon Smith, Albert; Stirrups, Kathleen; Stringham, Heather M; Sundström, Johan; Swertz, Morris A; Swift, Amy J; Syvänen, Ann-Christine; Tayo, Bamidele O; Thorand, Barbara; Thorleifsson, Gudmar; Tomaschitz, Andreas; Troffa, Chiara; van Oort, Floor V A; Verweij, Niek; Vonk, Judith M; Waite, Lindsay L; Wennauer, Roman; Wilsgaard, Tom; Wojczynski, Mary K; Wong, Andrew; Zhang, Qunyuan; Hua Zhao, Jing; Brennan, Eoin P; Choi, Murim; Eriksson, Per; Folkersen, Lasse; Franco-Cereceda, Anders; Gharavi, Ali G; Hedman, Åsa K; Hivert, Marie-France; Huang, Jinyan; Kanoni, Stavroula; Karpe, Fredrik; Keildson, Sarah; Kiryluk, Krzysztof; Liang, Liming; Lifton, Richard P; Ma, Baoshan; McKnight, Amy J; McPherson, Ruth; Metspalu, Andres; Min, Josine L; Moffatt, Miriam F; Montgomery, Grant W; Murabito, Joanne M; Nicholson, George; Nyholt, Dale R; Olsson, Christian; Perry, John R B; Reinmaa, Eva; Salem, Rany M; Sandholm, Niina; Schadt, Eric E; Scott, Robert A; Stolk, Lisette; Vallejo, Edgar E; Westra, Harm-Jan; Zondervan, Krina T; Amouyel, Philippe; Arveiler, Dominique; Bakker, Stephan J L; Beilby, John; Bergman, Richard N; Blangero, John; Brown, Morris J; Burnier, Michel; Campbell, Harry; Chakravarti, Aravinda; Chines, Peter S; Claudi-Boehm, Simone; Collins, Francis S; Crawford, Dana C; Danesh, John; de Faire, Ulf; de Geus, Eco J C; Dörr, Marcus; Erbel, Raimund; Eriksson, Johan G; Farrall, Martin; Ferrannini, Ele; Ferrières, Jean; Forouhi, Nita G; Forrester, Terrence; Franco, Oscar H; Gansevoort, Ron T; Gieger, Christian; Gudnason, Vilmundur; Haiman, Christopher A; Harris, Tamara B; Hattersley, Andrew T; Heliövaara, Markku; Hicks, Andrew A; Hingorani, Aroon D; Hoffmann, Wolfgang; Hofman, Albert; Homuth, Georg; Humphries, Steve E; Hyppönen, Elina; Illig, Thomas; Jarvelin, Marjo-Riitta; Johansen, Berit; Jousilahti, Pekka; Jula, Antti M; Kaprio, Jaakko; Kee, Frank; Keinanen-Kiukaanniemi, Sirkka M; Kooner, Jaspal S; Kooperberg, Charles; Kovacs, Peter; Kraja, Aldi T; Kumari, Meena; Kuulasmaa, Kari; Kuusisto, Johanna; Lakka, Timo A; Langenberg, Claudia; Le Marchand, Loic; Lehtimäki, Terho; Lyssenko, Valeriya; Männistö, Satu; Marette, André; Matise, Tara C; McKenzie, Colin A; McKnight, Barbara; Musk, Arthur W; Möhlenkamp, Stefan; Morris, Andrew D; Nelis, Mari; Ohlsson, Claes; Oldehinkel, Albertine J; Ong, Ken K; Palmer, Lyle J; Penninx, Brenda W; Peters, Annette; Pramstaller, Peter P; Raitakari, Olli T; Rankinen, Tuomo; Rao, D C; Rice, Treva K; Ridker, Paul M; Ritchie, Marylyn D; Rudan, Igor; Salomaa, Veikko; Samani, Nilesh J; Saramies, Jouko; Sarzynski, Mark A; Schwarz, Peter E H; Shuldiner, Alan R; Staessen, Jan A; Steinthorsdottir, Valgerdur; Stolk, Ronald P; Strauch, Konstantin; Tönjes, Anke; Tremblay, Angelo; Tremoli, Elena; Vohl, Marie-Claude; Völker, Uwe; Vollenweider, Peter; Wilson, James F; Witteman, Jacqueline C; Adair, Linda S; Bochud, Murielle; Boehm, Bernhard O; Bornstein, Stefan R; Bouchard, Claude; Cauchi, Stéphane; Caulfield, Mark J; Chambers, John C; Chasman, Daniel I; Cooper, Richard S; Dedoussis, George; Ferrucci, Luigi; Froguel, Philippe; Grabe, Hans-Jörgen; Hamsten, Anders; Hui, Jennie; Hveem, Kristian; Jöckel, Karl-Heinz; Kivimaki, Mika; Kuh, Diana; Laakso, Markku; Liu, Yongmei; März, Winfried; Munroe, Patricia B; Njølstad, Inger; Oostra, Ben A; Palmer, Colin N A; Pedersen, Nancy L; Perola, Markus; Pérusse, Louis; Peters, Ulrike; Power, Chris; Quertermous, Thomas; Rauramaa, Rainer; Rivadeneira, Fernando; Saaristo, Timo E; Saleheen, Danish; Sinisalo, Juha; Slagboom, P Eline; Snieder, Harold; Spector, Tim D; Thorsteinsdottir, Unnur; Stumvoll, Michael; Tuomilehto, Jaakko; Uitterlinden, André G; Uusitupa, Matti; van der Harst, Pim; Veronesi, Giovanni; Walker, Mark; Wareham, Nicholas J; Watkins, Hugh; Wichmann, H-Erich; Abecasis, Goncalo R; Assimes, Themistocles L; Berndt, Sonja I; Boehnke, Michael; Borecki, Ingrid B; Deloukas, Panos; Franke, Lude; Frayling, Timothy M; Groop, Leif C; Hunter, David J; Kaplan, Robert C; O'Connell, Jeffrey R; Qi, Lu; Schlessinger, David; Strachan, David P; Stefansson, Kari; van Duijn, Cornelia M; Willer, Cristen J; Visscher, Peter M; Yang, Jian; Hirschhorn, Joel N; Zillikens, M Carola; McCarthy, Mark I; Speliotes, Elizabeth K; North, Kari E; Fox, Caroline S; Barroso, Inês; Franks, Paul W; Ingelsson, Erik; Heid, Iris M; Loos, Ruth J F; Cupples, L Adrienne; Morris, Andrew P; Lindgren, Cecilia M; Mohlke, Karen L

    2015-02-12

    Body fat distribution is a heritable trait and a well-established predictor of adverse metabolic outcomes, independent of overall adiposity. To increase our understanding of the genetic basis of body fat distribution and its molecular links to cardiometabolic traits, here we conduct genome-wide association meta-analyses of traits related to waist and hip circumferences in up to 224,459 individuals. We identify 49 loci (33 new) associated with waist-to-hip ratio adjusted for body mass index (BMI), and an additional 19 loci newly associated with related waist and hip circumference measures (P < 5 × 10(-8)). In total, 20 of the 49 waist-to-hip ratio adjusted for BMI loci show significant sexual dimorphism, 19 of which display a stronger effect in women. The identified loci were enriched for genes expressed in adipose tissue and for putative regulatory elements in adipocytes. Pathway analyses implicated adipogenesis, angiogenesis, transcriptional regulation and insulin resistance as processes affecting fat distribution, providing insight into potential pathophysiological mechanisms.

  6. Recent Advances in Proteomic Studies of Adipose Tissues and Adipocytes

    PubMed Central

    Kim, Eun Young; Kim, Won Kon; Oh, Kyoung-Jin; Han, Baek Soo; Lee, Sang Chul; Bae, Kwang-Hee

    2015-01-01

    Obesity is a chronic disease that is associated with significantly increased levels of risk of a number of metabolic disorders. Despite these enhanced health risks, the worldwide prevalence of obesity has increased dramatically over the past few decades. Obesity is caused by the accumulation of an abnormal amount of body fat in adipose tissue, which is composed mostly of adipocytes. Thus, a deeper understanding of the regulation mechanism of adipose tissue and/or adipocytes can provide a clue for overcoming obesity-related metabolic diseases. In this review, we describe recent advances in the study of adipose tissue and/or adipocytes, focusing on proteomic approaches. In addition, we suggest future research directions for proteomic studies which may lead to novel treatments of obesity and obesity-related diseases. PMID:25734986

  7. Assessment of feline abdominal adipose tissue using computed tomography.

    PubMed

    Lee, Hyeyeon; Kim, Mieun; Choi, Mihyun; Lee, Namsoon; Chang, Jinhwa; Yoon, Junghee; Choi, Mincheol

    2010-12-01

    Obesity is a common nutritional disorder in cats and it increases the risk factors for various diseases. The aim of this study is to suggest a method for the evaluation of feline obesity using computed tomography. The attenuation range from -156 to -106 was determined as the range of feline abdominal adipose tissue. With this range, total (TAT), visceral (VAT) and subcutaneous (SAT) adipose tissues were measured. The best correlation between the adipose tissue in cross-sectional image and entire abdomen volume was obtained at the L3 and L5 levels. The mean VAT/SAT ratio was 1.18±0.32, which was much higher than in humans. The cats with an overweight body condition had a significantly lower VAT/SAT ratio than cats with an ideal body condition. This technique may contribute to both the clinical diagnosis and the experimental study of feline obesity.

  8. VEGF-A Expressing Adipose Tissue Shows Rapid Beiging, Enhanced Survival After Transplantation and Confers IL4-Independent Metabolic Improvements.

    PubMed

    Park, Jiyoung; Kim, Min; Sun, Kai; An, Yu Aaron; Gu, Xue; Scherer, Philipp E

    2017-03-02

    Adipocyte-derived VEGF-A plays a crucial role in angiogenesis and contributes to adipocyte function and systemic metabolism, such as insulin resistance, chronic inflammation and beigeing of subcutaneous adipose tissue. Utilizing a doxycycline (Dox)-inducible adipocyte-specific VEGF-A overexpressing mouse model, we investigated the dynamics of local VEGF-A effects on tissue beiging of adipose tissue transplants. VEGF-A overexpression in adipocytes triggers angiogenesis. We also observe a rapid appearance of beige fat cells in subcutaneous white adipose tissue (sWATs) within as early as 2 days post induction of VEGF-A. In contrast to conventional cold-induced beiging, VEGF-A - induced beiging is independent of IL-4. We subjected metabolically healthy VEGF-A overexpressing adipose tissue to autologous transplantation. Transfer of subcutaneous adipose tissues taken from VEGF-A overexpressing mice into diet-induced obese mice resulted in systemic metabolic benefits, associated with improved survival of adipocytes and a concomitant reduced inflammatory response. These effects of VEGF-A are tissue autonomous, inducing WAT beigeing and angiogenesis within the transplanted tissue. Our findings indicate that manipulation of adipocyte functions with a bona fide angiogenic factor, such as VEGF-A, significantly improves the survival and volume retention of fat grafts and can convey metabolically favorable properties on the recipient on the basis of beiging.

  9. Adipose Tissue Macrophages in Rheumatoid Arthritis: Prevalence, Disease Related Indicators, and Associations with Cardiometabolic Risk Factors.

    PubMed

    Giles, Jon T; Ferrante, Antony W; Broderick, Rachel; Zartoshti, Afshin; Rose, Janine; Downer, Kendall; Zhang, Hui-Zhu; Winchester, Robert J

    2017-04-07

    Objective Adipose tissue macrophages (ATMs) are a potent source of inflammatory cytokines with profound effects on adipose tissue function, yet their potential role in rheumatoid arthritis (RA) pathobiology is largely unstudied. Methods Periumbilical subcutaneous adipose tissue was obtained from 36 RA patients and 22 non-RA controls frequency matched on demographics and BMI. Samples were stained for the macrophage marker CD68 and the average proportion of ATMs, crown-like structures (CLSs: peri-adipocyte aggregates of three or more ATMs), and fibrosis were compared between groups. Results The adjusted proportion of ATMs among all nucleated cells was 76% higher in RA vs. non-RA samples (37.7 vs. 21.3%, respectively; p<0.001), and the adjusted average number of CLSs was more than 1.5-fold higher in the RA group compared with controls (0.58 vs. 0.23 CLSs/high-power field, respectively; p=0.001). ATMs were significantly more abundant in early RA and in those seropositive for anti-CCP. Users of methotrexate, leflunomide, and TNF inhibitors had a significantly lower proportion of ATMs compared with non-users. CLSs were significantly higher in patients seropositive for rheumatoid factor and those with C-reactive protein levels≥10 mg/L, and significantly lower among those treated with statins. Linear ATMs were significantly associated with whole-body insulin resistance, but not with serum lipids. Conclusions ATMs and CLSs were more abundant in RA and associated with systemic inflammation, autoimmunity, and whole-body insulin resistance, suggesting possible contributions to the RA disease process. Lower levels of ATMs and CLSs associated with specific RA treatments suggest that adipose tissue inflammation may be ameliorated by immunomodulation. This article is protected by copyright. All rights reserved.

  10. Effects of high carbohydrate and high fat diets on rat adipose tissue pyruvate dehydrogenase responses to concanavalin A and spermine.

    PubMed

    Begum, N; Tepperman, H M; Tepperman, J

    1982-11-01

    Rats were fed a high lard diet or a high glucose diet for 5-7 days. Basal and Concanavalin A (Con A)-stimulated epididymal fat pad pyruvate dehydrogenase (PDH) activities were decreased in fat diet-adapted rats compared to those fed the glucose diet. When adipocyte plasma membranes and mitochondria were coincubated with and without Con A, it was found that the lectin stimulation of PDH activity was lower in preparations from fat-fed rats. These results are comparable to our earlier observations with insulin on adipose tissue PDH. Spermine also stimulated PDH in whole adipose tissue pieces in both the absence and presence (0.5 mM) of medium glucose. The spermine stimulation of PDH in adipose tissue was decreased in fat-fed rats. In contrast to Con A, spermine failed to stimulate PDH in a cell-free system. This suggests that spermine activation of PDH in adipose tissue does not involve the generation of the second messenger responsible for the effects of insulin and Con A. The hypothesis was further substantiated by the findings that (1) the insulin and spermine effects were additive in whole adipose tissue and also in adipocytes, and (2) the spermine effect on fat cells was not significantly inhibited by protease inhibitors, which abolish the effects of insulin on fat cell PDH. The fat-induced decreases in response to Con A and spermine involve not only an adaptive change in the ability of the plasma membrane to generate the chemical modulator of PDH but are also related to postreceptor events.

  11. Osteopontin: Relation between Adipose Tissue and Bone Homeostasis

    PubMed Central

    Messina, Antonietta; Monda, Vincenzo; Viggiano, Emanuela; Valenzano, Anna; Esposito, Teresa; Cibelli, Giuseppe

    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. PMID:28194185

  12. Insulin, leptin, and adiponectin receptors in colon: regulation relative to differing body adiposity independent of diet and in response to dimethylhydrazine.

    PubMed

    Drew, Janice E; Farquharson, Andrew J; Padidar, Sara; Duthie, Garry G; Mercer, Julian G; Arthur, John R; Morrice, Philip C; Barrera, Lawrence N

    2007-10-01

    Obesity has recently become a focus of research to elucidate diet and lifestyle factors as important risk factors for colon cancer. Altered levels of insulin, leptin, and adiponectin have been identified as potential candidates increasing colon cancer risk within the prevailing obesogenic environment. There has been considerable research to characterize signaling via these hormones in the brain, liver, and adipose tissue; however, very little is known of their emerging role in peripheral signaling, particularly in epithelial tissues. This study profiles insulin, leptin, and adipokine receptors in the rat colon, revealing novel microanatomical location of these receptors and thereby supporting a potential role in regulating colonic tissue. Potential involvement of insulin, leptin, and adiponectin receptors in increased risk of colon cancer was investigated using Sprague-Dawley rats, either resistant or susceptible to diet-induced obesity. Regulation of insulin, leptin, and adiponectin receptors as a consequence of differing levels of adiposity was assessed regionally in the colon in response to treatment with the chemical carcinogen 1,2-dimethylhydrazine (DMH). However, significantly increased fat mass, increased levels of plasma insulin, leptin, and triglycerides, previously associated with an increased risk of colon cancer, were not associated with promotion of precancerous lesions in the experimental rats or deregulation of insulin, leptin, or adiponectin receptors. These findings do not support a direct link between the deregulation of insulin and adipokine levels observed in obese rats and an increased risk of colon carcinogenesis.

  13. Altered pattern of cannabinoid type 1 receptor expression in adipose tissue of dysmetabolic and overweight patients.

    PubMed

    Sarzani, Riccardo; Bordicchia, Marica; Marcucci, Pierfrancesco; Bedetta, Samuele; Santini, Silvia; Giovagnoli, Andrea; Scappini, Lorena; Minardi, Daniele; Muzzonigro, Giovanni; Dessì-Fulgheri, Paolo; Rappelli, Alessandro

    2009-03-01

    In overweight patients (OW), the increased peripheral activity of the endocannabinoid system in visceral adipose tissue (VAT) may be mediated by cannabinoid type 1 (CB1) receptor expression. We determined whether CB1 receptor splice variants and messenger RNA (mRNA) levels in perirenal and subcutaneous adipose tissues are associated with obesity and metabolic syndrome (MetS). Gene expression with multiple-primers real-time polymerase chain reaction (TaqMan; Applied Biosystem, Weiterstadt, Germany) was performed to study VAT and paired subcutaneous adipose tissue (SAT) mRNA from 36 consecutive patients undergoing nephrectomy. Cannabinoid type 1A and CB1E mRNAs variants with the longer version of exon 4 were expressed. The CB1 expression in perirenal VAT significantly correlated with body mass index (BMI). Paired subcutaneous/perirenal samples from normal-weight patients (BMI < 25 kg/m(2)) showed higher CB1 expression in SAT (P = .002), whereas in OW (BMI > or = 25 kg/m(2)), the higher CB1 expression was in VAT (P = .038). In unpaired samples, SAT of normal-weight patients had significantly higher CB1 mRNA levels compared with SAT of OW, whereas higher CB1 expression (P = .009) was found in VAT of OW (n = 25). Overweight patients with increased visceral CB1 expression had higher waist circumference (P < .01), insulin (P < .01), and homeostasis model assessment index (P < .01). In addition, patients with the MetS (n = 22) showed higher CB1 expression in perirenal adipose tissues (P = .007). Visceral adipose CB1 expression correlated with BMI. Overweight patients and those with MetS showed a CB1 expression pattern supporting a CB1-mediated overactivity of the endocannabinoid system in human VAT.

  14. Hkat, a novel nutritionally regulated transmembrane protein in adipose tissues.

    PubMed

    Zhang, Ren

    2012-01-01

    White adipose tissue is an active endocrine organ regulating many aspects of whole body physiology and pathology. Adipogenesis, a process in which premature cells differentiate into adipocytes, is a complex process that includes orchestrated changes in gene expression and cell morphology in response to various nutritional and hormonal stimuli. To profile transcriptome changes in response to nutritional stimulation, we performed RNA-seq on fat in mice treated with either a high-fat diet or fasting. We identified a novel nutritionally regulated gene, Gm12824, named Hkat (heart, kidney, adipose-enriched transmembrane protein). We show that both fasting and obesity dramatically reduce Hkat in white adipose tissue, and that fasting reduces while obesity increases its expression in brown fat. Hkat is localized to the plasma membrane and induced during adipogenesis. Therefore, Hkat is a novel nutritionally regulated gene that is potentially involved in metabolism.

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

    SciTech Connect

    Bai, Xiaowen; Alt, Eckhard

    2010-10-22

    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-derived 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 the

  16. Steroidogenic enzymes of adipose tissue in modulation of trivalent chromium in a mouse model of PCOS.

    PubMed

    Chen, Tsung-Sheng; Chen, Yi-Ting; Liu, Chia-Hsin; Sun, Chi-Ching; Mao, Frank Chiahung

    2017-01-01

    Polycystic ovary syndrome (PCOS) is a type of endocrine metabolic disorder with many different consequences to health, most commonly infertility, obesity and insulin resistance. Trivalent chromium (Cr(3+)) was previously found to improve the metabolic profiles of patients with PCOS. The aim of this study was to explore the effect of Cr on regulating steroidogenic enzymes in adipose tissue. Female BALB/c mice were divided into three groups (n = 6 per group): the control group, PCOS + placebo milk group and PCOS + Cr-containing milk group. The dietary intake of Cr significantly decreased fasting blood sugar (FBS) and homeostasis model assessment of insulin resistance levels in the murine model of PCOS. Importantly, we found significant correlations among the levels of Cr, insulin and dehydroepiandrosterone (DHEA). In adipose tissue, decreases in the enzyme expressions of 3β-hydroxysteroid dehydrogenase (3β-HSD) and 17β-hydroxysteroid dehydrogenase, but not of aromatase, were observed. By understanding the role of steroidogenic enzymes in PCOS in normal and pathological states, trace elements may be used as a form of adjunctive therapy in the management of patients with PCOS.

  17. Influence of secreted factors from human adipose tissue on glucose utilization and proinflammatory reaction.

    PubMed

    Tréguer, Karine; Dusaulcy, Rodolphe; Grès, Sandra; Wanecq, Estelle; Valet, Philippe; Saulnier-Blache, Jean Sébastien

    2013-09-01

    The objective of the present study was to characterize the nature of the autocrine/paracrine signal within human adipose tissue that may alter glucose metabolism and the inflammatory status in adipocytes. We prepared a conditioned medium from abdominal dermolipectomies in the absence (CM) or the presence (CMBSA) of bovine serum albumin (BSA), and we tested the influence of CM and CMBSA on glucose transport, maximal insulin response, and the expression of inflammation marker genes in differentiated human SGBS adipocytes. We found that CMBSA increased basal and reduced insulin-stimulated glucose incorporation along with a reduced mRNA level of the glucose transport GLUT4, and an increased expression of GLUT1. These effects were associated with a potent upregulation in the mRNA level of the proinflammatory cytokines IL-6 and MCP-1. These regulations were strongly attenuated in the absence of BSA during the preparation of CM, or after BSA depletion of CM, and were attributed to water-soluble molecules rather than lipids. Finally, fractionation of CMBSA by isoelectric focusing showed that part of its bioactivity could be reproduced with proteins with pHi ranging from 6.6 to 7.6. In conclusion, our results demonstrate that the production by human adipose tissue of autocrine/paracrine neutral proteins is able to increase the inflammatory status of the adipocytes and to deteriorate their glucose metabolism and maximal insulin response, and their release is greatly amplified by the presence of albumin.

  18. In vivo adeno-associated viral vector-mediated genetic engineering of white and brown adipose tissue in adult mice.

    PubMed

    Jimenez, Veronica; Muñoz, Sergio; Casana, Estefania; Mallol, Cristina; Elias, Ivet; Jambrina, Claudia; Ribera, Albert; Ferre, Tura; Franckhauser, Sylvie; Bosch, Fatima

    2013-12-01

    Adipose tissue is pivotal in the regulation of energy homeostasis through the balance of energy storage and expenditure and as an endocrine organ. An inadequate mass and/or alterations in the metabolic and endocrine functions of adipose tissue underlie the development of obesity, insulin resistance, and type 2 diabetes. To fully understand the metabolic and molecular mechanism(s) involved in adipose dysfunction, in vivo genetic modification of adipocytes holds great potential. Here, we demonstrate that adeno-associated viral (AAV) vectors, especially serotypes 8 and 9, mediated efficient transduction of white (WAT) and brown adipose tissue (BAT) in adult lean and obese diabetic mice. The use of short versions of the adipocyte protein 2 or uncoupling protein-1 promoters or micro-RNA target sequences enabled highly specific, long-term AAV-mediated transgene expression in white or brown adipocytes. As proof of concept, delivery of AAV vectors encoding for hexokinase or vascular endothelial growth factor to WAT or BAT resulted in increased glucose uptake or increased vessel density in targeted depots. This method of gene transfer also enabled the secretion of stable high levels of the alkaline phosphatase marker protein into the bloodstream by transduced WAT. Therefore, AAV-mediated genetic engineering of adipose tissue represents a useful tool for the study of adipose pathophysiology and, likely, for the future development of new therapeutic strategies for obesity and diabetes.

  19. The necroptosis-inducing kinase RIPK3 dampens adipose tissue inflammation and glucose intolerance

    PubMed Central

    Gautheron, Jérémie; Vucur, Mihael; Schneider, Anne T.; Severi, Ilenia; Roderburg, Christoph; Roy, Sanchari; Bartneck, Matthias; Schrammen, Peter; Diaz, Mauricio Berriel; Ehling, Josef; Gremse, Felix; Heymann, Felix; Koppe, Christiane; Lammers, Twan; Kiessling, Fabian; Van Best, Niels; Pabst, Oliver; Courtois, Gilles; Linkermann, Andreas; Krautwald, Stefan; Neumann, Ulf P.; Tacke, Frank; Trautwein, Christian; Green, Douglas R.; Longerich, Thomas; Frey, Norbert; Luedde, Mark; Bluher, Matthias; Herzig, Stephan; Heikenwalder, Mathias; Luedde, Tom

    2016-01-01

    Receptor-interacting protein kinase 3 (RIPK3) mediates necroptosis, a form of programmed cell death that promotes inflammation in various pathological conditions, suggesting that it might be a privileged pharmacological target. However, its function in glucose homeostasis and obesity has been unknown. Here we show that RIPK3 is over expressed in the white adipose tissue (WAT) of obese mice fed with a choline-deficient high-fat diet. Genetic inactivation of Ripk3 promotes increased Caspase-8-dependent adipocyte apoptosis and WAT inflammation, associated with impaired insulin signalling in WAT as the basis for glucose intolerance. Similarly to mice, in visceral WAT of obese humans, RIPK3 is overexpressed and correlates with the body mass index and metabolic serum markers. Together, these findings provide evidence that RIPK3 in WAT maintains tissue homeostasis and suppresses inflammation and adipocyte apoptosis, suggesting that systemic targeting of necroptosis might be associated with the risk of promoting insulin resistance in obese patients. PMID:27323669

  20. In humans the adiponectin receptor R2 is expressed predominantly in adipose tissue and linked to the adipose tissue expression of MMIF-1.

    PubMed

    Kos, K; Wong, S P Y; Huda, M S B; Cakir, M; Jernas, M; Carlsson, L; Kerrigan, D; Wilding, J P H; Pinkney, J H

    2010-04-01

    In this study, the regional adipose tissue-adiponectin (AT-ADN) and adiponectin receptor (R1 and R2) expression and their relation with metabolic parameters, circulating and AT-derived cytokine expressions were compared. Paired subcutaneous adipose tissue (SCAT) and visceral adipose tissue (VAT) were taken from 18 lean and 39 obese humans, AT-mRNA expression of adipokines analysed by RT-PCR and corresponding serum levels by enzyme-linked immunosorbent assay (ELISA). R1 and R2 adipocyte expression was compared with 17 other human tissues. ADN-gene expression was lower in VAT than SCAT [mean (SD) 1.54 (1.1) vs. 2.84 (0.87); p < 0.001], and lower in obese subjects (VAT : p = 0.01;SCAT : p < 0.001). SCAT-ADN correlated positively with serum ADN (r = 0.33;p = 0.036) but not VAT-ADN. AT expressions of ADN and macrophage migration inhibiting factor (MMIF), IL18 and cluster of differentiation factor 14 (CD14) in both depots showed inverse correlations. R1 and R2 were expressed ubiquitously and R2 highest in SCAT, and this is much higher (x100) than R1 (x100). R expression was similar in lean and obese subjects and unrelated to the metabolic syndrome, however, receptors correlated with VAT-MMIF (R 1: r = 0.4;p = 0.008;R 2: r = 0.35,p = 0.02) and SCAT-MMIF expression (R 2: r = 0.43;p = 0.004). Unlike ADN, its receptors are expressed in many human tissues. Human R2 expression is not highest in the liver but in AT where it is associated with MMIF expression. The adiponectin-dependent insulin-sensitizing action of thiazolidinediones is thus probably to differ amongst species with weaker effects on the human liver.

  1. Diabetic human adipose tissue-derived mesenchymal stem cells fail to differentiate in functional adipocytes.

    PubMed

    Barbagallo, Ignazio; Li Volti, Giovanni; Galvano, Fabio; Tettamanti, Guido; Pluchinotta, Francesca R; Bergante, Sonia; Vanella, Luca

    2016-11-30

    Adipose tissue dysfunction represents a hallmark of diabetic patients and is a consequence of the altered homeostasis of this tissue. Mesenchymal stem cells (MSCs) and their differentiation into adipocytes contribute significantly in maintaining the mass and function of adult adipose tissue. The aim of this study was to evaluate the differentiation of MSCs from patients suffering type 2 diabetes (dASC) and how such process results in hyperplasia or rather a stop of adipocyte turnover resulting in hypertrophy of mature adipocytes. Our results showed that gene profile of all adipogenic markers is not expressed in diabetic cells after differentiation indicating that diabetic cells fail to differentiate into adipocytes. Interestingly, delta like 1, peroxisome proliferator-activated receptor alpha, and interleukin 1β were upregulated whereas Sirtuin 1 and insulin receptor substrate 1 gene expression were found downregulated in dASC compared to cells obtained from healthy subjects. Taken together our data indicate that dASC lose their ability to differentiate into mature and functional adipocytes. In conclusion, our in vitro study is the first to suggest that diabetic patients might develop obesity through a hypertrophy of existing mature adipocytes due to failure turnover of adipose tissue.

  2. Increased inflammatory properties of adipose tissue macrophages recruited during diet-induced obesity.

    PubMed

    Lumeng, Carey N; Deyoung, Stephanie M; Bodzin, Jennifer L; Saltiel, Alan R

    2007-01-01

    Although recent studies show that adipose tissue macrophages (ATMs) participate in the inflammatory changes in obesity and contribute to insulin resistance, the properties of these cells are not well understood. We hypothesized that ATMs recruited to adipose tissue during a high-fat diet have unique inflammatory properties compared with resident tissue ATMs. Using a dye (PKH26) to pulse label ATMs in vivo, we purified macrophages recruited to white adipose tissue during a high-fat diet. Comparison of gene expression in recruited and resident ATMs using real-time RT-PCR and cDNA microarrays showed that recruited ATMs overexpress genes important in macrophage migration and phagocytosis, including interleukin-6 (IL-6), inducible nitric oxide synthase (iNOS), and C-C chemokine receptor 2 (CCR2). Many of these genes were not induced in ATMs from high-fat diet-fed CCR2 knockout mice, supporting the importance of CCR2 in regulating recruitment of inflammatory ATMs during obesity. Additionally, expression of Apoe was decreased, whereas genes important in lipid metabolism, such as Pparg, Adfp, Srepf1, and Apob48r, were increased in the recruited macrophages. In agreement with this, ATMs from obese mice had increased lipid content compared with those from lean mice. These studies demonstrate that recruited ATMs in obese animals represent a subclass of macrophages with unique properties.

  3. Exercise differentially affects metabolic functions and white adipose tissue in female letrozole- and dihydrotestosterone-induced mouse models of polycystic ovary syndrome.

    PubMed

    Marcondes, Rodrigo R; Maliqueo, Manuel; Fornes, Romina; Benrick, Anna; Hu, Min; Ivarsson, Niklas; Carlström, Mattias; Cushman, Samuel W; Stenkula, Karin G; Maciel, Gustavo A R; Stener-Victorin, Elisabet

    2017-03-24

    Here we hypothesized that exercise in dihydrotestosterone (DHT) or letrozole (LET)-induced polycystic ovary syndrome mouse models improves impaired insulin and glucose metabolism, adipose tissue morphology, and expression of genes related to adipogenesis, lipid metabolism, Notch pathway and browning in inguinal and mesenteric fat. DHT-exposed mice had increased body weight, increased number of large mesenteric adipocytes. LET-exposed mice displayed increased body weight and fat mass, decreased insulin sensitivity, increased frequency of small adipocytes and increased expression of genes related to lipolysis in mesenteric fat. In both models, exercise decreased fat mass and inguinal and mesenteric adipose tissue expression of Notch pathway genes, and restored altered mesenteric adipocytes morphology. In conclusion, exercise restored mesenteric adipocytes morphology in DHT- and LET-exposed mice, and insulin sensitivity and mesenteric expression of lipolysis-related genes in LET-exposed mice. Benefits could be explained by downregulation of Notch, and modulation of browning and lipolysis pathways in the adipose tissue.

  4. Molecular pathways regulating the formation of brown-like adipocytes in white adipose tissue.

    PubMed

    Fu, Jianfei; Li, Zhen; Zhang, Huiqin; Mao, Yushan; Wang, Anshi; Wang, Xin; Zou, Zuquan; Zhang, Xiaohong

    2015-07-01

    Adipose tissue is functionally composed of brown adipose tissue and white adipose tissue. The unique thermogenic capacity of brown adipose tissue results from expression of uncoupling protein 1 in the mitochondrial inner membrane. On the basis of recent findings that adult humans have functionally active brown adipose tissue, it is now recognized as playing a much more important role in human metabolism than was previously thought. More importantly, brown-like adipocytes can be recruited in white adipose tissue upon environmental stimulation and pharmacologic treatment, and this change is associated with increased energy expenditure, contributing to a lean and healthy phenotype. Thus, the promotion of brown-like adipocyte development in white adipose tissue offers novel possibilities for the development of therapeutic strategies to combat obesity and related metabolic diseases. In this review, we summarize recent advances in understanding the molecular mechanisms involved in the recruitment of brown-like adipocyte in white adipose tissue.

  5. Adipose HIF-1α causes obesity by suppressing brown adipose tissue thermogenesis.

    PubMed

    Jun, Jonathan C; Devera, Ronald; Unnikrishnan, Dileep; Shin, Mi-Kyung; Bevans-Fonti, Shannon; Yao, Qiaoling; Rathore, Aman; Younas, Haris; Halberg, Nils; Scherer, Philipp E; Polotsky, Vsevolod Y

    2017-03-01

    Hypoxia-inducible factor-1α (HIF-1α) in adipose tissue is known to promote obesity. We hypothesized that HIF-1α interferes with brown fat thermogenesis, thus decreasing energy expenditure. To test this hypothesis, we compared transgenic mice constitutively expressing HIF-1α in adipose tissues (HIF-1α++) at usual temperature (22 °C), where brown fat is somewhat active, or at thermoneutrality (30 °C), where brown fat is minimally active. HIF-1α++ mice or control litter mates were separated into room temperature (22 °C) or thermoneutrality (30 °C) groups. We assessed weight gain, food intake, calorimetry, activity, and oxygen consumption and transcriptional changes in isolated white and brown adipocytes. At 22 °C, HIF-1α++ mice exhibited accelerated weight gain, cold and glucose intolerance, hyperglycemia, and decreased energy expenditure without changes in food intake or activity. These changes were absent or minimal at thermoneutrality. In brown adipocytes of HIF-1α++ mice, oxygen consumption decreased ~50 % in association with reduced mitochondrial content, uncoupling protein 2, and peroxisome proliferator-activated receptor gamma coactivator 1 (PGC-1α). In conclusion, adipose HIF-1α overexpression inhibits thermogenesis and cellular respiration in brown adipose tissue, promoting obesity in the setting of reduced ambient temperature.

  6. Exercise Effects on White Adipose Tissue: Beiging and Metabolic Adaptations.

    PubMed

    Stanford, Kristin I; Middelbeek, Roeland J W; Goodyear, Laurie J

    2015-07-01

    Regular physical activity and exercise training have long been known to cause adaptations to white adipose tissue (WAT), including decreases in cell size and lipid content and increases in mitochondrial proteins. In this article, we discuss recent studies that have investigated the effects of exercise training on mitochondrial function, the "beiging" of WAT, regulation of adipokines, metabolic effects of trained adipose tissue on systemic metabolism, and depot-specific responses to exercise training. The major WAT depots in the body are found in the visceral cavity (vWAT) and subcutaneously (scWAT). In rodent models, exercise training increases mitochondrial biogenesis and activity in both these adipose tissue depots. Exercise training also increases expression of the brown adipocyte marker uncoupling protein 1 (UCP1) in both adipose tissue depots, although these effects are much more pronounced in scWAT. Consistent with the increase in UCP1, exercise training increases the presence of brown-like adipocytes in scWAT, also known as browning or beiging. Training results in changes in the gene expression of thousands of scWAT genes and an altered adipokine profile in both scWAT and vWAT. Transplantation of trained scWAT in sedentary recipient mice results in striking improvements in skeletal muscle glucose uptake and whole-body metabolic homeostasis. Human and rodent exercise studies have indicated that exercise training can alter circulating adipokine concentration as well as adipokine expression in adipose tissue. Thus, the profound changes to WAT in response to exercise training may be part of the mechanism by which exercise improves whole-body metabolic health.

  7. Exercise Effects on White Adipose Tissue: Beiging and Metabolic Adaptations

    PubMed Central

    Stanford, Kristin I.; Middelbeek, Roeland J.W.

    2015-01-01

    Regular physical activity and exercise training have long been known to cause adaptations to white adipose tissue (WAT), including decreases in cell size and lipid content and increases in mitochondrial proteins. In this article, we discuss recent studies that have investigated the effects of exercise training on mitochondrial function, the “beiging” of WAT, regulation of adipokines, metabolic effects of trained adipose tissue on systemic metabolism, and depot-specific responses to exercise training. The major WAT depots in the body are found in the visceral cavity (vWAT) and subcutaneously (scWAT). In rodent models, exercise training increases mitochondrial biogenesis and activity in both these adipose tissue depots. Exercise training also increases expression of the brown adipocyte marker uncoupling protein 1 (UCP1) in both adipose tissue depots, although these effects are much more pronounced in scWAT. Consistent with the increase in UCP1, exercise training increases the presence of brown-like adipocytes in scWAT, also known as browning or beiging. Training results in changes in the gene expression of thousands of scWAT genes and an altered adipokine profile in both scWAT and vWAT. Transplantation of trained scWAT in sedentary recipient mice results in striking improvements in skeletal muscle glucose uptake and whole-body metabolic homeostasis. Human and rodent exercise studies have indicated that exercise training can alter circulating adipokine concentration as well as adipokine expression in adipose tissue. Thus, the profound changes to WAT in response to exercise training may be part of the mechanism by which exercise improves whole-body metabolic health. PMID:26050668

  8. Growth hormone receptor antagonist (GHA) transgenic mice have increased subcutaneous adipose tissue mass, altered glucose homeostasis, and no change in white adipose tissue cellular senescence

    PubMed Central

    Comisford, Ross; Lubbers, Ellen R.; Householder, Lara; Suer, Ozan; Tchkonia, Tamara; Kirkland, James L.; List, Edward O.; Kopchick, John J.; Berryman, Darlene E.

    2015-01-01

    Background Growth hormone (GH) resistant/deficient mice experience improved glucose homeostasis and substantially increased lifespan. Recent evidence suggests long-lived GH resistant/deficient mice are protected from white adipose tissue (WAT) dysfunction, including WAT cellular senescence, impaired adipogenesis and loss of subcutaneous WAT in old age. This preservation of WAT function has been suggested to be a potential mechanism for the extended lifespan of these mice. OBJECTIVE The objective of this study was to examine white adipose tissue (WAT) senescence, WAT distribution, and glucose homeostasis in dwarf growth hormone receptor antagonist (GHA) transgenic mice, a unique mouse strain having decreased GH action but normal longevity. METHODS 18mo old female GHA mice and wild type (WT) littermate controls were used. Prior to dissection, body composition, fasting blood glucose, and glucose and insulin tolerance tests were performed. WAT distribution was determined by weighing four distinct WAT depots at the time of dissection. Cellular senescence in four WAT depots was assessed using senescence-associated β-galactosidase (SA-β-gal) staining to quantify the senescent cell burden and real time qPCR to quantify gene expression of senescence markers p16 and IL-6. RESULTS GHA mice had a 22% reduction in total body weight, 33% reduction in lean mass, and a 10% increase in body fat percentage compared to WT controls. GHA mice had normal fasting blood glucose and improved insulin sensitivity; however, they exhibited impaired glucose tolerance. Moreover, GHA mice displayed enhanced lipid storage in the inguinal subcutaneous WAT depot (p<.05) and a 1.7 fold increase in extra-/intraperitoneal WAT ratio compared to controls (p<.05). Measurements of WAT cellular senescence showed no difference between GHA mice and WT controls. CONCLUSIONS Similar to other mice with decreased GH action, female GHA mice display reduced age-related lipid redistribution and improved insulin

  9. Effect of Pioglitazone on the Fructose-Induced Abdominal Adipose Tissue Dysfunction

    PubMed Central

    Alzamendi, Ana; Giovambattista, Andrés; García, María E.; Rebolledo, Oscar R.; Gagliardino, Juan J.; Spinedi, Eduardo

    2012-01-01

    Aim. To test the potential role of PPARγ in the endocrine abdominal tissue dysfunction induced by feeding normal rats with a fructose rich diet (FRD) during three weeks. Methodology. Adult normal male rats received a standard commercial diet (CD) or FRD, (10% in drinking water) without or with pioglitazone (PIO) (i.p. 0.25 mg/Kg BW/day; CD-PIO and FRD-PIO). Thereafter, we measured circulating metabolic, endocrine, and oxidative stress (OS) markers, abdominal adipose tissue (AAT) mass, leptin (LEP) and plasminogen activator inhibitor-1 (PAI-1) tissue content/expression, and leptin release by isolated adipocytes incubated with different concentrations of insulin. Results. Plasma glucose, insulin, triglyceride, TBARS, LEP, and PAI-1 levels were higher in FRD rats; PIO coadministration fully prevented all these increments. AAT adipocytes from FRD rats were larger, secreted a higher amount of LEP, and displayed decreased sensitivity to insulin stimulation; these effects were significantly ameliorated by PIO. Whereas AAT LEP and PAI-1 (mRNA) concentrations increased significantly in FRD rats, those of insulin-receptor-substrate- (IRS-) 1 and IRS-2 were reduced. PIO coadministration prevented FRD effects on LEP, PAI-1, and IRS-2 (fully) and IRS-1 (partially) mRNAs in AAT. Conclusion. PPARγ would play a relevant role in the development of the FRD-induced metabolic-endocrine dysfunction. PMID:23091482

  10. Impact of Adiposity on Incident Hypertension Is Modified by Insulin Resistance in Adults: Longitudinal Observation From the Bogalusa Heart Study.

    PubMed

    Zhang, Tao; Zhang, Huijie; Li, Shengxu; Li, Ying; Liu, Yaozhong; Fernandez, Camilo; Harville, Emily; Bazzano, Lydia; He, Jiang; Chen, Wei

    2016-01-01

    Adiposity and insulin resistance are closely associated with hypertension. This study aims to investigate whether the association between adiposity and hypertension is modified by insulin resistance. The cohort consisted of 1624 middle-aged normotensive black and white adults aged 18 to 43 years at baseline who followed for 16 years on average. Overweight/obesity at baseline was defined as body mass index (BMI) ≥25, and insulin resistance was measured using homeostasis model assessment of insulin resistance. Prevalence of incident hypertension was compared between the insulin-sensitive adiposity and insulin-resistant adiposity groups. The prevalence of incident hypertension was higher in the insulin-resistant adiposity than in the insulin-sensitive adiposity group (32.1% versus 22.1%, P<0.001). In multivariable logistic analyses, adjusted for baseline age, race, sex, follow-up years, and smoking, baseline insulin-resistant obesity was associated with incident hypertension (odds ratio, 1.9; P=0.008). Odds ratios did not differ between blacks and whites (P=0.238). Of note, the odds ratios of BMI associated with hypertension significantly increased with increasing quartiles of baseline homeostasis model assessment (odds ratio, 1.3, 1.1, 1.5, and 2.5 in quartiles I, II, III, and IV, respectively; P=0.006 for trend). Slopes of increasing follow-up blood pressure with baseline BMI, measured as regression coefficients (β), were significantly greater in insulin-resistant than in insulin-sensitive individuals (β=0.74 versus β=0.35 for systolic blood pressure, P=0.004 for difference; β=0.51 versus β=0.23 for diastolic blood pressure, P=0.001 for difference). These findings suggest that insulin resistance has a synergistic effect on the obesity-hypertension association in young adults, indicating that the role of adiposity in the development of hypertension is modified by insulin resistance.

  11. Association between subcutaneous white adipose tissue and serum 25-hydroxyvitamin D in overweight and obese adults

    Technology Transfer Automated Retrieval System (TEKTRAN)

    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...

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

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Our data demonstrate that estrogens, estrogen receptor-alpha (ERalpha), and estrogen receptor-ßeta (ERßeta) regulate adipose tissue distribution, inflammation, fibrosis, and glucose homeostasis, by determining that alphaERKO mice have increased adipose tissue inflammation and fibrosis prior to obesi...

  13. Adipose-specific deletion of Kif5b exacerbates obesity and insulin resistance in a mouse model of diet-induced obesity.

    PubMed

    Cui, Ju; Pang, Jing; Lin, Ya-Jun; Gong, Huan; Wang, Zhen-He; Li, Yun-Xuan; Li, Jin; Wang, Zai; Jiang, Ping; Dai, Da-Peng; Li, Jian; Cai, Jian-Ping; Huang, Jian-Dong; Zhang, Tie-Mei

    2017-02-27

    Recent studies have shown that KIF5B (conventional kinesin heavy chain) mediates glucose transporter type 4 translocation and adiponectin secretion in 3T3-L1 adipocytes, suggesting an involvement of KIF5B in the homeostasis of metabolism. However, the in vivo physiologic function of KIF5B in adipose tissue remains to be determined. In this study, adipose-specific Kif5b knockout (F-K5bKO) mice were generated using the Cre-LoxP strategy. F-K5bKO mice had similar body weights to controls fed on a standard chow diet. However, F-K5bKO mice had hyperlipidemia and significant glucose intolerance and insulin resistance. Deletion of Kif5b aggravated the deleterious impact of a high-fat diet (HFD) on body weight gain, hepatosteatosis, glucose tolerance, and systematic insulin sensitivity. These changes were accompanied by impaired insulin signaling, decreased secretion of adiponectin, and increased serum levels of leptin and proinflammatory adipokines. F-K5bKO mice fed on a HFD exhibited lower energy expenditure and thermogenic dysfunction as a result of whitening of brown adipose due to decreased mitochondria biogenesis and down-regulation of key thermogenic gene expression. In conclusion, selective deletion of Kif5b in adipose tissue exacerbates HFD-induced obesity and its associated metabolic disorders, partly through a decrease in energy expenditure, dysregulation of adipokine secretion, and insulin signaling.-Cui, J., Pang, J., Lin, Y.-J., Gong, H., Wang, Z.-H., Li, Y.-X., Li, J., Wang, Z., Jiang, P., Dai, D.-P., Li, J., Cai, J.-P., Huang, J.-D., Zhang, T.-M. Adipose-specific deletion of Kif5b exacerbates obesity and insulin resistance in a mouse model of diet-induced obesity.

  14. 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

  15. FGF21 Lowers Plasma Triglycerides by Accelerating Lipoprotein Catabolism in White and Brown Adipose Tissues.

    PubMed

    Schlein, Christian; Talukdar, Saswata; Heine, Markus; Fischer, Alexander W; Krott, Lucia M; Nilsson, Stefan K; Brenner, Martin B; Heeren, Joerg; Scheja, Ludger

    2016-03-08

    FGF21 decreases plasma triglycerides (TGs) in rodents and humans; however, the underlying mechanism or mechanisms are unclear. In the present study, we examined the role of FGF21 in production and disposal of TG-rich lipoproteins (TRLs) in mice. Treatment with pharmacological doses of FGF21 acutely reduced plasma non-esterified fatty acids (NEFAs), liver TG content, and VLDL-TG secretion. In addition, metabolic turnover studies revealed that FGF21 facilitated the catabolism of TRL in white adipose tissue (WAT) and brown adipose tissue (BAT). FGF21-dependent TRL processing was strongly attenuated in CD36-deficient mice and transgenic mice lacking lipoprotein lipase in adipose tissues. Insulin resistance in diet-induced obese and ob/ob mice shifted FGF21 responses from WAT toward energy-combusting BAT. In conclusion, FGF21 lowers plasma TGs through a dual mechanism: first, by reducing NEFA plasma levels and consequently hepatic VLDL lipidation and, second, by increasing CD36 and LPL-dependent TRL disposal in WAT and BAT.

  16. Gene expression of adipose tissue, endothelial cells and platelets in subjects with metabolic syndrome (Review).

    PubMed

    Pérez, Pablo M; Moore-Carrasco, Rodrigo; González, Daniel R; Fuentes, Eduardo Q; Palomo, Iván G

    2012-05-01

    Metabolic syndrome is a combination of medical disorders including hypertension, dyslipidemia, hyperglycemia, insulin resistance and increased waist circumference, and is associated with a higher risk of cardiovascular disease. An increase in adipose tissue mass is associated with the augmented secretion of certain adipokines, such as interleukin-6, tumor necrosis factor-α and resistin, which cause endothelial dysfunction (an increase in vasoconstrictor molecules and in the expression of adhesion molecules as well as a decrease of vasodilator molecules, amongst other features) and hemostasis alterations that also favor a prothrombotic state (increased fibrinogen and plasminogen activator inhibitor-1 concentrations and platelet activation/aggregation). This interaction between adipose tissue, endothelial cells and platelets is associated with an increase or decrease in the expression of several transcription factors (peroxisome proliferator-activated receptors, CCAAT-enhancer-binding proteins, carbohydrate responsive element-binding proteins and sterol regulatory element-binding proteins) that play a crucial role in the regulation of distinct metabolic pathways related to the metabolic syndrome. In the present review, we present the primary changes in adipose tissue, endothelial cells and platelets in subjects with metabolic syndrome and their possible target sites at the gene expression level.

  17. Aging leads to a programmed loss of brown adipocytes in murine subcutaneous white adipose tissue.

    PubMed

    Rogers, Nicole H; Landa, Alejandro; Park, Seongjoon; Smith, Roy G

    2012-12-01

    Insulin sensitivity deteriorates with age, but mechanisms remain unclear. Age-related changes in the function of subcutaneous white adipose tissue (sWAT) are less characterized than those in visceral WAT. We hypothesized that metabolic alterations in sWAT, which in contrast to epididymal WAT, harbors a subpopulation of energy-dissipating UCP1+ brown adipocytes, promote age-dependent progression toward insulin resistance. Indeed, we show that a predominant consequence of aging in murine sWAT is loss of 'browning'. sWAT from young mice is histologically similar to brown adipose tissue (multilocular, UCP1+), but becomes morphologically white by 12 months of age. Correspondingly, sWAT expression of ucp1 precipitously declines (~300-fold) between 3 and 12 months. Loss continues into old age (24 months) and is inversely correlated with the development of insulin resistance. Additional age-dependent changes in sWAT include lower expression of adbr3 and higher expression of maoa, suggesting reduced local adrenergic tone as a potential mechanism. Indeed, treatment with a β3-adrenergic agonist to compensate for reduced tone rescues the aged sWAT phenotype. Age-related changes in sWAT are not explained by the differences in body weight; mice subjected to 40% caloric restriction for 12 months are of body weight similar to 3-month-old ad lib fed mice, but display sWAT resembling that of age-matched ad lib fed mice (devoid of brown adipose-like morphology). Overall, findings identify the loss of 'browning' in sWAT as a new aging phenomenon and provide insight into the pathogenesis of age-associated metabolic disease by revealing novel molecular changes tied to systemic metabolic dysfunction.

  18. Calcium Sensing Receptor as a Novel Mediator of Adipose Tissue Dysfunction: Mechanisms and Potential Clinical Implications

    PubMed Central

    Bravo-Sagua, Roberto; Mattar, Pamela; Díaz, Ximena; Lavandero, Sergio; Cifuentes, Mariana

    2016-01-01

    Obesity is currently a serious worldwide public health problem, reaching pandemic levels. For decades, dietary and behavioral approaches have failed to prevent this disease from expanding, and health authorities are challenged by the elevated prevalence of co-morbid conditions. Understanding how obesity-associated diseases develop from a basic science approach is recognized as an urgent task to face this growing problem. White adipose tissue (WAT) is an active endocrine organ, with a crucial influence on whole-body homeostasis. WAT dysfunction plays a key role linking obesity with its associated diseases such as type 2 diabetes mellitus, cardiovascular disease, and some cancers. Among the regulators of WAT physiology, the calcium-sensing receptor (CaSR) has arisen as a potential mediator of WAT dysfunction. Expression of the receptor has been described in human preadipocytes, adipocytes, and the human adipose cell lines LS14 and SW872. The evidence suggests that CaSR activation in the visceral (i.e., unhealthy) WAT is associated with an increased proliferation of adipose progenitor cells and elevated adipocyte differentiation. In addition, exposure of adipose cells to CaSR activators in vitro elevates proinflammatory cytokine expression and secretion. An increased proinflammatory environment in WAT plays a key role in the development of WAT dysfunction that leads to peripheral organ fat deposition and insulin resistance, among other consequences. We propose that CaSR may be one relevant therapeutic target in the struggle to confront the health consequences of the current worldwide obesity pandemic. PMID:27660614

  19. Computed tomography-measured adipose tissue attenuation and area both predict adipocyte size and cardiometabolic risk in women

    PubMed Central

    Côté, Julie Anne; Nazare, Julie-Anne; Nadeau, Mélanie; Leboeuf, Mathieu; Blackburn, Line; Després, Jean-Pierre; Tchernof, André

    2016-01-01

    abstract Objective: To assess the ability of CT-derived measurements including adipose tissue attenuation and area to predict fat cell hypertrophy and related cardiometabolic risk. Methods: Abdominal adipose tissue areas and radiologic attenuation were assessed using 4 CT images in 241 women (age: 47 years, BMI: 26.5 kg/m2). Fat cell weight was measured in paired VAT and SAT samples. Fasting plasma lipids, glucose and insulin levels were measured. Results: Adipose tissue attenuation was negatively correlated with SAT (r=-0.46) and VAT (r=-0.67) fat cell weight in the corresponding depot (p<0.0001 for both). Women with visceral adipocyte hypertrophy had higher total-, VLDL-, LDL- and HDL-triglyceride and apoB levels as well as a higher cholesterol/HDL-cholesterol ratio, fasting glucose and insulin levels compared to women with smaller visceral adipocytes. Adjustment for VAT area minimized these differences while subsequent adjustment for attenuation eliminated all differences, with the exception of fasting glycaemia. In SAT, adjustment for VAT area and attenuation eliminated all adipocyte hypertrophy-related alterations except for fasting hyperglycaemia. Conclusion: CT-derived adipose tissue attenuation and area both contribute to explain variation in the cardiometabolic risk profile associated with the same biological parameter: visceral fat cell hypertrophy. PMID:27144095

  20. A cis-eQTL in PFKFB2 is associated with diabetic nephropathy, adiposity and insulin secretion in American Indians.

    PubMed

    Muller, Yunhua L; Piaggi, Paolo; Hanson, Robert L; Kobes, Sayuko; Bhutta, Shujera; Abdussamad, Maryam; Leak-Johnson, Tennille; Kretzler, Matthias; Huang, Ke; Weil, E Jennifer; Nelson, Robert G; Knowler, William C; Bogardus, Clifton; Baier, Leslie J

    2015-05-15

    A prior genome-wide association study (GWAS) in Pima Indians identified a variant within PFKFB2 (rs17258746) associated with body mass index (BMI). PFKFB2 encodes 6-phosphofructo-2-kinase/fructose 2,6-bisphosphatase isoform 2, which plays a role in glucose metabolism. To follow-up on the GWAS, tag SNPs across PFKFB2 were genotyped in American Indians (AI) who had longitudinal data on BMI (n = 6839), type 2 diabetes (T2D; n = 7710), diabetic nephropathy (DN; n = 2452), % body fat (n = 555) and insulin secretion (n = 298). Two SNPs were further genotyped in urban AI to assess replication for DN (n = 864). PFKFB2 expression was measured in 201 adipose biopsies using real-time RT-PCR and 61 kidney biopsies using the Affymetrix U133 array. Two SNPs (rs17258746 and rs11120137), which capture the same signal, were associated with maximum BMI in adulthood (β = 1.02 per risk allele, P = 7.3 × 10(-4)), maximum BMI z-score in childhood (β = 0.079, P = 0.03) and % body fat in adulthood (β = 3.4%, P = 3 × 10(-7)). The adiposity-increasing allele correlated with lower PFKFB2 adipose expression (β = 0.81, P = 9.4 × 10(-4)). Lower expression of PFKFB2 further correlated with higher % body fat (r = -0.16, P = 0.02) and BMI (r = -0.17, P = 0.02). This allele was also associated with increased risk for DN in both cohorts of AI [odds ratio = 1.64 (1.32-2.02), P = 5.8 × 10(-6)], and similarly correlated with lower PFKFB2 expression in kidney glomeruli (β = 0.87, P = 0.03). The same allele was also associated with lower insulin secretion assessed by acute insulin response (β = 0.78, P = 0.03) and 30-min plasma insulin concentrations (β = 0.78, P = 1.1 × 10(-4)). Variation in PFKFB2 appears to reduce PFKFB2 expression in adipose and kidney tissues, and thereby increase risk for adiposity and DN.

  1. Abdominal Adiposity, Not Cardiorespiratory Fitness, Mediates the Exercise-Induced Change in Insulin Sensitivity in Older Adults

    PubMed Central

    Ko, Gifferd; Davidson, Lance E.; Brennan, Andrea M.; Lam, Miu; Ross, Robert

    2016-01-01

    Abdominal obesity and low cardiorespiratory fitness (CRF) are associated with insulin resistance in older adults. Exercise is associated with improvement in insulin sensitivity. Whether this association is mediated by change in CRF and/or abdominal obesity is unclear. The current study is a secondary analysis of data from a randomized controlled trial in Kingston, Ontario. Sedentary older adults (60–80 years) (N = 80) who completed the exercise (N = 59) or control (N = 21) conditions for 6 months were included. CRF was measured using a treadmill test, adipose tissue (AT) by magnetic resonance imaging, and insulin sensitivity by hyperinsulinemic-euglycemic clamp. Waist circumference (WC) was measured at the iliac crest. Mediation analyses were used to assess whether abdominal AT and/or CRF mediated the exercise-induced change in insulin sensitivity. By comparison to controls, reduction (mean ± SD) was observed for visceral (-0.4 ± 0.4 kg) and abdominal subcutaneous (-0.4 ± 0.4) AT depots, WC (-4.1 ± 3.2 cm) and BMI (-0.9 ± 0.8 kg/m2) (p < 0.05). Insulin sensitivity (4.2 ± 5.2 M/I) and CRF (0.2 ± 0.3 L/min) improved in the exercise group (p < 0.05). All AT variables, BMI and WC were mediators of the change in insulin sensitivity (p < 0.05). After adjustment for change in total AT, abdominal AT remained a mediator with an effect ratio of 0.79 (p < 0.05), whereas total AT was not significant when adjusted for abdominal AT (p > 0.05). The effect ratio for change in WC and BMI combined (0.63, p<0.05) was greater than either alone. In conclusion, CRF did not mediate the exercise-induced change in insulin sensitivity in older adults. Abdominal adiposity was a strong mediator independent of change in total adiposity. PMID:27936206

  2. Skin Tissue Engineering: Application of Adipose-Derived Stem Cells

    PubMed Central

    Zimoch, Jakub; Biedermann, Thomas

    2017-01-01

    Perception of the adipose tissue has changed dramatically over the last few decades. Identification of adipose-derived stem cells (ASCs) ultimately transformed paradigm of this tissue from a passive energy depot into a promising stem cell source with properties of self-renewal and multipotential differentiation. As compared to bone marrow-derived stem cells (BMSCs), ASCs are more easily accessible and their isolation yields higher amount of stem cells. Therefore, the ASCs are of high interest for stem cell-based therapies and skin tissue engineering. Currently, freshly isolated stromal vascular fraction (SVF), which may be used directly without any expansion, was also assessed to be highly effective in treating skin radiation injuries, burns, or nonhealing wounds such as diabetic ulcers. In this paper, we review the characteristics of SVF and ASCs and the efficacy of their treatment for skin injuries and disorders. PMID:28337463

  3. Angiotensin II stimulates sympathetic neurotransmission to adipose tissue

    PubMed Central

    King, Victoria L; English, Victoria L; Bharadwaj, Kalyani; Cassis, Lisa A

    2013-01-01

    Angiotensin II (AngII) facilitates sympathetic neurotransmission by regulating norepinephrine (NE) synthesis, release, and uptake. These effects of AngII contribute to cardiovascular control. Previous studies in our laboratory demonstrated that chronic AngII infusion decreased body weight of rats. We hypothesized that AngII facilitates sympathetic neurotransmission to adipose tissue and may thereby decrease body weight. The effect of chronic AngII infusion on the NE uptake transporter and NE turnover was examined in metabolic (interscapular brown adipose tissue, ISBAT; epididymal fat, EF) and cardiovascular tissues (left ventricle, LV; kidney) of rats. To examine the uptake transporter saturation isotherms were performed using [3H]nisoxetine (NIS). At doses that lowered body weight, AngII significantly increased ISBAT [3H]NIS binding density. To quantify NE turnover, alpha-methyl-para-tyrosine (AMPT) was injected in saline-infused, AngII-infused, or saline-infused rats that were pair-fed to food intake of AngII-infused rats. AngII significantly increased the rate of NE decline in all tissues compared to saline. The rate of NE decline in EF was increased to a similar extent by AngII and by pair feeding. In rats administered AngII and propranolol, reductions in food and water intake and body weight were eliminated. These data support the hypothesis that AngII facilitates sympathetic neurotransmission to adipose tissue. Increased sympathetic neurotransmission to adipose tissue following AngII exposure is suggested to contribute to reductions in body weight. PMID:24224084

  4. Tadalafil reduces visceral adipose tissue accumulation by promoting preadipocytes differentiation towards a metabolically healthy phenotype: Studies in rabbits.

    PubMed

    Maneschi, Elena; Cellai, Ilaria; Aversa, Antonio; Mello, Tommaso; Filippi, Sandra; Comeglio, Paolo; Bani, Daniele; Guasti, Daniele; Sarchielli, Erica; Salvatore, Giulia; Morelli, Annamaria; Mazzanti, Benedetta; Corcetto, Francesca; Corno, Chiara; Francomano, Davide; Galli, Andrea; Vannelli, Gabriella Barbara; Lenzi, Andrea; Mannucci, Edoardo; Maggi, Mario; Vignozzi, Linda

    2016-03-15