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Sample records for function metabolic control

  1. Hypothalamic inflammation in the control of metabolic function.

    PubMed

    Valdearcos, Martin; Xu, Allison W; Koliwad, Suneil K

    2015-01-01

    Diet-induced obesity leads to devastating and common chronic diseases, fueling ongoing interest in determining new mechanisms underlying both obesity and its consequences. It is now well known that chronic overnutrition produces a unique form of inflammation in peripheral insulin target tissues, and efforts to limit this inflammation have met with some success in preserving insulin sensitivity in obese individuals. Recently, the activation of inflammatory pathways by dietary excess has also been observed among cells located in the mediobasal hypothalamus, a brain area that exerts central control over peripheral glucose, fat, and energy metabolism. Here we review progress in the field of diet-induced hypothalamic inflammation, drawing key distinctions between metabolic inflammation in the hypothalamus and that occurring in peripheral tissues. We focus on specific stimuli of the inflammatory response, the roles of individual hypothalamic cell types, and the links between hypothalamic inflammation and metabolic function under normal and pathophysiological circumstances. Finally, we explore the concept of controlling hypothalamic inflammation to mitigate metabolic disease.

  2. microRNA control of HDL Metabolism and Function

    PubMed Central

    Rayner, Katey J; Moore, Kathryn J.

    2015-01-01

    Recent discoveries of microRNAs (miRNAs) that control HDL abundance and function have expanded our knowledge of the mechanisms regulating this important lipoprotein subclass. miRNAs have been shown to regulate gene networks that control HDL biogenesis and uptake, as well as discrete steps in the reverse cholesterol transport pathway. Furthermore, HDL itself has been shown to selectively transport miRNAs in health and disease, offering new possibilities of how this lipoprotein may alter gene expression in distal target cells and tissues. Collectively, these discoveries offer new insights into the mechanisms governing HDL metabolism and function, and open new avenues for the development of therapeutics for the treatment of cardiovascular disease. PMID:24385511

  3. Metabolically active functional food ingredients for weight control.

    PubMed

    Kovacs, E M R; Mela, D J

    2006-02-01

    The scale of the obesity epidemic creates a pressing consumer need as well as an enormous business opportunity for successful development and marketing of food products with added benefits for weight control. A number of proposed functional food ingredients have been shown to act post-absorptively to influence substrate utilization or thermogenesis. Characteristics and supporting data on conjugated linoleic acid, diglycerides, medium-chain triglycerides, green tea, ephedrine, caffeine, capsaicin and calcium, are reviewed here, giving examples of how these could act to alter energy expenditure or appetite control. Consideration is also given to other factors, in addition to efficacy, which must be satisfied to get such ingredients into foods. We conclude that, for each of the safe, putatively metabolically active agents, there remain gaps in clinical evidence or knowledge of mechanisms, which need to be addressed in order to specify the dietary conditions and food product compositions where these ingredients could be of most benefit for weight control.

  4. Brain glucose sensing, glucokinase and neural control of metabolism and islet function.

    PubMed

    Ogunnowo-Bada, E O; Heeley, N; Brochard, L; Evans, M L

    2014-09-01

    It is increasingly apparent that the brain plays a central role in metabolic homeostasis, including the maintenance of blood glucose. This is achieved by various efferent pathways from the brain to periphery, which help control hepatic glucose flux and perhaps insulin-stimulated insulin secretion. Also, critically important for the brain given its dependence on a constant supply of glucose as a fuel--emergency counter-regulatory responses are triggered by the brain if blood glucose starts to fall. To exert these control functions, the brain needs to detect rapidly and accurately changes in blood glucose. In this review, we summarize some of the mechanisms postulated to play a role in this and examine the potential role of the low-affinity hexokinase, glucokinase, in the brain as a key part of some of this sensing. We also discuss how these processes may become altered in diabetes and related metabolic diseases.

  5. The Deubiquitylase MATH-33 Controls DAF-16 Stability and Function in Metabolism and Longevity

    PubMed Central

    Heimbucher, Thomas; Liu, Zheng; Bossard, Carine; McCloskey, Richard; Carrano, Andrea C.; Riedel, Christian G.; Tanasa, Bogdan; Klammt, Christian; Fonslow, Bryan R.; Riera, Celine E.; Lillemeier, Bjorn F.; Kemphues, Kenneth; Yates, John R.; O'Shea, Clodagh; Hunter, Tony; Dillin, Andrew

    2015-01-01

    SUMMARY One of the major determinants of aging in organisms ranging from worms to man are FOXO family transcription factors, which are downstream effectors of Insulin/IGF-1 signaling (IIS). The molecular mechanisms that actively promote DAF16/FOXO stability and function are unknown. Here we identify the deubiquitylating enzyme MATH-33 as an essential DAF-16 regulator in IIS, which stabilizes active DAF-16 protein levels and, as a consequence, influences DAF-16 functions, such as metabolism, stress response and longevity in C. elegans. MATH-33 associates with DAF-16 in cellulo and in vitro. MATH-33 functions as a deubiquitylase by actively removing ubiquitin moieties from DAF-16, thus counteracting the action of the RLE-1 E3-ubiquitin ligase. Our findings support a model in which MATH-33 promotes DAF-16 stability in response to decreased IIS by directly modulating its ubiquitylation state, suggesting that regulated oscillations in the stability of DAF-16 protein play an integral role in controlling processes such as metabolism and longevity. PMID:26154057

  6. Interferon Regulatory Factor 4 controls TH1 cell effector function and metabolism

    PubMed Central

    Mahnke, Justus; Schumacher, Valéa; Ahrens, Stefanie; Käding, Nadja; Feldhoff, Lea Marie; Huber, Magdalena; Rupp, Jan; Raczkowski, Friederike; Mittrücker, Hans-Willi

    2016-01-01

    The transcription factor Interferon Regulatory Factor 4 (IRF4) is essential for TH2 and TH17 cell formation and controls peripheral CD8+ T cell differentiation. We used Listeria monocytogenes infection to characterize the function of IRF4 in TH1 responses. IRF4−/− mice generated only marginal numbers of listeria-specific TH1 cells. After transfer into infected mice, IRF4−/− CD4+ T cells failed to differentiate into TH1 cells as indicated by reduced T-bet and IFN-γ expression, and showed limited proliferation. Activated IRF4−/− CD4+ T cells exhibited diminished uptake of the glucose analog 2-NBDG, limited oxidative phosphorylation and strongly reduced aerobic glycolysis. Insufficient metabolic adaptation contributed to the limited proliferation and TH1 differentiation of IRF4−/− CD4+ T cells. Our study identifies IRF4 as central regulator of TH1 responses and cellular metabolism. We propose that this function of IRF4 is fundamental for the initiation and maintenance of all TH cell responses. PMID:27762344

  7. A sturgeon-derived bioactive compound beneficially modulates nuclear receptors controlling metabolic functions in patients with metabolic syndrome.

    PubMed

    Marotta, Francesco; Lorenzetti, Aldo; Catanzaro, Roberto; Zerbinati, Nicola; Jain, Shalini; Solimene, Umberto; Yaduvanshi, Santos K; Yadav, Hariom; Sapienza, Chiara; Srivastava, Nalini; Milazzo, Michele; Italia, Angelo

    2013-06-19

    The aim of the present study was to test the possible effects of a novel sturgeon-derived compound  (LD-1227) on inflammatory markers related to metabolic nuclear receptors in patients with metabolic syndrome. The study population consisted of 76 patients with metabolic syndrome and 30 healthy subjects who were maintained to their current treatments and randomly supplemented: A) LD-1227 (n=38) or B) placebo (n=38) as compared to C) healthy controls (n=30). LD-1227 or placebo (water-soluble starch) were given daily at breakfast and dinner for three months. Levels of hs-CRP, IL-6, TNF-α, leptin and adiponectin/ resistin index were assayed at the entry, 1 month and 3 months afterwards. At the end of the study period, as compared to B group, LD-1227-treated patients showed a significant improvement of all parameters tested, irrespective of the presence of diabetes. In particular, levels of adiponectin and adiponectin/ resistin index significantly increased following LD-1227 administration. Although the metabolic syndrome remains a multifaceted condition requiring a complex approach, LD-1227 could be a potential safe therapeutic tool to be integrated into a wider treatment and preventive medicine schedule strategy.

  8. Structural Control of Metabolic Flux

    PubMed Central

    Sajitz-Hermstein, Max; Nikoloski, Zoran

    2013-01-01

    Organisms have to continuously adapt to changing environmental conditions or undergo developmental transitions. To meet the accompanying change in metabolic demands, the molecular mechanisms of adaptation involve concerted interactions which ultimately induce a modification of the metabolic state, which is characterized by reaction fluxes and metabolite concentrations. These state transitions are the effect of simultaneously manipulating fluxes through several reactions. While metabolic control analysis has provided a powerful framework for elucidating the principles governing this orchestrated action to understand metabolic control, its applications are restricted by the limited availability of kinetic information. Here, we introduce structural metabolic control as a framework to examine individual reactions' potential to control metabolic functions, such as biomass production, based on structural modeling. The capability to carry out a metabolic function is determined using flux balance analysis (FBA). We examine structural metabolic control on the example of the central carbon metabolism of Escherichia coli by the recently introduced framework of functional centrality (FC). This framework is based on the Shapley value from cooperative game theory and FBA, and we demonstrate its superior ability to assign “share of control” to individual reactions with respect to metabolic functions and environmental conditions. A comparative analysis of various scenarios illustrates the usefulness of FC and its relations to other structural approaches pertaining to metabolic control. We propose a Monte Carlo algorithm to estimate FCs for large networks, based on the enumeration of elementary flux modes. We further give detailed biological interpretation of FCs for production of lactate and ATP under various respiratory conditions. PMID:24367246

  9. Engineering of metabolic control

    DOEpatents

    Liao, James C.

    2004-03-16

    The invention features a method of producing heterologous molecules in cells under the regulatory control of a metabolite and metabolic flux. The method can enhance the synthesis of heterologous polypeptides and metabolites.

  10. Engineering of metabolic control

    DOEpatents

    Liao, James C.

    2006-10-17

    The invention features a method of producing heterologous molecules in cells under the regulatory control of a metabolite and metabolic flux. The method can enhance the synthesis of heterologous polypeptides and metabolites.

  11. Small RNA-dependent expression of secondary metabolism is controlled by Krebs cycle function in Pseudomonas fluorescens.

    PubMed

    Takeuchi, Kasumi; Kiefer, Patrick; Reimmann, Cornelia; Keel, Christoph; Dubuis, Christophe; Rolli, Joëlle; Vorholt, Julia A; Haas, Dieter

    2009-12-11

    Pseudomonas fluorescens CHA0, an antagonist of phytopathogenic fungi in the rhizosphere of crop plants, elaborates and excretes several secondary metabolites with antibiotic properties. Their synthesis depends on three small RNAs (RsmX, RsmY, and RsmZ), whose expression is positively controlled by the GacS-GacA two-component system at high cell population densities. To find regulatory links between primary and secondary metabolism in P. fluorescens and in the related species Pseudomonas aeruginosa, we searched for null mutations that affected central carbon metabolism as well as the expression of rsmY-gfp and rsmZ-gfp reporter constructs but without slowing down the growth rate in rich media. Mutation in the pycAB genes (for pyruvate carboxylase) led to down-regulation of rsmXYZ and secondary metabolism, whereas mutation in fumA (for a fumarase isoenzyme) resulted in up-regulation of the three small RNAs and secondary metabolism in the absence of detectable nutrient limitation. These effects required the GacS sensor kinase but not the accessory sensors RetS and LadS. An analysis of intracellular metabolites in P. fluorescens revealed a strong positive correlation between small RNA expression and the pools of 2-oxoglutarate, succinate, and fumarate. We conclude that Krebs cycle intermediates (already known to control GacA-dependent virulence factors in P. aeruginosa) exert a critical trigger function in secondary metabolism via the expression of GacA-dependent small RNAs.

  12. Sleep and metabolic function

    PubMed Central

    Morselli, Lisa L.; Guyon, Aurore; Spiegel, Karine

    2012-01-01

    Evidence for the role of sleep on metabolic and endocrine function has been reported more than four decades ago. In the past 30 years, the prevalence of obesity and diabetes has greatly increased in industrialized countries, and self-imposed sleep curtailment, now very common, is starting to be recognized as a contributing factor, alongside with increased caloric intake and decreased physical activity. Furthermore, obstructive sleep apnea, a chronic condition characterized by recurrent upper airway obstruction leading to intermittent hypoxemia and sleep fragmentation, has also become highly prevalent as a consequence of the epidemic of obesity and has been shown to contribute, in a vicious circle, to the metabolic disturbances observed in obese patients. In this article, we summarize the current data supporting the role of sleep in the regulation of glucose homeostasis and the hormones involved in the regulation of appetite. We also review the results of the epidemiologic and laboratory studies that investigated the impact of sleep duration and quality on the risk of developing diabetes and obesity, as well as the mechanisms underlying this increased risk. Finally, we discuss how obstructive sleep apnea affects glucose metabolism and the beneficial impact of its treatment, the continuous positive airway pressure. In conclusion, the data available in the literature highlight the importance of getting enough good sleep for metabolic health. PMID:22101912

  13. L-arginine metabolism in myeloid cells controls T-lymphocyte functions.

    PubMed

    Bronte, Vincenzo; Serafini, Paolo; Mazzoni, Alessandra; Segal, David M; Zanovello, Paola

    2003-06-01

    Although current attention has focused on regulatory T lymphocytes as suppressors of autoimmune responses, powerful immunosuppression is also mediated by a subset of myeloid cells that enter the lymphoid organs and peripheral tissues during times of immune stress. If these myeloid suppressor cells (MSCs) receive signals from activated T lymphocytes in the lymphoid organs, they block T-cell proliferation. MSCs use two enzymes involved in arginine metabolism to control T-cell responses: inducible nitric oxide synthase (NOS2), which generates nitric oxide (NO) and arginase 1 (Arg1), which depletes the milieu of arginine. Th1 cytokines induce NOS2, whereas Th2 cytokines upregulate Arg1. Induction of either enzyme alone results in a reversible block in T-cell proliferation. When both enzymes are induced together, peroxynitrites, generated by NOS2 under conditions of limiting arginine, cause activated T lymphocytes to undergo apoptosis. Thus, NOS2 and Arg1 might act separately or synergistically in vivo to control specific types of T-cell responses, and selective antagonists of these enzymes might prove beneficial in fighting diseases in which T-cell responses are inappropriately suppressed. This Opinion is the second in a series on the regulation of the immune system by metabolic pathways.

  14. Nutritional control of immunity: Balancing the metabolic requirements with an appropriate immune function.

    PubMed

    De Rosa, Veronica; Galgani, Mario; Santopaolo, Marianna; Colamatteo, Alessandra; Laccetti, Roberta; Matarese, Giuseppe

    2015-09-01

    The immune system is a highly integrated network of cells sensitive to a number of environmental factors. Interestingly, recent years have seen a dramatic increase in our understanding of how diet makes a crucial contribution to human health, affecting the immune system, secretion of adipocytokines and metabolic pathways. Recent experimental evidence indicates that diet and its components are able to profoundly influence immune responses, thus affecting the development of inflammatory and autoimmune diseases. This review aims to discuss some of the main topics concerning the impact of nutrients and their relative composition on immune cell development and function that may be particularly important for regulating the balance between inflammatory and tolerogenic processes. We also highlight the effects of diet on commensal bacteria and how changes in the composition of the microbiota alter intestinal and systemic immune homeostasis. Finally, we summarize the effects of dietary compounds on epigenetic mechanisms involved in the regulation of several immune related genes.

  15. Structural and Functional Study of Yer067w, a New Protein Involved in Yeast Metabolism Control and Drug Resistance

    PubMed Central

    Domitrovic, Tatiana; Kozlov, Guennadi; Freire, João Claudio Gonçalves; Masuda, Claudio Akio; da Silva Almeida, Marcius; Montero-Lomeli, Mónica; Atella, Georgia Correa; Matta-Camacho, Edna; Gehring, Kalle; Kurtenbach, Eleonora

    2010-01-01

    The genome of Saccharomyces cerevisiae is arguably the best studied eukaryotic genome, and yet, it contains approximately 1000 genes that are still relatively uncharacterized. As the majority of these ORFs have no homologs with characterized sequence or protein structure, traditional sequence-based approaches cannot be applied to deduce their biological function. Here, we characterize YER067W, a conserved gene of unknown function that is strongly induced in response to many stress conditions and repressed in drug resistant yeast strains. Gene expression patterns of YER067W and its paralog YIL057C suggest an involvement in energy metabolism. We show that yeast lacking YER067W display altered levels of reserve carbohydrates and a growth deficiency in media that requires aerobic metabolism. Impaired mitochondrial function and overall reduction of ergosterol content in the YER067W deleted strain explained the observed 2- and 4-fold increase in resistance to the drugs fluconazole and amphotericin B, respectively. Cell fractionation and immunofluorescence microscopy revealed that Yer067w is associated with cellular membranes despite the absence of a transmembrane domain in the protein. Finally, the 1.7 Å resolution crystal structure of Yer067w shows an alpha-beta fold with low similarity to known structures and a putative functional site. YER067W's involvement with aerobic energetic metabolism suggests the assignment of the gene name RGI1, standing for respiratory growth induced 1. Altogether, the results shed light on a previously uncharacterized protein family and provide basis for further studies of its apparent role in energy metabolism control and drug resistance. PMID:20567505

  16. Combinatorial control of diverse metabolic and physiological functions by transcriptional regulators of the yeast sulfur assimilation pathway.

    PubMed

    Petti, Allegra A; McIsaac, R Scott; Ho-Shing, Olivia; Bussemaker, Harmen J; Botstein, David

    2012-08-01

    Methionine abundance affects diverse cellular functions, including cell division, redox homeostasis, survival under starvation, and oxidative stress response. Regulation of the methionine biosynthetic pathway involves three DNA-binding proteins-Met31p, Met32p, and Cbf1p. We hypothesized that there exists a "division of labor" among these proteins that facilitates coordination of methionine biosynthesis with diverse biological processes. To explore combinatorial control in this regulatory circuit, we deleted CBF1, MET31, and MET32 individually and in combination in a strain lacking methionine synthase. We followed genome-wide gene expression as these strains were starved for methionine. Using a combination of bioinformatic methods, we found that these regulators control genes involved in biological processes downstream of sulfur assimilation; many of these processes had not previously been documented as methionine dependent. We also found that the different factors have overlapping but distinct functions. In particular, Met31p and Met32p are important in regulating methionine metabolism, whereas p functions as a "generalist" transcription factor that is not specific to methionine metabolism. In addition, Met31p and Met32p appear to regulate iron-sulfur cluster biogenesis through direct and indirect mechanisms and have distinguishable target specificities. Finally, CBF1 deletion sometimes has the opposite effect on gene expression from MET31 and MET32 deletion.

  17. Combinatorial control of diverse metabolic and physiological functions by transcriptional regulators of the yeast sulfur assimilation pathway

    PubMed Central

    Petti, Allegra A.; McIsaac, R. Scott; Ho-Shing, Olivia; Bussemaker, Harmen J.; Botstein, David

    2012-01-01

    Methionine abundance affects diverse cellular functions, including cell division, redox homeostasis, survival under starvation, and oxidative stress response. Regulation of the methionine biosynthetic pathway involves three DNA-binding proteins—Met31p, Met32p, and Cbf1p. We hypothesized that there exists a “division of labor” among these proteins that facilitates coordination of methionine biosynthesis with diverse biological processes. To explore combinatorial control in this regulatory circuit, we deleted CBF1, MET31, and MET32 individually and in combination in a strain lacking methionine synthase. We followed genome-wide gene expression as these strains were starved for methionine. Using a combination of bioinformatic methods, we found that these regulators control genes involved in biological processes downstream of sulfur assimilation; many of these processes had not previously been documented as methionine dependent. We also found that the different factors have overlapping but distinct functions. In particular, Met31p and Met32p are important in regulating methionine metabolism, whereas p functions as a “generalist” transcription factor that is not specific to methionine metabolism. In addition, Met31p and Met32p appear to regulate iron–sulfur cluster biogenesis through direct and indirect mechanisms and have distinguishable target specificities. Finally, CBF1 deletion sometimes has the opposite effect on gene expression from MET31 and MET32 deletion. PMID:22696679

  18. Metabolic control of signalling pathways and metabolic auto-regulation.

    PubMed

    Lorendeau, Doriane; Christen, Stefan; Rinaldi, Gianmarco; Fendt, Sarah-Maria

    2015-08-01

    Metabolic alterations have emerged as an important hallmark in the development of various diseases. Thus, understanding the complex interplay of metabolism with other cellular processes such as cell signalling is critical to rationally control and modulate cellular physiology. Here, we review in the context of mammalian target of rapamycin, AMP-activated protein kinase and p53, the orchestrated interplay between metabolism and cellular signalling as well as transcriptional regulation. Moreover, we discuss recent discoveries in auto-regulation of metabolism (i.e. how metabolic parameters such as metabolite levels activate or inhibit enzymes and thus metabolic pathways). Finally, we review functional consequences of post-translational modification on metabolic enzyme abundance and/or activities.

  19. Mammalian Polyamine Metabolism and Function

    PubMed Central

    Pegg, Anthony E.

    2009-01-01

    Summary Polyamines are ubiquitous small basic molecules that play multiple essential roles in mammalian physiology. Their cellular content is highly regulated and there is convincing evidence that altered metabolism is involvement in many disease states. Drugs altering polyamine levels may therefore have a variety of important targets. This review will summarize the current state of understanding of polyamine metabolism and function, the regulation of polyamine content, and heritable pathological conditions that may be derived from altered polyamine metabolism. PMID:19603518

  20. Microtubule Control of Metabolism in Prostate Cancer

    DTIC Science & Technology

    2013-11-01

    Prostate Cancer PRINCIPAL INVESTIGATOR: Lynne Cassimeris CONTRACTING ORGANIZATION: Lehigh University Bethlehem, PA 18015-3008 REPORT...Control of Metabolism in Prostate Cancer Dr. Lynne Cassimeris lc07@lehigh.edu Lehigh University 526 Brodhead Avenue Bethlehem, PA 18015-3008 U.S...tested whether metabolic inhibitors, metformin or 2-deoxy-glucose, function synergistically with docetaxel to block prostate cancer cell proliferation

  1. Kupffer Cell Metabolism and Function

    PubMed Central

    Nguyen-Lefebvre, Anh Thu; Horuzsko, Anatolij

    2015-01-01

    Kupffer cells are resident liver macrophages and play a critical role in maintaining liver functions. Under physiological conditions, they are the first innate immune cells and protect the liver from bacterial infections. Under pathological conditions, they are activated by different components and can differentiate into M1-like (classical) or M2-like (alternative) macrophages. The metabolism of classical or alternative activated Kupffer cells will determine their functions in liver damage. Special functions and metabolism of Kupffer cells suggest that they are an attractive target for therapy of liver inflammation and related diseases, including cancer and infectious diseases. Here we review the different types of Kupffer cells and their metabolism and functions in physiological and pathological conditions. PMID:26937490

  2. Effect of pioglitazone on systemic inflammation is independent of metabolic control and cardiac autonomic function in patients with type 2 diabetes.

    PubMed

    Nerla, Roberto; Pitocco, Dario; Zaccardi, Francesco; Scalone, Giancarla; Coviello, Ilaria; Mollo, Roberto; Ghirlanda, Giovanni; Lanza, Gaetano A; Crea, Filippo

    2010-12-01

    The aim of this article is to investigate the relation of the anti-inflammatory effect of pioglitazone with cardiac autonomic function and metabolic control in diabetic patients. In this prospective open label trial, 36 type 2 diabetic patients (age 60 ± 10, 20 M) without overt cardiovascular disease were randomized to add pioglitazone (30 mg) to their therapy or to continue standard therapy. C-reactive protein (CRP) serum levels, metabolic parameters and cardiac autonomic function (assessed by heart rate variability [HRV] on 24-h ECG Holter monitoring) were measured at baseline and after 3 months. Clinical and laboratory variables were similar in the two groups. No significant changes were observed after 3 months for metabolic and anthropometric parameters, except for a mild increase in HDL levels in the pioglitazone group only (P = 0.04 vs. controls). CRP levels decreased significantly at follow-up in the pioglitazone group (3.2 ± 1.97 vs. 2.37 ± 1.56 mg/l) but not in the control group (3.0 ± 1.92 vs. 3.93 ± 2.14 mg/l; P = 0.003). No differences were found in basal and follow-up HRV variables between the two groups. In type 2 diabetic patients pioglitazone exerts favourable effects on inflammation even after short-term therapy. This effect precedes those on metabolic and anthropometric parameters and is not associated with changes in cardiac autonomic function.

  3. Metabolic control of renin secretion

    PubMed Central

    Gevorgyan, Haykanush; Lam, Lisa; Riquier-Brison, Anne

    2015-01-01

    One emerging topic in renin–angiotensin system (RAS) research is the direct local control of renin synthesis and release by endogenous metabolic intermediates. During the past few years, our laboratory has characterized the localization and signaling of the novel metabolic receptor GPR91 in the normal and diabetic kidney and established GPR91 as a new, direct link between high glucose and RAS activation in diabetes. GPR91 (also called SUCNR1) binds tricarboxylic acid (TCA) cycle intermediate succinate which can rapidly accumulate in the local tissue environment when energy supply and demand are out of balance. In a variety of physiological and pathological conditions associated with metabolic stress, succinate signaling via GPR91 appears to be an important mediator or modulator of renin secretion. This review summarizes our current knowledge on the control of renin release by molecules of endogenous metabolic pathways with the main focus on succinate/GPR91. PMID:22729752

  4. Metabolic control of renin secretion.

    PubMed

    Peti-Peterdi, János; Gevorgyan, Haykanush; Lam, Lisa; Riquier-Brison, Anne

    2013-01-01

    One emerging topic in renin-angiotensin system (RAS) research is the direct local control of renin synthesis and release by endogenous metabolic intermediates. During the past few years, our laboratory has characterized the localization and signaling of the novel metabolic receptor GPR91 in the normal and diabetic kidney and established GPR91 as a new, direct link between high glucose and RAS activation in diabetes. GPR91 (also called SUCNR1) binds tricarboxylic acid (TCA) cycle intermediate succinate which can rapidly accumulate in the local tissue environment when energy supply and demand are out of balance. In a variety of physiological and pathological conditions associated with metabolic stress, succinate signaling via GPR91 appears to be an important mediator or modulator of renin secretion. This review summarizes our current knowledge on the control of renin release by molecules of endogenous metabolic pathways with the main focus on succinate/GPR91.

  5. Matched and Mismatched Metabolic Fuels in Lymphocyte Function

    PubMed Central

    Caro-Maldonado, Alfredo; Gerriets, Valerie A.; Rathmell, Jeffrey C.

    2012-01-01

    Immunological function requires metabolic support to suit the needs of lymphocytes at a variety of distinct differentiation and activation states. It is now evident that the signaling pathways that drive lymphocyte survival and activity can directly control cellular metabolism. This linkage provides a mechanism by which activation and specific signaling pathways provide a supply of appropriate and required nutrients to support cell functions in a pro-active supply rather than consumption-based metabolic model. In this way, the metabolism and fuel choices of lymphocytes are guided to specifically match the anticipated needs. If the fuel choice or metabolic pathways of lymphocytes are dysregulated, however, metabolic checkpoints can become activated to disrupt immunological function. These changes are now shown in several immunological diseases and may open new opportunities to selectively enhance or suppress specific immune functions through targeting of glucose, lipid, or amino acid metabolism. PMID:23290889

  6. Blueberries improve endothelial function, but not blood pressure, in adults with metabolic syndrome: a randomized, double-blind, placebo-controlled clinical trial.

    PubMed

    Stull, April J; Cash, Katherine C; Champagne, Catherine M; Gupta, Alok K; Boston, Raymond; Beyl, Robbie A; Johnson, William D; Cefalu, William T

    2015-05-27

    Blueberry consumption has been shown to have various health benefits in humans. However, little is known about the effect of blueberry consumption on blood pressure, endothelial function and insulin sensitivity in humans. The present study investigated the role of blueberry consumption on modifying blood pressure in subjects with metabolic syndrome. In addition, endothelial function and insulin sensitivity (secondary measurements) were also assessed. A double-blind and placebo-controlled study was conducted in 44 adults (blueberry, n = 23; and placebo, n = 21). They were randomized to receive a blueberry or placebo smoothie twice daily for six weeks. Twenty-four-hour ambulatory blood pressure, endothelial function and insulin sensitivity were assessed pre- and post-intervention. The blood pressure and insulin sensitivity did not differ between the blueberry and placebo groups. However, the mean change in resting endothelial function, expressed as reactive hyperemia index (RHI), was improved significantly more in the group consuming the blueberries versus the placebo group (p = 0.024). Even after adjusting for confounding factors, i.e., the percent body fat and gender, the blueberry group still had a greater improvement in endothelial function when compared to their counterpart (RHI; 0.32 ± 0.13 versus -0.33 ± 0.14; p = 0.0023). In conclusion, daily dietary consumption of blueberries did not improve blood pressure, but improved (i.e., increased) endothelial function over six weeks in subjects with metabolic syndrome.

  7. Blueberries Improve Endothelial Function, but Not Blood Pressure, in Adults with Metabolic Syndrome: A Randomized, Double-Blind, Placebo-Controlled Clinical Trial

    PubMed Central

    Stull, April J.; Cash, Katherine C.; Champagne, Catherine M.; Gupta, Alok K.; Boston, Raymond; Beyl, Robbie A.; Johnson, William D.; Cefalu, William T.

    2015-01-01

    Blueberry consumption has been shown to have various health benefits in humans. However, little is known about the effect of blueberry consumption on blood pressure, endothelial function and insulin sensitivity in humans. The present study investigated the role of blueberry consumption on modifying blood pressure in subjects with metabolic syndrome. In addition, endothelial function and insulin sensitivity (secondary measurements) were also assessed. A double-blind and placebo-controlled study was conducted in 44 adults (blueberry, n = 23; and placebo, n = 21). They were randomized to receive a blueberry or placebo smoothie twice daily for six weeks. Twenty-four-hour ambulatory blood pressure, endothelial function and insulin sensitivity were assessed pre- and post-intervention. The blood pressure and insulin sensitivity did not differ between the blueberry and placebo groups. However, the mean change in resting endothelial function, expressed as reactive hyperemia index (RHI), was improved significantly more in the group consuming the blueberries versus the placebo group (p = 0.024). Even after adjusting for confounding factors, i.e., the percent body fat and gender, the blueberry group still had a greater improvement in endothelial function when compared to their counterpart (RHI; 0.32 ± 0.13 versus −0.33 ± 0.14; p = 0.0023). In conclusion, daily dietary consumption of blueberries did not improve blood pressure, but improved (i.e., increased) endothelial function over six weeks in subjects with metabolic syndrome. PMID:26024297

  8. Cell biology. Metabolic control of cell death.

    PubMed

    Green, Douglas R; Galluzzi, Lorenzo; Kroemer, Guido

    2014-09-19

    Beyond their contribution to basic metabolism, the major cellular organelles, in particular mitochondria, can determine whether cells respond to stress in an adaptive or suicidal manner. Thus, mitochondria can continuously adapt their shape to changing bioenergetic demands as they are subjected to quality control by autophagy, or they can undergo a lethal permeabilization process that initiates apoptosis. Along similar lines, multiple proteins involved in metabolic circuitries, including oxidative phosphorylation and transport of metabolites across membranes, may participate in the regulated or catastrophic dismantling of organelles. Many factors that were initially characterized as cell death regulators are now known to physically or functionally interact with metabolic enzymes. Thus, several metabolic cues regulate the propensity of cells to activate self-destructive programs, in part by acting on nutrient sensors. This suggests the existence of "metabolic checkpoints" that dictate cell fate in response to metabolic fluctuations. Here, we discuss recent insights into the intersection between metabolism and cell death regulation that have major implications for the comprehension and manipulation of unwarranted cell loss.

  9. Serum CA19-9 Level Associated with Metabolic Control and Pancreatic Beta Cell Function in Diabetic Patients

    PubMed Central

    Yu, Haoyong; Li, Ruixia; Zhang, Lei; Chen, Haibing; Bao, Yuqian; Jia, Weiping

    2012-01-01

    CA19-9 is a tumor-associated antigen. It is also a marker of pancreatic tissue damage that might be caused by diabetes. Long-term poor glycemic control may lead to pancreatic beta cell dysfunction which is reflected by elevated serum CA19-9 level. Intracellular cholesterol accumulation leads to islet dysfunction and impaired insulin secretion which provide a new lipotoxic model. This study firstly found total cholesterol was one of the independent contributors to CA19-9. Elevated serum CA19-9 level in diabetic patients may indicate further investigations of glycemic control, pancreatic beta cell function, and total cholesterol level. PMID:22778715

  10. Effect of keishibukuryogan on endothelial function in patients with at least one component of the diagnostic criteria for metabolic syndrome: a controlled clinical trial with crossover design.

    PubMed

    Nagata, Yutaka; Goto, Hirozo; Hikiami, Hiroaki; Nogami, Tatsuya; Fujimoto, Makoto; Shibahara, Naotoshi; Shimada, Yutaka

    2012-01-01

    We evaluated the effect of keishibukuryogan (KBG; Guizhi-Fuling-Wan), a traditional Japanese (Kampo) formula, on endothelial function assessed by reactive hyperemia peripheral arterial tonometry (Endo-PAT2000) in patients with metabolic syndrome-related factors by controlled clinical trial with crossover design. Ninety-two patients were assigned to group A (first KBG-treatment period, then control period; each lasting 4 weeks, with about one-year interval) or group B (first control, then KBG-treatment). In forty-nine (27, group A; 22, group B) patients completing all tests, the mean value of the natural logarithmic-scaled reactive hyperemia index (L_RHI) increased and those of serum nonesterified fatty acid (NEFA), malondialdehyde, and soluble vascular cell adhesion molecule 1 decreased significantly during the KBG-treatment period, but not during the control period, and 4-week changes of L_RHI, NEFA, and malondialdehyde between the 2 periods showed significance. These results suggest that KBG has beneficial effect on endothelial function in patients with metabolic syndrome-related factors.

  11. Effect of Keishibukuryogan on Endothelial Function in Patients with at Least One Component of the Diagnostic Criteria for Metabolic Syndrome: A Controlled Clinical Trial with Crossover Design

    PubMed Central

    Nagata, Yutaka; Goto, Hirozo; Hikiami, Hiroaki; Nogami, Tatsuya; Fujimoto, Makoto; Shibahara, Naotoshi; Shimada, Yutaka

    2012-01-01

    We evaluated the effect of keishibukuryogan (KBG; Guizhi-Fuling-Wan), a traditional Japanese (Kampo) formula, on endothelial function assessed by reactive hyperemia peripheral arterial tonometry (Endo-PAT2000) in patients with metabolic syndrome-related factors by controlled clinical trial with crossover design. Ninety-two patients were assigned to group A (first KBG-treatment period, then control period; each lasting 4 weeks, with about one-year interval) or group B (first control, then KBG-treatment). In forty-nine (27, group A; 22, group B) patients completing all tests, the mean value of the natural logarithmic-scaled reactive hyperemia index (L_RHI) increased and those of serum nonesterified fatty acid (NEFA), malondialdehyde, and soluble vascular cell adhesion molecule 1 decreased significantly during the KBG-treatment period, but not during the control period, and 4-week changes of L_RHI, NEFA, and malondialdehyde between the 2 periods showed significance. These results suggest that KBG has beneficial effect on endothelial function in patients with metabolic syndrome-related factors. PMID:22675380

  12. Hypothalamic control of bone metabolism.

    PubMed

    Sharan, Kunal; Yadav, Vijay K

    2014-10-01

    Bones are structures in vertebrates that provide support to organs, protect soft organs, and give them shape and defined features, functions that are essential for their survival. To perform these functions, bones are constantly renewed throughout life. The process through which bones are renewed is known as bone remodeling, an energy demanding process sensitive to changes in energy homeostasis of the organism. A close interplay takes place between the diversity of nutritional cues and metabolic signals with different elements of the hypothalamic circuits to co-ordinate energy metabolism with the regulation of bone mass. In this review, we focus on how mouse and human genetics have elucidated the roles of hormonal signals and neural circuits that originate in, or impinge on, the hypothalamus in the regulation of bone mass. This will help to understand the mechanisms whereby regulation of bone is gated and dynamically regulated by the hypothalamus.

  13. Hepatic Control of Energy Metabolism via the Autonomic Nervous System

    PubMed Central

    2017-01-01

    Although the human liver comprises approximately 2.8% of the body weight, it plays a central role in the control of energy metabolism. While the biochemistry of energy substrates such as glucose, fatty acids, and ketone bodies in the liver is well understood, many aspects of the overall control system for hepatic metabolism remain largely unknown. These include mechanisms underlying the ascertainment of its energy metabolism status by the liver, and the way in which this information is used to communicate and function together with adipose tissues and other organs involved in energy metabolism. This review article summarizes hepatic control of energy metabolism via the autonomic nervous system. PMID:27592630

  14. Metabolic Control of Redox and Redox Control of Metabolism in Plants

    PubMed Central

    Fernie, Alisdair R.

    2014-01-01

    Abstract Significance: Reduction-oxidation (Redox) status operates as a major integrator of subcellular and extracellular metabolism and is simultaneously itself regulated by metabolic processes. Redox status not only dominates cellular metabolism due to the prominence of NAD(H) and NADP(H) couples in myriad metabolic reactions but also acts as an effective signal that informs the cell of the prevailing environmental conditions. After relay of this information, the cell is able to appropriately respond via a range of mechanisms, including directly affecting cellular functioning and reprogramming nuclear gene expression. Recent Advances: The facile accession of Arabidopsis knockout mutants alongside the adoption of broad-scale post-genomic approaches, which are able to provide transcriptomic-, proteomic-, and metabolomic-level information alongside traditional biochemical and emerging cell biological techniques, has dramatically advanced our understanding of redox status control. This review summarizes redox status control of metabolism and the metabolic control of redox status at both cellular and subcellular levels. Critical Issues: It is becoming apparent that plastid, mitochondria, and peroxisome functions influence a wide range of processes outside of the organelles themselves. While knowledge of the network of metabolic pathways and their intraorganellar redox status regulation has increased in the last years, little is known about the interorganellar redox signals coordinating these networks. A current challenge is, therefore, synthesizing our knowledge and planning experiments that tackle redox status regulation at both inter- and intracellular levels. Future Directions: Emerging tools are enabling ever-increasing spatiotemporal resolution of metabolism and imaging of redox status components. Broader application of these tools will likely greatly enhance our understanding of the interplay of redox status and metabolism as well as elucidating and

  15. Ghrelin acylation and metabolic control.

    PubMed

    Al Massadi, O; Tschöp, M H; Tong, J

    2011-11-01

    Since its discovery, many physiologic functions have been ascribed to ghrelin, a gut derived hormone. The presence of a median fatty acid side chain on the ghrelin peptide is required for the binding and activation of the classical ghrelin receptor, the growth hormone secretagogue receptor (GHSR)-1a. Ghrelin O-acyl transferase (GOAT) was recently discovered as the enzyme responsible for this acylation process. GOAT is expressed in all tissues that have been found to express ghrelin and has demonstrated actions on several complex endocrine organ systems such as the hypothalamus-pituitary-gonadal, insular and adrenal axis as well as the gastrointestinal (GI) tract, bone and gustatory system. Ghrelin acylation is dependent on the function of GOAT and the availability of substrates such as proghrelin and short- to medium-chain fatty acids (MCFAs). This process is governed by GOAT activity and has been shown to be modified by dietary lipids. In this review, we provided evidence that support an important role of GOAT in the regulation of energy homeostasis and glucose metabolism by modulating acyl ghrelin (AG) production. The relevance of GOAT and AG during periods of starvation remains to be defined. In addition, we summarized the recent literature on the metabolic effects of GOAT specific inhibitors and shared our view on the potential of targeting GOAT for the treatment of metabolic disorders such as obesity and type 2 diabetes.

  16. Metabolic control of methylation and acetylation

    PubMed Central

    Su, Xiaoyang; Wellen, Kathryn E.; Rabinowitz, Joshua D

    2015-01-01

    Methylation and acetylation of DNA and histone proteins are the chemical basis for epigenetics. From bacteria to humans, methylation and acetylation are sensitive to cellular metabolic status. Modification rates depend on the availability of one-carbon and two-carbon substrates (S-adenosylmethionine, acetyl-CoA, and in bacteria also acetyl-phosphate). In addition, they are sensitive to demodification enzyme cofactors (α-ketoglutarate, NAD+) and structural analog metabolites that function as epigenetic enzyme inhibitors (e.g., S-adenosylhomocysteine, 2-hydroxyglutarate). Methylation and acetylation likely initially evolved to tailor protein activities in microbes to their metabolic milieu. While the extracellular environment of mammals is more tightly controlled, the combined impact of nutrient abundance and metabolic enzyme expression impacts epigenetics in mammals sufficiently to drive important biological outcomes such as stem cell fate and cancer. PMID:26629854

  17. Metabolic control of methylation and acetylation.

    PubMed

    Su, Xiaoyang; Wellen, Kathryn E; Rabinowitz, Joshua D

    2016-02-01

    Methylation and acetylation of DNA and histone proteins are the chemical basis for epigenetics. From bacteria to humans, methylation and acetylation are sensitive to cellular metabolic status. Modification rates depend on the availability of one-carbon and two-carbon substrates (S-adenosylmethionine, acetyl-CoA, and in bacteria also acetyl-phosphate). In addition, they are sensitive to demodification enzyme cofactors (α-ketoglutarate, NAD(+)) and structural analog metabolites that function as epigenetic enzyme inhibitors (e.g., S-adenosylhomocysteine, 2-hydroxyglutarate). Methylation and acetylation likely initially evolved to tailor protein activities in microbes to their metabolic milieu. While the extracellular environment of mammals is more tightly controlled, the combined impact of nutrient abundance and metabolic enzyme expression impacts epigenetics in mammals sufficiently to drive important biological outcomes such as stem cell fate and cancer.

  18. Effect of Probiotic Supplementation on Cognitive Function and Metabolic Status in Alzheimer's Disease: A Randomized, Double-Blind and Controlled Trial

    PubMed Central

    Akbari, Elmira; Asemi, Zatollah; Daneshvar Kakhaki, Reza; Bahmani, Fereshteh; Kouchaki, Ebrahim; Tamtaji, Omid Reza; Hamidi, Gholam Ali; Salami, Mahmoud

    2016-01-01

    Alzheimer's disease (AD) is associated with severe cognitive impairments as well as some metabolic defects. Scant studies in animal models indicate a link between probiotics and cognitive function. This randomized, double-blind, and controlled clinical trial was conducted among 60 AD patients to assess the effects of probiotic supplementation on cognitive function and metabolic status. The patients were randomly divided into two groups (n = 30 in each group) treating with either milk (control group) or a mixture of probiotics (probiotic group). The probiotic supplemented group took 200 ml/day probiotic milk containing Lactobacillus acidophilus, Lactobacillus casei, Bifidobacterium bifidum, and Lactobacillus fermentum (2 × 109 CFU/g for each) for 12 weeks. Mini-mental state examination (MMSE) score was recorded in all subjects before and after the treatment. Pre- and post-treatment fasting blood samples were obtained to determine the related markers. After 12 weeks intervention, compared with the control group (−5.03% ± 3.00), the probiotic treated (+27.90% ± 8.07) patients showed a significant improvement in the MMSE score (P <0.001). In addition, changes in plasma malondialdehyde (−22.01% ± 4.84 vs. +2.67% ± 3.86 μmol/L, P <0.001), serum high-sensitivity C-reactive protein (−17.61% ± 3.70 vs. +45.26% ± 3.50 μg/mL, P <0.001), homeostasis model of assessment-estimated insulin resistance (+28.84% ± 13.34 vs. +76.95% ± 24.60, P = 0.002), Beta cell function (+3.45% ± 10.91 vs. +75.62% ± 23.18, P = 0.001), serum triglycerides (−20.29% ± 4.49 vs. −0.16% ± 5.24 mg/dL, P = 0.003), and quantitative insulin sensitivity check index (−1.83 ± 1.26 vs. −4.66 ± 1.70, P = 0.006) in the probiotic group were significantly varied compared to the control group. We found that the probiotic treatment had no considerable effect on other biomarkers of oxidative stress and inflammation, fasting plasma glucose, and other lipid profiles. Overall, the current

  19. Intensive practical lifestyle intervention improves endothelial function in metabolic syndrome independent of weight loss: a randomized controlled trial.

    PubMed

    Seligman, Beatriz G S; Polanczyk, Carisi A; Santos, Angela S B; Foppa, Murilo; Junges, Mauricio; Bonzanini, Laisa; Nicolaidis, Gabriela; Camey, Suzi; Lopes, André L; Sehl, Paulo; Duncan, Bruce B; Clausell, Nadine

    2011-12-01

    The objective was to evaluate the metabolic and vascular effects of lifestyle interventions involving a healthy diet and either a moderate- or a high-intensity exercise regimen in nondiabetic subjects with metabolic syndrome. The effects of these interventions on flow-mediated vasodilation (FMD) and risk profiles were compared with a standard low-fat diet and engaging in daily walking (standard of care). Seventy-five healthy adults with metabolic syndrome (30-55 years old) were randomized to a 10,000-steps-a-day exercise program, a 3-times-a-week fitness (>75% peak VO(2)) program, or a 1-hour-walking-a-day program for 12 weeks. The first 2 interventions were combined with an accessible healthy, no-sugar diet; and the third was combined with a tailored low-fat diet. The outcomes, including FMD and risk factors, were examined at 12 weeks and at 1-year reassessment. Significant increase in FMD (mean difference = 1.51%, 95% confidence interval = 1.05%-3.017%, P = .0007) and decrease in arterial pressure (mean difference = 19.3 ± 2.3/-12.6 ± 1.8 mm Hg, P = .0001) were observed in all groups. However, the FMD changed most favorably in the high-intensity, low-sugar group (mean difference = 1.56%, 95% confidence interval = 0.1%-3.02%, P = .036). Significant improvements in body mass index, waist, insulin-like growth factor-1, homeostasis model assessment of insulin resistance, insulin, glucose, urinary albumin excretion, and lipid profiles occurred in all groups. Metabolic syndrome was resolved in 64%. One year later, weight loss (-9.1 ± 2.3 kg, P = .0001) and arterial pressure decrease (-18.5 ± 2.3/-12.3 ± 2.1 mm Hg, P = .0001) were maintained. Practical, health-centered diet combined with high-intensity exercise is associated with enhanced vascular protection. These data suggest that more intense exercise combined with a low-sugar diet modulates endothelium-dependent vasodilation.

  20. Primitive control of cellular metabolism

    NASA Technical Reports Server (NTRS)

    Mitz, M. A.

    1974-01-01

    It is pointed out that control substances must have existed from the earliest times in the evolution of life and that the same control mechanisms must exist today. The investigation reported is concerned with the concept that carbon dioxide is a primitive regulator of cell function. The effects of carbon dioxide on cellular materials are examined, taking into account questions of solubilization, dissociation, changes of charge, stabilization, structural changes, wettability, the exclusion of other gases, the activation of compounds, changes in plasticity, and changes in membrane permeability.

  1. Cellular Metabolic and Autophagic Pathways: Traffic Control by Redox Signaling

    PubMed Central

    Dodson, Matthew; Darley-Usmar, Victor; Zhang, Jianhua

    2013-01-01

    It has been established that the key metabolic pathways of glycolysis and oxidative phosphorylation are intimately related to redox biology through control of cell signaling. Under physiological conditions glucose metabolism is linked to control of the NADH/NAD redox couple, as well as providing the major reductant, NADPH, for thiol-dependent antioxidant defenses. Retrograde signaling from the mitochondrion to the nucleus or cytosol controls cell growth and differentiation. Under pathological conditions mitochondria are targets for reactive oxygen and nitrogen species and are critical in controlling apoptotic cell death. At the interface of these metabolic pathways, the autophagy-lysosomal pathway functions to maintain mitochondrial quality, and generally serves an important cytoprotective function. In this review we will discuss the autophagic response to reactive oxygen and nitrogen species that are generated from perturbations of cellular glucose metabolism and bioenergetic function. PMID:23702245

  2. Cellular metabolic and autophagic pathways: traffic control by redox signaling.

    PubMed

    Dodson, Matthew; Darley-Usmar, Victor; Zhang, Jianhua

    2013-10-01

    It has been established that the key metabolic pathways of glycolysis and oxidative phosphorylation are intimately related to redox biology through control of cell signaling. Under physiological conditions glucose metabolism is linked to control of the NADH/NAD redox couple, as well as providing the major reductant, NADPH, for thiol-dependent antioxidant defenses. Retrograde signaling from the mitochondrion to the nucleus or cytosol controls cell growth and differentiation. Under pathological conditions mitochondria are targets for reactive oxygen and nitrogen species and are critical in controlling apoptotic cell death. At the interface of these metabolic pathways, the autophagy-lysosomal pathway functions to maintain mitochondrial quality and generally serves an important cytoprotective function. In this review we will discuss the autophagic response to reactive oxygen and nitrogen species that are generated from perturbations of cellular glucose metabolism and bioenergetic function.

  3. Circadian control of glucose metabolism.

    PubMed

    Kalsbeek, Andries; la Fleur, Susanne; Fliers, Eric

    2014-07-01

    The incidence of obesity and type 2 diabetes mellitus (T2DM) has risen to epidemic proportions. The pathophysiology of T2DM is complex and involves insulin resistance, pancreatic β-cell dysfunction and visceral adiposity. It has been known for decades that a disruption of biological rhythms (which happens the most profoundly with shift work) increases the risk of developing obesity and T2DM. Recent evidence from basal studies has further sparked interest in the involvement of daily rhythms (and their disruption) in the development of obesity and T2DM. Most living organisms have molecular clocks in almost every tissue, which govern rhythmicity in many domains of physiology, such as rest/activity rhythms, feeding/fasting rhythms, and hormonal secretion. Here we present the latest research describing the specific role played by the molecular clock mechanism in the control of glucose metabolism and speculate on how disruption of these tissue clocks may lead to the disturbances in glucose homeostasis.

  4. Undercover: gene control by metabolites and metabolic enzymes

    PubMed Central

    van der Knaap, Jan A.; Verrijzer, C. Peter

    2016-01-01

    To make the appropriate developmental decisions or maintain homeostasis, cells and organisms must coordinate the expression of their genome and metabolic state. However, the molecular mechanisms that relay environmental cues such as nutrient availability to the appropriate gene expression response remain poorly understood. There is a growing awareness that central components of intermediary metabolism are cofactors or cosubstrates of chromatin-modifying enzymes. As such, their concentrations constitute a potential regulatory interface between the metabolic and chromatin states. In addition, there is increasing evidence for a direct involvement of classic metabolic enzymes in gene expression control. These dual-function proteins may provide a direct link between metabolic programing and the control of gene expression. Here, we discuss our current understanding of the molecular mechanisms connecting metabolism to gene expression and their implications for development and disease. PMID:27881599

  5. Metabolic function of the CTRP family of hormones

    PubMed Central

    Seldin, Marcus M.; Tan, Stefanie Y.; Wong, G. William

    2013-01-01

    Maintaining proper energy balance in mammals entails intimate crosstalk between various tissues and organs. These inter-organ communications are mediated, to a great extent, by secreted hormones that circulate in blood. Regulation of the complex metabolic networks by secreted hormones (e.g., insulin, glucagon, leptin, adiponectin, FGF21) constitutes an important mechanism governing the integrated control of whole-body metabolism. Disruption of hormone-mediated metabolic circuits frequently results in dysregulated energy metabolism and pathology. As part of an effort to identify novel metabolic hormones, we recently characterized a highly conserved family of fifteen secreted proteins, the C1q/TNF-related proteins (CTRP1–15). While related to adiponectin in sequence and structural organization, each CTRP has its own unique tissue expression profile and non-redundant function in regulating sugar and/or fat metabolism. Here, we summarize the current understanding of the physiological functions of CTRPs, emphasizing their metabolic roles. Future studies using gain-of-function and loss-of-function mouse models will provide greater mechanistic insights into the critical role CTRPs play in regulating systemic energy homeostasis. PMID:23963681

  6. Drug target identification in sphingolipid metabolism by computational systems biology tools: metabolic control analysis and metabolic pathway analysis.

    PubMed

    Ozbayraktar, F Betül Kavun; Ulgen, Kutlu O

    2010-08-01

    Sphingolipids regulate cellular processes that are critically important in cell's fate and function in cancer development and progression. This fact underlies the basics of the novel cancer therapy approach. The pharmacological manipulation of the sphingolipid metabolism in cancer therapeutics necessitates the detailed understanding of the pathway. Two computational systems biology tools are used to identify potential drug target enzymes among sphingolipid pathway that can be further utilized in drug design studies for cancer therapy. The enzymes in sphingolipid pathway were ranked according to their roles in controlling the metabolic network by metabolic control analysis. The physiologically connected reactions, i.e. biologically significant and functional modules of network, were identified by metabolic pathway analysis. The final set of candidate drug target enzymes are selected such that their manipulation leads to ceramide accumulation and long chain base phosphates depletion. The mathematical tools' efficiency for drug target identification performed in this study is validated by clinically available drugs.

  7. Control of fluxes in metabolic networks

    PubMed Central

    Basler, Georg; Nikoloski, Zoran; Larhlimi, Abdelhalim; Barabási, Albert-László; Liu, Yang-Yu

    2016-01-01

    Understanding the control of large-scale metabolic networks is central to biology and medicine. However, existing approaches either require specifying a cellular objective or can only be used for small networks. We introduce new coupling types describing the relations between reaction activities, and develop an efficient computational framework, which does not require any cellular objective for systematic studies of large-scale metabolism. We identify the driver reactions facilitating control of 23 metabolic networks from all kingdoms of life. We find that unicellular organisms require a smaller degree of control than multicellular organisms. Driver reactions are under complex cellular regulation in Escherichia coli, indicating their preeminent role in facilitating cellular control. In human cancer cells, driver reactions play pivotal roles in malignancy and represent potential therapeutic targets. The developed framework helps us gain insights into regulatory principles of diseases and facilitates design of engineering strategies at the interface of gene regulation, signaling, and metabolism. PMID:27197218

  8. Control of fluxes in metabolic networks.

    PubMed

    Basler, Georg; Nikoloski, Zoran; Larhlimi, Abdelhalim; Barabási, Albert-László; Liu, Yang-Yu

    2016-07-01

    Understanding the control of large-scale metabolic networks is central to biology and medicine. However, existing approaches either require specifying a cellular objective or can only be used for small networks. We introduce new coupling types describing the relations between reaction activities, and develop an efficient computational framework, which does not require any cellular objective for systematic studies of large-scale metabolism. We identify the driver reactions facilitating control of 23 metabolic networks from all kingdoms of life. We find that unicellular organisms require a smaller degree of control than multicellular organisms. Driver reactions are under complex cellular regulation in Escherichia coli, indicating their preeminent role in facilitating cellular control. In human cancer cells, driver reactions play pivotal roles in malignancy and represent potential therapeutic targets. The developed framework helps us gain insights into regulatory principles of diseases and facilitates design of engineering strategies at the interface of gene regulation, signaling, and metabolism.

  9. Functions for diverse metabolic activities in heterochromatin

    PubMed Central

    Su, Xue Bessie; Pillus, Lorraine

    2016-01-01

    Growing evidence demonstrates that metabolism and chromatin dynamics are not separate processes but that they functionally intersect in many ways. For example, the lysine biosynthetic enzyme homocitrate synthase was recently shown to have unexpected functions in DNA damage repair, raising the question of whether other amino acid metabolic enzymes participate in chromatin regulation. Using an in silico screen combined with reporter assays, we discovered that a diverse range of metabolic enzymes function in heterochromatin regulation. Extended analysis of the glutamate dehydrogenase 1 (Gdh1) revealed that it regulates silent information regulator complex recruitment to telomeres and ribosomal DNA. Enhanced N-terminal histone H3 proteolysis is observed in GDH1 mutants, consistent with telomeric silencing defects. A conserved catalytic Asp residue is required for Gdh1’s functions in telomeric silencing and H3 clipping. Genetic modulation of α-ketoglutarate levels demonstrates a key regulatory role for this metabolite in telomeric silencing. The metabolic activity of glutamate dehydrogenase thus has important and previously unsuspected roles in regulating chromatin-related processes. PMID:26936955

  10. Metabolic hormones in saliva: origins and functions

    PubMed Central

    Zolotukhin, S.

    2012-01-01

    The salivary proteome consists of thousands of proteins, which include, among others, hormonal modulators of energy intake and output. Although the functions of this prominent category of hormones in whole body energy metabolism are well characterized, their functions in the oral cavity, whether as a salivary component, or when expressed in taste cells, are less studied and poorly understood. The respective receptors for the majority of salivary metabolic hormones have been also shown to be expressed in salivary glands, taste cells, or other cells in the oral mucosa. This review provides a comprehensive account of the gastrointestinal hormones, adipokines, and neuropeptides identified in saliva, salivary glands, or lingual epithelium, as well as their respective cognate receptors expressed in the oral cavity. Surprisingly, few functions are assigned to salivary metabolic hormones, and these functions are mostly associated with the modulation of taste perception. Because of the well-characterized correlation between impaired oral nutrient sensing and increased energy intake and body mass index, a conceptually provocative point of view is introduced, whereupon it is argued that targeted changes in the composition of saliva could affect whole body metabolism in response to the activation of cognate receptors expressed locally in the oral mucosa. PMID:22994880

  11. Functions for diverse metabolic activities in heterochromatin.

    PubMed

    Su, Xue Bessie; Pillus, Lorraine

    2016-03-15

    Growing evidence demonstrates that metabolism and chromatin dynamics are not separate processes but that they functionally intersect in many ways. For example, the lysine biosynthetic enzyme homocitrate synthase was recently shown to have unexpected functions in DNA damage repair, raising the question of whether other amino acid metabolic enzymes participate in chromatin regulation. Using an in silico screen combined with reporter assays, we discovered that a diverse range of metabolic enzymes function in heterochromatin regulation. Extended analysis of the glutamate dehydrogenase 1 (Gdh1) revealed that it regulates silent information regulator complex recruitment to telomeres and ribosomal DNA. Enhanced N-terminal histone H3 proteolysis is observed in GDH1 mutants, consistent with telomeric silencing defects. A conserved catalytic Asp residue is required for Gdh1's functions in telomeric silencing and H3 clipping. Genetic modulation of α-ketoglutarate levels demonstrates a key regulatory role for this metabolite in telomeric silencing. The metabolic activity of glutamate dehydrogenase thus has important and previously unsuspected roles in regulating chromatin-related processes.

  12. A Randomized Controlled Trial Comparing the Effects of Sitagliptin and Glimepiride on Endothelial Function and Metabolic Parameters: Sapporo Athero-Incretin Study 1 (SAIS1)

    PubMed Central

    Nomoto, Hiroshi; Miyoshi, Hideaki; Furumoto, Tomoo; Oba, Koji; Tsutsui, Hiroyuki; Inoue, Atsushi; Atsumi, Tatsuya; Manda, Naoki; Kurihara, Yoshio; Aoki, Shin

    2016-01-01

    Objectives The DPP-4 inhibitors are incretin-related drugs that improve hyperglycemia in a glucose-dependent manner and have been reported to exert favorable effects on atherosclerosis. However, it has not been fully elucidated whether DPP-4 inhibitors are able to improve endothelial function in patients with type 2 diabetes. Therefore, we investigated the efficacy of sitagliptin, a DPP-4 inhibitor, on endothelial function and glycemic metabolism compared with that of the sulfonylurea glimepiride. Materials and Methods In this multicenter, prospective, randomized parallel-group comparison study, 103 outpatients with type 2 diabetes (aged 59.9 ± 9.9 years with HbA1c levels of 7.5 ± 0.4%) with dietary cure only and/or current metformin treatment were enrolled and randomly assigned to receive sitagliptin or glimepiride therapy once daily for 26 weeks. Flow-mediated dilation (FMD), a comprehensive panel of hemodynamic parameters (Task Force® Monitor), and serum metabolic markers were assessed before and after the treatment. Results During the study period, no statistically significant change in %FMD was seen in both groups (sitagliptin, 5.6 to 5.6%; glimepiride, 5.6 to 6.0%). Secretory units of islets in transplantation, TNF-α, adiponectin and biological antioxidant potential significantly improved in the sitagliptin group, and superoxide dismutase also tended to improve in the sitagliptin group, while improvements in HbA1c levels were similar between groups. Cardiac index, blood pressure and most other metabolic parameters were not different. Conclusions Regardless of glycemic improvement, early sitagliptin therapy did not affect endothelial function but may provide favorable effects on beta-cell function and on inflammatory and oxidative stress in patients with type 2 diabetes without advanced atherosclerosis. Trial Registration UMIN Clinical Trials Registry System UMIN 000004955 PMID:27711199

  13. Amino acids: metabolism, functions, and nutrition.

    PubMed

    Wu, Guoyao

    2009-05-01

    Recent years have witnessed the discovery that amino acids (AA) are not only cell signaling molecules but are also regulators of gene expression and the protein phosphorylation cascade. Additionally, AA are key precursors for syntheses of hormones and low-molecular weight nitrogenous substances with each having enormous biological importance. Physiological concentrations of AA and their metabolites (e.g., nitric oxide, polyamines, glutathione, taurine, thyroid hormones, and serotonin) are required for the functions. However, elevated levels of AA and their products (e.g., ammonia, homocysteine, and asymmetric dimethylarginine) are pathogenic factors for neurological disorders, oxidative stress, and cardiovascular disease. Thus, an optimal balance among AA in the diet and circulation is crucial for whole body homeostasis. There is growing recognition that besides their role as building blocks of proteins and polypeptides, some AA regulate key metabolic pathways that are necessary for maintenance, growth, reproduction, and immunity. They are called functional AA, which include arginine, cysteine, glutamine, leucine, proline, and tryptophan. Dietary supplementation with one or a mixture of these AA may be beneficial for (1) ameliorating health problems at various stages of the life cycle (e.g., fetal growth restriction, neonatal morbidity and mortality, weaning-associated intestinal dysfunction and wasting syndrome, obesity, diabetes, cardiovascular disease, the metabolic syndrome, and infertility); (2) optimizing efficiency of metabolic transformations to enhance muscle growth, milk production, egg and meat quality and athletic performance, while preventing excess fat deposition and reducing adiposity. Thus, AA have important functions in both nutrition and health.

  14. [Metabolic control of seed germination].

    PubMed

    Catusse, Julie; Strub, Jean-Marc; Job, Claudette; Van Dorsselaer, Alain; Job, Dominique

    2008-01-01

    We have used proteomics to better characterize germination and early seedling vigor in sugarbeet. Our strategy includes (1) construction of proteome reference maps for dry and germinating seeds of a high-vigor reference seed lot; (2) investigation of the specific tissue accumulation of proteins (root, cotyledon, perisperm); (3) investigation of changes in protein expression profiles detected in the reference seed lot subjected to different vigor-modifying treatments, e.g. aging and/or priming. More than 1 000 sugarbeet seed proteins have been identified by LC/MS-MS mass spectrometry (albumins, globulins and glutelins have been analyzed separately). Due to the conservation of protein sequences and the quality of MS sequencing (more than 10 000 peptide sequences have been obtained), the success rate of protein identification was on the average of 80%. This is to our knowledge the best detailed proteome analysis ever carried out in seeds. The data allowed us to build a detailed metabolic chart of the sugarbeet seed, generating new insights into the molecular mechanisms determining the development of a new seedling. Also, the proteome of a seed-storage tissue as the perisperm is described for the first time.

  15. Drug-metabolizing enzymes: mechanisms and functions.

    PubMed

    Sheweita, S A

    2000-09-01

    Drug-metabolizing enzymes are called mixed-function oxidase or monooxygenase and containing many enzymes including cytochrome P450, cytochrome b5, and NADPH-cytochrome P450 reductase and other components. The hepatic cytochrome P450s (Cyp) are a multigene family of enzymes that play a critical role in the metabolism of many drugs and xenobiotics with each cytochrome isozyme responding differently to exogenous chemicals in terms of its induction and inhibition. For example, Cyp 1A1 is particularly active towards polycyclic aromatic hydrocarbons (PAHs), activating them into reactive intermediates those covalently bind to DNA, a key event in the initiation of carcinogenesis. Likewise, Cyp 1A2 activates a variety of bladder carcinogens, such as aromatic amines and amides. Also, some forms of cytochrome P450 isozymes such as Cyp 3A and 2E1 activate the naturally occurring carcinogens (e.g. aflatoxin B1) and N-nitrosamines respectively into highly mutagenic and carcinogenic agents. The carcinogenic potency of PAHs, and other carcinogens and the extent of binding of their ultimate metabolites to DNA and proteins are correlated with the induction of cytochrome P450 isozymes. Phase II drug-metabolizing enzymes such as glutathione S-transferase, aryl sulfatase and UDP-glucuronyl transferase inactivate chemical carcinogens into less toxic or inactive metabolites. Many drugs change the rate of activation or detoxification of carcinogens by changing the activities of phases I and II drug-metabolizing enzymes. The balance of detoxification and activation reactions depends on the chemical structure of the agents, and is subjected to many variables that are a function of this structure, or genetic background, sex, endocrine status, age, diet, and the presence of other chemicals. It is important to realize that the enzymes involved in carcinogen metabolism are also involved in the metabolism of a variety of substrates, and thus the introduction of specific xenobiotics may change

  16. Effect of one year continuous subcutaneous infusion of a somatostatin analogue, octreotide, on early retinopathy, metabolic control and thyroid function in Type I (insulin-dependent) diabetes mellitus.

    PubMed

    Kirkegaard, C; Nørgaard, K; Snorgaard, O; Bek, T; Larsen, M; Lund-Andersen, H

    1990-06-01

    Growth hormone is assumed to be involved in the development of diabetic retinopathy. In a randomized study we evaluated the possible effects of one year treatment with a somatostatin (SRIH) analogue, octreotide, on early retinopathy and on metabolism in Type I (insulin-dependent) diabetes mellitus. Eleven patients were allocated to treatment with a continuous sc infusion of 400 micrograms octreotide per day and 9 served as controls. Only 7 patients from each group completed the study. Three octreotide-treated patients left the study owing to severe diarrhea. The subjects were evaluated at entry, after 2, 6 and 12 months treatment, and 2 months after withdrawal. Octreotide induced a decrease in GH secretion, expressed as the area under the 24 h serum GH profiles (p less than 0.05), and of the serum levels of IGF-I (p less than 0.05). The entire decline in GH levels occurred during the daytime, whereas the nocturnal levels were unaffected. Retinopathy, as assessed by determination of the blood retina barrier permeability, by colour fundus photography, and flurescein angiography was unchanged in both groups. Apart from a decline in insulin requirements, octreotide had no major effect on glycemic control, but induced a mild transient pituitary hypothyroidism, not clinically relevant. We conclude that treatment with octreotide for one year has modest effects on GH, IGF-I, and glucose metabolism, but has no significant effect on early retinopathy in Type I (insulin-dependent) diabetes.

  17. Microtubule Control of Metabolism in Prostate Cancer

    DTIC Science & Technology

    2013-06-01

    Prostate Cancer PRINCIPAL INVESTIGATOR: Lynne Cassimeris CONTRACTING ORGANIZATION...Microtubule Control of Metabolism in Prostate Cancer 5b. GRANT NUMBER W81XWH-12-1-0071 5c. PROGRAM ELEMENT NUMBER 6. AUTHOR(S) 5d. PROJECT...SUPPLEMENTARY NOTES 14. ABSTRACT The current standard chemotherapy treatment for metastatic castrate-resistant prostate cancer is the microtubule

  18. Functional Analysis of the N-Acetylglucosamine Metabolic Genes of Streptomyces coelicolor and Role in Control of Development and Antibiotic Production

    PubMed Central

    Świątek, Magdalena A.; Tenconi, Elodie; Rigali, Sébastien

    2012-01-01

    N-Acetylglucosamine, the monomer of chitin, is a favored carbon and nitrogen source for streptomycetes. Its intracellular catabolism requires the combined actions of the N-acetylglucosamine-6-phosphate (GlcNAc-6P) deacetylase NagA and the glucosamine-6-phosphate (GlcN-6P) deaminase/isomerase NagB. GlcNAc acts as a signaling molecule in the DasR-mediated nutrient sensing system, activating development and antibiotic production under poor growth conditions (famine) and blocking these processes under rich conditions (feast). In order to understand how a single nutrient can deliver opposite information according to the nutritional context, we carried out a mutational analysis of the nag metabolic genes nagA, nagB, and nagK. Here we show that the nag genes are part of the DasR regulon in Streptomyces coelicolor, which explains their transcriptional induction by GlcNAc. Most likely as the result of the intracellular accumulation of GlcN-6P, nagB deletion mutants fail to grow in the presence of GlcNAc. This toxicity can be alleviated by the additional deletion of nagA. We recently showed that in S. coelicolor, GlcNAc is internalized as GlcNAc-6P via the phosphoenolpyruvate-dependent sugar phosphotransferase system (PTS). Considering the relevance of GlcNAc for the control of antibiotic production, improved insight into GlcNAc metabolism in Streptomyces may provide new leads toward biotechnological applications. PMID:22194457

  19. Cutting Edge: Murine Mast Cells Rapidly Modulate Metabolic Pathways Essential for Distinct Effector Functions.

    PubMed

    Phong, Binh; Avery, Lyndsay; Menk, Ashley V; Delgoffe, Greg M; Kane, Lawrence P

    2017-01-15

    There is growing appreciation that cellular metabolic and bioenergetic pathways do not play merely passive roles in activated leukocytes. Rather, metabolism has important roles in controlling cellular activation, differentiation, survival, and effector function. Much of this work has been performed in T cells; however, there is still very little information regarding mast cell metabolic reprogramming and its effect on cellular function. Mast cells perform important barrier functions and help control type 2 immune responses. In this study we show that murine bone marrow-derived mast cells rapidly alter their metabolism in response to stimulation through the FcεRI. We also demonstrate that specific metabolic pathways appear to be differentially required for the control of mast cell function. Manipulation of metabolic pathways may represent a novel point for the manipulation of mast cell activation.

  20. Metabolic Functions of the Lung, Disorders and Associated Pathologies

    PubMed Central

    Alvarado, Alcibey; Arce, Isabel

    2016-01-01

    The primary function of the lungs is gas exchange. Approximately 400 million years ago, the Earth’s atmosphere gained enough oxygen in the gas phase for the animals that emerged from the sea to breathe air. The first lungs were merely primitive air sacs with a few vessels in the walls that served as accessory organs of gas exchange to supplement the gills. Eons later, as animals grew accustomed to a solely terrestrial life, the lungs became highly compartmentalized to provide the vast air-blood surface necessary for O2 uptake and CO2 elimination, and a respiratory control system was developed to regulate breathing in accordance with metabolic demands and other needs. With the evolution and phylogenetic development, lungs were taking a variety of other specialized functions to maintain homeostasis, which we will call the non-respiratory functions of the lung and that often, and by mistake, are believed to have little or no connection with the replacement gas. In this review, we focus on the metabolic functions of the lung, perhaps the least known, and mainly, in the lipid metabolism and blood-adult lung vascular endothelium interaction. When these functions are altered, respiratory disorders or diseases appear, which are discussed concisely, emphasizing how they impact the most important function of the lungs: external respiration. PMID:27635172

  1. Metabolic Functions of the Lung, Disorders and Associated Pathologies.

    PubMed

    Alvarado, Alcibey; Arce, Isabel

    2016-10-01

    The primary function of the lungs is gas exchange. Approximately 400 million years ago, the Earth's atmosphere gained enough oxygen in the gas phase for the animals that emerged from the sea to breathe air. The first lungs were merely primitive air sacs with a few vessels in the walls that served as accessory organs of gas exchange to supplement the gills. Eons later, as animals grew accustomed to a solely terrestrial life, the lungs became highly compartmentalized to provide the vast air-blood surface necessary for O2 uptake and CO2 elimination, and a respiratory control system was developed to regulate breathing in accordance with metabolic demands and other needs. With the evolution and phylogenetic development, lungs were taking a variety of other specialized functions to maintain homeostasis, which we will call the non-respiratory functions of the lung and that often, and by mistake, are believed to have little or no connection with the replacement gas. In this review, we focus on the metabolic functions of the lung, perhaps the least known, and mainly, in the lipid metabolism and blood-adult lung vascular endothelium interaction. When these functions are altered, respiratory disorders or diseases appear, which are discussed concisely, emphasizing how they impact the most important function of the lungs: external respiration.

  2. Metabolism and functions of copper in brain.

    PubMed

    Scheiber, Ivo F; Mercer, Julian F B; Dringen, Ralf

    2014-05-01

    Copper is an important trace element that is required for essential enzymes. However, due to its redox activity, copper can also lead to the generation of toxic reactive oxygen species. Therefore, cellular uptake, storage as well as export of copper have to be tightly regulated in order to guarantee sufficient copper supply for the synthesis of copper-containing enzymes but also to prevent copper-induced oxidative stress. In brain, copper is of importance for normal development. In addition, both copper deficiency as well as excess of copper can seriously affect brain functions. Therefore, this organ possesses ample mechanisms to regulate its copper metabolism. In brain, astrocytes are considered as important regulators of copper homeostasis. Impairments of homeostatic mechanisms in brain copper metabolism have been associated with neurodegeneration in human disorders such as Menkes disease, Wilson's disease and Alzheimer's disease. This review article will summarize the biological functions of copper in the brain and will describe the current knowledge on the mechanisms involved in copper transport, storage and export of brain cells. The role of copper in diseases that have been connected with disturbances in brain copper homeostasis will also be discussed.

  3. Control of lipid metabolism by Tachykinin in Drosophila

    PubMed Central

    Song, Wei; Veenstra, Jan A.; Perrimon, Norbert

    2015-01-01

    Summary The intestine is a key organ for lipid uptake and distribution, and abnormal intestinal lipid metabolism is associated with obesity and hyperlipidemia. Although multiple regulatory gut hormones secreted from enteroendocrine cells (EEs) regulate systemic lipid homeostasis, such as appetite control and energy balance in adipose tissue, their respective roles regarding lipid metabolism in the intestine are not well understood. We demonstrate that Tachykinins (TKs), one of the most abundant secreted peptides expressed in midgut EEs, regulate intestinal lipid production and subsequently control systemic lipid homeostasis in Drosophila, and that TKs repress lipogenesis in enterocytes (ECs) associated with the TKR99D receptor and PKA signaling. Interestingly, nutrient deprivation enhances the production of TKs in the midgut. Finally, unlike the physiological roles of TKs produced from the brain, gut-derived TKs do not affect behavior, thus demonstrating that gut TK hormones specifically regulate intestinal lipid metabolism without affecting neuronal functions. PMID:25263556

  4. Irisin levels in relation to metabolic and liver functions in Egyptian patients with metabolic syndrome.

    PubMed

    Rizk, Fatma H; Elshweikh, Samah A; Abd El-Naby, Amira Y

    2016-04-01

    Irisin is a new myokine that is suspected to influence metabolic syndrome (MetS). However, there is a great controversy with respect to its level in cases of MetS and its correlation with different metabolic parameters. The present study assesses irisin levels in MetS patients and studies its relationship to metabolic and liver functions to evaluate the possible role of the liver in regulation of this level. Sixty subjects were included in this experiment, who were divided into 3 groups: group I (normal control), group II (MetS patients with normal liver enzymes), and group III (MetS with elevated liver enzymes and fatty liver disease). Serum irisin levels showed significant increases in groups II and III compared with group I, and significant increases in group III compared with group II. Also, irisin levels were positively correlated with body mass index, serum triglycerides, homeostatic model assessment of insulin resistance index (HOMA-IR), and liver enzymes. We concluded that serum irisin levels increased in patients with MetS, especially those with elevated liver enzymes, and had a positive correlation with parameters of lipid metabolism and glucose homeostasis with the possibility of hepatic clearance to irisin.

  5. β-cell function is associated with metabolic syndrome in Mexican subjects

    PubMed Central

    Baez-Duarte, Blanca G; Sánchez-Guillén, María Del Carmen; Pérez-Fuentes, Ricardo; Zamora-Ginez, Irma; Leon-Chavez, Bertha Alicia; Revilla-Monsalve, Cristina; Islas-Andrade, Sergio

    2010-01-01

    Aims The clinical diagnosis of metabolic syndrome does not find any parameters to evaluate the insulin sensitivity (IS) or β-cell function. The evaluation of these parameters would detect early risk of developing metabolic syndrome. The aim of this study is to determine the relationship between β-cell function and presence of metabolic syndrome in Mexican subjects. Material and methods This study is part of the Mexican Survey on the Prevention of Diabetes (MexDiab Study) with headquarters in the city of Puebla, Mexico. The study comprised of 444 subjects of both genders, aged between 18 and 60 years and allocated into two study groups: (1) control group of individuals at metabolic balance without metabolic syndrome and (2) group composed of subjects with metabolic syndrome and diagnosed according to the criteria of the Third Report of the National Cholesterol Education Program Expert Panel on Defection, Evaluation, and Treatment of High Blood Cholesterol in Adults. Anthropometric, biochemical, and clinical assessments were carried out. Results Average age of the subjects in the control group (n = 254) was 35.7 ± 11.5 years and 42.0 ± 10.7 years for subjects in the metabolic syndrome group (n = 190). Subjects at metabolic balance without metabolic syndrome showed decreased IS, increased insulin resistance (IR), and altered β-cell function. Individuals with metabolic syndrome showed a high prevalence (P ≤ 0.05) of family history of type 2 diabetes (T2D). This group also showed a significant metabolic imbalance with glucose and insulin levels and lipid profile outside the ranges considered safe to prevent the development of cardiovascular disease and T2D. Conclusion The main finding in this study was the detection of altered β-cell function, decreased IS, an increased IR in subjects at metabolic balance, and the progressive deterioration of β-cell function and IS in subjects with metabolic syndrome as the number of features of metabolic syndrome increases

  6. Role and function of short chain fatty acids in rumen epithelial metabolism, development and importance of the rumen epithelium in understanding control of transcriptome

    Technology Transfer Automated Retrieval System (TEKTRAN)

    The epithelial lining of the rumen is uniquely placed to have impact on the nutrient metabolism of the animal. The symbiotic relationship with the microbial populations that inhabit the rumen, serves to provide a constant supply of nutrients from roughage that would otherwise be unusable. Metaboli...

  7. Control of immune response by amino acid metabolism.

    PubMed

    Grohmann, Ursula; Bronte, Vincenzo

    2010-07-01

    The interaction between pathogenic microorganisms and their hosts is regulated by reciprocal survival strategies, including competition for essential nutrients. Though paradoxical, mammalian hosts have learned to take advantage of amino acid catabolism for controlling pathogen invasion and, at the same time, regulating their own immune responses. In this way, ancient catabolic enzymes have acquired novel functions and evolved into new structures with highly specialized functions, which go beyond the struggle for survival. In this review, we analyze the evidence supporting a critical role for the metabolism of various amino acids in regulating different steps of both innate and adaptive immunity.

  8. Metabolic control analysis of eucaryotic pyruvate dehydrogenase multienzyme complex.

    PubMed

    Modak, Jayant; Deckwer, Wolf-Dieter; Zeng, An-Ping

    2002-01-01

    Metabolic control analysis (MCA) of pyruvate dehydrogenase multienzyme (PDH) complex of eucaryotic cells has been carried out using both in vitro and in vivo mechanistic models. Flux control coefficients (FCC) for the sensitivity of pyruvate decarboxylation rate to activities of various PDH complex reactions are determined. FCCs are shown to be strong functions of both pyruvate levels and various components of PDH complex. With the in vitro model, FCCs are shown to be sensitive to only the E1 component of the PDH complex at low pyruvate concentrations. At high pyruvate concentrations, the control is shared by all of the components, with E1 having a negative influence while the other three components, E2, X, and K, exert a positive control over the pyruvate decarboxylation rate. An unusual behavior of deactivation of the E1 component leading to higher net PDH activity is shown to be linked to the combined effect of protein X acylation and E1 deactivation. The steady-state analysis of the in vivo model reveals multiple steady state behavior of pyruvate metabolism with two stable and one unstable steady-states branches. FCCs also display multiplicity, showing completely different control distribution exerted by pyruvate and PDH components on three branches. At low pyruvate concentrations, pyruvate supply dominates the decarboxylation rate and PDH components do not exert any significant control. Reverse control distribution is observed at high pyruvate concentration. The effect of dilution due to cell growth on pyruvate metabolism is investigated in detail. While pyruvate dilution effects are shown to be negligible under all conditions, significant PDH complex dilution effects are observed under certain conditions. Comparison of in vitro and in vivo models shows that PDH components exert different degrees of control outside and inside the cells. At high pyruvate levels, PDH components are shown to exert a higher degree of control when reactions are taking place inside

  9. Sucrose metabolism gene families and their biological functions

    PubMed Central

    Jiang, Shu-Ye; Chi, Yun-Hua; Wang, Ji-Zhou; Zhou, Jun-Xia; Cheng, Yan-Song; Zhang, Bao-Lan; Ma, Ali; Vanitha, Jeevanandam; Ramachandran, Srinivasan

    2015-01-01

    Sucrose, as the main product of photosynthesis, plays crucial roles in plant development. Although studies on general metabolism pathway were well documented, less information is available on the genome-wide identification of these genes, their expansion and evolutionary history as well as their biological functions. We focused on four sucrose metabolism related gene families including sucrose synthase, sucrose phosphate synthase, sucrose phosphate phosphatase and UDP-glucose pyrophosphorylase. These gene families exhibited different expansion and evolutionary history as their host genomes experienced differentiated rates of the whole genome duplication, tandem and segmental duplication, or mobile element mediated gene gain and loss. They were evolutionarily conserved under purifying selection among species and expression divergence played important roles for gene survival after expansion. However, we have detected recent positive selection during intra-species divergence. Overexpression of 15 sorghum genes in Arabidopsis revealed their roles in biomass accumulation, flowering time control, seed germination and response to high salinity and sugar stresses. Our studies uncovered the molecular mechanisms of gene expansion and evolution and also provided new insight into the role of positive selection in intra-species divergence. Overexpression data revealed novel biological functions of these genes in flowering time control and seed germination under normal and stress conditions. PMID:26616172

  10. (Im)Perfect robustness and adaptation of metabolic networks subject to metabolic and gene-expression regulation: marrying control engineering with metabolic control analysis

    PubMed Central

    2013-01-01

    are being identified by genomics and systems biology, correspond to the ‘perfect’ regulatory structures designed by control engineering vis-à-vis optimal functions such as robustness. To the extent that they are not, the analyses suggest how they may become so and this in turn should facilitate synthetic biology and metabolic engineering. PMID:24261908

  11. Linking community size structure and ecosystem functioning using metabolic theory.

    PubMed

    Yvon-Durocher, Gabriel; Allen, Andrew P

    2012-11-05

    Understanding how biogeochemical cycles relate to the structure of ecological communities is a central research question in ecology. Here we approach this problem by focusing on body size, which is an easily measured species trait that has a pervasive influence on multiple aspects of community structure and ecosystem functioning. We test the predictions of a model derived from metabolic theory using data on ecosystem metabolism and community size structure. These data were collected as part of an aquatic mesocosm experiment that was designed to simulate future environmental warming. Our analyses demonstrate significant linkages between community size structure and ecosystem functioning, and the effects of warming on these links. Specifically, we show that carbon fluxes were significantly influenced by seasonal variation in temperature, and yielded activation energies remarkably similar to those predicted based on the temperature dependencies of individual-level photosynthesis and respiration. We also show that community size structure significantly influenced fluxes of ecosystem respiration and gross primary production, particularly at the annual time-scale. Assessing size structure and the factors that control it, both empirically and theoretically, therefore promises to aid in understanding links between individual organisms and biogeochemical cycles, and in predicting the responses of key ecosystem functions to future environmental change.

  12. Estrogen and Mitochondria Function in Cardiorenal Metabolic Syndrome

    PubMed Central

    Jia, Guanghong; Aroor, Annayya R.; Sowers, James R.

    2015-01-01

    The cardiorenal metabolic syndrome (CRS) consists of a constellation of cardiac, renal, and metabolic disorders including insulin resistance (IR), obesity, metabolic dyslipidemia, high-blood pressure, and evidence of early cardiac and renal disease. Mitochondria dysfunction often occurs in the CRS, and this dysfunction is promoted by excess reactive oxygen species, genetic factors, IR, aging, and altered mitochondrial biogenesis. Recently, it has been shown that there are important sex-related differences in mitochondria function and metabolic, cardiovascular, and renal components. Sex differences in the CRS have mainly been attributed to the estrogen’s effects that are mainly mediated by estrogen receptor (ER) α, ERβ, and G-protein coupled receptor 30. In this review, we discuss the effects of estrogen on the mitochondrial function, insulin metabolic signaling, glucose transport, lipid metabolism, and inflammatory responses from liver, pancreatic β cells, adipocytes, skeletal muscle, and cardiovascular tissue. PMID:25149220

  13. Fueling Immunity: Insights into Metabolism and Lymphocyte Function

    PubMed Central

    Pearce, Erika L.; Poffenberger, Maya C.; Chang, Chih-Hao; Jones, Russell G.

    2015-01-01

    Lymphocytes face major metabolic challenges upon activation. They must meet the bioenergetic and biosynthetic demands of increased cell proliferation and also adapt to changing environmental conditions, in which nutrients and oxygen may be limiting. An emerging theme in immunology is that metabolic reprogramming and lymphocyte activation are intricately linked. However, why T cells adopt specific metabolic programs and the impact that these programs have on T cell function and, ultimately, immunological outcome remain unclear. Research on tumor cell metabolism has provided valuable insight into metabolic pathways important for cell proliferation and the influence of metabolites themselves on signal transduction and epigenetic programming. In this Review, we highlight emerging concepts regarding metabolic reprogramming in proliferating cells and discuss their potential impact on T cell fate and function. PMID:24115444

  14. Calcitonin control of calcium metabolism during weightlessness

    NASA Technical Reports Server (NTRS)

    Soliman, Karam F. A.

    1993-01-01

    The main objective of this proposal is to elucidate calcitonin role in calcium homeostasis during weightlessness. In this investigation our objectives are to study: the effect of weightlessness on thyroid and serum calcitonin, the effect of weightlessness on the circadian variation of calcitonin in serum and the thyroid gland, the role of light as zeitgeber for calcitonin circadian rhythm, the circadian pattern of thyroid sensitivity to release calcitonin in response to calcium load, and the role of serotonin and norepinephrine in the control of calcitonin release. The main objective of this research/proposal is to establish the role of calcitonin in calcium metabolism during weightlessness condition. Understanding the mechanism of these abnormalities will help in developing therapeutic means to counter calcium imbalance in spaceflights.

  15. Exercising for metabolic control: is timing important?

    PubMed

    Haxhi, Jonida; Scotto di Palumbo, Alessandro; Sacchetti, Massimo

    2013-01-01

    Atherosclerosis-related cardiovascular disease and diabetes mellitus are leading causes of mortality in the world and both disorders are closely related to the postprandial phenomena. Regular exercise is being strongly advocated as a precious tool in easing the global burden of chronic disease. Although exercise intensity, duration and frequency are well established in current guidelines for healthy and diabetic individuals, there is still no consensus on the optimal timing of exercise in relation to the last meal. The present paper reviews the existing literature on the 'when?' of aerobic exercise for metabolic control in healthy and diabetic individuals. Effective control of postprandial phenomena might prove to be a useful tool in the prevention of chronic disease. Exercise appears to influence glycemic and triglyceridemic responses differently depending on the meal composition and time lapse from meals. In healthy individuals, fasted-state exercise favors postprandial triglyceridemic control and the insulin sensitivity related to it. However, there is a lack of data on this matter in diabetic patients. On the other hand, when postprandial glycemia is of concern, aerobic exercise works better when performed after a meal, both in healthy and in diabetic patients.

  16. Maternal metabolic stress may affect oviduct gatekeeper function.

    PubMed

    Jordaens, Lies; Van Hoeck, Veerle; Maillo, Veronica; Gutierrez-Adan, Alfonso; Marei, Waleed Fawzy A; Vlaeminck, Bruno; Thys, Sofie; Sturmey, Roger G S; Bols, Peter; Leroy, Jo

    2017-03-03

    We hypothesized that elevated non-esterified fatty acids (NEFA) modify in vitro bovine oviduct epithelial cell (BOEC) metabolism and barrier function. Hereto, BOECs were studied in a polarized system with 24h-treatments at day 9: 1) CONTROL (0µM NEFA + 0%EtOH), 2) SOLVENT CONTROL (0µM NEFA + 0.45%EtOH), 3) BASAL NEFA (720µM NEFA + 0.45%EtOH in the basal compartment), 4) APICAL NEFA (720µM NEFA + 0.45%EtOH in the apical compartment). FITC-albumin was used for monolayer permeability assessment, and related to Transepithelial Electric Resistance (TER). Fatty acid (FA), glucose, lactate and pyruvate concentrations were measured in spent medium. Intracellular lipid droplets (LD) and FA-uptake were studied using Bodipy 493/503 and immunolabelling of FA-transporters (FAT/CD36, FABP3 and caveolin1). BOEC-mRNA was retrieved for qRT-PCR. Results revealed that APICAL NEFA reduced relative TER-increase (46.85%) during treatment, and increased FITC-albumin flux (27.59%) compared to other treatments. In BASAL NEFA, FAs were transferred to the apical compartment as free FAs: mostly palmitic and oleic acid increased, respectively 56.0 % and 33.5% of initial FA-concentrations. APICAL NEFA allowed no FA-transfer, but induced LD-accumulation and upregulated FA-transporter expression (↑CD36, ↑FABP3, ↑CAV1-protein-expression). Gene expression in APICAL NEFA indicated increased anti-apoptotic (↑BCL2) and anti-oxidative (↑SOD1) capacity, upregulated lipid metabolism (↑CPT1, ↑ACSL1 and ↓ACACA), and FA-uptake (↑CAV1). All treatments had similar carbohydrate metabolism and oviduct function specific gene expression (=OVGP1, ESR1, FOXJ1). Overall, elevated NEFAs affected BOEC-metabolism and barrier function differently depending on NEFA-exposure side. Data substantiate the concept of the oviduct as a gatekeeper that may actively alter early embryonic developmental conditions.

  17. 2011 Plant Lipids: Structure, Metabolism, & Function Gordon Research Conference

    SciTech Connect

    Christopher Benning

    2011-02-04

    This is the second Gordon Research Conference on 'Plant Lipids: Structure, Metabolism & Function'. It covers current topics in lipid structure, metabolism and function in eukaryotic photosynthetic organisms including seed plants, algae, mosses and ferns. Work in photosynthetic bacteria is considered as well as it serves the understanding of specific aspects of lipid metabolism in plants. Breakthroughs are discussed in research on plant lipids as diverse as glycerolipids, sphingolipids, lipids of the cell surface, isoprenoids, fatty acids and their derivatives. The program covers nine concepts at the forefront of research under which afore mentioned plant lipid classes are discussed. The goal is to integrate areas such as lipid signaling, basic lipid metabolism, membrane function, lipid analysis, and lipid engineering to achieve a high level of stimulating interaction among diverse researchers with interests in plant lipids. One Emphasis is on the dynamics and regulation of lipid metabolism during plant cell development and in response to environmental factors.

  18. The central melanocortin system directly controls peripheral lipid metabolism

    PubMed Central

    Nogueiras, Ruben; Wiedmer, Petra; Perez-Tilve, Diego; Veyrat-Durebex, Christelle; Keogh, Julia M.; Sutton, Gregory M.; Pfluger, Paul T.; Castaneda, Tamara R.; Neschen, Susanne; Hofmann, Susanna M.; Howles, Philip N.; Morgan, Donald A.; Benoit, Stephen C.; Szanto, Ildiko; Schrott, Brigitte; Schürmann, Annette; Joost, Hans-Georg; Hammond, Craig; Hui, David Y.; Woods, Stephen C.; Rahmouni, Kamal; Butler, Andrew A.; Farooqi, I. Sadaf; O’Rahilly, Stephen; Rohner-Jeanrenaud, Françoise; Tschöp, Matthias H.

    2007-01-01

    Disruptions of the melanocortin signaling system have been linked to obesity. We investigated a possible role of the central nervous melanocortin system (CNS-Mcr) in the control of adiposity through effects on nutrient partitioning and cellular lipid metabolism independent of nutrient intake. We report that pharmacological inhibition of melanocortin receptors (Mcr) in rats and genetic disruption of Mc4r in mice directly and potently promoted lipid uptake, triglyceride synthesis, and fat accumulation in white adipose tissue (WAT), while increased CNS-Mcr signaling triggered lipid mobilization. These effects were independent of food intake and preceded changes in adiposity. In addition, decreased CNS-Mcr signaling promoted increased insulin sensitivity and glucose uptake in WAT while decreasing glucose utilization in muscle and brown adipose tissue. Such CNS control of peripheral nutrient partitioning depended on sympathetic nervous system function and was enhanced by synergistic effects on liver triglyceride synthesis. Our findings offer an explanation for enhanced adiposity resulting from decreased melanocortin signaling, even in the absence of hyperphagia, and are consistent with feeding-independent changes in substrate utilization as reflected by respiratory quotient, which is increased with chronic Mcr blockade in rodents and in humans with loss-of-function mutations in MC4R. We also reveal molecular underpinnings for direct control of the CNS-Mcr over lipid metabolism. These results suggest ways to design more efficient pharmacological methods for controlling adiposity. PMID:17885689

  19. Cell-selective metabolic labeling of biomolecules with bioorthogonal functionalities.

    PubMed

    Xie, Ran; Hong, Senlian; Chen, Xing

    2013-10-01

    Metabolic labeling of biomolecules with bioorthogonal functionalities enables visualization, enrichment, and analysis of the biomolecules of interest in their physiological environments. This versatile strategy has found utility in probing various classes of biomolecules in a broad range of biological processes. On the other hand, metabolic labeling is nonselective with respect to cell type, which imposes limitations for studies performed in complex biological systems. Herein, we review the recent methodological developments aiming to endow metabolic labeling strategies with cell-type selectivity. The cell-selective metabolic labeling strategies have emerged from protein and glycan labeling. We envision that these strategies can be readily extended to labeling of other classes of biomolecules.

  20. Regulatory functions of PPARbeta in metabolism: implications for the treatment of metabolic syndrome.

    PubMed

    Grimaldi, Paul A

    2007-08-01

    The prevalence of metabolic disturbances, collectively known as metabolic syndrome, has reached an epidemic proportion in industrialized countries. Lifestyle interventions and pharmacological treatments of such pathologies are only partially efficient and new therapeutic approaches are urgently needed. This review focuses on the recent findings describing the regulatory functions of peroxisome proliferator-activated receptor beta (PPARbeta) on lipid metabolism in several tissues and on the implications of such findings on the therapeutic usefulness of PPARbeta agonists in the treatment of particular features of the metabolic syndrome, such as insulin resistance, obesity, dyslipidemia and cardiac dysfunctions.

  1. Steviol glycosides: chemical diversity, metabolism, and function.

    PubMed

    Ceunen, Stijn; Geuns, Jan M C

    2013-06-28

    Steviol glycosides are a group of highly sweet diterpene glycosides discovered in only a few plant species, most notably the Paraguayan shrub Stevia rebaudiana. During the past few decades, the nutritional and pharmacological benefits of these secondary metabolites have become increasingly apparent. While these properties are now widely recognized, many aspects related to their in vivo biochemistry and metabolism and their relationship to the overall plant physiology of S. rebaudiana are not yet understood. Furthermore, the large size of the steviol glycoside pool commonly found within S. rebaudiana leaves implies a significant metabolic investment and poses questions regarding the benefits S. rebaudiana might gain from their accumulation. The current review intends to thoroughly discuss the available knowledge on these issues.

  2. Calcium metabolism and cardiovascular function after spaceflight

    NASA Technical Reports Server (NTRS)

    Hatton, Daniel C.; Yue, Qi; Dierickx, Jacqueline; Roullet, Chantal; Otsuka, Keiichi; Watanabe, Mitsuaki; Coste, Sarah; Roullet, Jean Baptiste; Phanouvang, Thongchan; Orwoll, Eric; Orwoll, Shiela; McCarron, David A.

    2002-01-01

    To determine the influence of dietary calcium on spaceflight-induced alterations in calcium metabolism and blood pressure (BP), 9-wk-old spontaneously hypertensive rats, fed either high- (2%) or low-calcium (0.02%) diets, were flown on an 18-day shuttle flight. On landing, flight animals had increased ionized calcium (P < 0.001), elevated parathyroid hormone levels (P < 0.001), reduced calcitonin levels (P < 0.05), unchanged 1,25(OH)(2)D(3) levels, and elevated skull (P < 0.01) and reduced femur bone mineral density. Basal and thrombin-stimulated platelet free calcium (intracellular calcium concentration) were also reduced (P < 0.05). There was a tendency for indirect systolic BP to be reduced in conscious flight animals (P = 0.057). However, mean arterial pressure was elevated (P < 0.001) after anesthesia. Dietary calcium altered all aspects of calcium metabolism (P < 0.001), as well as BP (P < 0.001), but the only interaction with flight was a relatively greater increase in ionized calcium in flight animals fed low- compared with high-calcium diets (P < 0.05). The results indicate that 1) flight-induced disruptions of calcium metabolism are relatively impervious to dietary calcium in the short term, 2) increased ionized calcium did not normalize low-calcium-induced elevations of BP, and 3) parathyroid hormone was paradoxically increased in the high-calcium-fed flight animals after landing.

  3. Optimal control of metabolic networks with saturable enzyme kinetics.

    PubMed

    Oyarzuun, D A

    2011-03-01

    This note addresses the optimal control of non-linear metabolic networks by means of time-dependent enzyme synthesis rates. The authors consider networks with general topologies described by a control-affine dynamical system coupled with a linear model for enzyme synthesis and degradation. The problem formulation accounts for transitions between two metabolic equilibria, which typically arise in metabolic adaptations to environmental changes, and the minimisation of a quadratic functional that weights the cost/benefit relation between the transcriptional effort required for enzyme synthesis and the transition to the new phenotype. Using a linear time-variant approximation of the non-linear dynamics, the problem is recast as a sequence of linear-quadratic problems, the solution of which involves a sequence of differential Lyapunov equations. The authors provide conditions for convergence to an approximate solution of the original problem, which are naturally satisfied by a wide class of models for saturable enzyme kinetics. As a case study the authors use the method to examine the robustness of an optimal just-in-time gene expression pattern with respect to heterogeneity in the biosynthetic costs of individual proteins.

  4. A cellular perspective on brain energy metabolism and functional imaging.

    PubMed

    Magistretti, Pierre J; Allaman, Igor

    2015-05-20

    The energy demands of the brain are high: they account for at least 20% of the body's energy consumption. Evolutionary studies indicate that the emergence of higher cognitive functions in humans is associated with an increased glucose utilization and expression of energy metabolism genes. Functional brain imaging techniques such as fMRI and PET, which are widely used in human neuroscience studies, detect signals that monitor energy delivery and use in register with neuronal activity. Recent technological advances in metabolic studies with cellular resolution have afforded decisive insights into the understanding of the cellular and molecular bases of the coupling between neuronal activity and energy metabolism and point at a key role of neuron-astrocyte metabolic interactions. This article reviews some of the most salient features emerging from recent studies and aims at providing an integration of brain energy metabolism across resolution scales.

  5. Physiology of leptin: energy homeostasis, neuroendocrine function and metabolism

    PubMed Central

    Park, Hyeong-Kyu; Ahima, Rexford S.

    2014-01-01

    Leptin is secreted by adipose tissue and regulates energy homeostasis, neuroendocrine function, metabolism, immune function and other systems through its effects on the central nervous system and peripheral tissues. Leptin administration has been shown to restore metabolic and neuroendocrine abnormalities in individuals with leptin-deficient states, including hypothalamic amenorrhea and lipoatrophy. In contrast, obese individuals are resistant to leptin. Recombinant leptin is beneficial in patients with congenital leptin deficiency or generalized lipodystrophy. However, further research on molecular mediators of leptin resistance is needed for the development of targeted leptin sensitizing therapies for obesity and related metabolic diseases. PMID:25199978

  6. Control of macrophage metabolism and activation by mTOR and Akt signaling

    PubMed Central

    Covarrubias, Anthony J.; Aksoylar, H. Ibrahim; Horng, Tiffany

    2015-01-01

    Macrophages are pleiotropic cells that assume a variety of functions depending on their tissue of residence and tissue state. They maintain homeostasis as well as coordinate responses to stresses such as infection and metabolic challenge. The ability of macrophages to acquire diverse, context-dependent activities requires their activation (or polarization) to distinct functional states. While macrophage activation is well understood at the level of signal transduction and transcriptional regulation, the metabolic underpinnings are poorly understood. Importantly, emerging studies indicate that metabolic shifts play a pivotal role in control of macrophage activation and acquisition of context-dependent effector activities. The signals that drive macrophage activation impinge on metabolic pathways, allowing for coordinate control of macrophage activation and metabolism. Here we discuss how mTOR and Akt, major metabolic regulators and targets of such activation signals, control macrophage metabolism and activation. Dysregulated macrophage activities contribute to many diseases, including infectious, inflammatory, and metabolic diseases and cancer, thus a better understanding of metabolic control of macrophage activation could pave the way to the development of new therapeutic strategies. PMID:26360589

  7. Control of macrophage metabolism and activation by mTOR and Akt signaling.

    PubMed

    Covarrubias, Anthony J; Aksoylar, H Ibrahim; Horng, Tiffany

    2015-08-01

    Macrophages are pleiotropic cells that assume a variety of functions depending on their tissue of residence and tissue state. They maintain homeostasis as well as coordinate responses to stresses such as infection and metabolic challenge. The ability of macrophages to acquire diverse, context-dependent activities requires their activation (or polarization) to distinct functional states. While macrophage activation is well understood at the level of signal transduction and transcriptional regulation, the metabolic underpinnings are poorly understood. Importantly, emerging studies indicate that metabolic shifts play a pivotal role in control of macrophage activation and acquisition of context-dependent effector activities. The signals that drive macrophage activation impinge on metabolic pathways, allowing for coordinate control of macrophage activation and metabolism. Here we discuss how mTOR and Akt, major metabolic regulators and targets of such activation signals, control macrophage metabolism and activation. Dysregulated macrophage activities contribute to many diseases, including infectious, inflammatory, and metabolic diseases and cancer, thus a better understanding of metabolic control of macrophage activation could pave the way to the development of new therapeutic strategies.

  8. Functional modules, structural topology, and optimal activity in metabolic networks.

    PubMed

    Resendis-Antonio, Osbaldo; Hernández, Magdalena; Mora, Yolanda; Encarnación, Sergio

    2012-01-01

    Modular organization in biological networks has been suggested as a natural mechanism by which a cell coordinates its metabolic strategies for evolving and responding to environmental perturbations. To understand how this occurs, there is a need for developing computational schemes that contribute to integration of genomic-scale information and assist investigators in formulating biological hypotheses in a quantitative and systematic fashion. In this work, we combined metabolome data and constraint-based modeling to elucidate the relationships among structural modules, functional organization, and the optimal metabolic phenotype of Rhizobium etli, a bacterium that fixes nitrogen in symbiosis with Phaseolus vulgaris. To experimentally characterize the metabolic phenotype of this microorganism, we obtained the metabolic profile of 220 metabolites at two physiological stages: under free-living conditions, and during nitrogen fixation with P. vulgaris. By integrating these data into a constraint-based model, we built a refined computational platform with the capability to survey the metabolic activity underlying nitrogen fixation in R. etli. Topological analysis of the metabolic reconstruction led us to identify modular structures with functional activities. Consistent with modular activity in metabolism, we found that most of the metabolites experimentally detected in each module simultaneously increased their relative abundances during nitrogen fixation. In this work, we explore the relationships among topology, biological function, and optimal activity in the metabolism of R. etli through an integrative analysis based on modeling and metabolome data. Our findings suggest that the metabolic activity during nitrogen fixation is supported by interacting structural modules that correlate with three functional classifications: nucleic acids, peptides, and lipids. More fundamentally, we supply evidence that such modular organization during functional nitrogen fixation is

  9. Can Cholesterol Metabolism Modulation Affect Brain Function and Behavior?

    PubMed

    Cartocci, Veronica; Servadio, Michela; Trezza, Viviana; Pallottini, Valentina

    2017-02-01

    Cholesterol is an important component for cell physiology. It regulates the fluidity of cell membranes and determines the physical and biochemical properties of proteins. In the central nervous system, cholesterol controls synapse formation and function and supports the saltatory conduction of action potential. In recent years, the role of cholesterol in the brain has caught the attention of several research groups since a breakdown of cholesterol metabolism has been associated with different neurodevelopmental and neurodegenerative diseases, and interestingly also with psychiatric conditions. The aim of this review is to summarize the current knowledge about the connection between cholesterol dysregulation and various neurologic and psychiatric disorders based on clinical and preclinical studies. J. Cell. Physiol. 232: 281-286, 2017. © 2016 Wiley Periodicals, Inc.

  10. Impact of Metabolism on T-Cell Differentiation and Function and Cross Talk with Tumor Microenvironment

    PubMed Central

    Kouidhi, Soumaya; Elgaaied, Amel Benammar; Chouaib, Salem

    2017-01-01

    The immune system and metabolism are highly integrated and multilevel interactions between metabolic system and T lymphocyte signaling and fate exist. Accumulating evidence indicates that the regulation of nutrient uptake and utilization in T cells is critically important for the control of their differentiation and manipulating metabolic pathways in these cells can shape their function and survival. This review will discuss some potential cell metabolism pathways involved in shaping T lymphocyte function and differentiation. It will also describe show subsets of T cells have specific metabolic requirements and signaling pathways that contribute to their respective function. Examples showing the apparent similarity between cancer cell metabolism and T cells during activation are illustrated and finally some mechanisms being used by tumor microenvironment to orchestrate T-cell metabolic dysregulation and the subsequent emergence of immune suppression are discussed. We believe that targeting T-cell metabolism may provide an additional opportunity to manipulate T-cell function in the development of novel therapeutics. PMID:28348562

  11. Thiamine in plants: aspects of its metabolism and functions.

    PubMed

    Goyer, Aymeric

    2010-10-01

    Thiamine diphosphate (vitamin B(1)) plays a fundamental role as an enzymatic cofactor in universal metabolic pathways including glycolysis, the pentose phosphate pathway, and the tricarboxylic acid cycle. In addition, thiamine diphosphate has recently been shown to have functions other than as a cofactor in response to abiotic and biotic stress in plants. Recently, several steps of the plant thiamine biosynthetic pathway have been characterized, and a mechanism of feedback regulation of thiamine biosynthesis via riboswitch has been unraveled. This review focuses on these most recent advances made in our understanding of thiamine metabolism and functions in plants. Phenotypes of plant mutants affected in thiamine biosynthesis are described, and genomics, proteomics, and metabolomics data that have increased further our knowledge of plant thiamine metabolic pathways and functions are summarized. Aspects of thiamine metabolism such as catabolism, salvage, and transport in plants are discussed.

  12. Carbon metabolism and the sign of control coefficients in metabolic adaptations underlying K-ras transformation.

    PubMed

    de Atauri, Pedro; Benito, Adrian; Vizán, Pedro; Zanuy, Miriam; Mangues, Ramón; Marín, Silvia; Cascante, Marta

    2011-06-01

    Metabolic adaptations are associated with changes in enzyme activities. These adaptations are characterized by patterns of positive and negative changes in metabolic fluxes and concentrations of intermediate metabolites. Knowledge of the mechanism and parameters governing enzyme kinetics is rarely available. However, the signs-increases or decreases-of many of these changes can be predicted using the signs of metabolic control coefficients. These signs require the only knowledge of the structure of the metabolic network and a limited qualitative knowledge of the regulatory dependences, which is widely available for carbon metabolism. Here, as a case study, we identified control coefficients with fixed signs in order to predict the pattern of changes in key enzyme activities which can explain the observed changes in fluxes and concentrations underlying the metabolic adaptations in oncogenic K-ras transformation in NIH-3T3 cells. The fixed signs of control coefficients indicate that metabolic changes following the oncogenic transformation-increased glycolysis and oxidative branch of the pentose-phosphate pathway, and decreased concentration in sugar-phosphates-could be associated with increases in activity for glucose-6-phosphate dehydrogenase, pyruvate kinase and lactate dehydrogenase, and decrease for transketolase. These predictions were validated experimentally by measuring specific activities. We conclude that predictions based on fixed signs of control coefficients are a very robust tool for the identification of changes in enzyme activities that can explain observed metabolic adaptations in carbon metabolism.

  13. Functional crosstalk of CAR-LXR and ROR-LXR in drug metabolism and lipid metabolism.

    PubMed

    Xiao, Lei; Xie, Xinni; Zhai, Yonggong

    2010-10-30

    Nuclear receptor crosstalk represents an important mechanism to expand the functions of individual receptors. The liver X receptors (LXR, NR1H2/3), both the α and β isoforms, are nuclear receptors that can be activated by the endogenous oxysterols and other synthetic agonists. LXRs function as cholesterol sensors, which protect mammals from cholesterol overload. LXRs have been shown to regulate the expression of a battery of metabolic genes, especially those involved in lipid metabolism. LXRs have recently been suggested to play a novel role in the regulation of drug metabolism. The constitutive androstane receptor (CAR, NR1I3) is a xenobiotic receptor that regulates the expression of drug-metabolizing enzymes and transporters. Disruption of CAR alters sensitivity to toxins, increasing or decreasing it depending on the compounds. More recently, additional roles for CAR have been discovered. These include the involvement of CAR in lipid metabolism. Mechanistically, CAR forms an intricate regulatory network with other members of the nuclear receptor superfamily, foremost the LXRs, in exerting its effect on lipid metabolism. Retinoid-related orphan receptors (RORs, NR1F1/2/3) have three isoforms, α, β and γ. Recent reports have shown that loss of RORα and/or RORγ can positively or negatively influence the expression of multiple drug-metabolizing enzymes and transporters in the liver. The effects of RORs on expression of drug-metabolizing enzymes were reasoned to be, at least in part, due to the crosstalk with LXR. This review focuses on the CAR-LXR and ROR-LXR crosstalk, and the implications of this crosstalk in drug metabolism and lipid metabolism.

  14. Precision metabolic engineering: The design of responsive, selective, and controllable metabolic systems.

    PubMed

    McNerney, Monica P; Watstein, Daniel M; Styczynski, Mark P

    2015-09-01

    Metabolic engineering is generally focused on static optimization of cells to maximize production of a desired product, though recently dynamic metabolic engineering has explored how metabolic programs can be varied over time to improve titer. However, these are not the only types of applications where metabolic engineering could make a significant impact. Here, we discuss a new conceptual framework, termed "precision metabolic engineering," involving the design and engineering of systems that make different products in response to different signals. Rather than focusing on maximizing titer, these types of applications typically have three hallmarks: sensing signals that determine the desired metabolic target, completely directing metabolic flux in response to those signals, and producing sharp responses at specific signal thresholds. In this review, we will first discuss and provide examples of precision metabolic engineering. We will then discuss each of these hallmarks and identify which existing metabolic engineering methods can be applied to accomplish those tasks, as well as some of their shortcomings. Ultimately, precise control of metabolic systems has the potential to enable a host of new metabolic engineering and synthetic biology applications for any problem where flexibility of response to an external signal could be useful.

  15. Transcriptional control of circadian metabolic rhythms in the liver

    PubMed Central

    Li, Siming; Lin, Jiandie D.

    2015-01-01

    Diurnal metabolic rhythms add an important temporal dimension to metabolic homeostasis in mammals. While it remains a challenge to untangle the intricate networks of crosstalk among the body clock, nutrient signaling, and tissue metabolism, there is little doubt that the rhythmic nature of nutrient and energy metabolism is a central aspect of metabolic physiology. Disruption of the synchrony between clock and metabolism has been causally linked to diverse pathophysiological states. As such, restoring the rhythmicity of body physiology and therapeutic targeting directed at specific time windows during the day may have important implications in human health and medicine. In this review, we summarize recent findings on the integration of hepatic glucose metabolism and the body clock through a regulatory network centered on the PGC-1 transcriptional coactivators. In addition, we discuss the transcriptional mechanisms underlying circadian control of the autophagy gene program and autophagy in the liver. PMID:26332966

  16. Insulin action in brain regulates systemic metabolism and brain function.

    PubMed

    Kleinridders, André; Ferris, Heather A; Cai, Weikang; Kahn, C Ronald

    2014-07-01

    Insulin receptors, as well as IGF-1 receptors and their postreceptor signaling partners, are distributed throughout the brain. Insulin acts on these receptors to modulate peripheral metabolism, including regulation of appetite, reproductive function, body temperature, white fat mass, hepatic glucose output, and response to hypoglycemia. Insulin signaling also modulates neurotransmitter channel activity, brain cholesterol synthesis, and mitochondrial function. Disruption of insulin action in the brain leads to impairment of neuronal function and synaptogenesis. In addition, insulin signaling modulates phosphorylation of tau protein, an early component in the development of Alzheimer disease. Thus, alterations in insulin action in the brain can contribute to metabolic syndrome, and the development of mood disorders and neurodegenerative diseases.

  17. Space Station CMIF extended duration metabolic control test

    NASA Technical Reports Server (NTRS)

    Schunk, Richard G.; Bagdigian, Robert M.; Carrasquillo, Robyn L.; Ogle, Kathryn Y.; Wieland, Paul O.

    1989-01-01

    The Space Station Extended Duration Metabolic Control Test (EMCT) was conducted at the MSFC Core Module Integration Facility. The primary objective of the EMCT was to gather performance data from a partially-closed regenerative Environmental Control and Life Support (ECLS) system functioning under steady-state conditions. Included is a description of the EMCT configuration, a summary of events, a discussion of anomalies that occurred during the test, and detailed results and analysis from individual measurements of water and gas samples taken during the test. A comparison of the physical, chemical, and microbiological methods used in the post test laboratory analyses of the water samples is included. The preprototype ECLS hardware used in the test, providing an overall process description and theory of operation for each hardware item. Analytical results pertaining to a system level mass balance and selected system power estimates are also included.

  18. Metabolic Assessment of Suited Mobility Using Functional Tasks

    NASA Technical Reports Server (NTRS)

    Norcross, J. R.; McFarland, S. M.; Ploutz-Snyder, Robert

    2016-01-01

    Existing methods for evaluating extravehicular activity (EVA) suit mobility have typically focused on isolated joint range of motion or torque, but these techniques have little to do with how well a crewmember functionally performs in an EVA suit. To evaluate suited mobility at the system level through measuring metabolic cost (MC) of functional tasks.

  19. Patterns of control of maximum metabolic rate in humans.

    PubMed

    Hochachka, Peter W; Beatty, Cheryl L

    2003-09-01

    In this analysis, four performance phenotypes were used to compare mechanisms of control of aerobic maximum metabolic rate (MMR): (i) untrained sedentary (US) subjects, as a reference group against which to compare (ii) power trained (PT), (iii) endurance trained (ET) and (iv) high altitude adapted native (HA) subject groups. Sprinters represented the PT group; long distance runners illustrated the ET group; and Quechuas represented the HA group. Numerous recent studies have identified contributors to control on both the adenosine triphosphate (ATP) supply side and the ATP demand side of ATP turnover. Control coefficients or c(i) values were defined as fractional change in MMR/fractional change in the capacity of any given step in ATP turnover. From the best available evidence it appears that at MMR all five of the major steps in energy delivery (namely, ventilation, pulmonary diffusion, cardiac output, tissue capillary - mitochondrial O(2) transfer, and aerobic cell metabolism per se) approach an upper functional ceiling, with control strength being distributed amongst the various O(2) flux steps. On the energy demand side, the situation is somewhat simplified since at MMR approximately 90% of O(2)-based ATP synthesis is used for actomyosin (AM) and Ca(2+) ATPases; at MMR these two ATP demand rates also appear to be near an upper functional ceiling. In consequence, at MMR the control contributions or c(i) values are rather evenly divided amongst all seven major steps in ATP supply and ATP demand pathways right to the point of fatigue. Relative to US (the reference group), in PT subjects at MMR control strength shifts towards O(2) delivery steps (ventilation, pulmonary diffusion and cardiac output). In contrast in ET and HA subjects at MMR control shifts towards the energy demand steps (AM and Ca(2+) ATPases), and more control strength is focussed on tissue level ATP supply and ATP demand. One obvious advantage of the ET and HA control pattern is improved

  20. Circadian rhythms in myocardial metabolism and function

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Circadian rhythms in myocardial function and dysfunction are firmly established in both animal models and humans. For example, the incidence of arrhythmias and sudden cardiac death increases when organisms awaken. Such observations have classically been explained by circadian rhythms in neurohumoral...

  1. Diabetes, insulin-mediated glucose metabolism and Sertoli/blood-testis barrier function

    PubMed Central

    Alves, Marco G.; Martins, Ana D.; Cavaco, José E.; Socorro, Sílvia; Oliveira, Pedro F.

    2013-01-01

    Blood testis barrier (BTB) is one of the tightest blood-barriers controlling the entry of substances into the intratubular fluid. Diabetes Mellitus (DM) is an epidemic metabolic disease concurrent with falling fertility rates, which provokes severe detrimental BTB alterations. It induces testicular alterations, disrupting the metabolic cooperation between the cellular constituents of BTB, with dramatic consequences on sperm quality and fertility. As Sertoli cells are involved in the regulation of spermatogenesis, providing nutritional support for germ cells, any metabolic alteration in these cells derived from DM may be responsible for spermatogenesis disruption, playing a crucial role in fertility/subfertility associated with this pathology. These cells have a glucose sensing machinery that reacts to hormonal fluctuations and several mechanisms to counteract hyper/hypoglycemic events. The role of DM on Sertoli/BTB glucose metabolism dynamics and the metabolic molecular mechanisms through which DM and insulin deregulation alter its functioning, affecting male reproductive potential will be discussed. PMID:24665384

  2. Preserved pontine glucose metabolism in Alzheimer disease: A reference region for functional brain image (PET) analysis

    SciTech Connect

    Minoshima, Satoshi; Frey, K.A.; Foster, N.L.; Kuhl, D.W.

    1995-07-01

    Our goal was to examine regional preservation of energy metabolism in Alzheimer disease (AD) and to evaluate effects of PET data normalization to reference regions. Regional metabolic rates in the pons, thalamus, putamen, sensorimotor cortex, visual cortex, and cerebellum (reference regions) were determined stereotaxically and examined in 37 patients with probable AD and 22 normal controls based on quantitative {sup 18}FDG-PET measurements. Following normalization of metabolic rates of the parietotemporal association cortex and whole brain to each reference region, distinctions of the two groups were assessed. The pons showed the best preservation of glucose metabolism in AD. Other reference regions showed relatively preserved metabolism compared with the parietotemporal association cortex and whole brain, but had significant metabolic reduction. Data normalization to the pons not only enhanced statistical significance of metabolic reduction in the parietotemporal association cortex, but also preserved the presence of global cerebral metabolic reduction indicated in analysis of the quantitative data. Energy metabolism in the pons in probable AD is well preserved. The pons is a reliable reference for data normalization and will enhance diagnostic accuracy and efficiency of quantitative and nonquantitative functional brain imaging. 39 refs., 2 figs., 3 tabs.

  3. Metabolism Is Central to Tolerogenic Dendritic Cell Function

    PubMed Central

    Sim, Wen Jing; Ahl, Patricia Jennifer; Connolly, John Edward

    2016-01-01

    Immunological tolerance is a fundamental tenant of immune homeostasis and overall health. Self-tolerance is a critical component of the immune system that allows for the recognition of self, resulting in hyporeactivity instead of immunogenicity. Dendritic cells are central to the establishment of dominant immune tolerance through the secretion of immunosuppressive cytokines and regulatory polarization of T cells. Cellular metabolism holds the key to determining DC immunogenic or tolerogenic cell fate. Recent studies have demonstrated that dendritic cell maturation leads to a shift toward a glycolytic metabolic state and preferred use of glucose as a carbon source. In contrast, tolerogenic dendritic cells favor oxidative phosphorylation and fatty acid oxidation. This dichotomous metabolic reprogramming of dendritic cells drives differential cellular function and plays a role in pathologies, such as autoimmune disease. Pharmacological alterations in metabolism have promising therapeutic potential. PMID:26980944

  4. [Basic mechanisms: structure, function and metabolism of plasma lipoproteins].

    PubMed

    Errico, Teresa L; Chen, Xiangyu; Martin Campos, Jesús M; Julve, Josep; Escolà-Gil, Joan Carles; Blanco-Vaca, Francisco

    2013-01-01

    The aim of this work is to present basic information on the lipoprotein physiology. The protein fraction of lipoproteins consists of several apolipoproteins and enzymes whose functions are lipid transport and metabolism. Classification of lipoproteins is based on their density. Chylomicrons, VLDL, IDL, LDL and HDL can be isolated by ultracentrifugation. Both chylomicrons- and VLDL-triglycerides are transported from the intestine and liver, respectively, to the peripheral tissues. The metabolism of VLDL originates IDL and LDL. LDL is the main transporter of cholesterol to extrahepatic tissues. HDL mobilizes cholesterol from peripheral tissues to the liver where it is secreted to bile as free cholesterol or bile salts, a process termed reverse cholesterol transport. Lipoprotein metabolism can be regulated by nuclear receptors that regulate the expression of genes involved in triglyceride and apolipoprotein metabolism.

  5. Metabolism

    MedlinePlus

    ... and intestines. Several of the hormones of the endocrine system are involved in controlling the rate and direction ... For Kids For Parents MORE ON THIS TOPIC Endocrine System What Can I Do About My High Metabolism? ...

  6. Phosphatidylserine in the brain: metabolism and function.

    PubMed

    Kim, Hee-Yong; Huang, Bill X; Spector, Arthur A

    2014-10-01

    Phosphatidylserine (PS) is the major anionic phospholipid class particularly enriched in the inner leaflet of the plasma membrane in neural tissues. PS is synthesized from phosphatidylcholine or phosphatidylethanolamine by exchanging the base head group with serine, and this reaction is catalyzed by phosphatidylserine synthase 1 and phosphatidylserine synthase 2 located in the endoplasmic reticulum. Activation of Akt, Raf-1 and protein kinase C signaling, which supports neuronal survival and differentiation, requires interaction of these proteins with PS localized in the cytoplasmic leaflet of the plasma membrane. Furthermore, neurotransmitter release by exocytosis and a number of synaptic receptors and proteins are modulated by PS present in the neuronal membranes. Brain is highly enriched with docosahexaenoic acid (DHA), and brain PS has a high DHA content. By promoting PS synthesis, DHA can uniquely expand the PS pool in neuronal membranes and thereby influence PS-dependent signaling and protein function. Ethanol decreases DHA-promoted PS synthesis and accumulation in neurons, which may contribute to the deleterious effects of ethanol intake. Improvement of some memory functions has been observed in cognitively impaired subjects as a result of PS supplementation, but the mechanism is unclear.

  7. Vitamin D metabolism, sex hormones, and male reproductive function.

    PubMed

    Blomberg Jensen, Martin

    2012-08-01

    The spectrum of vitamin D (VD)-mediated effects has expanded in recent years, and VD is now recognized as a versatile signaling molecule rather than being solely a regulator of bone health and calcium homeostasis. One of the recently identified target areas of VD is male reproductive function. The VD receptor (VDR) and the VD metabolizing enzyme expression studies documented the presence of this system in the testes, mature spermatozoa, and ejaculatory tract, suggesting that both systemic and local VD metabolism may influence male reproductive function. However, it is still debated which cell is the main VD target in the testis and to what extent VD is important for sex hormone production and function of spermatozoa. This review summarizes descriptive studies on testicular VD metabolism and spatial distribution of VDR and the VD metabolizing enzymes in the mammalian testes and discusses mechanistic and association studies conducted in animals and humans. The reviewed evidence suggests some effects of VD on estrogen and testosterone biosynthesis and implicates involvement of both systemic and local VD metabolism in the regulation of male fertility potential.

  8. Metabolic Derangements in Lichen Planus - A Case Control Study

    PubMed Central

    Kar, Bikash Ranjan; Panda, Maitreyee

    2016-01-01

    Introduction An association between psoriasis and metabolic syndrome has been established in previous studies. Lichen Planus (LP) is also a chronic inflammatory disease morphologically related to psoriasis and few studies have shown association of metabolic derangements in LP. Aim To study the association of metabolic derangements in LP. Materials and Methods A prospective case control study was undertaken for a period of one year. Age and sex matched patients of LP and other non-inflammatory diseases were taken as cases and controls respectively. Data on height, weight, lipid profile and fasting blood glucose levels were collected for all the patients. Body Mass Index (BMI) was calculated. Results A total of 80 patients were recruited, 40 cases and 40 controls. The mean values for all the lipid and glucose parameters were high in cases as compared to controls with significant p-values. Conclusion In the present study metabolic derangements were seen in patients with LP. PMID:28050485

  9. Metabolic control of cancer cell stemness: Lessons from iPS cells

    PubMed Central

    Menendez, Javier A

    2015-01-01

    The Nobel prized discovery of nuclear reprogramming is swiftly providing mechanistic evidence of a role for metabolism in the generation of cancer stem cells (CSC). Traditionally, the metabolic demands of tumors have been viewed as drivers of the genetic programming detected in cancer tissues. Beyond the energetic requirements of specific cancer cell states, it is increasingly recognized that metabolism per se controls epi-transcriptional networks to dictate cancer cell fate, i.e., metabolism can define CSC. Here I review the CSC-related metabolic features found in induced pluripotent stem (iPS) cells to provide an easily understandable framework in which the infrastructure and functioning of cellular metabolism might control the efficiency and kinetics of reprogramming in the re-routing of non-CSC to CSC-like cellular states. I suggest exploring how metabolism-dependent regulation of epigenetics can play a role in directing CSC states beyond conventional energetic demands of stage-specific cancer cell states, opening a new dimension of cancer in which the “physiological state” of CSC might be governed not only by cell-autonomous cues but also by local micro-environmental and systemic metabolo-epigenetic interactions. Forthcoming studies should decipher how specific metabolites integrate and mediate the overlap between the CSC-intrinsic “micro-epigenetics” and the “upstream” local and systemic “macro-epigenetics," thus paving the way for targeted epigenetic regulation of CSCs through metabolic modulation including "smart foods" or systemic "metabolic nichotherapies." PMID:25738999

  10. Psychosocial and metabolic function by smoking status in individuals with binge eating disorder and obesity.

    PubMed

    Udo, Tomoko; White, Marney A; Barnes, Rachel D; Ivezaj, Valentina; Morgan, Peter; Masheb, Robin M; Grilo, Carlos M

    2016-02-01

    Individuals with binge eating disorder (BED) report smoking to control appetite and weight. Smoking in BED is associated with increased risk for comorbid psychiatric disorders, but its impact on psychosocial functioning and metabolic function has not been evaluated. Participants were 429 treatment-seeking adults (72.4% women; mean age 46.2±11.0years old) with BED comorbid with obesity. Participants were categorized into current smokers (n=66), former smokers (n=145), and never smokers (n=218). Smoking status was unrelated to most historical eating/weight variables and to current eating disorder psychopathology. Smoking status was associated with psychiatric, psychosocial, and metabolic functioning. Compared with never smokers, current smokers were more likely to meet lifetime diagnostic criteria for alcohol (OR=5.51 [95% CI=2.46-12.33]) and substance use disorders (OR=7.05 [95% CI=3.37-14.72]), poorer current physical quality of life, and increased risk for metabolic syndrome (OR=1.80 [95% CI=0.97-3.35]) and related metabolic risks (reduced HDL, elevated total cholesterol). On the other hand, the odds of meeting criteria for lifetime psychiatric comorbidity or metabolic abnormalities were not significantly greater in former smokers, relative to never smokers. Our findings suggest the importance of promoting smoking cessation in treatment-seeking patients with BED and obesity for its potential long-term implications for psychiatric and metabolic functioning.

  11. Myocardial Function and Lipid Metabolism in the Chronic Alcoholic Animal

    PubMed Central

    Regan, Timothy J.; Khan, Mohammad I.; Ettinger, Philip O.; Haider, Bunyad; Lyons, Michael M.; Oldewurtel, Henry A.; Weber, Marilyn

    1974-01-01

    In view of the variables that obscure the pathogenesis of cardiomyopathy, a study was undertaken in mongrel dogs fed ethanol as 36% of calories for up to 22 mo. Both the experimental and control groups maintained body weight, hematocrit, plasma vitamin, and protein levels. Left ventricular function was evaluated in the intact anesthetized dog using indicator dilution for end-diastolic and stroke volume determinations. During increased afterload with angiotensin, the ethanol group exhibited a larger rise of end-diastolic pressure (P<0.01), whereas end-diastolic and stroke volume responses were significantly less than in controls. Preload increments with saline elicited a significantly higher end-diastolic pressure rise in the ethanol group (P<0.01). No hypertrophy, inflammation, or fibrosis was present and it was postulated that the enhanced diastolic stiffness was related to accumulation of Alcian Blue-positive material in the ventricular interstitium. To evaluate myocardial lipid metabolism, [1-14C]oleic acid was infused systemically. Plasma specific activity and myocardial lipid uptake were similar in both groups. There was a significantly increased incorporation of label into triglyceride, associated with a reduced 14CO2 production, considered the basis for a twofold increment of triglyceride content. In addition, diminished incorporation of [14C]oleic acid into phospholipid was observed accompanied by morphologic abnormalities of cardiac cell membranes. Potassium loss and sodium gain, like the lipid alteration, was more prominent in the subendocardium. Thus, chronic ethanol ingestion in this animal model is associated with abnormalities of ventricular function without evident malnutrition, analogous to the preclinical malfunction described in the human alcoholic. Images PMID:4368946

  12. Trypanosoma brucei metabolism is under circadian control.

    PubMed

    Rijo-Ferreira, Filipa; Pinto-Neves, Daniel; Barbosa-Morais, Nuno L; Takahashi, Joseph S; Figueiredo, Luisa M

    2017-03-13

    The Earth's rotation forced life to evolve under cyclic day and night environmental changes. To anticipate such daily cycles, prokaryote and eukaryote free-living organisms evolved intrinsic clocks that regulate physiological and behavioural processes. Daily rhythms have been observed in organisms living within hosts, such as parasites. Whether parasites have intrinsic molecular clocks or whether they simply respond to host rhythmic physiological cues remains unknown. Here, we show that Trypanosoma brucei, the causative agent of human sleeping sickness, has an intrinsic circadian clock that regulates its metabolism in two different stages of the life cycle. We found that, in vitro, ∼10% of genes in T. brucei are expressed with a circadian rhythm. The maximum expression of these genes occurs at two different phases of the day and may depend on a post-transcriptional mechanism. Circadian genes are enriched in cellular metabolic pathways and coincide with two peaks of intracellular adenosine triphosphate concentration. Moreover, daily changes in the parasite population lead to differences in suramin sensitivity, a drug commonly used to treat this infection. These results demonstrate that parasites have an intrinsic circadian clock that is independent of the host, and which regulates parasite biology throughout the day.

  13. Cocoa flavanol consumption improves cognitive function, blood pressure control, and metabolic profile in elderly subjects: the Cocoa, Cognition, and Aging (CoCoA) Study—a randomized controlled trial1234

    PubMed Central

    Mastroiacovo, Daniela; Kwik-Uribe, Catherine; Grassi, Davide; Necozione, Stefano; Raffaele, Angelo; Pistacchio, Luana; Righetti, Roberta; Bocale, Raffaella; Lechiara, Maria Carmela; Marini, Carmine; Ferri, Claudio; Desideri, Giovambattista

    2015-01-01

    Background: Recent evidence has indicated that flavanol consumption may have many health benefits in humans, including improved cognitive activities. Objective: The aim was to evaluate the effect of flavanol consumption on cognitive performance in cognitively intact elderly subjects. Design: This was a double-blind, controlled, parallel-arm study conducted in 90 elderly individuals without clinical evidence of cognitive dysfunction who were randomly assigned to consume daily for 8 wk a drink containing 993 mg [high flavanol (HF)], 520 mg [intermediate flavanol (IF)], or 48 mg [low flavanol (LF)] cocoa flavanols (CFs). Cognitive function was assessed at baseline and after 8 wk by using the Mini-Mental State Examination (MMSE), the Trail Making Test (TMT) A and B, and the Verbal Fluency Test (VFT). Results: The changes in MMSE score in response to the 3 different treatments were not different. In contrast, there was a positive impact of the intervention on specific aspects of cognitive function. Mean changes (±SEs) in the time required to complete the TMT A and B after consumption of the HF (−8.6 ± 0.4 and −16.5 ± 0.8 s, respectively) and IF (−6.7 ± 0.5 and −14.2 ± 0.5 s, respectively) drinks significantly (P < 0.0001) differed from that after consumption of the LF drinks (−0.8 ± 1.6 and −1.1 ± 0.7 s, respectively). Similarly, VFT scores significantly improved among all treatment groups, but the magnitude of improvement in the VFT score was significantly (P < 0.0001) greater in the HF group (7.7 ± 1.1 words/60 s) than in the IF (3.6 ± 1.2 words/60 s) and LF (1.3 ± 0.5 words/60 s) groups. Significantly different improvements in insulin resistance (P < 0.0001), blood pressure (P < 0.0001), and lipid peroxidation (P = 0.001) were also observed for the HF and IF groups in comparison with the LF group. Changes in insulin resistance explained ∼17% of changes in composite z score (partial r2 = 0.1703, P < 0.0001). Conclusions: This dietary

  14. Metabolic functions of FABPs— mechanisms and therapeutic implications

    PubMed Central

    Hotamisligil, Gökhan S.; Bernlohr, David A.

    2015-01-01

    Intracellular and extracellular interactions with proteins enables the functional and mechanistic diversity of lipids. Fatty acid-binding proteins (FABPs) were originally described as intracellular proteins that can affect lipid fluxes, metabolism and signalling within cells. As the functions of this protein family have been further elucidated, it has become evident that they are critical mediators of metabolism and inflammatory processes, both locally and systemically, and therefore are potential therapeutic targets for immunometabolic diseases. In particular, genetic deficiency and small molecule-mediated inhibition of FABP4 (also known as aP2) and FABP5 can potently improve glucose homeostasis and reduce atherosclerosis in mouse models. Further research has shown that in addition to their intracellular roles, some FABPs are found outside the cells, and FABP4 undergoes regulated, vesicular secretion. The circulating form of FABP4 has crucial hormonal functions in systemic metabolism. In this Review we discuss the roles and regulation of both intracellular and extracellular FABP actions, highlighting new insights that might direct drug discovery efforts and opportunities for management of chronic metabolic diseases. PMID:26260145

  15. You Are What You Eat: Metabolic Control of Bacterial Division.

    PubMed

    Monahan, Leigh G; Harry, Elizabeth J

    2016-03-01

    Fluctuations in nutrient availability are a fact of life for bacterial cells in the 'wild'. To survive and compete, bacteria must rapidly modulate cell-cycle processes to accommodate changing nutritional conditions and concomitant changes in cell growth. Our understanding of how this is achieved has been transformed in recent years, with cellular metabolism emerging as a central player. Several metabolic enzymes, in addition to their normal catalytic functions, have been shown to directly modulate cell-cycle processes in response to changing nutrient levels. Here we focus on cell division, the final event in the bacterial cell cycle, and discuss recent compelling evidence connecting division regulation to nutritional status and metabolic activity.

  16. Control of glutamine metabolism by the tumor suppressor Rb.

    PubMed

    Reynolds, M R; Lane, A N; Robertson, B; Kemp, S; Liu, Y; Hill, B G; Dean, D C; Clem, B F

    2014-01-30

    Retinoblastoma (Rb) protein is a tumor suppressor that is dysregulated in a majority of human cancers. Rb functions to inhibit cell cycle progression in part by directly disabling the E2F family of cell cycle-promoting transcription factors. Because the de novo synthesis of multiple glutamine-derived anabolic precursors is required for cell cycle progression, we hypothesized that Rb also may directly regulate proteins involved in glutamine metabolism. We examined glutamine metabolism in mouse embryonic fibroblasts (MEFs) isolated from mice that have triple knock-outs (TKO) of all three Rb family members (Rb-1, Rbl1 and Rbl2) and found that loss of global Rb function caused a marked increase in (13)C-glutamine uptake and incorporation into glutamate and tricarboxylic acid cycle (TCA) intermediates in part via upregulated expression of the glutamine transporter ASCT2 and the activity of glutaminase 1 (GLS1). The Rb-controlled transcription factor E2F-3 altered glutamine uptake by direct regulation of ASCT2 mRNA and protein expression, and E2F-3 was observed to associate with the ASCT2 promoter. We next examined the functional consequences of the observed increase in glutamine uptake and utilization and found that glutamine exposure potently increased oxygen consumption, whereas glutamine deprivation selectively decreased ATP concentration in the Rb TKO MEFs but not the wild-type (WT) MEFs. In addition, TKO MEFs exhibited elevated production of glutathione from exogenous glutamine and had increased expression of gamma-glutamylcysteine ligase relative to WT MEFs. Importantly, this metabolic shift towards glutamine utilization was required for the proliferation of Rb TKO MEFs but not for the proliferation of the WT MEFs. Last, addition of the TCA cycle intermediate α-ketoglutarate to the Rb TKO MEFs reversed the inhibitory effects of glutamine deprivation on ATP, GSH levels and viability. Taken together, these studies demonstrate that the Rb/E2F cascade directly

  17. Insulin Action in Brain Regulates Systemic Metabolism and Brain Function

    PubMed Central

    Kleinridders, André; Ferris, Heather A.; Cai, Weikang

    2014-01-01

    Insulin receptors, as well as IGF-1 receptors and their postreceptor signaling partners, are distributed throughout the brain. Insulin acts on these receptors to modulate peripheral metabolism, including regulation of appetite, reproductive function, body temperature, white fat mass, hepatic glucose output, and response to hypoglycemia. Insulin signaling also modulates neurotransmitter channel activity, brain cholesterol synthesis, and mitochondrial function. Disruption of insulin action in the brain leads to impairment of neuronal function and synaptogenesis. In addition, insulin signaling modulates phosphorylation of tau protein, an early component in the development of Alzheimer disease. Thus, alterations in insulin action in the brain can contribute to metabolic syndrome, and the development of mood disorders and neurodegenerative diseases. PMID:24931034

  18. The skin function: a factor of anti-metabolic syndrome

    PubMed Central

    2012-01-01

    The body’s total antioxidant capacity represents a sum of the antioxidant capacity of various tissues/organs. A decrease in the body’s antioxidant capacity may induce oxidative stress and subsequent metabolic syndrome, a clustering of risk factors for type 2 diabetes and cardiovascular disease. The skin, the largest organ of the body, is one of the major components of the body’s total antioxidant defense system, primarily through its xenobiotic/drug biotransformation system, reactive oxygen species-scavenging system, and sweat glands- and sebaceous glands-mediated excretion system. Notably, unlike other contributors, the skin contribution is variable, depending on lifestyles and ambient temperature or seasonal variations. Emerging evidence suggests that decreased skin’s antioxidant and excretory functions (e.g., due to sedentary lifestyles and low ambient temperature) may increase the risk for metabolic syndrome. This review focuses on the relationship between the variability of skin-mediated detoxification and elimination of exogenous and endogenous toxic substances and the development of metabolic syndrome. The potential role of sebum secretion in lipid and cholesterol homeostasis and its impact on metabolic syndrome, and the association between skin disorders (acanthosis nigricans, acne, and burn) and metabolic syndrome are also discussed. PMID:22537765

  19. The metabolic control of schistosome egg production

    PubMed Central

    Pearce, Edward J.; Huang, Stanley Ching-Cheng

    2015-01-01

    Schistosomiasis is a Neglected Tropical Disease caused by infection with trematode parasites of the genus Schistosoma. Despite ongoing treatment programs, the prevalence of schistosomiasis has failed to decline and the disease remains a cause of severe morbidity in millions of people. Understanding the biology of egg production by schistosomes is critical since eggs allow transmission of the infection, and when trapped in host tissues induce the immune responses that are responsible for the pathologic changes that underlie disease development. Unusually among trematodes, adult schistosomes exhibit sexual dimorphism and display a fascinating codependency in that the female is dependent on the male to grow and sexually mature. Thus virgin females are developmentally stunted compared to females from mixed-sex infections and are unable to lay eggs. Moreover, fecund female schistosomes rapidly lose the ability to produce eggs when placed in tissue culture. Here we discuss the metabolic regulation of egg production in schistosomes, and in particular the critical role played by fatty acid oxidation in this process. PMID:25850569

  20. [Nitrogen metabolism and its control mechanisms].

    PubMed

    Bergner, H

    1989-01-01

    N intake in the form of protein has neither got an upper nor a lower limit for agricultural working animals within a diet and there is no control mechanism for it. A high surplus of certain amino acids results in a reduction of feed intake. N excretion in faeces depends on 1) the excretion of N containing indigestible feedstuffs, 2) bacterial nitrogen synthesis in the large intestine and 3) the excretion of true endogenous N containing substances (digestion enzymes, intestinal epithelium, N containing endogenous secretion). There are no other control mechanisms for N excretion in faeces. N excretion in urine mainly comprises the nitrogen from the degeneration of amino acids and nucleic acids. The interrelations between urea, NH3, allantoin, creatine and creatinine, uric acid and hippuric acid depend on the species (monogastric or ruminants), on the nitrogen and N amount consumed and on the recycling ratio of the amino acids. The absolute amount of N excretion is not subject to any control mechanism, it depends on the intake of protein and NPN substances, the interim stages, however, which lead to the formation of excretory products, are intermediately controlled. The most important interim stage is protein biosynthesis, which is a fixed, intermediately controlled value in maintenance level. Under growth conditions only, the protein synthesis quota can exceed the protein degradation quota of the total organism (positive N balance). The control mechanisms of protein biosynthesis have, according to current knowledge, the following structure: Stimulation: 1) growth hormone (STH) stimulates protein synthesis by means of somatomedins; 2) hormones of the thyroid gland (T4 and T3) are controlled by the hormone stimulating the thyroid gland (TSH); 3) insulin. Inhibition: 1) somatostatin inhibits STH, TSH and insulin; 2) cortisol directly inhibits protein synthesis and stimulates protein degradation. The control mechanisms of protein turnover in addition to genetic coding

  1. A Comparison of the Effects of the GLP-1 Analogue Liraglutide and Insulin Glargine on Endothelial Function and Metabolic Parameters: A Randomized, Controlled Trial Sapporo Athero-Incretin Study 2 (SAIS2)

    PubMed Central

    Nomoto, Hiroshi; Miyoshi, Hideaki; Furumoto, Tomoo; Oba, Koji; Tsutsui, Hiroyuki; Miyoshi, Arina; Kondo, Takuma; Tsuchida, Kenichi; Atsumi, Tatsuya; Manda, Naoki; Kurihara, Yoshio; Aoki, Shin

    2015-01-01

    Objectives GLP-1 improves hyperglycemia, and it has been reported to have favorable effects on atherosclerosis. However, it has not been fully elucidated whether GLP-1 is able to improve endothelial function in patients with type 2 diabetes. Therefore, we investigated the efficacy of the GLP-1 analogue, liraglutide on endothelial function and glycemic metabolism compared with insulin glargine therapy. Materials and Methods In this multicenter, prospective randomized parallel-group comparison study, 31 diabetic outpatients (aged 60.3 ± 10.3 years with HbA1c levels of 8.6 ± 0.8%) with current metformin and/or sulfonylurea treatment were enrolled and randomly assigned to receive liraglutide or glargine therapy once daily for 14 weeks. Flow mediated dilation (FMD), a comprehensive panel of hemodynamic parameters (Task Force Monitor), and serum metabolic markers were assessed before and after the treatment period. Results A greater reduction (worsening) in %FMD was observed in the glargine group, although this change was not statistically different from the liraglutide group (liraglutide; 5.7 to 5.4%, glargine 6.7 to 5.7%). The augmentation index, C-peptide index, derivatives of reactive oxygen metabolites and BMI were significantly improved in the liraglutide group. Central systolic blood pressure and NT-proBNP also tended to be improved in the liraglutide-treated group, while improvements in HbA1c levels were similar between groups. Cardiac index, blood pressure and most other metabolic parameters were not different. Conclusions Regardless of glycemic improvement, early liraglutide therapy did not affect endothelial function but may provide favorable effects on beta-cell function and cardioprotection in type 2 diabetics without advanced atherosclerosis. Trial Registration UMIN Clinical Trials Registry System as trial ID UMIN000005331. PMID:26284918

  2. Functional analysis of colonic bacterial metabolism: relevant to health?

    PubMed

    Hamer, Henrike M; De Preter, Vicky; Windey, Karen; Verbeke, Kristin

    2012-01-01

    With the use of molecular techniques, numerous studies have evaluated the composition of the intestinal microbiota in health and disease. However, it is of major interest to supplement this with a functional analysis of the microbiota. In this review, the different approaches that have been used to characterize microbial metabolites, yielding information on the functional end products of microbial metabolism, have been summarized. To analyze colonic microbial metabolites, the most conventional way is by application of a hypothesis-driven targeted approach, through quantification of selected metabolites from carbohydrate (e.g., short-chain fatty acids) and protein fermentation (e.g., p-cresol, phenol, ammonia, or H(2)S), secondary bile acids, or colonic enzymes. The application of stable isotope-labeled substrates can provide an elegant solution to study these metabolic pathways in vivo. On the other hand, a top-down approach can be followed by applying metabolite fingerprinting techniques based on (1)H-NMR or mass spectrometric analysis. Quantification of known metabolites and characterization of metabolite patterns in urine, breath, plasma, and fecal samples can reveal new pathways and give insight into physiological regulatory processes of the colonic microbiota. In addition, specific metabolic profiles can function as a diagnostic tool for the identification of several gastrointestinal diseases, such as ulcerative colitis and Crohn's disease. Nevertheless, future research will have to evaluate the relevance of associations between metabolites and different disease states.

  3. Controllability in cancer metabolic networks according to drug targets as driver nodes.

    PubMed

    Asgari, Yazdan; Salehzadeh-Yazdi, Ali; Schreiber, Falk; Masoudi-Nejad, Ali

    2013-01-01

    Networks are employed to represent many nonlinear complex systems in the real world. The topological aspects and relationships between the structure and function of biological networks have been widely studied in the past few decades. However dynamic and control features of complex networks have not been widely researched, in comparison to topological network features. In this study, we explore the relationship between network controllability, topological parameters, and network medicine (metabolic drug targets). Considering the assumption that targets of approved anticancer metabolic drugs are driver nodes (which control cancer metabolic networks), we have applied topological analysis to genome-scale metabolic models of 15 normal and corresponding cancer cell types. The results show that besides primary network parameters, more complex network metrics such as motifs and clusters may also be appropriate for controlling the systems providing the controllability relationship between topological parameters and drug targets. Consequently, this study reveals the possibilities of following a set of driver nodes in network clusters instead of considering them individually according to their centralities. This outcome suggests considering distributed control systems instead of nodal control for cancer metabolic networks, leading to a new strategy in the field of network medicine.

  4. Detection of driver metabolites in the human liver metabolic network using structural controllability analysis

    PubMed Central

    2014-01-01

    Background Abnormal states in human liver metabolism are major causes of human liver diseases ranging from hepatitis to hepatic tumor. The accumulation in relevant data makes it feasible to derive a large-scale human liver metabolic network (HLMN) and to discover important biological principles or drug-targets based on network analysis. Some studies have shown that interesting biological phenomenon and drug-targets could be discovered by applying structural controllability analysis (which is a newly prevailed concept in networks) to biological networks. The exploration on the connections between structural controllability theory and the HLMN could be used to uncover valuable information on the human liver metabolism from a fresh perspective. Results We applied structural controllability analysis to the HLMN and detected driver metabolites. The driver metabolites tend to have strong ability to influence the states of other metabolites and weak susceptibility to be influenced by the states of others. In addition, the metabolites were classified into three classes: critical, high-frequency and low-frequency driver metabolites. Among the identified 36 critical driver metabolites, 27 metabolites were found to be essential; the high-frequency driver metabolites tend to participate in different metabolic pathways, which are important in regulating the whole metabolic systems. Moreover, we explored some other possible connections between the structural controllability theory and the HLMN, and find that transport reactions and the environment play important roles in the human liver metabolism. Conclusion There are interesting connections between the structural controllability theory and the human liver metabolism: driver metabolites have essential biological functions; the crucial role of extracellular metabolites and transport reactions in controlling the HLMN highlights the importance of the environment in the health of human liver metabolism. PMID:24885538

  5. Metabolic functions of glucocorticoid receptor in skeletal muscle.

    PubMed

    Kuo, Taiyi; Harris, Charles A; Wang, Jen-Chywan

    2013-11-05

    Glucocorticoids (GCs) exert key metabolic influences on skeletal muscle. GCs increase protein degradation and decrease protein synthesis. The released amino acids are mobilized from skeletal muscle to liver, where they serve as substrates for hepatic gluconeogenesis. This metabolic response is critical for mammals' survival under stressful conditions, such as fasting and starvation. GCs suppress insulin-stimulated glucose uptake and utilization and glycogen synthesis, and play a permissive role for catecholamine-induced glycogenolysis, thus preserving the level of circulating glucose, the major energy source for the brain. However, chronic or excess exposure of GCs can induce muscle atrophy and insulin resistance. GCs convey their signal mainly through the intracellular glucocorticoid receptor (GR). While GR can act through different mechanisms, one of its major actions is to regulate the transcription of its primary target genes through genomic glucocorticoid response elements (GREs) by directly binding to DNA or tethering onto other DNA-binding transcription factors. These GR primary targets trigger physiological and pathological responses of GCs. Much progress has been made to understand how GCs regulate protein and glucose metabolism. In this review, we will discuss how GR primary target genes confer metabolic functions of GCs, and the mechanisms governing the transcriptional regulation of these targets. Comprehending these processes not only contributes to the fundamental understanding of mammalian physiology, but also will provide invaluable insight for improved GC therapeutics.

  6. Sialic acid metabolism and sialyltransferases: natural functions and applications

    PubMed Central

    Li, Yanhong

    2012-01-01

    Sialic acids are a family of negatively charged monosaccharides which are commonly presented as the terminal residues in glycans of the glycoconjugates on eukaryotic cell surface or as components of capsular polysaccharides or lipooligosaccharides of some pathogenic bacteria. Due to their important biological and pathological functions, the biosynthesis, activation, transfer, breaking down, and recycle of sialic acids are attracting increasing attention. The understanding of the sialic acid metabolism in eukaryotes and bacteria leads to the development of metabolic engineering approaches for elucidating the important functions of sialic acid in mammalian systems and for large-scale production of sialosides using engineered bacterial cells. As the key enzymes in biosynthesis of sialylated structures, sialyltransferases have been continuously identified from various sources and characterized. Protein crystal structures of seven sialyltransferases have been reported. Wild-type sialyltransferases and their mutants have been applied with or without other sialoside biosynthetic enzymes for producing complex sialic acid-containing oligosaccharides and glycoconjugates. This mini-review focuses on current understanding and applications of sialic acid metabolism and sialyltransferases. PMID:22526796

  7. Brain glycogen—new perspectives on its metabolic function and regulation at the subcellular level

    PubMed Central

    Obel, Linea F.; Müller, Margit S.; Walls, Anne B.; Sickmann, Helle M.; Bak, Lasse K.; Waagepetersen, Helle S.; Schousboe, Arne

    2012-01-01

    Glycogen is a complex glucose polymer found in a variety of tissues, including brain, where it is localized primarily in astrocytes. The small quantity found in brain compared to e.g., liver has led to the understanding that brain glycogen is merely used during hypoglycemia or ischemia. In this review evidence is brought forward highlighting what has been an emerging understanding in brain energy metabolism: that glycogen is more than just a convenient way to store energy for use in emergencies—it is a highly dynamic molecule with versatile implications in brain function, i.e., synaptic activity and memory formation. In line with the great spatiotemporal complexity of the brain and thereof derived focus on the basis for ensuring the availability of the right amount of energy at the right time and place, we here encourage a closer look into the molecular and subcellular mechanisms underlying glycogen metabolism. Based on (1) the compartmentation of the interconnected second messenger pathways controlling glycogen metabolism (calcium and cAMP), (2) alterations in the subcellular location of glycogen-associated enzymes and proteins induced by the metabolic status and (3) a sequential component in the intermolecular mechanisms of glycogen metabolism, we suggest that glycogen metabolism in astrocytes is compartmentalized at the subcellular level. As a consequence, the meaning and importance of conventional terms used to describe glycogen metabolism (e.g., turnover) is challenged. Overall, this review represents an overview of contemporary knowledge about brain glycogen and its metabolism and function. However, it also has a sharp focus on what we do not know, which is perhaps even more important for the future quest of uncovering the roles of glycogen in brain physiology and pathology. PMID:22403540

  8. Control of mitochondrial metabolism and systemic energy homeostasis by microRNAs 378 and 378*

    PubMed Central

    Carrer, Michele; Liu, Ning; Grueter, Chad E.; Williams, Andrew H.; Frisard, Madlyn I.; Hulver, Matthew W.; Bassel-Duby, Rhonda; Olson, Eric N.

    2012-01-01

    Obesity and metabolic syndrome are associated with mitochondrial dysfunction and deranged regulation of metabolic genes. Peroxisome proliferator-activated receptor γ coactivator 1β (PGC-1β) is a transcriptional coactivator that regulates metabolism and mitochondrial biogenesis through stimulation of nuclear hormone receptors and other transcription factors. We report that the PGC-1β gene encodes two microRNAs (miRNAs), miR-378 and miR-378*, which counterbalance the metabolic actions of PGC-1β. Mice genetically lacking miR-378 and miR-378* are resistant to high-fat diet-induced obesity and exhibit enhanced mitochondrial fatty acid metabolism and elevated oxidative capacity of insulin-target tissues. Among the many targets of these miRNAs, carnitine O-acetyltransferase, a mitochondrial enzyme involved in fatty acid metabolism, and MED13, a component of the Mediator complex that controls nuclear hormone receptor activity, are repressed by miR-378 and miR-378*, respectively, and are elevated in the livers of miR-378/378* KO mice. Consistent with these targets as contributors to the metabolic actions of miR-378 and miR-378*, previous studies have implicated carnitine O-acetyltransferase and MED13 in metabolic syndrome and obesity. Our findings identify miR-378 and miR-378* as integral components of a regulatory circuit that functions under conditions of metabolic stress to control systemic energy homeostasis and the overall oxidative capacity of insulin target tissues. Thus, these miRNAs provide potential targets for pharmacologic intervention in obesity and metabolic syndrome. PMID:22949648

  9. The evolution, metabolism and functions of the apicoplast

    PubMed Central

    Lim, Liting; McFadden, Geoffrey Ian

    2010-01-01

    The malaria parasite, Plasmodium falciparum, harbours a relict plastid known as the ‘apicoplast’. The discovery of the apicoplast ushered in an exciting new prospect for drug development against the parasite. The eubacterial ancestry of the organelle offers a wealth of opportunities for the development of therapeutic interventions. Morphological, biochemical and bioinformatic studies of the apicoplast have further reinforced its ‘plant-like’ characteristics and potential as a drug target. However, we are still not sure why the apicoplast is essential for the parasite's survival. This review explores the origins and metabolic functions of the apicoplast. In an attempt to decipher the role of the organelle within the parasite we also take a closer look at the transporters decorating the plastid to better understand the metabolic exchanges between the apicoplast and the rest of the parasite cell. PMID:20124342

  10. Triacylglycerol Metabolism, Function, and Accumulation in Plant Vegetative Tissues

    DOE PAGES

    Xu, Changcheng; Shanklin, John

    2016-02-03

    One of the most abundant energy-dense storage compounds in eukaryotes are oils in the form of triacylglycerols , and their metabolism plays a key role in cellular energy balance, lipid homeostasis, growth, and maintenance. Plants accumulate oils primarily in seeds and fruits. Moreover, plant oils are used for food and feed and, increasingly, as feedstocks for biodiesel and industrial chemicals. Although plant vegetative tissues do not accumulate significant levels of triacylglycerols, they possess a high capacity for their synthesis, storage, and metabolism. The development of plants that accumulate oil in vegetative tissues presents an opportunity for expanded production of triacylglycerolsmore » as a renewable and sustainable bioenergy source. We review recent progress in the understanding of triacylglycerol synthesis, turnover, storage, and function in leaves and discuss emerging genetic engineering strategies targeted at enhancing triacylglycerol accumulation in biomass crops. Such plants could potentially be modified to produce oleochemical feedstocks or nutraceuticals.« less

  11. Triacylglycerol Metabolism, Function, and Accumulation in Plant Vegetative Tissues

    SciTech Connect

    Xu, Changcheng; Shanklin, John

    2016-02-03

    One of the most abundant energy-dense storage compounds in eukaryotes are oils in the form of triacylglycerols , and their metabolism plays a key role in cellular energy balance, lipid homeostasis, growth, and maintenance. Plants accumulate oils primarily in seeds and fruits. Moreover, plant oils are used for food and feed and, increasingly, as feedstocks for biodiesel and industrial chemicals. Although plant vegetative tissues do not accumulate significant levels of triacylglycerols, they possess a high capacity for their synthesis, storage, and metabolism. The development of plants that accumulate oil in vegetative tissues presents an opportunity for expanded production of triacylglycerols as a renewable and sustainable bioenergy source. We review recent progress in the understanding of triacylglycerol synthesis, turnover, storage, and function in leaves and discuss emerging genetic engineering strategies targeted at enhancing triacylglycerol accumulation in biomass crops. Such plants could potentially be modified to produce oleochemical feedstocks or nutraceuticals.

  12. Physiology and genetics of metabolic flux control in Zymomonas mobilis

    SciTech Connect

    Conway, T.

    1992-01-01

    This work seeks to understand the role of gene expression in regulating glycolytic enzyme synthesis in a balance that allows proper glycoltic flux control. The seven genes targeted for study in this laboratory have been cloned and sequenced, and molecular details of regulation have been investigated. Clear that glycolytic enzyme synthesis is coordinated to prevent the build up of toxic metabolic intermediates. The genetic mechanisms responsible for regulating balanced expression of the EntnerDoudoroff and glycolytic genes in Z. mobilis are beginning to be understood. Several layers of genetic control, perhaps in a hierarchal arrangement act in concert to determine the relative abundance of the glycolytic enzymes. These genetic controls involve differential translational efficiency, highly conserved promoter sequences, transcription factors, differential mRNA stabilities, and nucleolytic mRNA processing. The serendipitous cloning of the glucose facilitator, glf, as a result of linkage to several other genes of interest will have a significant impact on the study of Z. mobilis metabolism. The glucose facilitator is being characterized in a genetically reconstituted system in E. coli. Molecular genetic studies indicate that the ratio of glf expression to that of glk, zmf, and edd is carefully regulated, and suggests a critical role in metabolic control. Regulation of glycolytic gene expression is now sufficiently well understood to allow use of the glycolytic genes as tools to manipulate specified enzyme levels for the purpose of analyzing metabolic flux control. The critical genes have been subcloned for stable expression in Z. mobilis and placed under control of a regulated promoter system involving the tac promoter, the lacI repressor, and gene induction in by IPTG. HPLC methods have been developed that allow quantitation of virtually all of the metabolic intermediates in the cell pool.

  13. The human NAD metabolome: Functions, metabolism and compartmentalization

    PubMed Central

    Nikiforov, Andrey; Kulikova, Veronika; Ziegler, Mathias

    2015-01-01

    Abstract The metabolism of NAD has emerged as a key regulator of cellular and organismal homeostasis. Being a major component of both bioenergetic and signaling pathways, the molecule is ideally suited to regulate metabolism and major cellular events. In humans, NAD is synthesized from vitamin B3 precursors, most prominently from nicotinamide, which is the degradation product of all NAD-dependent signaling reactions. The scope of NAD-mediated regulatory processes is wide including enzyme regulation, control of gene expression and health span, DNA repair, cell cycle regulation and calcium signaling. In these processes, nicotinamide is cleaved from NAD+ and the remaining ADP-ribosyl moiety used to modify proteins (deacetylation by sirtuins or ADP-ribosylation) or to generate calcium-mobilizing agents such as cyclic ADP-ribose. This review will also emphasize the role of the intermediates in the NAD metabolome, their intra- and extra-cellular conversions and potential contributions to subcellular compartmentalization of NAD pools. PMID:25837229

  14. The human NAD metabolome: Functions, metabolism and compartmentalization.

    PubMed

    Nikiforov, Andrey; Kulikova, Veronika; Ziegler, Mathias

    2015-01-01

    The metabolism of NAD has emerged as a key regulator of cellular and organismal homeostasis. Being a major component of both bioenergetic and signaling pathways, the molecule is ideally suited to regulate metabolism and major cellular events. In humans, NAD is synthesized from vitamin B3 precursors, most prominently from nicotinamide, which is the degradation product of all NAD-dependent signaling reactions. The scope of NAD-mediated regulatory processes is wide including enzyme regulation, control of gene expression and health span, DNA repair, cell cycle regulation and calcium signaling. In these processes, nicotinamide is cleaved from NAD(+) and the remaining ADP-ribosyl moiety used to modify proteins (deacetylation by sirtuins or ADP-ribosylation) or to generate calcium-mobilizing agents such as cyclic ADP-ribose. This review will also emphasize the role of the intermediates in the NAD metabolome, their intra- and extra-cellular conversions and potential contributions to subcellular compartmentalization of NAD pools.

  15. Controlling Cell Function with Geometry

    NASA Astrophysics Data System (ADS)

    Mrksich, Milan

    2012-02-01

    This presentation will describe the use of patterned substrates to control cell shape with examples that illustrate the ways in which cell shape can regulate cell function. Most cells are adherent and must attach to and spread on a surface in order to survive, proliferate and function. In tissue, this surface is the extracellular matrix (ECM), an insoluble scaffold formed by the assembly of several large proteins---including fibronectin, the laminins and collagens and others---but in the laboratory, the surface is prepared by adsorbing protein to glass slides. To pattern cells, gold-coated slides are patterned with microcontact printing to create geometric features that promote cell attachment and that are surrounded by inert regions. Cells attach to these substrates and spread to adopt the shape defined by the underlying pattern and remain stable in culture for several days. Examples will be described that used a series of shapes to reveal the relationship between the shape of the cell and the structure of its cytoskeleton. These geometric cues were used to control cell polarity and the tension, or contractility, present in the cytoskeleton. These rules were further used to control the shapes of mesenchymal stem cells and in turn to control the differentiation of these cells into specialized cell types. For example, stem cells that were patterned into a ``star'' shape preferentially differentiated into bone cells whereas those that were patterned into a ``flower'' shape preferred a fat cell fate. These influences of shape on differentiation depend on the mechanical properties of the cytoskeleton. These examples, and others, reveal that shape is an important cue that informs cell function and that can be combined with the more common soluble cues to direct and study cell function.

  16. Akt-mTORC1 signaling regulates Acly to integrate metabolic input to control of macrophage activation

    PubMed Central

    Covarrubias, Anthony J; Aksoylar, Halil Ibrahim; Yu, Jiujiu; Snyder, Nathaniel W; Worth, Andrew J; Iyer, Shankar S; Wang, Jiawei; Ben-Sahra, Issam; Byles, Vanessa; Polynne-Stapornkul, Tiffany; Espinosa, Erika C; Lamming, Dudley; Manning, Brendan D; Zhang, Yijing; Blair, Ian A; Horng, Tiffany

    2016-01-01

    Macrophage activation/polarization to distinct functional states is critically supported by metabolic shifts. How polarizing signals coordinate metabolic and functional reprogramming, and the potential implications for control of macrophage activation, remains poorly understood. Here we show that IL-4 signaling co-opts the Akt-mTORC1 pathway to regulate Acly, a key enzyme in Ac-CoA synthesis, leading to increased histone acetylation and M2 gene induction. Only a subset of M2 genes is controlled in this way, including those regulating cellular proliferation and chemokine production. Moreover, metabolic signals impinge on the Akt-mTORC1 axis for such control of M2 activation. We propose that Akt-mTORC1 signaling calibrates metabolic state to energetically demanding aspects of M2 activation, which may define a new role for metabolism in supporting macrophage activation. DOI: http://dx.doi.org/10.7554/eLife.11612.001 PMID:26894960

  17. Akt-mTORC1 signaling regulates Acly to integrate metabolic input to control of macrophage activation.

    PubMed

    Covarrubias, Anthony J; Aksoylar, Halil Ibrahim; Yu, Jiujiu; Snyder, Nathaniel W; Worth, Andrew J; Iyer, Shankar S; Wang, Jiawei; Ben-Sahra, Issam; Byles, Vanessa; Polynne-Stapornkul, Tiffany; Espinosa, Erika C; Lamming, Dudley; Manning, Brendan D; Zhang, Yijing; Blair, Ian A; Horng, Tiffany

    2016-02-19

    Macrophage activation/polarization to distinct functional states is critically supported by metabolic shifts. How polarizing signals coordinate metabolic and functional reprogramming, and the potential implications for control of macrophage activation, remains poorly understood. Here we show that IL-4 signaling co-opts the Akt-mTORC1 pathway to regulate Acly, a key enzyme in Ac-CoA synthesis, leading to increased histone acetylation and M2 gene induction. Only a subset of M2 genes is controlled in this way, including those regulating cellular proliferation and chemokine production. Moreover, metabolic signals impinge on the Akt-mTORC1 axis for such control of M2 activation. We propose that Akt-mTORC1 signaling calibrates metabolic state to energetically demanding aspects of M2 activation, which may define a new role for metabolism in supporting macrophage activation.

  18. Metabolic Control Analysis: A Tool for Designing Strategies to Manipulate Metabolic Pathways

    PubMed Central

    Moreno-Sánchez, Rafael; Saavedra, Emma; Rodríguez-Enríquez, Sara; Olín-Sandoval, Viridiana

    2008-01-01

    The traditional experimental approaches used for changing the flux or the concentration of a particular metabolite of a metabolic pathway have been mostly based on the inhibition or over-expression of the presumed rate-limiting step. However, the attempts to manipulate a metabolic pathway by following such approach have proved to be unsuccessful. Metabolic Control Analysis (MCA) establishes how to determine, quantitatively, the degree of control that a given enzyme exerts on flux and on the concentration of metabolites, thus substituting the intuitive, qualitative concept of rate limiting step. Moreover, MCA helps to understand (i) the underlying mechanisms by which a given enzyme exerts high or low control and (ii) why the control of the pathway is shared by several pathway enzymes and transporters. By applying MCA it is possible to identify the steps that should be modified to achieve a successful alteration of flux or metabolite concentration in pathways of biotechnological (e.g., large scale metabolite production) or clinical relevance (e.g., drug therapy). The different MCA experimental approaches developed for the determination of the flux-control distribution in several pathways are described. Full understanding of the pathway properties when is working under a variety of conditions can help to attain a successful manipulation of flux and metabolite concentration. PMID:18629230

  19. Ongoing resolution of duplicate gene functions shapes the diversification of a metabolic network

    PubMed Central

    Kuang, Meihua Christina; Hutchins, Paul D; Russell, Jason D; Coon, Joshua J; Hittinger, Chris Todd

    2016-01-01

    The evolutionary mechanisms leading to duplicate gene retention are well understood, but the long-term impacts of paralog differentiation on the regulation of metabolism remain underappreciated. Here we experimentally dissect the functions of two pairs of ancient paralogs of the GALactose sugar utilization network in two yeast species. We show that the Saccharomyces uvarum network is more active, even as over-induction is prevented by a second co-repressor that the model yeast Saccharomyces cerevisiae lacks. Surprisingly, removal of this repression system leads to a strong growth arrest, likely due to overly rapid galactose catabolism and metabolic overload. Alternative sugars, such as fructose, circumvent metabolic control systems and exacerbate this phenotype. We further show that S. cerevisiae experiences homologous metabolic constraints that are subtler due to how the paralogs have diversified. These results show how the functional differentiation of paralogs continues to shape regulatory network architectures and metabolic strategies long after initial preservation. DOI: http://dx.doi.org/10.7554/eLife.19027.001 PMID:27690225

  20. Beyond intestinal soap--bile acids in metabolic control.

    PubMed

    Kuipers, Folkert; Bloks, Vincent W; Groen, Albert K

    2014-08-01

    Over the past decade, it has become apparent that bile acids are involved in a host of activities beyond their classic functions in bile formation and fat absorption. The identification of the farnesoid X receptor (FXR) as a nuclear receptor directly activated by bile acids and the discovery that bile acids are also ligands for the membrane-bound, G-protein coupled bile acid receptor 1 (also known as TGR5) have opened new avenues of research. Both FXR and TGR5 regulate various elements of glucose, lipid and energy metabolism. Consequently, a picture has emerged of bile acids acting as modulators of (postprandial) metabolism. Therefore, strategies that interfere with either bile acid metabolism or signalling cascades mediated by bile acids may represent novel therapeutic approaches for metabolic diseases. Synthetic modulators of FXR have been designed and tested, primarily in animal models. Furthermore, the use of bile acid sequestrants to reduce plasma cholesterol levels has unexpected benefits. For example, treatment of patients with type 2 diabetes mellitus (T2DM) with sequestrants causes substantial reductions in plasma levels of glucose and HbA1c. This Review aims to provide an overview of the molecular mechanisms by which bile acids modulate glucose and energy metabolism, particularly focusing on the glucose-lowering actions of bile acid sequestrants in insulin resistant states and T2DM.

  1. A dynamic method for the investigation of induced state metabolic capacities as a function of temperature

    PubMed Central

    2013-01-01

    Background Science-based recombinant bioprocess designs as well as the design of statistical experimental plans for process optimization (Design of Experiments, DoE) demand information on physiological bioprocess boundaries, such as the onset of acetate production, adaptation times, mixed feed metabolic capabilities or induced state maximum metabolic rates as at the desired cultivation temperature. Dynamic methods provide experimental alternatives to determine this information in a fast and efficient way. Information on maximum metabolic capabilities as a function of temperature is needed in case a reduced cultivation temperature is desirable (e.g. to avoid inclusion body formation) and an appropriate feeding profile is to be designed. Results Here, we present a novel dynamic method for the determination of the specific growth rate as a function of temperature for induced recombinant bacterial bioprocesses. The method is based on the control of the residual substrate concentration at non-limiting conditions with dynamic changes in cultivation temperature. The presented method was automated in respect to information extraction and closed loop control by means of in-line Fourier Transformation Infrared Spectroscopy (FTIR) residual substrate measurements and on-line first principle rate-based soft-sensors. Maximum induced state metabolic capabilities as a function of temperature were successfully extracted for a recombinant E. coli C41 fed-batch bioprocess without the need for sampling in a time frame of 20 hours. Conclusions The presented method was concluded to allow the fast and automated extraction of maximum metabolic capabilities (specific growth rate) as a function of temperature. This complements the dynamic toolset necessary for science-based recombinant bacterial bioprocess design and DoE design. PMID:24127686

  2. Metabolic and Physical Control of Cell Elongation Rate

    PubMed Central

    Green, P. B.; Erickson, R. O.; Buggy, J.

    1971-01-01

    Several levels of control of elongation rate are revealed through the detailed study of responses of the Nitella internode to abrupt shifts in turgor. The immediate response, which apparently reflects the physical state of the cell, is approximately described by the equation r = (P — Y)m where r is rate, P is pressure, Y is the wall's yielding threshold, and m is related to the wall's apparent fluidity (reciprocal viscosity). Because P and Y are in the range 5 to 6 atmospheres, and (P — Y) is roughly 0.2 atmosphere, elongation rate is initially extremely sensitive to changes in P. A small step-down in turgor (0.7 atmosphere) stops growth, and a similar rise greatly accelerates it. These initial responses are, however, soon (15 minutes) compensated by changes in Y. An apparent metabolism-dependent reaction (azide-sensitive) lowers Y; strain hardening (azide-insensitive) raises it. These two opposing processes, acting on Y, serve as a governor on (P — Y), tending to maintain it at a given value despite changes in P. This ability to compensate is itself a function of turgor. Turgor step-downs are less and less well compensated, leading to lower rate, as turgor falls from 5 atmospheres to about 2 atmospheres where growth appears not to resume. This is the lowest attainable yield value, Y1. The turgor dependency of compensation reflects a turgor requirement of the Y-lowering (“wall-softening”) process. Thus the relation between steady state, rs, and turgor is an indirect one, derived from time-dependent alterations of the cell wall. This relationship superficially resembles the instantaneously valid one in that, roughly, rs = (P — Y1)ms. Y1 and ms, however, have much lower values than Y and m. The duality of the elongation rate versus turgor relation and the prominent role of Y in regulating rate are the major features of growth control in Nitella. PMID:16657635

  3. The role of metabolic reprogramming in T cell fate and function

    PubMed Central

    Patsoukis, Nikolaos; Bardhan, Kankana; Weaver, Jessica; Herbel, Christoph; Seth, Pankaj; Li, Lequn; Boussiotis, Vassiliki A.

    2016-01-01

    T lymphocytes undergo extensive changes in their metabolic properties during their transition through various differentiation states, from naïve to effector to memory or regulatory roles. The cause and effect relationship between metabolism and differentiation is a field of intense investigation. Many recent studies demonstrate the dependency of T cell functional outcomes on metabolic pathways and the possibility of metabolic intervention to modify these functions. In this review, we describe the basic metabolic features of T cells and new findings on how these correlate with various differentiation fates and functions. We also highlight the latest information regarding the main factors that affect T cell metabolic reprogramming. PMID:28356677

  4. Lipopolysaccharide markedly changes glucose metabolism and mitochondrial function in the longissimus muscle of pigs.

    PubMed

    Sun, H; Huang, Y; Yin, C; Guo, J; Zhao, R; Yang, X

    2016-07-01

    Most previous studies on the effects of lipopolysaccharide (LPS) in pigs focused on the body's immune response, and few reports paid attention to body metabolism changes. To better understand the glucose metabolism changes in skeletal muscle following LPS challenge and to clarify the possible mechanism, 12 growing pigs were employed. Animals were treated with either 2 ml of saline or 15 µg/kg BW LPS, and samples were collected 6 h later. The glycolysis status and mitochondrial function in the longissimus dorsi (LD) muscle of pigs were analyzed. The results showed that serum lactate content and NADH content in LD muscle significantly increased compared with the control group. Most glycolysis-related genes expression, as well as hexokinase, pyruvate kinase and lactic dehydrogenase activity, in LD muscle was significantly higher compared with the control group. Mitochondrial complexes I and IV significantly increased, while mitochondrial ATP concentration markedly decreased. Significantly increased calcium content in the mitochondria was observed, and endoplasm reticulum (ER) stress has been demonstrated in the present study. The results showed that LPS treatment markedly changes glucose metabolism and mitochondrial function in the LD muscle of pigs, and increased calcium content induced by ER stress was possibly involved. The results provide new clues for clarifying metabolic diseases in muscle induced by LPS.

  5. Vitamin D Metabolism and Function in the Skin

    PubMed Central

    Bikle, Daniel D

    2011-01-01

    The keratinocytes of the skin are unique in being not only the primary source of vitamin D for the body, but in possessing the enzymatic machinery to metabolize vitamin D to its active metabolite 1,25(OH)2D. Furthermore, these cells also express the vitamin D receptor (VDR) that enables them to respond to the 1,25(OH)2D they produce. Numerous functions of the skin are regulated by 1,25(OH)2D and/or its receptor. These include inhibition of proliferation, stimulation of differentiation including formation of the permeability barrier, promotion of innate immunity, and promotion of the hair follicle cycle. Regulation of these actions is exerted by a number of different coregulators including the coactivators DRIP and SRC, the cosuppressor hairless (Hr), and β-catenin. This review will examine the regulation of vitamin D production and metabolism in the skin, and explore the various functions regulated by 1,25(OH)2D and its receptor. PMID:21664236

  6. Metabolism and biological functions of human milk oligosaccharides.

    PubMed

    Bertino, E; Peila, C; Giuliani, F; Martano, C; Cresi, F; Di Nicola, P; Occhi, L; Sabatino, G; Fabris, C

    2012-01-01

    It is well known that breastfeeding is beneficial both for its nutritional properties and for the presence of biologically active compounds. Among these, human milk oligosaccharides (HMOs), representing the third largest fraction of human milk, have been assigned important biological functions, such as prebiotic and immunomodulatory and antimicrobial effects. HMOs are synthesized in the mammary gland by glycosyltransferase enzymes and can be divided in core-oligosaccharides, sialo-oligosaccharides, fucosyl-oligosaccharides and sialo-fucosyl-oligosaccharides on the basis of their chemical structure. Glycosyltransferases enzymes are partially regulated by genetic mechanisms; according to the expression of secretory and Lewis' genes, it is possible to classify human milk in 4 different secretory groups. We hereby present a review of the current knowledge concerning HMOs, their metabolism and main biological functions.

  7. Physical, metabolic and developmental functions of the seed coat

    PubMed Central

    Radchuk, Volodymyr; Borisjuk, Ljudmilla

    2014-01-01

    The conventional understanding of the role of the seed coat is that it provides a protective layer for the developing zygote. Recent data show that the picture is more nuanced. The seed coat certainly represents a first line of defense against adverse external factors, but it also acts as channel for transmitting environmental cues to the interior of the seed. The latter function primes the seed to adjust its metabolism in response to changes in its external environment. The purpose of this review is to provide the reader with a comprehensive view of the structure and functionality of the seed coat, and to expose its hidden interaction with both the endosperm and embryo. Any breeding and/or biotechnology intervention seeking to increase seed size or modify seed features will have to consider the implications on this tripartite interaction. PMID:25346737

  8. Effect of Dance Exercise on Cognitive Function in Elderly Patients with Metabolic Syndrome: A Pilot Study

    PubMed Central

    Kim, Se-Hong; Kim, Minjeong; Ahn, Yu-Bae; Lim, Hyun-Kook; Kang, Sung-Goo; Cho, Jung-hyoun; Park, Seo-Jin; Song, Sang-Wook

    2011-01-01

    Metabolic syndrome is associated with an increased risk of cognitive impairment. The purpose of this prospective pilot study was to examine the effects of dance exercise on cognitive function in elderly patients with metabolic syndrome. The participants included 38 elderly metabolic syndrome patients with normal cognitive function (26 exercise group and 12 control group). The exercise group performed dance exercise twice a week for 6 months. Cognitive function was assessed in all participants using the Korean version of the Consortium to Establish a Registry for Alzheimer’s disease (CERAD-K). Repeated-measures ANCOVA was used to assess the effect of dance exercise on cognitive function and cardiometabolic risk factors. Compared with the control group, the exercise group significantly improved in verbal fluency (p = 0.048), word list delayed recall (p = 0.038), word list recognition (p = 0.007), and total CERAD-K score (p = 0.037). However, no significance difference was found in body mass index, blood pressure, waist circumference, fasting plasma glucose, triglyceride, and HDL cholesterol between groups over the 6-month period. In the present study, six months of dance exercise improved cognitive function in older adults with metabolic syndrome. Thus, dance exercise may reduce the risk for cognitive disorders in elderly people with metabolic syndrome. Key points Metabolic syndrome (MS) is associated with an increased risk of cognitive impairment. Aerobic exercise improves cognitive function in elderly people and contributes to the prevention of degenerative neurological disease and brain damage. Dance sport is a form of aerobic exercise that has the additional benefits of stimulating the emotions, promoting social interaction, and exposing subjects to acoustic stimulation and music. In the present study, dance exercise for a 6-month period improved cognitive function in older adults with MS. In particular, positive effects were observed in verbal fluency, word

  9. Effect of dance exercise on cognitive function in elderly patients with metabolic syndrome: a pilot study.

    PubMed

    Kim, Se-Hong; Kim, Minjeong; Ahn, Yu-Bae; Lim, Hyun-Kook; Kang, Sung-Goo; Cho, Jung-Hyoun; Park, Seo-Jin; Song, Sang-Wook

    2011-01-01

    Metabolic syndrome is associated with an increased risk of cognitive impairment. The purpose of this prospective pilot study was to examine the effects of dance exercise on cognitive function in elderly patients with metabolic syndrome. The participants included 38 elderly metabolic syndrome patients with normal cognitive function (26 exercise group and 12 control group). The exercise group performed dance exercise twice a week for 6 months. Cognitive function was assessed in all participants using the Korean version of the Consortium to Establish a Registry for Alzheimer's disease (CERAD-K). Repeated-measures ANCOVA was used to assess the effect of dance exercise on cognitive function and cardiometabolic risk factors. Compared with the control group, the exercise group significantly improved in verbal fluency (p = 0.048), word list delayed recall (p = 0.038), word list recognition (p = 0.007), and total CERAD-K score (p = 0.037). However, no significance difference was found in body mass index, blood pressure, waist circumference, fasting plasma glucose, triglyceride, and HDL cholesterol between groups over the 6-month period. In the present study, six months of dance exercise improved cognitive function in older adults with metabolic syndrome. Thus, dance exercise may reduce the risk for cognitive disorders in elderly people with metabolic syndrome. Key pointsMetabolic syndrome (MS) is associated with an increased risk of cognitive impairment.Aerobic exercise improves cognitive function in elderly people and contributes to the prevention of degenerative neurological disease and brain damage. Dance sport is a form of aerobic exercise that has the additional benefits of stimulating the emotions, promoting social interaction, and exposing subjects to acoustic stimulation and music.In the present study, dance exercise for a 6-month period improved cognitive function in older adults with MS. In particular, positive effects were observed in verbal fluency, word list

  10. Using exercise training to understand control of skeletal muscle metabolism.

    PubMed

    Gibala, Martin J

    2017-01-01

    Bengt Saltin believed that exercise was the unsurpassed tool to study human integrative physiology. He demonstrated this over the course of his career by employing physical training as a model to advance our understanding of skeletal muscle metabolic control and the impact of physical activity on performance and health. Bengt was also a pioneer in advocating the concept of exercise is medicine. His scientific curiosity was perhaps exceeded only by his generosity.

  11. Leptin and the CNS Control of Glucose Metabolism

    PubMed Central

    Morton, Gregory J.; Schwartz, Michael W.

    2012-01-01

    The regulation of body fat stores and blood glucose levels is critical for survival. This review highlights growing evidence that leptin action in the central nervous system (CNS) plays a key role in both processes. Investigation into underlying mechanisms has begun to clarify the physiological role of leptin in the control of glucose metabolism and raises interesting new possibilities for the treatment of diabetes and related disorders. PMID:21527729

  12. Intraspecific variation in flight metabolic rate in the bumblebee Bombus impatiens: repeatability and functional determinants in workers and drones.

    PubMed

    Darveau, Charles-A; Billardon, Fannie; Bélanger, Kasandra

    2014-02-15

    The evolution of flight energetics requires that phenotypes be variable, repeatable and heritable. We studied intraspecific variation in flight energetics in order to assess the repeatability of flight metabolic rate and wingbeat frequency, as well as the functional basis of phenotypic variation in workers and drones of the bumblebee species Bombus impatiens. We showed that flight metabolic rate and wingbeat frequency were highly repeatable in workers, even when controlling for body mass variation using residual analysis. We did not detect significant repeatability in drones, but a smaller range of variation might have prevented us from finding significant values in our sample. Based on our results and previous findings, we associated the high repeatability of flight phenotypes in workers to the functional links between body mass, thorax mass, wing size, wingbeat frequency and metabolic rate. Moreover, differences between workers and drones were as predicted from these functional associations, where drones had larger wings for their size, lower wingbeat frequency and lower flight metabolic rate. We also investigated thoracic muscle metabolic phenotypes by measuring the activity of carbohydrate metabolism enzymes, and we found positive correlations between mass-independent metabolic rate and the activity of all enzymes measured, but in workers only. When comparing workers and drones that differ in flight metabolic rate, only the activity of the enzymes hexokinase and trehalase showed the predicted differences. Overall, our study indicates that there should be correlated evolution among physiological phenotypes at multiple levels of organization and morphological traits associated with flight.

  13. Sequence- and Structure-Based Functional Annotation and Assessment of Metabolic Transporters in Aspergillus oryzae: A Representative Case Study

    PubMed Central

    Raethong, Nachon; Wong-ekkabut, Jirasak; Laoteng, Kobkul; Vongsangnak, Wanwipa

    2016-01-01

    Aspergillus oryzae is widely used for the industrial production of enzymes. In A. oryzae metabolism, transporters appear to play crucial roles in controlling the flux of molecules for energy generation, nutrients delivery, and waste elimination in the cell. While the A. oryzae genome sequence is available, transporter annotation remains limited and thus the connectivity of metabolic networks is incomplete. In this study, we developed a metabolic annotation strategy to understand the relationship between the sequence, structure, and function for annotation of A. oryzae metabolic transporters. Sequence-based analysis with manual curation showed that 58 genes of 12,096 total genes in the A. oryzae genome encoded metabolic transporters. Under consensus integrative databases, 55 unambiguous metabolic transporter genes were distributed into channels and pores (7 genes), electrochemical potential-driven transporters (33 genes), and primary active transporters (15 genes). To reveal the transporter functional role, a combination of homology modeling and molecular dynamics simulation was implemented to assess the relationship between sequence to structure and structure to function. As in the energy metabolism of A. oryzae, the H+-ATPase encoded by the AO090005000842 gene was selected as a representative case study of multilevel linkage annotation. Our developed strategy can be used for enhancing metabolic network reconstruction. PMID:27274991

  14. Selenium and the control of thyroid hormone metabolism.

    PubMed

    Köhrle, Josef

    2005-08-01

    Thyroid hormone synthesis, metabolism and action require adequate availability of the essential trace elements iodine and selenium, which affect homeostasis of thyroid hormone-dependent metabolic pathways. The three selenocysteine-containing iodothyronine deiodinases constitute a novel gene family. Selenium is retained and deiodinase expression is maintained at almost normal levels in the thyroid gland, the brain and several other endocrine tissues during selenium deficiency, thus guaranteeing adequate local and systemic levels of the active thyroid hormone T(3). Due to their low tissue concentrations and their mRNA SECIS elements deiodinases rank high in the cellular and tissue-specific hierarchy of selenium distribution among various selenoproteins. While systemic selenium status and expression of abundant selenoproteins (glutathione peroxidase or selenoprotein P) is already impaired in patients with cancer, disturbed gastrointestinal resorption, unbalanced nutrition or patients requiring intensive care treatment, selenium-dependent deiodinase function might still be adequate. However, disease-associated alterations in proinflammatory cytokines, growth factors, hormones and pharmaceuticals modulate deiodinase isoenzyme expression independent from altered selenium status and might thus pretend causal relationships between systemic selenium status and altered thyroid hormone metabolism. Limited or inadequate supply of both trace elements, iodine and selenium, leads to complex rearrangements of thyroid hormone metabolism enabling adaptation to unfavorable conditions.

  15. Muscle metabolic function and free-living physical activity.

    PubMed

    Hunter, Gary R; Larson-Meyer, D Enette; Sirikul, Bovorn; Newcomer, Bradley R

    2006-11-01

    We have previously shown that muscle metabolic function measured during exercise is related to exercise performance and subsequent 1-yr weight gain. Because it is well established that physical activity is important in weight maintenance, we examined muscle function relationships with free-living energy expenditure and physical activity. Subjects were 71 premenopausal black and white women. Muscle metabolism was evaluated by (31)P magnetic resonance spectroscopy during 90-s isometric plantar flexion contractions (45% maximum). Free-living energy expenditure (TEE) was measured using doubly labeled water, activity-related energy expenditure (AEE) was calculated as 0.9 x TEE - sleeping energy expenditure from room calorimetry, and free-living physical activity (ARTE) was calculated by dividing AEE by energy cost of standard physical activities. At the end of exercise, anaerobic glycolytic rate (ANGLY) and muscle concentration of phosphomonoesters (PME) were negatively related to TEE, AEE, and ARTE (P < 0.05). Multiple regression analysis showed that both PME (partial r = -0.29, <0.02) and ANGLY (partial r = -0.24, P < 0.04) were independently related to ARTE. PME, primarily glucose-6-phosphate and fructose-6-phosphate, was significantly related to ratings of perceived exertion (r = 0.21, P < or = 0.05) during a maximal treadmill test. PME was not related to ARTE after inclusion of RPE in the multiple regression model, suggesting that PME may be obtaining its relationship with ARTE through an increased perception of effort during physical activity. In conclusion, physically inactive individuals tend to be more dependent on anaerobic glycolysis during exercise while relying on a glycolytic pathway that may not be functioning optimally.

  16. Experimental nonalcoholic steatohepatitis compromises ureagenesis, an essential hepatic metabolic function.

    PubMed

    Thomsen, Karen Louise; Grønbæk, Henning; Glavind, Emilie; Hebbard, Lionel; Jessen, Niels; Clouston, Andrew; George, Jacob; Vilstrup, Hendrik

    2014-08-01

    Nonalcoholic steatohepatitis (NASH) is increasing in prevalence, yet its consequences for liver function are unknown. We studied ureagenesis, an essential metabolic liver function of importance for whole body nitrogen homeostasis, in a rodent model of diet-induced NASH. Rats were fed a high-fat, high-cholesterol diet for 4 and 16 wk, resulting in early and advanced experimental NASH, respectively. We examined the urea cycle enzyme mRNAs in liver tissue, the hepatocyte urea cycle enzyme proteins, and the in vivo capacity of urea-nitrogen synthesis (CUNS). Early NASH decreased all of the urea cycle mRNAs to an average of 60% and the ornithine transcarbamylase protein to 10%, whereas the CUNS remained unchanged. Advanced NASH further decreased the carbamoyl phosphate synthetase protein to 63% and, in addition, decreased the CUNS by 20% [from 5.65 ± 0.23 to 4.58 ± 0.30 μmol × (min × 100 g)(-1); P = 0.01]. Early NASH compromised the genes and enzyme proteins involved in ureagenesis, whereas advanced NASH resulted in a functional reduction in the capacity for ureagenesis. The pattern of urea cycle perturbations suggests a prevailing mitochondrial impairment by NASH. The decrease in CUNS has consequences for the ability of the body to adjust to changes in the requirements for nitrogen homeostasis e.g., at stressful events. NASH, thus, in terms of metabolic consequences, is not an innocuous lesion, and the manifestations of the damage seem to be a continuum with increasing disease severity.

  17. Exploring metabolic pathways and regulation through functional chemoproteomic and metabolomic platforms.

    PubMed

    Medina-Cleghorn, Daniel; Nomura, Daniel K

    2014-09-18

    Genome sequencing efforts have revealed a strikingly large number of uncharacterized genes, including poorly or uncharacterized metabolic enzymes, metabolites, and metabolic networks that operate in normal physiology, and those enzymes and pathways that may be rewired under pathological conditions. Although deciphering the functions of the uncharacterized metabolic genome is a challenging prospect, it also presents an opportunity for identifying novel metabolic nodes that may be important in disease therapy. In this review, we will discuss the chemoproteomic and metabolomic platforms used in identifying, characterizing, and targeting nodal metabolic pathways important in physiology and disease, describing an integrated workflow for functional mapping of metabolic enzymes.

  18. Retinol Dehydrogenases Regulate Vitamin A Metabolism for Visual Function

    PubMed Central

    Sahu, Bhubanananda; Maeda, Akiko

    2016-01-01

    The visual system produces visual chromophore, 11-cis-retinal from dietary vitamin A, all-trans-retinol making this vitamin essential for retinal health and function. These metabolic events are mediated by a sequential biochemical process called the visual cycle. Retinol dehydrogenases (RDHs) are responsible for two reactions in the visual cycle performed in retinal pigmented epithelial (RPE) cells, photoreceptor cells and Müller cells in the retina. RDHs in the RPE function as 11-cis-RDHs, which oxidize 11-cis-retinol to 11-cis-retinal in vivo. RDHs in rod photoreceptor cells in the retina work as all-trans-RDHs, which reduce all-trans-retinal to all-trans-retinol. Dysfunction of RDHs can cause inherited retinal diseases in humans. To facilitate further understanding of human diseases, mouse models of RDHs-related diseases have been carefully examined and have revealed the physiological contribution of specific RDHs to visual cycle function and overall retinal health. Herein we describe the function of RDHs in the RPE and the retina, particularly in rod photoreceptor cells, their regulatory properties for retinoid homeostasis and future therapeutic strategy for treatment of retinal diseases. PMID:27879662

  19. Is there more to learn about functional vitamin D metabolism?

    PubMed

    DeLuca, Hector F

    2015-04-01

    The state of information on the enzymes responsible for the conversion of vitamin D3 to 1α,25-dhydroxyvitamin D3 (1,25-(OH)2D3), the metabolic active form responsible for the well-known function of vitamin D on calcium metabolism and bone mineralization has been briefly reviewed. There remains an unidentified enzyme responsible for 25% of the 25-hydroxylation of vitamin D3, while 75% of serum 25-hydroxyvitamin D3 (25-OH-D3) arises from CYP2R1. The well-established suppression of multiple sclerosis (MS) by sunlight has been confirmed using the mouse model, experimental autoimmune encephalomyelitis (EAE). This suppression results from a narrow band of ultraviolet light (300-315nm) that does not increase serum 25-OH-D3. Thus, UV light suppresses EAE by a mechanism not involving vitamin D. Vitamin D deficiency unexpectedly suppresses the development of EAE. Further, vitamin D receptor knockout in susceptible mice also prevents the development of EAE. On the other hand, deletion of CYP2R1 and the 1α-hydroxylase, CYP27B1, does not impair the development of EAE. Thus, either vitamin D itself or a heretofore-unknown metabolite is needed for the development of a component of the immune system necessary for development of EAE. This article is part of a Special Issue entitled '17th Vitamin D Workshop'.

  20. Effects of metabolic syndrome on language functions in aging.

    PubMed

    Cahana-Amitay, Dalia; Spiro, Avron; Cohen, Jason A; Oveis, Abigail C; Ojo, Emmanuel A; Sayers, Jesse T; Obler, Loraine K; Albert, Martin L

    2015-02-01

    This study explored effects of the metabolic syndrome (MetS) on language in aging. MetS is a constellation of five vascular and metabolic risk factors associated with the development of chronic diseases and increased risk of mortality, as well as brain and cognitive impairments. We tested 281 English-speaking older adults aged 55-84, free of stroke and dementia. Presence of MetS was based on the harmonized criteria (Alberti et al., 2009). Language performance was assessed by measures of accuracy and reaction time on two tasks of lexical retrieval and two tasks of sentence processing. Regression analyses, adjusted for age, education, gender, diabetes, hypertension, and heart disease, demonstrated that participants with MetS had significantly lower accuracy on measures of lexical retrieval (action naming) and sentence processing (embedded sentences, both subject and object relative clauses). Reaction time was slightly faster on the test of embedded sentences among those with MetS. MetS adversely affects the language performance of older adults, impairing accuracy of both lexical retrieval and sentence processing. This finding reinforces and extends results of earlier research documenting the negative influence of potentially treatable medical conditions (diabetes, hypertension) on language performance in aging. The unanticipated finding that persons with MetS were faster in processing embedded sentences may represent an impairment of timing functions among older individuals with MetS.

  1. Moonlighting transcriptional activation function of a fungal sulfur metabolism enzyme

    PubMed Central

    Levati, Elisabetta; Sartini, Sara; Bolchi, Angelo; Ottonello, Simone; Montanini, Barbara

    2016-01-01

    Moonlighting proteins, including metabolic enzymes acting as transcription factors (TF), are present in a variety of organisms but have not been described in higher fungi so far. In a previous genome-wide analysis of the TF repertoire of the plant-symbiotic fungus Tuber melanosporum, we identified various enzymes, including the sulfur-assimilation enzyme phosphoadenosine-phosphosulfate reductase (PAPS-red), as potential transcriptional activators. A functional analysis performed in the yeast Saccharomyces cerevisiae, now demonstrates that a specific variant of this enzyme, PAPS-red A, localizes to the nucleus and is capable of transcriptional activation. TF moonlighting, which is not present in the other enzyme variant (PAPS-red B) encoded by the T. melanosporum genome, relies on a transplantable C-terminal polypeptide containing an alternating hydrophobic/hydrophilic amino acid motif. A similar moonlighting activity was demonstrated for six additional proteins, suggesting that multitasking is a relatively frequent event. PAPS-red A is sulfur-state-responsive and highly expressed, especially in fruitbodies, and likely acts as a recruiter of transcription components involved in S-metabolism gene network activation. PAPS-red B, instead, is expressed at low levels and localizes to a highly methylated and silenced region of the genome, hinting at an evolutionary mechanism based on gene duplication, followed by epigenetic silencing of this non-moonlighting gene variant. PMID:27121330

  2. THE IMPACT OF SLEEP DISTURBANCES ON ADIPOCYTE FUNCTION AND LIPID METABOLISM

    PubMed Central

    Broussard, Josiane

    2010-01-01

    Classically, sleep has been considered to serve an essential restorative function for the brain. However, there are an increasing number of studies linking decreased sleep quantity and/or quality in humans to an increased obesity and diabetes risk. Reductions in sleep quantity or quality lead to an increase in hunger and appetite, which chronically could predispose an individual to obesity. Carefully controlled studies have shown that two nights of insufficient sleep is causally linked to a decrease in disposition index, the most commonly used predictor of an individual’s diabetes risk, and impairments in glucose tolerance and insulin sensitivity. Thus, sleep appears to play a critical role in modulating energy metabolism in peripheral tissues. Here we will discuss recent work implicating adipose tissue as a potential direct target of disruption of sleep quality, and explore the potential mechanistic links between sleep, adipose tissue and the global control of energy metabolism in humans. PMID:21112024

  3. [Review on periodontal disease and metabolic control of diabetes mellitus].

    PubMed

    Steffens, João Paulo; Glaci Reinke, Stella Maria; Angel Muñoz, Miguel; Santos, Fábio André dos; Luiz Pilatti, Gibson

    2010-09-01

    There may be an interaction between periodontal disease and some systemic diseases such as diabetes mellitus. The objective of this review was to verify, by means of a review of clinical trials, if there is a positive association between periodontal disease and the glycemic control of type 2 diabetes mellitus (DM-2) patients. Eleven articles that fi t the study criteria were revised. It was concluded that periodontal disease may influence the metabolic control of DM-2. Additional studies with larger sample sizes and longer follow up are necessary for a better clarification of this issue.

  4. Molecular and cellular regulation of hypothalamic melanocortin neurons controlling food intake and energy metabolism.

    PubMed

    Koch, M; Horvath, T L

    2014-07-01

    The brain receives and integrates environmental and metabolic information, transforms these signals into adequate neuronal circuit activities, and generates physiological behaviors to promote energy homeostasis. The responsible neuronal circuitries show lifetime plasticity and guaranty metabolic health and survival. However, this highly evolved organization has become challenged nowadays by chronic overload with nutrients and reduced physical activity, which results in an ever-increasing number of obese individuals worldwide. Research within the last two decades has aimed to decipher the responsible molecular and cellular mechanisms for regulation of the hypothalamic melanocortin neurons, which have a key role in the control of food intake and energy metabolism. This review maps the central connections of the melanocortin system and highlights its global position and divergent character in physiological and pathological metabolic events. Moreover, recently uncovered molecular and cellular processes in hypothalamic neurons and glial cells that drive plastic morphological and physiological changes in these cells, and account for regulation of food intake and energy metabolism, are brought into focus. Finally, potential functional interactions between metabolic disorders and psychiatric diseases are discussed.

  5. Overexpressing Superoxide Dismutase 2 Induces a Supernormal Cardiac Function by Enhancing Redox-dependent Mitochondrial Function and Metabolic Dilation*

    PubMed Central

    Kang, Patrick T.; Chen, Chwen-Lih; Ohanyan, Vahagn; Luther, Daniel J.; Meszaros, J. Gary; Chilian, William M.; Chen, Yeong-Renn

    2015-01-01

    During heightened cardiac work, O2 consumption by the heart benefits energy production via mitochondria. However, some electrons leak from the respiratory chain and yield superoxide, which is rapidly metabolized into H2O2 by SOD2. To understand the systemic effects of the metabolic dilator, H2O2, we studied mice with cardiac-specific SOD2 overexpression (SOD2-tg), which increases the H2O2 produced by cardiac mitochondria. Contrast echocardiography was employed to evaluate cardiac function, indicating that SOD2-tg had a significantly greater ejection fraction and a lower mean arterial pressure (MAP) that was partially normalized by intravenous injection of catalase. Norepinephrine-mediated myocardial blood flow (MBF) was significantly enhanced in SOD2-tg mice. Coupling of MBF to the double product (Heart Rate × MAP) was increased in SOD2-tg mice, indicating that the metabolic dilator, “spilled” over, inducing systemic vasodilation. The hypothesis that SOD2 overexpression effectively enhances mitochondrial function was further evaluated. Mitochondria of SOD2-tg mice had a decreased state 3 oxygen consumption rate, but maintained the same ATP production flux under the basal and L-NAME treatment conditions, indicating a higher bioenergetic efficiency. SOD2-tg mitochondria produced less superoxide, and had lower redox activity in converting cyclic hydroxylamine to stable nitroxide, and a lower GSSG concentration. EPR analysis of the isolated mitochondria showed a significant decrease in semiquinones at the SOD2-tg Qi site. These results support a more reductive physiological setting in the SOD2-tg murine heart. Cardiac mitochondria exhibited no significant differences in the respiratory control index between WT and SOD2-tg. We conclude that SOD2 overexpression in myocytes enhances mitochondrial function and metabolic vasodilation, leading to a phenotype of supernormal cardiac function. PMID:26374996

  6. Overexpressing superoxide dismutase 2 induces a supernormal cardiac function by enhancing redox-dependent mitochondrial function and metabolic dilation.

    PubMed

    Kang, Patrick T; Chen, Chwen-Lih; Ohanyan, Vahagn; Luther, Daniel J; Meszaros, J Gary; Chilian, William M; Chen, Yeong-Renn

    2015-11-01

    During heightened cardiac work, O2 consumption by the heart benefits energy production via mitochondria. However, some electrons leak from the respiratory chain and yield superoxide, which is rapidly metabolized into H2O2 by SOD2. To understand the systemic effects of the metabolic dilator, H2O2, we studied mice with cardiac-specific SOD2 overexpression (SOD2-tg), which increases the H2O2 produced by cardiac mitochondria. Contrast echocardiography was employed to evaluate cardiac function, indicating that SOD2-tg had a significantly greater ejection fraction and a lower mean arterial pressure (MAP) that was partially normalized by intravenous injection of catalase. Norepinephrine-mediated myocardial blood flow (MBF) was significantly enhanced in SOD2-tg mice. Coupling of MBF to the double product (Heart Rate×MAP) was increased in SOD2-tg mice, indicating that the metabolic dilator, "spilled" over, inducing systemic vasodilation. The hypothesis that SOD2 overexpression effectively enhances mitochondrial function was further evaluated. Mitochondria of SOD2-tg mice had a decreased state 3 oxygen consumption rate, but maintained the same ATP production flux under the basal and L-NAME treatment conditions, indicating a higher bioenergetic efficiency. SOD2-tg mitochondria produced less superoxide, and had lower redox activity in converting cyclic hydroxylamine to stable nitroxide, and a lower GSSG concentration. EPR analysis of the isolated mitochondria showed a significant decrease in semiquinones at the SOD2-tg Qi site. These results support a more reductive physiological setting in the SOD2-tg murine heart. Cardiac mitochondria exhibited no significant differences in the respiratory control index between WT and SOD2-tg. We conclude that SOD2 overexpression in myocytes enhances mitochondrial function and metabolic vasodilation, leading to a phenotype of supernormal cardiac function.

  7. PPAR signaling in the control of cardiac energy metabolism.

    PubMed

    Barger, P M; Kelly, D P

    2000-08-01

    Cardiac energy metabolic shifts occur as a normal response to diverse physiologic and dietary conditions and as a component of the pathophysiologic processes which accompany cardiac hypertrophy, heart failure, and myocardial ischemia. The capacity to produce energy via the utilization of fats by the mammalian postnatal heart is controlled in part at the level of expression of nuclear genes encoding enzymes involved in mitochondrial fatty acid beta-oxidation (FAO). The principal transcriptional regulator of FAO enzyme genes is the peroxisome proliferator-activated receptor alpha (PPARalpha), a member of the ligand-activated nuclear receptor superfamily. Among the ligand activators of PPARalpha are long-chain fatty acids; therefore, increased uptake of fatty acid substrate into the cardiac myocyte induces a transcriptional response leading to increased expression of FAO enzymes. PPARalpha-mediated control of cardiac metabolic gene expression is activated during postnatal development, short-term starvation, and in response to exercise training. In contrast, certain pathophysiologic states, such as pressure overload-induced hypertrophy, result in deactivation of PPARalpha and subsequent dysregulation of FAO enzyme gene expression, which sets the stage for abnormalities in cardiac lipid homeostasis and energy production, some of which are influenced by gender. Thus, PPARalpha not only serves a critical role in normal cardiac metabolic homeostasis, but alterations in PPARalpha signaling likely contribute to the pathogenesis of a variety of disease states. PPARalpha as a ligand-activated transcription factor is a potential target for the development of new therapeutic strategies aimed at the prevention of pathologic cardiac remodeling.

  8. Rebamipide ameliorates atherosclerosis by controlling lipid metabolism and inflammation

    PubMed Central

    Jeong, Jeong-Hee; Na, Hyun Sik; Kim, Eun-Kyung; Lee, Seung Hoon; Jung, KyungAh; Min, Jun-Ki; Cho, Mi-La

    2017-01-01

    Atherosclerosis is a chronic inflammatory disease caused by the accumulation of excess lipid in the aorta and the severity is regulated by T lymphocytes subsets. Rebamipide has therapeutic activity in collagen induced arthritis (CIA) by controlling the balance between T helper (Th) 17 and regulatory T (Treg) cells. In this study, we aimed to determine whether rebamipide reduces the development of atherosclerosis. To investigate the therapeutic effect of rebamipide, ApoE-KO mice fed a western diet were administered rebamipide orally for 8 weeks. Mice were sacrificed followed by the evaluation of plaque formation in the aorta or immunohistochemistry for IL-17 and Foxp3. Serum was also prepared to determine the pro-inflammatory cytokine levels. The ability of rebamipide to regulate lipid metabolism or inflammation was confirmed ex vivo. Results The oral administration of rebamipide decreased plaque formation in atherosclerotic lesions as well as the markers of metabolic disorder in ApoE-deficient mice with atherosclerosis. Pro-inflammatory cytokines were also suppressed by rebamapide. In addition, the population of Th17 was decreased, whereas Treg was increased in the spleen of rebamipide-treated ApoE deficient mice. Rebamipide also ameliorated the severity of obese arthritis and has the capability to reduce the development of atherosclerosis by controlling the balance between Th17 and Treg cells. Thus, rebamipide could be a therapeutic agent to improve the progression of inflammation in metabolic diseases. PMID:28241014

  9. Sense and Nonsense in Metabolic Control of Reproduction

    PubMed Central

    Schneider, Jill E.; Klingerman, Candice M.; Abdulhay, Amir

    2012-01-01

    An exciting synergistic interaction occurs among researchers working at the interface of reproductive biology and energy homeostasis. Reproductive biologists benefit from the theories, experimental designs, and methodologies used by experts on energy homeostasis while they bring context and meaning to the study of energy homeostasis. There is a growing recognition that identification of candidate genes for obesity is little more than meaningless reductionism unless those genes and their expression are placed in a developmental, environmental, and evolutionary context. Reproductive biology provides this context because metabolic energy is the most important factor that controls reproductive success and gonadal hormones affect energy intake, storage, and expenditure. Reproductive hormone secretion changes during development, and reproductive success is key to evolutionary adaptation, the process that most likely molded the mechanisms that control energy balance. It is likely that by viewing energy intake, storage, and expenditure in the context of reproductive success, we will gain insight into human obesity, eating disorders, diabetes, and other pathologies related to fuel homeostasis. This review emphasizes the metabolic hypothesis: a sensory system monitors the availability of oxidizable metabolic fuels and orchestrates behavioral motivation to optimize reproductive success in environments where energy availability fluctuates or is unpredictable. PMID:22649413

  10. Maternal blood metal levels and fetal markers of metabolic function

    SciTech Connect

    Ashley-Martin, Jillian; Dodds, Linda; Arbuckle, Tye E.; Ettinger, Adrienne S.; Shapiro, Gabriel D.; Fisher, Mandy; Taback, Shayne; Bouchard, Maryse F.; Monnier, Patricia; Dallaire, Renee; Fraser, William D.

    2015-01-15

    Exposure to metals commonly found in the environment has been hypothesized to be associated with measures of fetal growth but the epidemiological literature is limited. The Maternal–Infant Research on Environmental Chemicals (MIREC) study recruited 2001 women during the first trimester of pregnancy from 10 Canadian sites. Our objective was to assess the association between prenatal exposure to metals (lead, arsenic, cadmium, and mercury) and fetal metabolic function. Average maternal metal concentrations in 1st and 3rd trimester blood samples were used to represent prenatal metals exposure. Leptin and adiponectin were measured in 1363 cord blood samples and served as markers of fetal metabolic function. Polytomous logistic regression models were used to estimate odds ratios (OR) and 95% confidence intervals (CI) for the association between metals and both high (≥90%) and low (≤10%) fetal adiponectin and leptin levels. Leptin levels were significantly higher in female infants compared to males. A significant relationship between maternal blood cadmium and odds of high leptin was observed among males but not females in adjusted models. When adjusting for birth weight z-score, lead was associated with an increased odd of high leptin. No other significant associations were found at the top or bottom 10th percentile in either leptin or adiponectin models. This study supports the proposition that maternal levels of cadmium influence cord blood adipokine levels in a sex-dependent manner. Further investigation is required to confirm these findings and to determine how such findings at birth will translate into childhood anthropometric measures. - Highlights: • We determined relationships between maternal metal levels and cord blood adipokines. • Cord blood leptin levels were higher among female than male infants. • Maternal cadmium was associated with elevated leptin in male, not female infants. • No significant associations were observed between metals and

  11. Glycogen metabolism protects against metabolic insult to preserve carotid body function during glucose deprivation.

    PubMed

    Holmes, Andrew P; Turner, Philip J; Carter, Paul; Leadbeater, Wendy; Ray, Clare J; Hauton, David; Buckler, Keith J; Kumar, Prem

    2014-10-15

    The view that the carotid body (CB) type I cells are direct physiological sensors of hypoglycaemia is challenged by the finding that the basal sensory neuronal outflow from the whole organ is unchanged in response to low glucose. The reason for this difference in viewpoint and how the whole CB maintains its metabolic integrity when exposed to low glucose is unknown. Here we show that, in the intact superfused rat CB, basal sensory neuronal activity was sustained during glucose deprivation for 29.1 ± 1.2 min, before irreversible failure following a brief period of excitation. Graded increases in the basal discharge induced by reducing the superfusate PO2 led to proportional decreases in the time to the pre-failure excitation during glucose deprivation which was dependent on a complete run-down in glycolysis and a fall in cellular energy status. A similar ability to withstand prolonged glucose deprivation was observed in isolated type I cells. Electron micrographs and immunofluorescence staining of rat CB sections revealed the presence of glycogen granules and the glycogen conversion enzymes glycogen synthase I and glycogen phosphorylase BB, dispersed throughout the type I cell cytoplasm. Furthermore, pharmacological attenuation of glycogenolysis and functional depletion of glycogen both significantly reduced the time to glycolytic run-down by ∼33 and 65%, respectively. These findings suggest that type I cell glycogen metabolism allows for the continuation of glycolysis and the maintenance of CB sensory neuronal output in periods of restricted glucose delivery and this may act as a key protective mechanism for the organ during hypoglycaemia. The ability, or otherwise, to preserve energetic status may thus account for variation in the reported capacity of the CB to sense physiological glucose concentrations and may even underlie its function during pathological states associated with augmented CB discharge.

  12. Role of glycolytic intermediate in regulation: Improving lycopene production in Escherichia coli by engineering metabolic control

    SciTech Connect

    Farmer, W.R.; Liao, J.C.

    2001-06-01

    Metabolic engineering in the postgenomic era is expected to benefit from a full understanding of the biosynthetic capability of microorganisms as a result of the progress being made in bioinformatics and functional genomics. The immediate advantage of such information is to allow the rational design of novel pathways and the elimination of native reactions that are detrimental or unnecessary for the desired purpose. However, with the ability to manipulate metabolic pathways becoming more effective, metabolic engineering will need to face a new challenge: the reengineering of the regulatory hierarchy that controls gene expression in those pathways. In addition to constructing the genetic composition of a metabolic pathway, they propose that it will become just as important to consider the dynamics of pathways gene expression. It has been widely observed that high-level induction of a recombinant protein or pathway leads to growth retardation and reduced metabolic activity. These phenotypic characteristics result from the fact that the constant demands of production placed upon the cell interfere with its changing requirements for growth. They believe that this common situation in metabolic engineering can be alleviated by designing a dynamic controller that is able to sense the metabolic state of the cell and regulate the expression of the recombinant pathway accordingly. This approach, which is termed metabolic control engineering, involves redesigning the native regulatory circuits and applying them to the recombinant pathway. The general goal of such an effort will be to control the flux to the recombinant pathway adaptively according to the cell's metabolic state. The dynamically controlled recombinant pathway can potentially lead to enhanced production, minimized growth retardation, and reduced toxic by-product formation. The regulation of gene expression in response to the physiological state is also essential to the success of gene therapy. Here they

  13. Executive Functioning and the Metabolic Syndrome: A Project FRONTIER Study

    PubMed Central

    Falkowski, Jed; Atchison, Timothy; DeButte-Smith, Maxine; Weiner, Myron F.; O'Bryant, Sid

    2014-01-01

    Decrements in cognitive functioning have been linked to the metabolic syndrome (MetS), a risk factor for cardiovascular disease defined by the presence of three of the following: elevated blood pressure, increased waist circumference, elevated blood glucose, elevated triglycerides, and low high-density lipoprotein cholesterol. We examined the relationship between four measures of executive functioning (EF) and MetS as diagnosed by National Heart, Lung, and Blood Institute-American Heart Association criteria. MetS was examined in a rural population of 395 persons with a mean age of 61.3 years, 71.4% women, 37.0% Hispanic, 53.7% White non-Hispanic. There was a 61.0% prevalence of MetS. We derived a factor score from the four executive function measures which was used to compare those with and without the syndrome, as well as any additive effects of components of the syndrome. Those with MetS exhibited significantly poorer performance than those without the syndrome. However, there was no additive effect, having more components of the syndrome was not related to lower performance. The presence of MetS was associated with poorer EF in this rural cohort of community dwelling volunteers. PMID:24152591

  14. Sphingolipid Metabolism, Oxidant Signaling, and Contractile Function of Skeletal Muscle

    PubMed Central

    Nikolova-Karakashian, Mariana N.

    2011-01-01

    Abstract Significance Sphingolipids are a class of bioactive lipids that regulate diverse cell functions. Ceramide, sphingosine, and sphingosine-1-phosphate accumulate in tissues such as liver, brain, and lung under conditions of cellular stress, including oxidative stress. The activity of some sphingolipid metabolizing enzymes, chiefly the sphingomyelinases, is stimulated during inflammation and in response to oxidative stress. Ceramide, the sphingomyelinase product, as well as the ceramide metabolite, sphingosine-1-phosphate, can induce the generation of more reactive oxygen species, propagating further inflammation. Recent Advances This review article summarizes information on sphingolipid biochemistry and signaling pertinent to skeletal muscle and describes the potential influence of sphingolipids on contractile function. Critical Issues It encompasses topics related to (1) the pathways for complex sphingolipid biosynthesis and degradation, emphasizing sphingolipid regulation in various muscle fiber types and subcellular compartments; (2) the emerging evidence that implicates ceramide, sphingosine, and sphingosine-1-phosphate as regulators of muscle oxidant activity, and (3) sphingolipid effects on contractile function and fatigue. Future Directions We propose that prolonged inflammatory conditions alter ceramide, sphingosine, and sphingosine-1-phosphate levels in skeletal muscle and that these changes promote the weakness, premature fatigue, and cachexia that plague individuals with heart failure, cancer, diabetes, and other chronic inflammatory diseases. Antioxid. Redox Signal. 15, 2501–2517. PMID:21453197

  15. Arginase 1 is an innate lymphoid-cell-intrinsic metabolic checkpoint controlling type 2 inflammation.

    PubMed

    Monticelli, Laurel A; Buck, Michael D; Flamar, Anne-Laure; Saenz, Steven A; Tait Wojno, Elia D; Yudanin, Naomi A; Osborne, Lisa C; Hepworth, Matthew R; Tran, Sara V; Rodewald, Hans-Reimer; Shah, Hardik; Cross, Justin R; Diamond, Joshua M; Cantu, Edward; Christie, Jason D; Pearce, Erika L; Artis, David

    2016-06-01

    Group 2 innate lymphoid cells (ILC2s) regulate tissue inflammation and repair after activation by cell-extrinsic factors such as host-derived cytokines. However, the cell-intrinsic metabolic pathways that control ILC2 function are undefined. Here we demonstrate that expression of the enzyme arginase-1 (Arg1) during acute or chronic lung inflammation is a conserved trait of mouse and human ILC2s. Deletion of mouse ILC-intrinsic Arg1 abrogated type 2 lung inflammation by restraining ILC2 proliferation and dampening cytokine production. Mechanistically, inhibition of Arg1 enzymatic activity disrupted multiple components of ILC2 metabolic programming by altering arginine catabolism, impairing polyamine biosynthesis and reducing aerobic glycolysis. These data identify Arg1 as a key regulator of ILC2 bioenergetics that controls proliferative capacity and proinflammatory functions promoting type 2 inflammation.

  16. Arginase 1 is an innate lymphoid cell-intrinsic metabolic checkpoint controlling type 2 inflammation

    PubMed Central

    Monticelli, Laurel A; Buck, Michael D; Flamar, Anne-Laure; Saenz, Steven A; Wojno, Elia D Tait; Yudanin, Naomi A; Osborne, Lisa C; Hepworth, Matthew R; Tran, Sara V; Rodewald, Hans-Reimer; Shah, Hardik; Cross, Justin R; Diamond, Joshua M; Cantu, Edward; Christie, Jason D; Pearce, Erika L; Artis, David

    2016-01-01

    Group 2 innate lymphoid cells (ILC2s) regulate tissue inflammation and repair following activation by cell-extrinsic factors including host-derived cytokines. However, the cell-intrinsic metabolic pathways that control ILC2 function are undefined. Here we demonstrate that expression of the enzyme Arginase 1 (Arg1) is a conserved trait of murine and human ILC2s during acute or chronic lung inflammation. Deletion of murine ILC-intrinsic Arg1 abrogated type 2 lung inflammation by restraining ILC2 proliferation and dampening cytokine production. Mechanistically, inhibition of Arg1 enzymatic activity disrupted multiple components of ILC2 metabolic programming by altering arginine catabolism, impairing polyamine biosynthesis and reducing aerobic glycolysis. These data identify Arg1 as a key regulator of ILC2 bioenergetics, controlling proliferative capacity and pro-inflammatory functions that promote type 2 inflammation. PMID:27043409

  17. Strain/strain rate imaging of impaired left atrial function in patients with metabolic syndrome.

    PubMed

    Fang, Ning-Ning; Sui, Dong-Xin; Yu, Jin-Gui; Gong, Hui-Ping; Zhong, Ming; Zhang, Yun; Zhang, Wei

    2015-11-01

    Left ventricular (LV) dysfunction has been demonstrated in patients with metabolic syndrome (MetS). However, alterations in left atrial (LA) function in MetS are unknown. We aimed to use strain/strain rate (SR) imaging to investigate the effect of MetS on LA function. A total of 177 MetS patients and 156 normal subjects underwent echocardiography. Strain and SR tissue Doppler imaging values were used to evaluate LA function. Partial correlation and multiple stepwise regression analyses were used to determine the risk factors for impaired LA function. Compared with the controls, the MetS patients showed significantly lower levels of mean strain, mean peak systolic SR and mean peak early diastolic SR (P<0.001 for all), with no difference in the mean peak late diastolic SR. Central obesity, hypertension, dyslipidemia and LV diastolic abnormality were independent risk factors for impaired LA function. LA function was impaired in patients with MetS as a result of metabolic disturbance and LV diastolic abnormality. SR imaging is reliable in assessing LA function in MetS patients.

  18. Metabolic control by target of rapamycin and autophagy during ageing - a mini-review.

    PubMed

    Markaki, Maria; Tavernarakis, Nektarios

    2013-01-01

    The conserved target of rapamycin (TOR) pathway integrates signals from nutrient and energy availability, growth factors and stress to regulate cell growth and proliferation, development and metabolism. Growing evidence suggests that TOR signalling controls the rate at which cells and tissues age, thereby contributing to whole-organism ageing. Although significant progress has been made in the last decades towards understanding fundamental aspects of the ageing process, the precise mechanisms underlying the age-related effects of TOR are still not fully understood. TOR interfaces with several cellular processes, such as DNA transcription, mRNA translation, protein turnover and autophagy, among others. Interestingly, TOR regulates various aspects of metabolism including mitochondrial function and lipid metabolism. Inhibition of TOR activity stimulates autophagy, a conserved lysosomal catabolic pathway that controls the degradation and turnover of macromolecules and organelles. Autophagy also has an important role in maintaining metabolic homeostasis at both the cellular and whole-organism level. Ageing in diverse organisms ranging from yeast to mammals appears to be associated with insufficient autophagy. Here, we summarize recent developments that outline how TOR and autophagy modulate the ageing process, with special emphasis on their role in the regulation of metabolism. A better understanding of the complex interplay between TOR, autophagy and ageing will pave the way for the development of novel therapeutic strategies to treat age-related pathologies.

  19. Metabolite Valves: Dynamic Control of Metabolic Flux for Pathway Engineering

    NASA Astrophysics Data System (ADS)

    Prather, Kristala

    2015-03-01

    Microbial strains have been successfully engineered to produce a wide variety of chemical compounds, several of which have been commercialized. As new products are targeted for biological synthesis, yield is frequently considered a primary driver towards determining feasibility. Theoretical yields can be calculated, establishing an upper limit on the potential conversion of starting substrates to target compounds. Such yields typically ignore loss of substrate to byproducts, with the assumption that competing reactions can be eliminated, usually by deleting the genes encoding the corresponding enzymes. However, when an enzyme encodes an essential gene, especially one involved in primary metabolism, deletion is not a viable option. Reducing gene expression in a static fashion is possible, but this solution ignores the metabolic demand needed for synthesis of the enzymes required for the desired pathway. We have developed Metabolite valves to address this challenge. The valves are designed to allow high flux through the essential enzyme during an initial period where growth is favored. Following an external perturbation, enzyme activity is then reduced, enabling a higher precursor pool to be diverted towards the pathway of interest. We have designed valves with control at both the transcriptional and post-translational levels. In both cases, key enzymes in glucose metabolism are regulated, and two different compounds are targeted for heterologous production. We have measured increased concentrations of intracellular metabolites once the valve is closed, and have demonstrated that these increased pools lead to increased product yields. These metabolite valves should prove broadly useful for dynamic control of metabolic flux, resulting in improvements in product yields.

  20. Understanding the control of acyl flux through the lipid metabolic network of plant oil biosynthesis.

    PubMed

    Bates, Philip D

    2016-09-01

    Plant oil biosynthesis involves a complex metabolic network with multiple subcellular compartments, parallel pathways, cycles, and pathways that have a dual function to produce essential membrane lipids and triacylglycerol. Modern molecular biology techniques provide tools to alter plant oil compositions through bioengineering, however with few exceptions the final composition of triacylglycerol cannot be predicted. One reason for limited success in oilseed bioengineering is the inadequate understanding of how to control the flux of fatty acids through various fatty acid modification, and triacylglycerol assembly pathways of the lipid metabolic network. This review focuses on the mechanisms of acyl flux through the lipid metabolic network, and highlights where uncertainty resides in our understanding of seed oil biosynthesis. This article is part of a Special Issue entitled: Plant Lipid Biology edited by Kent D. Chapman and Ivo Feussner.

  1. Metabolism and Ovarian Function in PCOS Women: A Therapeutic Approach with Inositols

    PubMed Central

    Rossetti, Paola; Buscema, Massimo; Condorelli, Rosita Angela; Gullo, Giuseppe; Triolo, Onofrio

    2016-01-01

    Polycystic ovary syndrome (PCOS) is characterized by chronical anovulation and hyperandrogenism which may be present in a different degree of severity. Insulin-resistance and hyperinsulinemia are the main physiopathological basis of this syndrome and the failure of inositol-mediated signaling may concur to them. Myo (MI) and D-chiro-inositol (DCI), the most studied inositol isoforms, are classified as insulin sensitizers. In form of glycans, DCI-phosphoglycan and MI-phosphoglycan control key enzymes were involved in glucose and lipid metabolism. In form of phosphoinositides, they play an important role as second messengers in several cellular biological functions. Considering the key role played by insulin-resistance and androgen excess in PCOS patients, the insulin-sensitizing effects of both MI and DCI were tested in order to ameliorate symptoms and signs of this syndrome, including the possibility to restore patients' fertility. Accumulating evidence suggests that both isoforms of inositol are effective in improving ovarian function and metabolism in patients with PCOS, although MI showed the most marked effect on the metabolic profile, whereas DCI reduced hyperandrogenism better. The purpose of this review is to provide an update on inositol signaling and correlate data on biological functions of these multifaceted molecules, in view of a rational use for the therapy in women with PCOS. PMID:27579037

  2. Minireview: Nuclear Receptor-Controlled Steroid Hormone Synthesis and Metabolism

    PubMed Central

    He, Jinhan; Cheng, Qiuqiong; Xie, Wen

    2010-01-01

    Steroid hormones are essential in normal physiology whereas disruptions in hormonal homeostasis represent an important etiological factor for many human diseases. Steroid hormones exert most of their functions through the binding and activation of nuclear hormone receptors (NRs or NHRs), a superfamily of DNA-binding and often ligand-dependent transcription factors. In recent years, accumulating evidence has suggested that NRs can also regulate the biosynthesis and metabolism of steroid hormones. This review will focus on the recent progress in our understanding of the regulatory role of NRs in hormonal homeostasis and the implications of this regulation in physiology and diseases. PMID:19762543

  3. Yeast diversity of sourdoughs and associated metabolic properties and functionalities.

    PubMed

    De Vuyst, Luc; Harth, Henning; Van Kerrebroeck, Simon; Leroy, Frédéric

    2016-12-19

    Together with acidifying lactic acid bacteria, yeasts play a key role in the production process of sourdough, where they are either naturally present or added as a starter culture. Worldwide, a diversity of yeast species is encountered, with Saccharomyces cerevisiae, Candida humilis, Kazachstania exigua, Pichia kudriavzevii, Wickerhamomyces anomalus, and Torulaspora delbrueckii among the most common ones. Sourdough-adapted yeasts are able to withstand the stress conditions encountered during their growth, including nutrient starvation as well as the effects of acidic, oxidative, thermal, and osmotic stresses. From a technological point of view, their metabolism primarily contributes to the leavening and flavour of sourdough products. Besides ethanol and carbon dioxide, yeasts can produce metabolites that specifically affect flavour, such as organic acids, diacetyl, higher alcohols from branched-chain amino acids, and esters derived thereof. Additionally, several yeast strains possess functional properties that can potentially lead to nutritional and safety advantages. These properties encompass the production of vitamins, an improvement of the bioavailability of phenolic compounds, the dephosphorylation of phytic acid, the presence of probiotic potential, and the inhibition of fungi and their mycotoxin production. Strains of diverse species are new candidate functional starter cultures, offering opportunities beyond the conventional use of baker's yeast.

  4. Effect of metabolic syndrome on sexual function in pre- and postmenopausal women.

    PubMed

    Otunctemur, Alper; Dursun, Murat; Ozbek, Emin; Sahin, Suleyman; Besiroglu, Huseyin; Koklu, Ismail; Polat, Emre Can; Erkoc, Mustafa; Danis, Eyyup; Bozkurt, Muammer

    2015-01-01

    Female sexual dysfunction is a prevalent and multidimensional disorder related to many biological, psychological, and social determinants. The authors assessed the effect of one of the many factors affect sexual function-metabolic syndrome-on female sexual function. They equally divided 400 women participants among 4 groups: (a) premenopausal with metabolic syndrome, (b) premenopausal without metabolic syndrome, (c) postmenopausal with metabolic syndrome, and (d) postmenopausal without metabolic syndrome. The authors used the Female Sexual Function Index to assess women's sexual function. Female sexual dysfunction was found more often in both pre- and postmenopausal women with metabolic syndrome (p =.001). Overall Female Sexual Function Index score and satisfaction, pain, and desire domain scores independently of the menopause status showed statistically significant differences across women with metabolic syndrome in comparison with participants with no metabolic syndrome (p <.05). The authors also evaluated the associations among 5 components of metabolic syndrome and Female Sexual Function Index scores. Higher fasting glucose levels were significantly associated with the Female Sexual Function Index score (p <.05). This study shows that sexual dysfunction is more prevalent in pre- and postmenopausal women with the metabolic syndrome.

  5. Metabolic footprinting in microbiology: methods and applications in functional genomics and biotechnology.

    PubMed

    Mapelli, Valeria; Olsson, Lisbeth; Nielsen, Jens

    2008-09-01

    Metabolomics embraces several strategies that aim to quantify cell metabolites in order to increase our understanding of how metabolite levels and interactions influence phenotypes. Metabolic footprinting represents a niche within metabolomics, because it focuses on the analysis of extracellular metabolites. Although metabolic footprinting represents only a fraction of the entire metabolome, it provides important information for functional genomics and strain characterization, and it can also provide scientists with a key understanding of cell communication mechanisms, metabolic engineering and industrial biotechnological processes. Due to the tight and convoluted relationship between intracellular metabolism and metabolic footprinting, metabolic footprinting can provide precious information about the intracellular metabolic status. Hereby, we state that integrative information from metabolic footprinting can assist in further interpretation of metabolic networks.

  6. ERRα metabolic nuclear receptor controls growth of colon cancer cells.

    PubMed

    Bernatchez, Gérald; Giroux, Véronique; Lassalle, Thomas; Carpentier, André C; Rivard, Nathalie; Carrier, Julie C

    2013-10-01

    The estrogen-related receptor alpha (ERRα) is a nuclear receptor that acts primarily as a regulator of metabolic processes, particularly in tissues subjected to high-energy demand. In addition to its control of energy metabolism and mitochondrial biogenesis, ERRα has recently been associated with cancer progression. Notably, increased expression of ERRα has been shown in several cancerous tissues, including breast, ovary and colon. However, additional studies are required to gain insight into the action of ERRα in cancer biology, particularly in non-endocrine-related cancers. Therefore, using a short hairpin RNA-mediated approach, we investigated whether ERRα is required for the rapid growth of colon cancer cells and to maintain their neoplastic metabolic state. Results show that silencing ERRα significantly impaired colon cancer cell proliferation and colony formation in vitro as well as their in vivo tumorigenic capacity. A pronounced delay in G1-to-S cell cycle phase transition was observed in ERRα-depleted cells in association with reduced cyclin-dependent kinase 2 activity and hyperphosphorylated state of the retinoblastoma protein along with disturbed expression of several cell cycle regulators, including p15 and p27. Interestingly, ERRα-depleted HCT116 cells also displayed significant reduction in expression of a large set of key genes to glycolysis, tricarboxylic acid cycle and lipid synthesis. Furthermore, using (14)C isotope tracer analysis, ERRα depletion in colon cancer cells resulted in reduced glucose incorporation and glucose-mediated lipogenesis in these cells. These findings suggest that ERRα coordinates colon cancer cell proliferation and tumorigenic capacity with energy metabolism. Thus, ERRα could represent a promising therapeutic target in colon cancer.

  7. The Secret Life of NAD+: An Old Metabolite Controlling New Metabolic Signaling Pathways

    PubMed Central

    Houtkooper, Riekelt H.; Cantó, Carles; Wanders, Ronald J.; Auwerx, Johan

    2010-01-01

    A century after the identification of a coenzymatic activity for NAD+, NAD+ metabolism has come into the spotlight again due to the potential therapeutic relevance of a set of enzymes whose activity is tightly regulated by the balance between the oxidized and reduced forms of this metabolite. In fact, the actions of NAD+ have been extended from being an oxidoreductase cofactor for single enzymatic activities to acting as substrate for a wide range of proteins. These include NAD+-dependent protein deacetylases, poly(ADP-ribose) polymerases, and transcription factors that affect a large array of cellular functions. Through these effects, NAD+ provides a direct link between the cellular redox status and the control of signaling and transcriptional events. Of particular interest within the metabolic/endocrine arena are the recent results, which indicate that the regulation of these NAD+-dependent pathways may have a major contribution to oxidative metabolism and life span extension. In this review, we will provide an integrated view on: 1) the pathways that control NAD+ production and cycling, as well as its cellular compartmentalization; 2) the signaling and transcriptional pathways controlled by NAD+; and 3) novel data that show how modulation of NAD+-producing and -consuming pathways have a major physiological impact and hold promise for the prevention and treatment of metabolic disease. PMID:20007326

  8. Predicting epistasis: an experimental test of metabolic control theory with bacterial transcription and translation.

    PubMed

    MacLean, R C

    2010-03-01

    Epistatic interactions between mutations are thought to play a crucial role in a number of evolutionary processes, including adaptation and sex. Evidence for epistasis is abundant, but tests of general theoretical models that can predict epistasis are lacking. In this study, I test the ability of metabolic control theory to predict epistasis using a novel experimental approach that combines phenotypic and genetic perturbations of enzymes involved in gene expression and protein synthesis in the bacterium Pseudomonas aeruginosa. These experiments provide experimental support for two key predictions of metabolic control theory: (i) epistasis between genes involved in the same pathway is antagonistic; (ii) epistasis becomes increasingly antagonistic as mutational severity increases. Metabolic control theory is a general theory that applies to any set of genes that are involved in the same linear processing chain, not just metabolic pathways, and I argue that this theory is likely to have important implications for predicting epistasis between functionally coupled genes, such as those involved in antibiotic resistance. Finally, this study highlights the fact that phenotypic manipulations of gene activity provide a powerful method for studying epistasis that complements existing genetic methods.

  9. Lifestyle Intervention on Metabolic Syndrome and its Impact on Quality of Life: A Randomized Controlled Trial

    PubMed Central

    Saboya, Patrícia Pozas; Bodanese, Luiz Carlos; Zimmermann, Paulo Roberto; Gustavo, Andreia da Silva; Macagnan, Fabricio Edler; Feoli, Ana Pandolfo; Oliveira, Margareth da Silva

    2017-01-01

    Background Lifestyle intervention programs can reduce the prevalence of metabolic syndrome (MetS) and, therefore, reduce the risk for cardiac disease, one of the main public health problems nowadays. Objective The aim of this study was to compare the effects of three types of approach for lifestyle change programs in the reduction of metabolic parameters, and to identify its impact on the quality of life (QOL) of individuals with MetS. Methods A randomized controlled trial included 72 individuals with MetS aged 30-59 years. Individuals were randomized into three groups of multidisciplinary intervention [Standard Intervention (SI) - control group; Group Intervention (GI); and Individual Intervention (II)] during 12 weeks. The primary outcome was change in the metabolic parameters, and secondarily, the improvement in QOL measures at three moments: baseline, 3 and 9 months. Results Group and individual interventions resulted in a significant reduction in body mass index, waist circumference, systolic blood pressure at 3 months and the improvement of QOL, although it was significantly associated with the physical functioning domain. However, these changes did not remain 6 months after the end of intervention. Depression and anxiety were significantly associated with worse QOL, although they showed no effect on the response to intervention. Conclusion Multidisciplinary intervention, especially in a group, might be an effective and economically feasible strategy in the control of metabolic parameters of MetS and improvement of QOL compared to SI, even in a dose-effect relationship. PMID:27982160

  10. miR-125b controls monocyte adaptation to inflammation through mitochondrial metabolism and dynamics

    PubMed Central

    Duroux-Richard, Isabelle; Roubert, Christine; Ammari, Meryem; Présumey, Jessy; Grün, Joachim R.; Häupl, Thomas; Grützkau, Andreas; Lecellier, Charles-Henri; Boitez, Valérie; Codogno, Patrice; Escoubet, Johanna; Pers, Yves-Marie; Jorgensen, Christian

    2016-01-01

    Metabolic changes drive monocyte differentiation and fate. Although abnormal mitochondria metabolism and innate immune responses participate in the pathogenesis of many inflammatory disorders, molecular events regulating mitochondrial activity to control life and death in monocytes remain poorly understood. We show here that, in human monocytes, microRNA-125b (miR-125b) attenuates the mitochondrial respiration through the silencing of the BH3-only proapoptotic protein BIK and promotes the elongation of the mitochondrial network through the targeting of the mitochondrial fission process 1 protein MTP18, leading to apoptosis. Proinflammatory activation of monocyte-derived macrophages is associated with a concomitant increase in miR-125b expression and decrease in BIK and MTP18 expression, which lead to reduced oxidative phosphorylation and enhanced mitochondrial fusion. In a chronic inflammatory systemic disorder, CD14+ blood monocytes display reduced miR-125b expression as compared with healthy controls, inversely correlated with BIK and MTP18 messenger RNA expression. Our findings not only identify BIK and MTP18 as novel targets for miR-125b that control mitochondrial metabolism and dynamics, respectively, but also reveal a novel function for miR-125b in regulating metabolic adaptation of monocytes to inflammation. Together, these data unravel new molecular mechanisms for a proapoptotic role of miR-125b in monocytes and identify potential targets for interfering with excessive inflammatory activation of monocytes in inflammatory disorders. PMID:27702798

  11. Metabolic profiling of Lolium perenne shows functional integration of metabolic responses to diverse subtoxic conditions of chemical stress.

    PubMed

    Serra, Anne-Antonella; Couée, Ivan; Renault, David; Gouesbet, Gwenola; Sulmon, Cécile

    2015-04-01

    Plant communities are confronted with a great variety of environmental chemical stresses. Characterization of chemical stress in higher plants has often been focused on single or closely related stressors under acute exposure, or restricted to a selective number of molecular targets. In order to understand plant functioning under chemical stress conditions close to environmental pollution conditions, the C3 grass Lolium perenne was subjected to a panel of different chemical stressors (pesticide, pesticide degradation compound, polycyclic aromatic hydrocarbon, and heavy metal) under conditions of seed-level or root-level subtoxic exposure. Physiological and metabolic profiling analysis on roots and shoots revealed that all of these subtoxic chemical stresses resulted in discrete physiological perturbations and complex metabolic shifts. These metabolic shifts involved stressor-specific effects, indicating multilevel mechanisms of action, such as the effects of glyphosate and its degradation product aminomethylphosphonic acid on quinate levels. They also involved major generic effects that linked all of the subtoxic chemical stresses with major modifications of nitrogen metabolism, especially affecting asparagine, and of photorespiration, especially affecting alanine and glycerate. Stress-related physiological effects and metabolic adjustments were shown to be integrated through a complex network of metabolic correlations converging on Asn, Leu, Ser, and glucose-6-phosphate, which could potentially be modulated by differential dynamics and interconversion of soluble sugars (sucrose, trehalose, fructose, and glucose). Underlying metabolic, regulatory, and signalling mechanisms linking these subtoxic chemical stresses with a generic impact on nitrogen metabolism and photorespiration are discussed in relation to carbohydrate and low-energy sensing.

  12. Relation Between Obesity, Metabolic Syndrome, Successful Long-Term Weight Reduction, and Right Ventricular Function.

    PubMed

    Zeller, Judith; Strack, Christina; Fenk, Sabine; Mohr, Margareta; Loew, Thomas; Schmitz, Gerd; Maier, Lars; Fischer, Marcus; Baessler, Andrea

    2016-07-27

    This study sought to examine the relationships between right ventricular (RV) function and geometry, morbid obesity with and without the metabolic syndrome, and the effect of long-term weight loss. Obese (n = 153, BMI 41.2 ± 8.7 kg/m(2)) and healthy non-obese control subjects (n = 38, BMI 25.5 ± 3.3 kg/m(2)) of similar age and gender distribution were prospectively studied during the course of a 1-year weight reduction program with echocardiography at baseline and after one year of follow up. Function and geometry of the right heart were evaluated by tricuspid annular plane systolic excursion (TAPSE), tricuspid annular systolic velocity (TDI S'), RV myocardial performance index (TEI), RV end-diastolic (RVEDD) and end-systolic diameter (RVESD), area of the right atrium (RAA), and systolic pulmonary artery pressure (PAP). Whereas parameters of systolic and diastolic LV function were significantly worse in the obese subjects than those in the non-obese subjects (EF 66 ± 6 versus 69 ± 6%, P = 0.004; E/E' 7.4 ± 2.5 versus 6.3 ± 2.6, P = 0.010), parameters of RV function (TAPSE 25.6 ± 4.5 versus 25.1 ± 3.5 mm, P = 0.528; TDI S' 13.5 ± 2.9 versus 13.8 ± 2.9 mm/second, P = 0.553; TEI 0.25 ± 0.13 versus 0.28 ± 0.09, P = 0.283) as well as geometry measurements were comparable between the obese and non-obese participants and also in obese subjects with full blown metabolic syndrome. Additionally, successful weight reduction did not alter the RV parameters. Nevertheless, in the few obese subjects with RV dysfunction (n = 7), metabolic syndrome parameters were more pronounced than in obese with normal RV function.Morbid obesity with and without the metabolic syndrome is accompanied by an impaired LV systolic and diastolic function. In contrast, RV function appears to be less affected by obesity independent of the presence of the metabolic syndrome.

  13. Metabolic gatekeeper function of B-lymphoid transcription factors.

    PubMed

    Chan, Lai N; Chen, Zhengshan; Braas, Daniel; Lee, Jae-Woong; Xiao, Gang; Geng, Huimin; Cosgun, Kadriye Nehir; Hurtz, Christian; Shojaee, Seyedmehdi; Cazzaniga, Valeria; Schjerven, Hilde; Ernst, Thomas; Hochhaus, Andreas; Kornblau, Steven M; Konopleva, Marina; Pufall, Miles A; Cazzaniga, Giovanni; Liu, Grace J; Milne, Thomas A; Koeffler, H Phillip; Ross, Theodora S; Sánchez-García, Isidro; Borkhardt, Arndt; Yamamoto, Keith R; Dickins, Ross A; Graeber, Thomas G; Müschen, Markus

    2017-02-23

    B-lymphoid transcription factors, such as PAX5 and IKZF1, are critical for early B-cell development, yet lesions of the genes encoding these transcription factors occur in over 80% of cases of pre-B-cell acute lymphoblastic leukaemia (ALL). The importance of these lesions in ALL has, until now, remained unclear. Here, by combining studies using chromatin immunoprecipitation with sequencing and RNA sequencing, we identify a novel B-lymphoid program for transcriptional repression of glucose and energy supply. Our metabolic analyses revealed that PAX5 and IKZF1 enforce a state of chronic energy deprivation, resulting in constitutive activation of the energy-stress sensor AMPK. Dominant-negative mutants of PAX5 and IKZF1, however, relieved this glucose and energy restriction. In a transgenic pre-B ALL mouse model, the heterozygous deletion of Pax5 increased glucose uptake and ATP levels by more than 25-fold. Reconstitution of PAX5 and IKZF1 in samples from patients with pre-B ALL restored a non-permissive state and induced energy crisis and cell death. A CRISPR/Cas9-based screen of PAX5 and IKZF1 transcriptional targets identified the products of NR3C1 (encoding the glucocorticoid receptor), TXNIP (encoding a glucose-feedback sensor) and CNR2 (encoding a cannabinoid receptor) as central effectors of B-lymphoid restriction of glucose and energy supply. Notably, transport-independent lipophilic methyl-conjugates of pyruvate and tricarboxylic acid cycle metabolites bypassed the gatekeeper function of PAX5 and IKZF1 and readily enabled leukaemic transformation. Conversely, pharmacological TXNIP and CNR2 agonists and a small-molecule AMPK inhibitor strongly synergized with glucocorticoids, identifying TXNIP, CNR2 and AMPK as potential therapeutic targets. Furthermore, our results provide a mechanistic explanation for the empirical finding that glucocorticoids are effective in the treatment of B-lymphoid but not myeloid malignancies. Thus, B-lymphoid transcription factors

  14. How aneuploidy affects metabolic control and causes cancer.

    PubMed Central

    Rasnick, D; Duesberg, P H

    1999-01-01

    The complexity and diversity of cancer-specific phenotypes, including de-differentiation, invasiveness, metastasis, abnormal morphology and metabolism, genetic instability and progression to malignancy, have so far eluded explanation by a simple, coherent hypothesis. However, an adaptation of Metabolic Control Analysis supports the 100-year-old hypothesis that aneuploidy, an abnormal number of chromosomes, is the cause of cancer. The results demonstrate the currently counter-intuitive principle that it is the fraction of the genome undergoing differential expression, not the magnitude of the differential expression, that controls phenotypic transformation. Transforming the robust normal phenotype into cancer requires a twofold increase in the expression of thousands of normal gene products. The massive change in gene dose produces highly non-linear (i.e. qualitative) changes in the physiology and metabolism of cells and tissues. Since aneuploidy disrupts the natural balance of mitosis proteins, it also explains the notorious genetic instability of cancer cells as a consequence of the perpetual regrouping of chromosomes. In view of this and the existence of non-cancerous aneuploidy, we propose that cancer is the phenotype of cells above a certain threshold of aneuploidy. This threshold is reached either by the gradual, stepwise increase in the level of aneuploidy as a consequence of the autocatalysed genetic instability of aneuploid cells or by tetraploidization followed by a gradual loss of chromosomes. Thus the initiation step of carcinogenesis produces aneuploidy below the threshold for cancer, and the promotion step increases the level of aneuploidy above this threshold. We conclude that aneuploidy offers a simple and coherent explanation for all the cancer-specific phenotypes. Accordingly, the gross biochemical abnormalities, abnormal cellular size and morphology, the appearance of tumour-associated antigens, the high levels of secreted proteins responsible for

  15. A Modeling and Simulation Approach to the Study of Metabolic Control Analysis

    ERIC Educational Resources Information Center

    Rodriguez-Caso, Carlos; Sanchez-Jimenez, Francisca; Medina, Miguel Angel

    2002-01-01

    Metabolic control analysis has contributed to the rapid advance in our understanding of metabolic regulation. However, up to now this topic has not been covered properly in biochemistry courses. This work reports the development and implementation of a practical lesson on metabolic control analysis (MCA) using modeling and simulation. The…

  16. Mitochondrial metabolism, reactive oxygen species, and macrophage function-fishing for insights.

    PubMed

    Hall, Christopher J; Sanderson, Leslie E; Crosier, Kathryn E; Crosier, Philip S

    2014-11-01

    Metabolism and defense mechanisms that protect against pathogens are two fundamental requirements for the survival of multicellular organisms. Research into metabolic disease has revealed these core mechanisms are highly co-dependent. This emerging field of research, termed immunometabolism, focuses on understanding how metabolism influences immunological processes and vice versa. It is now accepted that obesity influences the immune system and that obesity-driven inflammation contributes to many diseases including type 2 diabetes, cardiovascular disease and Alzheimer's disease. The immune response requires the reallocation of nutrients within immune cells to different metabolic pathways to satisfy energy demands and the production of necessary macromolecules. One aspect of immunometabolic research is understanding how these metabolic changes help regulate specific immune cell functions. It is hoped that further understanding of the pathways involved in managing this immunological-metabolic interface will reveal new ways to treat metabolic disease. Given their growing status as principle drivers of obesity-associated inflammation, monocytes/macrophages have received much attention when studying the consequences of inflammation within adipose tissue. Less is known regarding how metabolic changes within macrophages (metabolic reprogramming) influence their immune cell function. In this review, we focus on our current understanding of how monocytes/macrophages alter their intracellular metabolism during the immune response and how these changes dictate specific effector functions. In particular, the immunomodulatory functions of mitochondrial metabolism and mitochondrial reactive oxygen species. We also highlight how the attributes of the zebrafish model system can be exploited to reveal new mechanistic insights into immunometabolic processes.

  17. Liver disease alters high-density lipoprotein composition, metabolism and function.

    PubMed

    Trieb, Markus; Horvath, Angela; Birner-Gruenberger, Ruth; Spindelboeck, Walter; Stadlbauer, Vanessa; Taschler, Ulrike; Curcic, Sanja; Stauber, Rudolf E; Holzer, Michael; Pasterk, Lisa; Heinemann, Akos; Marsche, Gunther

    2016-07-01

    High-density lipoproteins (HDL) are important endogenous inhibitors of inflammatory responses. Functional impairment of HDL might contribute to the excess mortality experienced by patients with liver disease, but the effect of cirrhosis on HDL metabolism and function remain elusive. To get an integrated measure of HDL quantity and quality, we assessed several metrics of HDL function using apolipoprotein (apo) B-depleted sera from patients with compensated cirrhosis, patients with acutely decompensated cirrhosis and healthy controls. We observed that sera of cirrhotic patients showed reduced levels of HDL-cholesterol and profoundly suppressed activities of several enzymes involved in HDL maturation and metabolism. Native gel electrophoresis analyses revealed that cirrhotic serum HDL shifts towards the larger HDL2 subclass. Proteomic assessment of isolated HDL identified several proteins, including apoA-I, apoC-III, apoE, paraoxonase 1 and acute phase serum amyloid A to be significantly altered in cirrhotic patients. With regard to function, these alterations in levels, composition and structure of HDL were strongly associated with metrics of function of apoB-depleted sera, including cholesterol efflux capability, paraoxonase activity, the ability to inhibit monocyte production of cytokines and endothelial regenerative activities. Of particular interest, cholesterol efflux capacity appeared to be strongly associated with liver disease mortality. Our findings may be clinically relevant and improve our ability to monitor cirrhotic patients at high risk.

  18. (Physiology and genetics of metabolic flux control in Zymomonas mobilis)

    SciTech Connect

    Conway, T.

    1992-01-01

    The funded research deals with the physiology and genetics of glycolytic flux control in Zymomonas mobilis. Two fundamental biological questions are begin addressed: First, how do the enzymes of glycolytic pathways act in concert to regulate metabolic flux Second, what is the role of gene expression in regulating high level synthesis of the glycolytic enzymes in a balance that allows proper glycolytic flux control The specific objectives of the grant are as follows: 1. To clone the structural and regulatory regions of the Z. mobilis genes encoding glucose-6-phosphate dehydrogenase, phosphoglucose isomerase, enolase, 6-phosphogluconate dehydratase, 2- keto-3-deoxy- 6-phosphogluconate aldolase, glucokinase and fructokinase. 2. To characterize the structure of these genes with respect to nucleotide sequence, transcriptional initiation sites promoter location, evolutionary relatedness to similar genes from other organisms, and organization of these genes on the genome. 3. To investigate the effects of genetically engineered alterations in the levels of the cloned enzymes on metabolic flux and cell growth. 4. To study transcriptional and post-transcriptional regulation of the genes encoding the enzymes of the Entner-Doudoroff pathway. The first two specific objectives have now been fully completed. Significant progress has been made on the fourth objective and work on the third objective is well underway.

  19. Updated knowledge about polyphenols: functions, bioavailability, metabolism, and health.

    PubMed

    Landete, J M

    2012-01-01

    Polyphenols are important constituents of food products of plant origin. Fruits, vegetables, and beverages are the main sources of phenolic compounds in the human diet. These compounds are directly related to sensory characteristics of foods such as flavor, astringency and color. Polyphenols are extensively metabolized both in tissues and by the colonic microbiota. Normally, the circulating polyphenols are glucuronidated and/or sulphated and no free aglycones are found in plasma. The presence of phenolic compounds in the diet is beneficial to health due to their antioxidant, anti-inflammatory, and vasodilating properties. The health effects of polyphenols depend on the amount consumed and their bioavailability. Moreover, polyphenols are able to kill or inhibit the growth of microorganisms such as bacteria, fungi, or protozoans. Some dietary polyphenols may have significant effects on the colonic flora providing a type of prebiotic effect. The anti-nutrient properties of polyphenols are also discussed in this paper. The antioxidant, anti-inflammatory, vasodilating, and prebiotic properties of polyphenols make them potential functional foods.

  20. Functional compartmentalization of oxidative and glycolytic metabolism in frog skin

    SciTech Connect

    Skul'skii, I.A.; Lapin, A.V.

    1985-07-01

    One of the basic functions of the epithelial cells of the skin of amphibians is unidirectional transport of Na/sup +/ from the environment into the blood. This transport is carried out in two stages. First, Na/sup +/ is absorbed from the environment by the epithelial cells through their apical membranes. Next, Na/sup +/ is actively drawn into the blood stream with the help of Na-K pumps which are located on the basolateral membranes. Huf, as early as 1957, proposed that ionic homeostasis of Na-transporting epithelial cells may be maintained at the expense of glycolysis, whereas the unidirectional transport of Na/sup +/ requires exclusively energy from oxidative metabolism. At that time, however, little was known about the nature of the Na-K pump and there were no isotopic data on permeability of epithelial cells to Na/sup +/ and K/sup +/. The authors confirm and update Huf's hypothesis in accordance with current knowledge. It was shown that anaerobic conditions (argon atmosphere) and various respiration inhibitors (rotenone, thallium) selectively inhibit unidirectional transport of Na/sup +/, as measured with the help of /sup 22/Na or short-circuit current, without influencing the concentration of sodium and potassium in the cells. The rate of penetration of Na/sup +/ through the apical membrane decrease by at least twice, but, irrespective of a significant flow of Na/sup +/ through the epithelial layer disappears.

  1. A MED13-dependent skeletal muscle gene program controls systemic glucose homeostasis and hepatic metabolism

    PubMed Central

    Amoasii, Leonela; Holland, William; Sanchez-Ortiz, Efrain; Baskin, Kedryn K.; Pearson, Mackenzie; Burgess, Shawn C.; Nelson, Benjamin R.; Bassel-Duby, Rhonda; Olson, Eric N.

    2016-01-01

    The Mediator complex governs gene expression by linking upstream signaling pathways with the basal transcriptional machinery. However, how individual Mediator subunits may function in different tissues remains to be investigated. Through skeletal muscle-specific deletion of the Mediator subunit MED13 in mice, we discovered a gene regulatory mechanism by which skeletal muscle modulates the response of the liver to a high-fat diet. Skeletal muscle-specific deletion of MED13 in mice conferred resistance to hepatic steatosis by activating a metabolic gene program that enhances muscle glucose uptake and storage as glycogen. The consequent insulin-sensitizing effect within skeletal muscle lowered systemic glucose and insulin levels independently of weight gain and adiposity and prevented hepatic lipid accumulation. MED13 suppressed the expression of genes involved in glucose uptake and metabolism in skeletal muscle by inhibiting the nuclear receptor NURR1 and the MEF2 transcription factor. These findings reveal a fundamental molecular mechanism for the governance of glucose metabolism and the control of hepatic lipid accumulation by skeletal muscle. Intriguingly, MED13 exerts opposing metabolic actions in skeletal muscle and the heart, highlighting the customized, tissue-specific functions of the Mediator complex. PMID:26883362

  2. A MED13-dependent skeletal muscle gene program controls systemic glucose homeostasis and hepatic metabolism.

    PubMed

    Amoasii, Leonela; Holland, William; Sanchez-Ortiz, Efrain; Baskin, Kedryn K; Pearson, Mackenzie; Burgess, Shawn C; Nelson, Benjamin R; Bassel-Duby, Rhonda; Olson, Eric N

    2016-02-15

    The Mediator complex governs gene expression by linking upstream signaling pathways with the basal transcriptional machinery. However, how individual Mediator subunits may function in different tissues remains to be investigated. Through skeletal muscle-specific deletion of the Mediator subunit MED13 in mice, we discovered a gene regulatory mechanism by which skeletal muscle modulates the response of the liver to a high-fat diet. Skeletal muscle-specific deletion of MED13 in mice conferred resistance to hepatic steatosis by activating a metabolic gene program that enhances muscle glucose uptake and storage as glycogen. The consequent insulin-sensitizing effect within skeletal muscle lowered systemic glucose and insulin levels independently of weight gain and adiposity and prevented hepatic lipid accumulation. MED13 suppressed the expression of genes involved in glucose uptake and metabolism in skeletal muscle by inhibiting the nuclear receptor NURR1 and the MEF2 transcription factor. These findings reveal a fundamental molecular mechanism for the governance of glucose metabolism and the control of hepatic lipid accumulation by skeletal muscle. Intriguingly, MED13 exerts opposing metabolic actions in skeletal muscle and the heart, highlighting the customized, tissue-specific functions of the Mediator complex.

  3. Metabolic transistor strategy for controlling electron transfer chain activity in Escherichia coli.

    PubMed

    Wu, Hui; Tuli, Leepika; Bennett, George N; San, Ka-Yiu

    2015-03-01

    A novel strategy to finely control a large metabolic flux by using a "metabolic transistor" approach was established. In this approach a small change in the level or availability of an essential component for the process is controlled by adding a competitive reaction that affects a precursor or an intermediate in its biosynthetic pathway. The change of the basal level of the essential component, considered as a base current in a transistor, has a large effect on the flux through the major pathway. In this way, the fine-tuning of a large flux can be accomplished. The "metabolic transistor" strategy was applied to control electron transfer chain function by manipulation of the quinone synthesis pathway in Escherichia coli. The achievement of a theoretical yield of lactate production under aerobic conditions via this strategy upon manipulation of the biosynthetic pathway of the key participant, ubiquinone-8 (Q8), in an E. coli strain provides an in vivo, genetically tunable means to control the activity of the electron transfer chain and manipulate the production of reduced products while limiting consumption of oxygen to a defined amount.

  4. Mitochondrial metabolism in hematopoietic stem cells requires functional FOXO3

    PubMed Central

    Rimmelé, Pauline; Liang, Raymond; Bigarella, Carolina L; Kocabas, Fatih; Xie, Jingjing; Serasinghe, Madhavika N; Chipuk, Jerry; Sadek, Hesham; Zhang, Cheng Cheng; Ghaffari, Saghi

    2015-01-01

    Hematopoietic stem cells (HSC) are primarily dormant but have the potential to become highly active on demand to reconstitute blood. This requires a swift metabolic switch from glycolysis to mitochondrial oxidative phosphorylation. Maintenance of low levels of reactive oxygen species (ROS), a by-product of mitochondrial metabolism, is also necessary for sustaining HSC dormancy. Little is known about mechanisms that integrate energy metabolism with hematopoietic stem cell homeostasis. Here, we identify the transcription factor FOXO3 as a new regulator of metabolic adaptation of HSC. ROS are elevated in Foxo3−/− HSC that are defective in their activity. We show that Foxo3−/− HSC are impaired in mitochondrial metabolism independent of ROS levels. These defects are associated with altered expression of mitochondrial/metabolic genes in Foxo3−/− hematopoietic stem and progenitor cells (HSPC). We further show that defects of Foxo3−/− HSC long-term repopulation activity are independent of ROS or mTOR signaling. Our results point to FOXO3 as a potential node that couples mitochondrial metabolism with HSC homeostasis. These findings have critical implications for mechanisms that promote malignant transformation and aging of blood stem and progenitor cells. PMID:26209246

  5. Genome-Scale Metabolic Modeling of Archaea Lends Insight into Diversity of Metabolic Function

    PubMed Central

    2017-01-01

    Decades of biochemical, bioinformatic, and sequencing data are currently being systematically compiled into genome-scale metabolic reconstructions (GEMs). Such reconstructions are knowledge-bases useful for engineering, modeling, and comparative analysis. Here we review the fifteen GEMs of archaeal species that have been constructed to date. They represent primarily members of the Euryarchaeota with three-quarters comprising representative of methanogens. Unlike other reviews on GEMs, we specially focus on archaea. We briefly review the GEM construction process and the genealogy of the archaeal models. The major insights gained during the construction of these models are then reviewed with specific focus on novel metabolic pathway predictions and growth characteristics. Metabolic pathway usage is discussed in the context of the composition of each organism's biomass and their specific energy and growth requirements. We show how the metabolic models can be used to study the evolution of metabolism in archaea. Conservation of particular metabolic pathways can be studied by comparing reactions using the genes associated with their enzymes. This demonstrates the utility of GEMs to evolutionary studies, far beyond their original purpose of metabolic modeling; however, much needs to be done before archaeal models are as extensively complete as those for bacteria. PMID:28133437

  6. Correlating structure and function of drug-metabolizing enzymes: progress and ongoing challenges.

    PubMed

    Johnson, Eric F; Connick, J Patrick; Reed, James R; Backes, Wayne L; Desai, Manoj C; Xu, Lianhong; Estrada, D Fernando; Laurence, Jennifer S; Scott, Emily E

    2014-01-01

    This report summarizes a symposium sponsored by the American Society for Pharmacology and Experimental Therapeutics at Experimental Biology held April 20-24 in Boston, MA. Presentations discussed the status of cytochrome P450 (P450) knowledge, emphasizing advances and challenges in relating structure with function and in applying this information to drug design. First, at least one structure of most major human drug-metabolizing P450 enzymes is known. However, the flexibility of these active sites can limit the predictive value of one structure for other ligands. A second limitation is our coarse-grain understanding of P450 interactions with membranes, other P450 enzymes, NADPH-cytochrome P450 reductase, and cytochrome b5. Recent work has examined differential P450 interactions with reductase in mixed P450 systems and P450:P450 complexes in reconstituted systems and cells, suggesting another level of functional control. In addition, protein nuclear magnetic resonance is a new approach to probe these protein/protein interactions, identifying interacting b5 and P450 surfaces, showing that b5 and reductase binding are mutually exclusive, and demonstrating ligand modulation of CYP17A1/b5 interactions. One desired outcome is the application of such information to control drug metabolism and/or design selective P450 inhibitors. A final presentation highlighted development of a CYP3A4 inhibitor that slows clearance of human immunodeficiency virus drugs otherwise rapidly metabolized by CYP3A4. Although understanding P450 structure/function relationships is an ongoing challenge, translational advances will benefit from continued integration of existing and new biophysical approaches.

  7. Correlating Structure and Function of Drug-Metabolizing Enzymes: Progress and Ongoing Challenges

    PubMed Central

    Johnson, Eric F.; Connick, J. Patrick; Reed, James R.; Backes, Wayne L.; Desai, Manoj C.; Xu, Lianhong; Estrada, D. Fernando; Laurence, Jennifer S.

    2014-01-01

    This report summarizes a symposium sponsored by the American Society for Pharmacology and Experimental Therapeutics at Experimental Biology held April 20-24 in Boston, MA. Presentations discussed the status of cytochrome P450 (P450) knowledge, emphasizing advances and challenges in relating structure with function and in applying this information to drug design. First, at least one structure of most major human drug-metabolizing P450 enzymes is known. However, the flexibility of these active sites can limit the predictive value of one structure for other ligands. A second limitation is our coarse-grain understanding of P450 interactions with membranes, other P450 enzymes, NADPH–cytochrome P450 reductase, and cytochrome b5. Recent work has examined differential P450 interactions with reductase in mixed P450 systems and P450:P450 complexes in reconstituted systems and cells, suggesting another level of functional control. In addition, protein nuclear magnetic resonance is a new approach to probe these protein/protein interactions, identifying interacting b5 and P450 surfaces, showing that b5 and reductase binding are mutually exclusive, and demonstrating ligand modulation of CYP17A1/b5 interactions. One desired outcome is the application of such information to control drug metabolism and/or design selective P450 inhibitors. A final presentation highlighted development of a CYP3A4 inhibitor that slows clearance of human immunodeficiency virus drugs otherwise rapidly metabolized by CYP3A4. Although understanding P450 structure/function relationships is an ongoing challenge, translational advances will benefit from continued integration of existing and new biophysical approaches. PMID:24130370

  8. Metabolism

    MedlinePlus

    Metabolism refers to all the physical and chemical processes in the body that convert or use energy, ... Tortora GJ, Derrickson BH. Metabolism. In: Tortora GJ, Derrickson ... Physiology . 14th ed. Hoboken, NJ: John Wiley & Sons; 2014:chap ...

  9. Metabolism

    MedlinePlus

    ... El metabolismo Metabolism Basics Our bodies get the energy they need from food through metabolism, the chemical ... that convert the fuel from food into the energy needed to do everything from moving to thinking ...

  10. The function of oxalic acid in the human metabolism.

    PubMed

    Robertson, Daniel Stewart

    2011-09-01

    Biochemical reactions in cells which involve oxalic acid are described. It is shown that this compound is required for the formation of uracil and orotic acid. The former is a component of RNA which is common to all cells in the human metabolism. On the basis of the biochemical reactions described a possible treatment to relieve the effects of calcium oxalate renal calculi whose origin is related to the metabolic concentration of oxalic acid is proposed.

  11. Pyruvate kinase triggers a metabolic feedback loop that controls redox metabolism in respiring cells.

    PubMed

    Grüning, Nana-Maria; Rinnerthaler, Mark; Bluemlein, Katharina; Mülleder, Michael; Wamelink, Mirjam M C; Lehrach, Hans; Jakobs, Cornelis; Breitenbach, Michael; Ralser, Markus

    2011-09-07

    In proliferating cells, a transition from aerobic to anaerobic metabolism is known as the Warburg effect, whose reversal inhibits cancer cell proliferation. Studying its regulator pyruvate kinase (PYK) in yeast, we discovered that central metabolism is self-adapting to synchronize redox metabolism when respiration is activated. Low PYK activity activated yeast respiration. However, levels of reactive oxygen species (ROS) did not increase, and cells gained resistance to oxidants. This adaptation was attributable to accumulation of the PYK substrate phosphoenolpyruvate (PEP). PEP acted as feedback inhibitor of the glycolytic enzyme triosephosphate isomerase (TPI). TPI inhibition stimulated the pentose phosphate pathway, increased antioxidative metabolism, and prevented ROS accumulation. Thus, a metabolic feedback loop, initiated by PYK, mediated by its substrate and acting on TPI, stimulates redox metabolism in respiring cells. Originating from a single catalytic step, this autonomous reconfiguration of central carbon metabolism prevents oxidative stress upon shifts between fermentation and respiration.

  12. A regulatory framework for shoot stem cell control integrating metabolic, transcriptional, and phytohormone signals.

    PubMed

    Schuster, Christoph; Gaillochet, Christophe; Medzihradszky, Anna; Busch, Wolfgang; Daum, Gabor; Krebs, Melanie; Kehle, Andreas; Lohmann, Jan U

    2014-02-24

    Plants continuously maintain pluripotent stem cells embedded in specialized tissues called meristems, which drive long-term growth and organogenesis. Stem cell fate in the shoot apical meristem (SAM) is controlled by the homeodomain transcription factor WUSCHEL (WUS) expressed in the niche adjacent to the stem cells. Here, we demonstrate that the bHLH transcription factor HECATE1 (HEC1) is a target of WUS and that it contributes to SAM function by promoting stem cell proliferation, while antagonizing niche cell activity. HEC1 represses the stem cell regulators WUS and CLAVATA3 (CLV3) and, like WUS, controls genes with functions in metabolism and hormone signaling. Among the targets shared by HEC1 and WUS are phytohormone response regulators, which we show to act as mobile signals in a universal feedback system. Thus, our work sheds light on the mechanisms guiding meristem function and suggests that the underlying regulatory system is far more complex than previously anticipated.

  13. Storage Reserve Accumulation in Arabidopsis: Metabolic and Developmental Control of Seed Filling

    PubMed Central

    Baud, Sébastien; Dubreucq, Bertrand; Miquel, Martine; Rochat, Christine; Lepiniec, Loïc

    2008-01-01

    In the life cycle of higher plants, seed development is a key process connecting two distinct sporophytic generations. Seed development can be divided into embryo morphogenesis and seed maturation. An essential metabolic function of maturing seeds is the deposition of storage compounds that are mobilised to fuel post-germinative seedling growth. Given the importance of seeds for food and animal feed and considering the tremendous interest in using seed storage products as sustainable industrial feedstocks to replace diminishing fossil reserves, understanding the metabolic and developmental control of seed filling constitutes a major focus of plant research. Arabidopsis thaliana is an oilseed species closely related to the agronomically important Brassica oilseed crops. The main storage compounds accumulated in seeds of A. thaliana consist of oil stored as triacylglycerols (TAGs) and seed storage proteins (SSPs). Extensive tools developed for the molecular dissection of A. thaliana development and metabolism together with analytical and cytological procedures adapted for very small seeds have led to a good description of the biochemical pathways producing storage compounds. In recent years, studies using these tools have shed new light on the intricate regulatory network controlling the seed maturation process. This network involves sugar and hormone signalling together with a set of developmentally regulated transcription factors. Although much remains to be elucidated, the framework of the regulatory system controlling seed filling is coming into focus. PMID:22303238

  14. Control of sugar transport and metabolism in Zymomonas mobilis. Final report

    SciTech Connect

    Conway, T.

    1995-09-01

    This research deals with the physiology and genetics of sugar transport and metabolic control in Zymomonas mobilis. The specific objectives of the grant as as follows: First, the complex interactions of transcriptional, post-transcriptional and translational control mechanisms on regulation of the glf operon will be investigated. Second, the structure and function of the unique glucose facilitator will be examined by a combination of in vitro and in vivo approaches, making use of the genetically reconstituted system in E. coli. Third, the possibility that physical association or indirect interactions between the glucose facilitator and glucokinase are involved in metabolic control will be analyzed. Fourth, the Z. mobilis glucose transport and phosphorylation system will be utilized to metabolically engineer recombinant E. coli with altered cell pool metabolite profiles. Work on the third and fourth objectives is complete, work on the first and second objectives is progressing nicely. Publication of this work has been admittedly slow, due primarily to a change n location of the research program from the University of Nebraska to The Ohio State University. However, it should be noted that much of the unpublished data outlined below represented completed studies, and are contained in graduate student theses which are being prepared for submission this summer. Since a full year remains in the current funding period, and the new laboratory is now up and running, we fully expect to make reasonable progress on the remaining objectives and to publish the results in a timely fashion.

  15. Mitochondrial function, fatty acid metabolism, and immune system are relevant features of pig adipose tissue development.

    PubMed

    Vincent, Annie; Louveau, Isabelle; Gondret, Florence; Lebret, Bénédicte; Damon, Marie

    2012-11-15

    The molecular mechanisms underlying the genetic control of fat development in humans and livestock species still require characterization. To gain insights on gene expression patterns associated with genetic propensity for adiposity, we compared subcutaneous adipose tissue (SCAT) transcriptomics profiles from two contrasted pig breeds for body fatness. Samples were obtained from Large White (LW; lean phenotype) and Basque pigs (B; low growth and high fat content) at 35 kg (n = 5 per breed) or 145 kg body weight (n = 10 per breed). Using a custom adipose tissue microarray, we found 271 genes to be differentially expressed between the two breeds at both stages, out of which 123 were highly expressed in LW pigs and 148 genes were highly expressed in B pigs. Functional enrichment analysis based on gene ontology (GO) terms highlighted gene groups corresponding to the mitochondrial energy metabolism in LW pigs, whereas immune response was found significantly enriched in B pigs. Genes associated with lipid metabolism, such as ELOVL6, a gene involved in fatty acid elongation, had a lower expression in B compared with LW pigs. Furthermore, despite enlarged adipocyte diameters and higher plasma leptin concentration, B pigs displayed reduced lipogenic enzyme activities compared with LW pigs at 145 kg. Altogether, our results suggest that the development of adiposity was associated with a progressive worsening of the metabolic status, leading to a low-grade inflammatory state, and may thus be of significant interest for both livestock production and human health.

  16. Impact of obesity and bariatric surgery on metabolism and coronary circulatory function.

    PubMed

    Valenta, Ines; Dilsizian, Vasken; Quercioli, Alessandra; Jüngling, Freimut D; Ambrosio, Giuseppe; Wahl, Richard; Schindler, Thomas H

    2014-01-01

    Increases in intra-abdominal visceral adipose tissue have been widely appreciated as a risk factor for metabolic disorders such as dyslipidemia, hypertension, insulin resistance, and type 2 diabetes, whereas this is not the case for peripheral or subcutaneous obesity. While the underlying mechanisms that contribute to these differences in adipose tissue activity remain uncertain, increases in visceral fat commonly induce metabolic dysregulation, in part because of increased venous effluent of fatty acids and/or adipokines/cytokines to the liver. Increased body weight, paralleled by an increase in plasma markers of the insulin-resistance syndrome and chronic inflammation, is independently associated with coronary circulatory dysfunction. Recent data suggest that plasma proteins originating from the adipose tissue, such as endocannabinoids (EC), leptin, and adiponectin (termed adipocytes) play a central role in the regulation and control of coronary circulatory function in obesity. Positron emission tomography (PET) in concert with tracer kinetic modeling is a well established technique for quantifying regional myocardial blood flow at rest and in response to various forms of vasomotor stress. Myocardial flow reserve assessed by PET provides a noninvasive surrogate of coronary circulatory function. PET also enables the monitoring and characterization of coronary circulatory function in response to gastric bypass-induced weight loss in initially morbidly obese individuals, to medication and/or behavioral interventions related to weight, diet, and physical activity. Whether the observed improvement in coronary circulatory dysfunction via weight loss may translate to diminution in cardiovascular events awaits clinical confirmation.

  17. Mammalian flavin-containing monooxygenases: structure/function, genetic polymorphisms and role in drug metabolism

    PubMed Central

    Krueger, Sharon K.; Williams, David E.

    2005-01-01

    Flavin-containing monooxygenase (FMO) oxygenates drugs and xenobiotics containing a “soft-nucleophile”, usually nitrogen or sulfur. FMO, like cytochrome P450 (CYP), is a monooxygenase, utilizing the reducing equivalents of NADPH to reduce 1 atom of molecular oxygen to water, while the other atom is used to oxidize the substrate. FMO and CYP also exhibit similar tissue and cellular location, molecular weight, substrate specificity, and exist as multiple enzymes under developmental control. The human FMO functional gene family is much smaller (5 families each with a single member) than CYP. FMO does not require a reductase to transfer electrons from NADPH and the catalytic cycle of the 2 monooxygenases is strikingly different. Another distinction is the lack of induction of FMOs by xenobiotics. In general, CYP is the major contributor to oxidative xenobiotic metabolism. However, FMO activity may be of significance in a number of cases and should not be overlooked. FMO and CYP have overlapping substrate specificities, but often yield distinct metabolites with potentially significant toxicological/pharmacological consequences. The physiological function(s) of FMO are poorly understood. Three of the 5 expressed human FMO genes, FMO1, FMO2 and FMO3, exhibit genetic polymorphisms. The most studied of these is FMO3 (adult human liver) in which mutant alleles contribute to the disease known as trimethylaminuria. The consequences of these FMO genetic polymorphisms in drug metabolism and human health are areas of research requiring further exploration. PMID:15922018

  18. Identification of Functional Differences in Metabolic Networks Using Comparative Genomics and Constraint-Based Models

    PubMed Central

    Hamilton, Joshua J.; Reed, Jennifer L.

    2012-01-01

    Genome-scale network reconstructions are useful tools for understanding cellular metabolism, and comparisons of such reconstructions can provide insight into metabolic differences between organisms. Recent efforts toward comparing genome-scale models have focused primarily on aligning metabolic networks at the reaction level and then looking at differences and similarities in reaction and gene content. However, these reaction comparison approaches are time-consuming and do not identify the effect network differences have on the functional states of the network. We have developed a bilevel mixed-integer programming approach, CONGA, to identify functional differences between metabolic networks by comparing network reconstructions aligned at the gene level. We first identify orthologous genes across two reconstructions and then use CONGA to identify conditions under which differences in gene content give rise to differences in metabolic capabilities. By seeking genes whose deletion in one or both models disproportionately changes flux through a selected reaction (e.g., growth or by-product secretion) in one model over another, we are able to identify structural metabolic network differences enabling unique metabolic capabilities. Using CONGA, we explore functional differences between two metabolic reconstructions of Escherichia coli and identify a set of reactions responsible for chemical production differences between the two models. We also use this approach to aid in the development of a genome-scale model of Synechococcus sp. PCC 7002. Finally, we propose potential antimicrobial targets in Mycobacterium tuberculosis and Staphylococcus aureus based on differences in their metabolic capabilities. Through these examples, we demonstrate that a gene-centric approach to comparing metabolic networks allows for a rapid comparison of metabolic models at a functional level. Using CONGA, we can identify differences in reaction and gene content which give rise to different

  19. A Strategy for Functional Interpretation of Metabolomic Time Series Data in Context of Metabolic Network Information

    PubMed Central

    Nägele, Thomas; Fürtauer, Lisa; Nagler, Matthias; Weiszmann, Jakob; Weckwerth, Wolfram

    2016-01-01

    The functional connection of experimental metabolic time series data with biochemical network information is an important, yet complex, issue in systems biology. Frequently, experimental analysis of diurnal, circadian, or developmental dynamics of metabolism results in a comprehensive and multidimensional data matrix comprising information about metabolite concentrations, protein levels, and/or enzyme activities. While, irrespective of the type of organism, the experimental high-throughput analysis of the transcriptome, proteome, and metabolome has become a common part of many systems biological studies, functional data integration in a biochemical and physiological context is still challenging. Here, an approach is presented which addresses the functional connection of experimental time series data with biochemical network information which can be inferred, for example, from a metabolic network reconstruction. Based on a time-continuous and variance-weighted regression analysis of experimental data, metabolic functions, i.e., first-order derivatives of metabolite concentrations, were related to time-dependent changes in other biochemically relevant metabolic functions, i.e., second-order derivatives of metabolite concentrations. This finally revealed time points of perturbed dependencies in metabolic functions indicating a modified biochemical interaction. The approach was validated using previously published experimental data on a diurnal time course of metabolite levels, enzyme activities, and metabolic flux simulations. To support and ease the presented approach of functional time series analysis, a graphical user interface including a test data set and a manual is provided which can be run within the numerical software environment Matlab®. PMID:27014700

  20. A Strategy for Functional Interpretation of Metabolomic Time Series Data in Context of Metabolic Network Information.

    PubMed

    Nägele, Thomas; Fürtauer, Lisa; Nagler, Matthias; Weiszmann, Jakob; Weckwerth, Wolfram

    2016-01-01

    The functional connection of experimental metabolic time series data with biochemical network information is an important, yet complex, issue in systems biology. Frequently, experimental analysis of diurnal, circadian, or developmental dynamics of metabolism results in a comprehensive and multidimensional data matrix comprising information about metabolite concentrations, protein levels, and/or enzyme activities. While, irrespective of the type of organism, the experimental high-throughput analysis of the transcriptome, proteome, and metabolome has become a common part of many systems biological studies, functional data integration in a biochemical and physiological context is still challenging. Here, an approach is presented which addresses the functional connection of experimental time series data with biochemical network information which can be inferred, for example, from a metabolic network reconstruction. Based on a time-continuous and variance-weighted regression analysis of experimental data, metabolic functions, i.e., first-order derivatives of metabolite concentrations, were related to time-dependent changes in other biochemically relevant metabolic functions, i.e., second-order derivatives of metabolite concentrations. This finally revealed time points of perturbed dependencies in metabolic functions indicating a modified biochemical interaction. The approach was validated using previously published experimental data on a diurnal time course of metabolite levels, enzyme activities, and metabolic flux simulations. To support and ease the presented approach of functional time series analysis, a graphical user interface including a test data set and a manual is provided which can be run within the numerical software environment Matlab®.

  1. A spectroscopic approach toward depression diagnosis: local metabolism meets functional connectivity.

    PubMed

    Demenescu, Liliana Ramona; Colic, Lejla; Li, Meng; Safron, Adam; Biswal, B; Metzger, Coraline Danielle; Li, Shijia; Walter, Martin

    2017-03-01

    Abnormal anterior insula (AI) response and functional connectivity (FC) is associated with depression. In addition to clinical features, such as severity, AI FC and its metabolism further predicted therapeutic response. Abnormal FC between anterior cingulate and AI covaried with reduced glutamate level within cingulate cortex. Recently, deficient glial glutamate conversion was found in AI in major depression disorder (MDD). We therefore postulate a local glutamatergic mechanism in insula cortex of depressive patients, which is correlated with symptoms severity and itself influences AI's network connectivity in MDD. Twenty-five MDD patients and 25 healthy controls (HC) matched on age and sex underwent resting state functional magnetic resonance imaging and magnetic resonance spectroscopy scans. To determine the role of local glutamate-glutamine complex (Glx) ratio on whole brain AI FC, we conducted regression analysis with Glx relative to creatine (Cr) ratio as factor of interest and age, sex, and voxel tissue composition as nuisance factors. We found that in MDD, but not in HC, AI Glx/Cr ratio correlated positively with AI FC to right supramarginal gyrus and negatively with AI FC toward left occipital cortex (p < 0.05 family wise error). AI Glx/Cr level was negatively correlated with HAMD score (p < 0.05) in MDD patients. We showed that the local AI ratio of glutamatergic-creatine metabolism is an underlying candidate subserving functional network disintegration of insula toward low level and supramodal integration areas, in MDD. While causality cannot directly be inferred from such correlation, our finding helps to define a multilevel network of response-predicting regions based on local metabolism and connectivity strength.

  2. Controller Chips Preserve Microprocessor Function

    NASA Technical Reports Server (NTRS)

    2012-01-01

    Above the Atlantic Ocean, off the coast of Brazil, there is a dip in the Earth s surrounding magnetic field called the South Atlantic Anomaly. Here, space radiation can reach into Earth s upper atmosphere to interfere with the functioning of satellites, aircraft, and even the International Space Station. "The South Atlantic Anomaly is a hot spot of radiation that the space station goes through at a certain point in orbit," Miria Finckenor, a physicist at Marshall Space Flight Center, describes, "If there s going to be a problem with the electronics, 90 percent of that time, it is going to be in that spot." Space radiation can cause physical damage to microchips and can actually change the software commands in computers. When high-energy particles penetrate a satellite or other spacecraft, the electrical components can absorb the energy and temporarily switch off. If the energy is high enough, it can cause the device to enter a hung state, which can only be addressed by restarting the system. When space radiation affects the operational status of microprocessors, the occurrence is called single event functional interrupt (SEFI). SEFI happens not only to the computers onboard spacecraft in Earth orbit, but to the computers on spacecraft throughout the solar system. "One of the Mars rovers had this problem in the radiation environment and was rebooting itself several times a day. On one occasion, it rebooted 40 times in one day," Finckenor says. "It s hard to obtain any data when you have to constantly reboot and start over."

  3. Distinct metabolic network states manifest in the gene expression profiles of pediatric inflammatory bowel disease patients and controls

    PubMed Central

    Knecht, Carolin; Fretter, Christoph; Rosenstiel, Philip; Krawczak, Michael; Hütt, Marc-Thorsten

    2016-01-01

    Information on biological networks can greatly facilitate the function-orientated interpretation of high-throughput molecular data. Genome-wide metabolic network models of human cells, in particular, can be employed to contextualize gene expression profiles of patients with the goal of both, a better understanding of individual etiologies and an educated reclassification of (clinically defined) phenotypes. We analyzed publicly available expression profiles of intestinal tissues from treatment-naive pediatric inflammatory bowel disease (IBD) patients and age-matched control individuals, using a reaction-centric metabolic network derived from the Recon2 model. By way of defining a measure of ‘coherence’, we quantified how well individual patterns of expression changes matched the metabolic network. We observed a bimodal distribution of metabolic network coherence in both patients and controls, albeit at notably different mixture probabilities. Multidimensional scaling analysis revealed a bisectional pattern as well that overlapped widely with the metabolic network-based results. Expression differences driving the observed bimodality were related to cellular transport of thiamine and bile acid metabolism, thereby highlighting the crosstalk between metabolism and other vital pathways. We demonstrated how classical data mining and network analysis can jointly identify biologically meaningful patterns in gene expression data. PMID:27585741

  4. MIRAGE: a functional genomics-based approach for metabolic network model reconstruction and its application to cyanobacteria networks.

    PubMed

    Vitkin, Edward; Shlomi, Tomer

    2012-11-29

    Genome-scale metabolic network reconstructions are considered a key step in quantifying the genotype-phenotype relationship. We present a novel gap-filling approach, MetabolIc Reconstruction via functionAl GEnomics (MIRAGE), which identifies missing network reactions by integrating metabolic flux analysis and functional genomics data. MIRAGE's performance is demonstrated on the reconstruction of metabolic network models of E. coli and Synechocystis sp. and validated via existing networks for these species. Then, it is applied to reconstruct genome-scale metabolic network models for 36 sequenced cyanobacteria amenable for constraint-based modeling analysis and specifically for metabolic engineering. The reconstructed network models are supplied via standard SBML files.

  5. Functional genomics tools applied to plant metabolism: a survey on plant respiration, its connections and the annotation of complex gene functions

    PubMed Central

    Araújo, Wagner L.; Nunes-Nesi, Adriano; Williams, Thomas C. R.

    2012-01-01

    The application of post-genomic techniques in plant respiration studies has greatly improved our ability to assign functions to gene products. In addition it has also revealed previously unappreciated interactions between distal elements of metabolism. Such results have reinforced the need to consider plant respiratory metabolism as part of a complex network and making sense of such interactions will ultimately require the construction of predictive and mechanistic models. Transcriptomics, proteomics, metabolomics, and the quantification of metabolic flux will be of great value in creating such models both by facilitating the annotation of complex gene function, determining their structure and by furnishing the quantitative data required to test them. In this review, we highlight how these experimental approaches have contributed to our current understanding of plant respiratory metabolism and its interplay with associated process (e.g., photosynthesis, photorespiration, and nitrogen metabolism). We also discuss how data from these techniques may be integrated, with the ultimate aim of identifying mechanisms that control and regulate plant respiration and discovering novel gene functions with potential biotechnological implications. PMID:22973288

  6. Thyroid function in childhood obesity and metabolic comorbidity.

    PubMed

    Pacifico, Lucia; Anania, Caterina; Ferraro, Flavia; Andreoli, Gian Marco; Chiesa, Claudio

    2012-02-18

    Childhood obesity is a worldwide health problem and its prevalence is increasing steadily and dramatically all over the world. Obese subjects have a much greater likelihood than normal-weight children of acquiring dyslipidemia, elevated blood pressure, and impaired glucose metabolism, which significantly increase their risk of cardiovascular and metabolic diseases. Elevated TSH concentrations in association with normal or slightly elevated free T4 and/or free T3 levels have been consistently found in obese subjects, but the mechanisms underlying these thyroid hormonal changes are still unclear. Whether higher TSH in childhood obesity is adaptive, increasing metabolic rate in an attempt to reduce further weight gain, or indicates subclinical hypothyroidism or resistance and thereby contributes to lipid and/or glucose dysmetabolism, remains controversial. This review highlights current evidence on thyroid involvement in obese children and discusses the current controversy regarding the relationship between thyroid hormonal derangements and obesity-related metabolic changes (hypertension, dyslipidemia, hyperglycemia and insulin resistance, nonalcoholic fatty liver disease) in such population. Moreover, the possible mechanisms linking thyroid dysfunction and pediatric obesity are reviewed. Finally, the potential role of lifestyle intervention as well as of therapy with thyroid hormone in the treatment of thyroid abnormalities in childhood obesity is discussed.

  7. Metabolic fate and function of dietary glutamate in the gut

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Glutamate is a major constituent of dietary protein and is also consumed in many prepared foods as an additive in the form of monosodium glutamate. Evidence from human and animal studies indicates that glutamate is a major oxidative fuel for the gut and that dietary glutamate is extensively metabol...

  8. Control of human trophoblast function

    PubMed Central

    Lunghi, Laura; Ferretti, Maria E; Medici, Silvia; Biondi, Carla; Vesce, Fortunato

    2007-01-01

    The trophoblast, i.e. the peripheral part of the human conceptus, exerts a crucial role in implantation and placentation. Both processes properly occur as a consequence of an intimate dialogue between fetal and maternal tissues, fulfilled by membrane ligands and receptors, as well as by hormone and local factor release. During blastocyst implantation, generation of distinct trophoblast cell types begins, namely the villous and the extravillous trophoblast, the former of which is devoted to fetal-maternal exchanges and the latter binds the placental body to the uterine wall. Physiological placentation is characterized by the invasion of the uterine spiral arteries by extravillous trophoblast cells arising from anchoring villi. Due to this invasion, the arterial structure is replaced by amorphous fibrinoid material and endovascular trophoblastic cells. This transformation establishes a low-resistance, high-capacity perfusion system from the radial arteries to the intervillous space, in which the villous tree is embedded. The physiology of pregnancy depends upon the orderly progress of structural and functional changes of villous and extravillous trophoblast, whereas a derangement of such processes can lead to different types of complications of varying degrees of gravity, including possible pregnancy loss and maternal life-threatening diseases. In this review we describe the mechanisms which regulate trophoblast differentiation, proliferation, migration and invasiveness, and the alterations in these mechanisms which lead to pathological conditions. Furthermore, based on the growing evidence that proper inflammatory changes and oxidative balance are needed for successful gestation, we explain the mechanisms by which agents able to influence such processes may be useful in the prevention and treatment of pregnancy disorders. PMID:17288592

  9. Metabolic network structure and function in bacteria goes beyond conserved enzyme components

    PubMed Central

    Bazurto, Jannell V.; Downs, Diana M.

    2016-01-01

    For decades, experimental work has laid the foundation for our understanding of the linear and branched pathways that are integrated to form the metabolic networks on which life is built. Genetic and biochemical approaches applied in model organisms generate empirical data that correlate genes, gene products and their biological activities. In the post-genomic era, these results have served as the basis for the genome annotation that is routinely used to infer the metabolic capabilities of an organism and mathematically model the presumed metabolic network structure. At large, genome annotation and metabolic network reconstructions have demystified genomic content of non-culturable microorganisms and allowed researchers to explore the breadth of metabolisms in silico. Mis-annotation aside, it is unclear whether in silico reconstructions of metabolic structure from component parts accurately captures the higher levels of network organization and flux distribution. For this approach to provide accurate predictions, one must assume that the conservation of metabolic components leads to conservation of metabolic network architecture and function. This assumption has not been rigorously tested. Here we describe the implications of a recent study (MBio 5;7(1): e01840-15), which demonstrated that conservation of metabolic components was not sufficient to predict network structure and function. PMID:28357363

  10. The Amyloid Precursor Protein Controls PIKfyve Function.

    PubMed

    Balklava, Zita; Niehage, Christian; Currinn, Heather; Mellor, Laura; Guscott, Benjamin; Poulin, Gino; Hoflack, Bernard; Wassmer, Thomas

    2015-01-01

    While the Amyloid Precursor Protein (APP) plays a central role in Alzheimer's disease, its cellular function still remains largely unclear. It was our goal to establish APP function which will provide insights into APP's implication in Alzheimer's disease. Using our recently developed proteo-liposome assay we established the interactome of APP's intracellular domain (known as AICD), thereby identifying novel APP interactors that provide mechanistic insights into APP function. By combining biochemical, cell biological and genetic approaches we validated the functional significance of one of these novel interactors. Here we show that APP binds the PIKfyve complex, an essential kinase for the synthesis of the endosomal phosphoinositide phosphatidylinositol-3,5-bisphosphate. This signalling lipid plays a crucial role in endosomal homeostasis and receptor sorting. Loss of PIKfyve function by mutation causes profound neurodegeneration in mammals. Using C. elegans genetics we demonstrate that APP functionally cooperates with PIKfyve in vivo. This regulation is required for maintaining endosomal and neuronal function. Our findings establish an unexpected role for APP in the regulation of endosomal phosphoinositide metabolism with dramatic consequences for endosomal biology and important implications for our understanding of Alzheimer's disease.

  11. Relationship between baseline brain metabolism measured using [¹⁸F]FDG PET and memory and executive function in prodromal and early Alzheimer's disease.

    PubMed

    Habeck, Christian; Risacher, Shannon; Lee, Grace J; Glymour, M Maria; Mormino, Elizabeth; Mukherjee, Shubhabrata; Kim, Sungeun; Nho, Kwangsik; DeCarli, Charles; Saykin, Andrew J; Crane, Paul K

    2012-12-01

    Differences in brain metabolism as measured by FDG-PET in prodromal and early Alzheimer's disease (AD) have been consistently observed, with a characteristic parietotemporal hypometabolic pattern. However, exploration of brain metabolic correlates of more nuanced measures of cognitive function has been rare, particularly in larger samples. We analyzed the relationship between resting brain metabolism and memory and executive functioning within diagnostic group on a voxel-wise basis in 86 people with AD, 185 people with mild cognitive impairment (MCI), and 86 healthy controls (HC) from the Alzheimer's Disease Neuroimaging Initiative (ADNI). We found positive associations within AD and MCI but not in HC. For MCI and AD, impaired executive functioning was associated with reduced parietotemporal metabolism, suggesting a pattern consistent with known AD-related hypometabolism. These associations suggest that decreased metabolic activity in the parietal and temporal lobes may underlie the executive function deficits in AD and MCI. For memory, hypometabolism in similar regions of the parietal and temporal lobes were significantly associated with reduced performance in the MCI group. However, for the AD group, memory performance was significantly associated with metabolism in frontal and orbitofrontal areas, suggesting the possibility of compensatory metabolic activity in these areas. Overall, the associations between brain metabolism and cognition in this study suggest the importance of parietal and temporal lobar regions in memory and executive function in the early stages of disease and an increased importance of frontal regions for memory with increasing impairment.

  12. Complex pectin metabolism by gut bacteria reveals novel catalytic functions.

    PubMed

    Ndeh, Didier; Rogowski, Artur; Cartmell, Alan; Luis, Ana S; Baslé, Arnaud; Gray, Joseph; Venditto, Immacolata; Briggs, Jonathon; Zhang, Xiaoyang; Labourel, Aurore; Terrapon, Nicolas; Buffetto, Fanny; Nepogodiev, Sergey; Xiao, Yao; Field, Robert A; Zhu, Yanping; O'Neill, Malcolm A; Urbanowicz, Breeanna R; York, William S; Davies, Gideon J; Abbott, D Wade; Ralet, Marie-Christine; Martens, Eric C; Henrissat, Bernard; Gilbert, Harry J

    2017-03-22

    The metabolism of carbohydrate polymers drives microbial diversity in the human gut microbiota. It is unclear, however, whether bacterial consortia or single organisms are required to depolymerize highly complex glycans. Here we show that the gut bacterium Bacteroides thetaiotaomicron uses the most structurally complex glycan known: the plant pectic polysaccharide rhamnogalacturonan-II, cleaving all but 1 of its 21 distinct glycosidic linkages. The deconstruction of rhamnogalacturonan-II side chains and backbone are coordinated to overcome steric constraints, and the degradation involves previously undiscovered enzyme families and catalytic activities. The degradation system informs revision of the current structural model of rhamnogalacturonan-II and highlights how individual gut bacteria orchestrate manifold enzymes to metabolize the most challenging glycan in the human diet.

  13. Factors Controlling Carbon Metabolism and Humification in Different Soil Agroecosystems

    PubMed Central

    Doni, S.; Macci, C.; Peruzzi, E.; Ceccanti, B.; Masciandaro, G.

    2014-01-01

    The aim of this study was to describe the processes that control humic carbon sequestration in soil. Three experimental sites differing in terms of management system and climate were selected: (i) Abanilla-Spain, soil treated with municipal solid wastes in Mediterranean semiarid climate; (ii) Puch-Germany, soil under intensive tillage and conventional agriculture in continental climate; and (iii) Alberese-Italy, soil under organic and conventional agriculture in Mediterranean subarid climate. The chemical-structural and biochemical soil properties at the initial sampling time and one year later were evaluated. The soils under organic (Alberese, soil cultivated with Triticum durum Desf.) and nonintensive management practices (Puch, soil cultivated with Triticum aestivum L. and Avena sativa L.) showed higher enzymatically active humic carbon, total organic carbon, humification index (B/E3s), and metabolic potential (dehydrogenase activity/water soluble carbon) if compared with conventional agriculture and plough-based tillage, respectively. In Abanilla, the application of municipal solid wastes stimulated the specific β-glucosidase activity (extracellular β-glucosidase activity/extractable humic carbon) and promoted the increase of humic substances with respect to untreated soil. The evolution of the chemical and biochemical status of the soils along a climatic gradient suggested that the adoption of certain management practices could be very promising in increasing SOC sequestration potential. PMID:25614887

  14. Glycolate Metabolism Is Under Nitrogen Control in Chlorella1

    PubMed Central

    Beudeker, Rob F.; Tabita, F. Robert

    1984-01-01

    The utilization of nitrate and ammonia as nitrogen sources had different effects on the metabolism of glycolate in Cholorella sorokiniana. During photolithotrophic growth with nitrate as nitrogen source, glycolate was metabolized via the glycine-serine pathway. Ammonia, produced as a result of glycolate metabolism, was reassimilated by glutamine synthetase. Two isoforms of this enzyme were present at different relative abundance in C. sorokiniana wild type and in a mutant with an increased capacity for the metabolism of glycolate (strain OR). During photolithotrophic growth in the presence of ammonia as sole nitrogen source, several lines of evidence indicated that glycolate was metabolized to malate, pyruvate, tricarboxylic acid cycle intermediates and related amino acids in C. sorokiniana wild-type cells. Malate synthase was induced and glycine decarboxylase and serine-glyoxylate aminotransferase were repressed in cells grown with ammonia. An inverse correlation was observed between aminating NADPH-glutamate dehydrogenase and the in vivo glycine decarboxylation rate. PMID:16663657

  15. The Mitochondrial Permeability Transition Pore Regulator Cyclophilin D Exhibits Tissue-Specific Control of Metabolic Homeostasis

    PubMed Central

    Laker, Rhianna C.; Taddeo, Evan P.; Akhtar, Yasir N.; Zhang, Mei; Hoehn, Kyle L.; Yan, Zhen

    2016-01-01

    The mitochondrial permeability transition pore (mPTP) is a key regulator of mitochondrial function that has been implicated in the pathogenesis of metabolic disease. Cyclophilin D (CypD) is a critical regulator that directly binds to mPTP constituents to facilitate the pore opening. We previously found that global CypD knockout mice (KO) are protected from diet-induced glucose intolerance; however, the tissue-specific function of CypD and mPTP, particularly in the control of glucose homeostasis, has not been ascertained. To this end, we performed calcium retention capacity (CRC) assay to compare the importance of CypD in the liver versus skeletal muscle. We found that liver mitochondria are more dependent on CypD for mPTP opening than skeletal muscle mitochondria. To ascertain the tissue-specific role of CypD in metabolic homeostasis, we generated liver-specific and muscle-specific CypD knockout mice (LKO and MKO, respectively) and fed them either a chow diet or 45% high-fat diet (HFD) for 14 weeks. MKO mice displayed similar body weight gain and glucose intolerance compared with wild type littermates (WT), whereas LKO mice developed greater visceral obesity, glucose intolerance and pyruvate intolerance compared with WT mice. These findings demonstrate that loss of muscle CypD is not sufficient to alter whole body glucose metabolism, while the loss of liver CypD exacerbates obesity and whole-body metabolic dysfunction in mice fed HFD. PMID:28005946

  16. Transfer Function Control for Biometric Monitoring System

    NASA Technical Reports Server (NTRS)

    Chmiel, Alan J. (Inventor); Humphreys, Bradley T. (Inventor); Grodinsky, Carlos M. (Inventor)

    2015-01-01

    A modular apparatus for acquiring biometric data may include circuitry operative to receive an input signal indicative of a biometric condition, the circuitry being configured to process the input signal according to a transfer function thereof and to provide a corresponding processed input signal. A controller is configured to provide at least one control signal to the circuitry to programmatically modify the transfer function of the modular system to facilitate acquisition of the biometric data.

  17. Control of methionine metabolism by the SahR transcriptional regulator in Proteobacteria.

    PubMed

    Novichkov, Pavel S; Li, Xiaoqing; Kuehl, Jennifer V; Deutschbauer, Adam M; Arkin, Adam P; Price, Morgan N; Rodionov, Dmitry A

    2014-01-01

    Sulphur is an essential element in the metabolism. The sulphur-containing amino acid methionine is a metabolic precursor for S-adenosylmethionine (SAM), which serves as a coenzyme for ubiquitous methyltrtansferases. Recycling of organic sulphur compounds, e.g. via the SAM cycle, is an important metabolic process that needs to be tightly regulated. Knowledge about transcriptional regulation of these processes is still limited for many free-living bacteria. We identified a novel transcription factor SahR from the ArsR family that controls the SAM cycle genes in diverse microorganisms from soil and aquatic ecosystems. By using comparative genomics, we predicted SahR-binding DNA motifs and reconstructed SahR regulons in the genomes of 62 Proteobacteria. The conserved core of SahR regulons includes all enzymes required for the SAM cycle: the SAH hydrolase AhcY, the methionine biosynthesis enzymes MetE/MetH and MetF, and the SAM synthetase MetK. By using a combination of experimental techniques, we validated the SahR regulon in the sulphate-reducing Deltaproteobacterium Desulfovibrio alaskensis. SahR functions as a negative regulator that responds to the S-adenosylhomocysteine (SAH). The elevated SAH level in the cell dissociates SahR from its DNA operators and induces the expression of SAM cycle genes. The effector-sensing domain in SahR is related to SAM-dependent methylases that are able to tightly bind SAH. SahR represents a novel type of transcriptional regulators for the control of sulphur amino acid metabolism.

  18. Metabolic benefits of dietary prebiotics in human subjects: a systematic review of randomised controlled trials.

    PubMed

    Kellow, Nicole J; Coughlan, Melinda T; Reid, Christopher M

    2014-04-14

    Complex relationships exist between the gut microflora and their human hosts. Emerging evidence suggests that bacterial dysbiosis within the colon may be involved in the pathogenesis of the metabolic syndrome, type 2 diabetes and CVD. The use of dietary prebiotic supplements to restore an optimal balance of intestinal flora may positively affect host metabolism, representing a potential treatment strategy for individuals with cardiometabolic disorders. The present review aimed to examine the current evidence supporting that dietary prebiotic supplementation in adults has beneficial effects on biochemical parameters associated with the development of metabolic abnormalities including obesity, glucose intolerance, dyslipidaemia, hepatic steatosis and low-grade chronic inflammation. Between January 2000 and September 2013, eight computer databases were searched for randomised controlled trials published in English. Human trials were included if at least one group received a dietary prebiotic intervention. In the present review, twenty-six randomised controlled trials involving 831 participants were included. Evidence indicated that dietary prebiotic supplementation increased self-reported feelings of satiety in healthy adults (standardised mean difference -0.57, 95% CI -1.13, -0.01). Prebiotic supplementation also significantly reduced postprandial glucose (-0.76, 95% CI -1.41, -0.12) and insulin (-0.77, 95% CI -1.50, -0.04) concentrations. The effects of dietary prebiotics on total energy intake, body weight, peptide YY and glucagon-like peptide-1 concentrations, gastric emptying times, insulin sensitivity, lipids, inflammatory markers and immune function were contradictory. Dietary prebiotic consumption was found to be associated with subjective improvements in satiety and reductions in postprandial glucose and insulin concentrations. Additional evidence is required before recommending prebiotic supplements to individuals with metabolic abnormalities. Large

  19. Functional Role of PPARs in Ruminants: Potential Targets for Fine-Tuning Metabolism during Growth and Lactation

    PubMed Central

    Chen, Shuowen; Khan, Muhammad J.; Loor, Juan J.

    2013-01-01

    Characterization and biological roles of the peroxisome proliferator-activated receptor (PPAR) isotypes are well known in monogastrics, but not in ruminants. However, a wealth of information has accumulated in little more than a decade on ruminant PPARs including isotype tissue distribution, response to synthetic and natural agonists, gene targets, and factors affecting their expression. Functional characterization demonstrated that, as in monogastrics, the PPAR isotypes control expression of genes involved in lipid metabolism, anti-inflammatory response, development, and growth. Contrary to mouse, however, the PPARγ gene network appears to controls milk fat synthesis in lactating ruminants. As in monogastrics, PPAR isotypes in ruminants are activated by long-chain fatty acids, therefore, making them ideal candidates for fine-tuning metabolism in this species via nutrients. In this regard, using information accumulated in ruminants and monogastrics, we propose a model of PPAR isotype-driven biological functions encompassing key tissues during the peripartal period in dairy cattle. PMID:23737762

  20. Design of pathway-level bioprocess monitoring and control strategies supported by metabolic networks.

    PubMed

    Isidro, Inês A; Ferreira, Ana R; Clemente, João J; Cunha, António E; Dias, João M L; Oliveira, Rui

    2013-01-01

    In this chapter we explore the basic tools for the design of bioprocess monitoring, optimization, and control algorithms that incorporate a priori knowledge of metabolic networks. The main advantage is that this ultimately enables the targeting of intracellular control variables such as metabolic reactions or metabolic pathways directly linked with productivity and product quality. We analyze in particular design methods that target elementary modes of metabolic networks. The topics covered include the analysis of the structure of metabolic networks, computation and reduction of elementary modes, measurement methods for the envirome, envirome-guided metabolic reconstruction, and macroscopic dynamic modeling and control. These topics are illustrated with applications to a cultivation process of a recombinant Pichia pastoris X33 strain expressing a single-chain antibody fragment (scFv).

  1. Targeting polyamine metabolism and function in cancer and other hyperproliferative diseases.

    PubMed

    Casero, Robert A; Marton, Laurence J

    2007-05-01

    The polyamines spermidine and spermine and their diamine precursor putrescine are naturally occurring, polycationic alkylamines that are essential for eukaryotic cell growth. The requirement for and the metabolism of polyamines are frequently dysregulated in cancer and other hyperproliferative diseases, thus making polyamine function and metabolism attractive targets for therapeutic intervention. Recent advances in our understanding of polyamine function, metabolic regulation, and differences between normal cells and tumour cells with respect to polyamine biology, have reinforced the interest in this target-rich pathway for drug development.

  2. Effects of nutritional restriction on metabolic, endocrine, and ovarian function in llamas (Lama glama).

    PubMed

    Norambuena, M C; Silva, M; Urra, F; Ulloa-Leal, C; Fernández, A; Adams, G P; Huanca, W; Ratto, M H

    2013-05-01

    The objectives of the study were to determine the effects of nutritional restriction on ovarian function in llamas. Mature female llamas were assigned randomly to a Control group, fed 100% of maintenance energy requirements (MER) (n=8), or a Restricted group (n=8) fed from 70% to 40% of MER until a body condition score of 2.5 was attained. Blood samples were taken every-other-day to determine plasma concentrations of LH, estradiol, leptin and metabolic markers, and follicular dynamics were monitored daily by ultrasonography for 30 days (Experiment 1). Llamas were then treated with GnRH to compare the ovulatory response and corpus luteus (CL) development between groups (Experiment 2). Blood samples were taken to measure LH, leptin, progesterone and metabolic markers and ovarian structures were assessed as in Experiment 1. Llamas in the Restricted group had lower body mass and body condition scores than those in the Control group (P<0.001). Plasma concentrations of cholesterol, non-esterified fatty acids, triglycerides, and urea were higher in the Restricted group (P<0.05) than in the Control group. The day-to-day diameter profiles of the dominant follicles were smaller (P<0.05) in the Restricted group than in the Control group but plasma estradiol concentration did not differ. The ovulation rate and LH secretion in response to GnRH did not differ. Day-to-day profiles of CL diameter, plasma progesterone and leptin concentrations were smaller (P<0.01) in the Restricted group. In conclusion, nutritional restriction in llamas was associated with suppressed follicle and CL development, and lower plasma concentrations of progesterone and leptin.

  3. Improvement of mitochondrial function and dynamics by the metabolic enhancer piracetam.

    PubMed

    Stockburger, Carola; Kurz, Christopher; Koch, Konrad A; Eckert, Schamim H; Leuner, Kristina; Müller, Walter E

    2013-10-01

    The metabolic enhancer piracetam is used in many countries to treat cognitive impairment in aging, brain injuries, as well as dementia such as AD (Alzheimer's disease). As a specific feature of piracetam, beneficial effects are usually associated with mitochondrial dysfunction. In previous studies we were able to show that piracetam enhanced ATP production, mitochondrial membrane potential as well as neurite outgrowth in cell and animal models for aging and AD. To investigate further the effects of piracetam on mitochondrial function, especially mitochondrial fission and fusion events, we decided to assess mitochondrial morphology. Human neuroblastoma cells were treated with the drug under normal conditions and under conditions imitating aging and the occurrence of ROS (reactive oxygen species) as well as in stably transfected cells with the human wild-type APP (amyloid precursor protein) gene. This AD model is characterized by expressing only 2-fold more human Aβ (amyloid β-peptide) compared with control cells and therefore representing very early stages of AD when Aβ levels gradually increase over decades. Interestingly, these cells exhibit an impaired mitochondrial function and morphology under baseline conditions. Piracetam is able to restore this impairment and shifts mitochondrial morphology back to elongated forms, whereas there is no effect in control cells. After addition of a complex I inhibitor, mitochondrial morphology is distinctly shifted to punctate forms in both cell lines. Under these conditions piracetam is able to ameliorate morphology in cells suffering from the mild Aβ load, as well as mitochondrial dynamics in control cells.

  4. High-fat diet decreases energy expenditure and expression of genes controlling lipid metabolism, mitochondrial function and skeletal system development in the adipose tissue, along with increased expression of extracellular matrix remodelling- and inflammation-related genes.

    PubMed

    Choi, Myung-Sook; Kim, Young-Je; Kwon, Eun-Young; Ryoo, Jae Young; Kim, Sang Ryong; Jung, Un Ju

    2015-03-28

    The aim of the present study was to identify the genes differentially expressed in the visceral adipose tissue in a well-characterised mouse model of high-fat diet (HFD)-induced obesity. Male C57BL/6J mice (n 20) were fed either HFD (189 % of energy from fat) or low-fat diet (LFD, 42 % of energy from fat) for 16 weeks. HFD-fed mice exhibited obesity, insulin resistance, dyslipidaemia and adipose collagen accumulation, along with higher levels of plasma leptin, resistin and plasminogen activator inhibitor type 1, although there were no significant differences in plasma cytokine levels. Energy intake was similar in the two diet groups owing to lower food intake in the HFD group; however, energy expenditure was also lower in the HFD group than in the LFD group. Microarray analysis revealed that genes related to lipolysis, fatty acid metabolism, mitochondrial energy transduction, oxidation-reduction, insulin sensitivity and skeletal system development were down-regulated in HFD-fed mice, and genes associated with extracellular matrix (ECM) components, ECM remodelling and inflammation were up-regulated. The top ten up- or down-regulated genes include Acsm3, mt-Nd6, Fam13a, Cyp2e1, Rgs1 and Gpnmb, whose roles in the deterioration of obesity-associated adipose tissue are poorly understood. In conclusion, the genes identified here provide new therapeutic opportunities for prevention and treatment of diet-induced obesity.

  5. Metabolism

    MedlinePlus

    ... symptoms. Metabolic diseases and conditions include: Hyperthyroidism (pronounced: hi-per-THIGH-roy-dih-zum). Hyperthyroidism is caused ... or through surgery or radiation treatments. Hypothyroidism (pronounced: hi-po-THIGH-roy-dih-zum). Hypothyroidism is caused ...

  6. Functional characterization of an invertase inhibitor gene involved in sucrose metabolism in tomato fruit.

    PubMed

    Zhang, Ning; Jiang, Jing; Yang, Yan-li; Wang, Zhi-he

    2015-10-01

    In this study, we produced tomato plants overexpressing an invertase inhibitor gene (Sly-INH) from tomato, using a simple and efficient transient transformation system. Compared with control plants, the expression of Sly-INH was highly upregulated in Sly-INH overexpressing plants, as indicated by real-time polymerase chain reaction (PCR). Physiological analysis revealed that Sly-INH inhibited the activity of cell wall invertase (CWIN), which increased sugar accumulation in tomato fruit. Furthermore, Sly-INH mediated sucrose metabolism by regulating CWIN activity. Our results suggest that invertase activity is potentially regulated by the Sly-INH inhibitor at the post-translational level, and they demonstrate that the transient transformation system is an effective method for determining the functions of genes in tomato.

  7. High density lipoprotein and metabolic disease: Potential benefits of restoring its functional properties

    PubMed Central

    Klancic, Teja; Woodward, Lavinia; Hofmann, Susanna M.; Fisher, Edward A.

    2016-01-01

    Background High density lipoproteins (HDLs) are thought to be atheroprotective and to reduce the risk of cardiovascular disease (CVD). Besides their antioxidant, antithrombotic, anti-inflammatory, anti-apoptotic properties in the vasculature, HDLs also improve glucose metabolism in skeletal muscle. Scope of the review Herein, we review the functional role of HDLs to improve metabolic disorders, especially those involving insulin resistance and to induce regression of CVD with a particular focus on current pharmacological treatment options as well as lifestyle interventions, particularly exercise. Major conclusions Functional properties of HDLs continue to be considered important mediators to reverse metabolic dysfunction and to regress atherosclerotic cardiovascular disease. Lifestyle changes are often recommended to reduce the risk of CVD, with exercise being one of the most important of these. Understanding how exercise improves HDL function will likely lead to new approaches to battle the expanding burden of obesity and the metabolic syndrome. PMID:27110484

  8. Rodent Models for the Analysis of Tissue Clock Function in Metabolic Rhythms Research

    PubMed Central

    Tsang, Anthony H.; Astiz, Mariana; Leinweber, Brinja; Oster, Henrik

    2017-01-01

    The circadian timing system consists on a distributed network of cellular clocks that together coordinate 24-h rhythms of physiology and behavior. Clock function and metabolism are tightly coupled, from the cellular to the organismal level. Genetic and non-genetic approaches in rodents have been employed to study circadian clock function in the living organism. Due to the ubiquitous expression of clock genes and the intricate interaction between the circadian system and energy metabolism, genetic approaches targeting specific tissue clocks have been used to assess their contribution in systemic metabolic processes. However, special requirements regarding specificity and efficiency have to be met to allow for valid conclusions from such studies. In this review, we provide a brief summary of different approaches developed for dissecting tissue clock function in the metabolic context in rodents, compare their strengths and weaknesses, and suggest new strategies in assessing tissue clock output and the consequences of circadian clock disruption in vivo. PMID:28243224

  9. Protein Kinase B Controls Transcriptional Programs that Direct Cytotoxic T Cell Fate but Is Dispensable for T Cell Metabolism

    PubMed Central

    Macintyre, Andrew N.; Finlay, David; Preston, Gavin; Sinclair, Linda V.; Waugh, Caryll M.; Tamas, Peter; Feijoo, Carmen; Okkenhaug, Klaus; Cantrell, Doreen A.

    2011-01-01

    Summary In cytotoxic T cells (CTL), Akt, also known as protein kinase B, is activated by the T cell antigen receptor (TCR) and the cytokine interleukin 2 (IL-2). Akt can control cell metabolism in many cell types but whether this role is important for CTL function has not been determined. Here we have shown that Akt does not mediate IL-2- or TCR-induced cell metabolic responses; rather, this role is assumed by other Akt-related kinases. There is, however, a nonredundant role for sustained and strong activation of Akt in CTL to coordinate the TCR- and IL-2-induced transcriptional programs that control expression of key cytolytic effector molecules, adhesion molecules, and cytokine and chemokine receptors that distinguish effector versus memory and naive T cells. Akt is thus dispensable for metabolism, but the strength and duration of Akt activity dictates the CTL transcriptional program and determines CTL fate. PMID:21295499

  10. Metabolic and Demographic Feedbacks Shape the Emergent Spatial Structure and Function of Microbial Communities

    PubMed Central

    Estrela, Sylvie; Brown, Sam P.

    2013-01-01

    Microbes are predominantly found in surface-attached and spatially structured polymicrobial communities. Within these communities, microbial cells excrete a wide range of metabolites, setting the stage for interspecific metabolic interactions. The links, however, between metabolic and ecological interactions (functional relationships), and species spatial organization (structural relationships) are still poorly understood. Here, we use an individual-based modelling framework to simulate the growth of a two-species surface-attached community where food (resource) is traded for detoxification (service) and investigate how metabolic constraints of individual species shape the emergent structural and functional relationships of the community. We show that strong metabolic interdependence drives the emergence of mutualism, robust interspecific mixing, and increased community productivity. Specifically, we observed a striking and highly stable emergent lineage branching pattern, generating a persistent lineage mixing that was absent when the metabolic exchange was removed. These emergent community properties are driven by demographic feedbacks, such that aid from neighbouring cells directly enhances focal cell growth, which in turn feeds back to neighbour fecundity. In contrast, weak metabolic interdependence drives conflict (exploitation or competition), and in turn greater interspecific segregation. Together, these results support the idea that species structural and functional relationships represent the net balance of metabolic interdependencies. PMID:24385891

  11. Acetylation control of cardiac fatty acid β-oxidation and energy metabolism in obesity, diabetes, and heart failure.

    PubMed

    Fukushima, Arata; Lopaschuk, Gary D

    2016-12-01

    Alterations in cardiac energy metabolism are an important contributor to the cardiac pathology associated with obesity, diabetes, and heart failure. High rates of fatty acid β-oxidation with cardiac insulin resistance represent a cardiac metabolic hallmark of diabetes and obesity, while a marginal decrease in fatty acid oxidation and a prominent decrease in insulin-stimulated glucose oxidation are commonly seen in the early stages of heart failure. Alterations in post-translational control of energy metabolic processes have recently been identified as an important contributor to these metabolic changes. In particular, lysine acetylation of non-histone proteins, which controls a diverse family of mitochondrial metabolic pathways, contributes to the cardiac energy derangements seen in obesity, diabetes, and heart failure. Lysine acetylation is controlled both via acetyltransferases and deacetylases (sirtuins), as well as by non-enzymatic lysine acetylation due to increased acetyl CoA pool size or dysregulated nicotinamide adenine dinucleotide (NAD(+)) metabolism (which stimulates sirtuin activity). One of the important mitochondrial acetylation targets are the fatty acid β-oxidation enzymes, which contributes to alterations in cardiac substrate preference during the course of obesity, diabetes, and heart failure, and can ultimately lead to cardiac dysfunction in these disease states. This review will summarize the role of lysine acetylation and its regulatory control in the context of mitochondrial fatty acid β-oxidation. The functional contribution of cardiac protein lysine acetylation to the shift in cardiac energy substrate preference that occurs in obesity, diabetes, and especially in the early stages of heart failure will also be reviewed. This article is part of a Special Issue entitled: The role of post-translational protein modifications on heart and vascular metabolism edited by Jason R.B. Dyck & Jan F.C. Glatz.

  12. A gut–brain neural circuit controlled by intestinal gluconeogenesis is crucial in metabolic health

    PubMed Central

    Soty, Maud; Penhoat, Armelle; Amigo-Correig, Marta; Vinera, Jennifer; Sardella, Anne; Vullin-Bouilloux, Fanny; Zitoun, Carine; Houberdon, Isabelle; Mithieux, Gilles

    2014-01-01

    Objectives Certain nutrients positively regulate energy homeostasis via intestinal gluconeogenesis (IGN). The objective of this study was to evaluate the impact of a deficient IGN in glucose control independently of nutritional environment. Methods We used mice deficient in the intestine glucose-6 phosphatase catalytic unit, the key enzyme of IGN (I-G6pc−/− mice). We evaluated a number of parameters involved in energy homeostasis, including insulin sensitivity (hyperinsulinemic euglycaemic clamp), the pancreatic function (insulin secretion in vivo and in isolated islets) and the hypothalamic homeostatic function (leptin sensitivity). Results Intestinal-G6pc−/− mice exhibit slight fasting hyperglycaemia and hyperinsulinemia, glucose intolerance, insulin resistance and a deteriorated pancreatic function, despite normal diet with no change in body weight. These defects evoking type 2 diabetes (T2D) derive from the basal activation of the sympathetic nervous system (SNS). They are corrected by treatment with an inhibitor of α-2 adrenergic receptors. Deregulation in a key target of IGN, the homeostatic hypothalamic function (highlighted here through leptin resistance) is a mechanistic link. Hence the leptin resistance and metabolic disorders in I-G6pc−/− mice are corrected by rescuing IGN by portal glucose infusion. Finally, I-G6pc−/− mice develop the hyperglycaemia characteristic of T2D more rapidly under high fat/high sucrose diet. Conclusions Intestinal gluconeogenesis is a mandatory function for the healthy neural control of glucose homeostasis. PMID:25685698

  13. Dynamics and Design Principles of a Basic Regulatory Architecture Controlling Metabolic Pathways

    PubMed Central

    Jolly, Emmitt R; DeRisi, Joe; Li, Hao

    2008-01-01

    The dynamic features of a genetic network's response to environmental fluctuations represent essential functional specifications and thus may constrain the possible choices of network architecture and kinetic parameters. To explore the connection between dynamics and network design, we have analyzed a general regulatory architecture that is commonly found in many metabolic pathways. Such architecture is characterized by a dual control mechanism, with end product feedback inhibition and transcriptional regulation mediated by an intermediate metabolite. As a case study, we measured with high temporal resolution the induction profiles of the enzymes in the leucine biosynthetic pathway in response to leucine depletion, using an automated system for monitoring protein expression levels in single cells. All the genes in the pathway are known to be coregulated by the same transcription factors, but we observed drastically different dynamic responses for enzymes upstream and immediately downstream of the key control point—the intermediate metabolite α-isopropylmalate (αIPM), which couples metabolic activity to transcriptional regulation. Analysis based on genetic perturbations suggests that the observed dynamics are due to differential regulation by the leucine branch-specific transcription factor Leu3, and that the downstream enzymes are strictly controlled and highly expressed only when αIPM is available. These observations allow us to build a simplified mathematical model that accounts for the observed dynamics and can correctly predict the pathway's response to new perturbations. Our model also suggests that transient dynamics and steady state can be separately tuned and that the high induction levels of the downstream enzymes are necessary for fast leucine recovery. It is likely that principles emerging from this work can reveal how gene regulation has evolved to optimize performance in other metabolic pathways with similar architecture. PMID:18563967

  14. Contribution of voltage-dependent K+ channels to metabolic control of coronary blood flow

    PubMed Central

    Berwick, Zachary C.; Dick, Gregory M.; Moberly, Steven P.; Kohr, Meredith C.; Sturek, Michael; Tune, Johnathan D.

    2011-01-01

    The purpose of this investigation was to test the hypothesis that KV channels contribute to metabolic control of coronary blood flow and that decreases in KV channel function and/or expression significantly attenuate myocardial oxygen supply-demand balance in the metabolic syndrome (MetS). Experiments were conducted in conscious, chronically instrumented Ossabaw swine fed either a normal maintenance diet or an excess calorie atherogenic diet that produces the clinical phenotype of early MetS. Data were obtained under resting conditions and during graded treadmill exercise before and after inhibition of KV channels with 4-aminopyridine (4-AP, 0.3 mg/kg, i.v.). In lean-control swine, 4-AP reduced coronary blood flow ~15% at rest and ~20% during exercise. Inhibition of KV channels also increased aortic pressure (P < 0.01) while reducing coronary venous Po2 (P < 0.01) at a given level of myocardial oxygen consumption (MVo2). Administration of 4-AP had no effect on coronary blood flow, aortic pressure, or coronary venous Po2 in swine with MetS. The lack of response to 4-AP in MetS swine was associated with a ~20% reduction in coronary KV current (P < 0.01) and decreased expression of KV1.5 channels in coronary arteries (P < 0.01). Together, these data demonstrate that KV channels play an important role in balancing myocardial oxygen delivery with metabolism at rest and during exercise-induced increases in MVo2. Our findings also indicate that decreases in KV channel current and expression contribute to impaired control of coronary blood flow in the MetS. PMID:21771599

  15. Microbial community assembly and metabolic function during mammalian corpse decomposition.

    PubMed

    Metcalf, Jessica L; Xu, Zhenjiang Zech; Weiss, Sophie; Lax, Simon; Van Treuren, Will; Hyde, Embriette R; Song, Se Jin; Amir, Amnon; Larsen, Peter; Sangwan, Naseer; Haarmann, Daniel; Humphrey, Greg C; Ackermann, Gail; Thompson, Luke R; Lauber, Christian; Bibat, Alexander; Nicholas, Catherine; Gebert, Matthew J; Petrosino, Joseph F; Reed, Sasha C; Gilbert, Jack A; Lynne, Aaron M; Bucheli, Sibyl R; Carter, David O; Knight, Rob

    2016-01-08

    Vertebrate corpse decomposition provides an important stage in nutrient cycling in most terrestrial habitats, yet microbially mediated processes are poorly understood. Here we combine deep microbial community characterization, community-level metabolic reconstruction, and soil biogeochemical assessment to understand the principles governing microbial community assembly during decomposition of mouse and human corpses on different soil substrates. We find a suite of bacterial and fungal groups that contribute to nitrogen cycling and a reproducible network of decomposers that emerge on predictable time scales. Our results show that this decomposer community is derived primarily from bulk soil, but key decomposers are ubiquitous in low abundance. Soil type was not a dominant factor driving community development, and the process of decomposition is sufficiently reproducible to offer new opportunities for forensic investigations.

  16. Biosynthesis, function and metabolic engineering of plant volatile organic compounds.

    PubMed

    Dudareva, Natalia; Klempien, Antje; Muhlemann, Joëlle K; Kaplan, Ian

    2013-04-01

    Plants synthesize an amazing diversity of volatile organic compounds (VOCs) that facilitate interactions with their environment, from attracting pollinators and seed dispersers to protecting themselves from pathogens, parasites and herbivores. Recent progress in -omics technologies resulted in the isolation of genes encoding enzymes responsible for the biosynthesis of many volatiles and contributed to our understanding of regulatory mechanisms involved in VOC formation. In this review, we largely focus on the biosynthesis and regulation of plant volatiles, the involvement of floral volatiles in plant reproduction as well as their contribution to plant biodiversity and applications in agriculture via crop-pollinator interactions. In addition, metabolic engineering approaches for both the improvement of plant defense and pollinator attraction are discussed in light of methodological constraints and ecological complications that limit the transition of crops with modified volatile profiles from research laboratories to real-world implementation.

  17. Microbial community assembly and metabolic function during mammalian corpse decomposition

    USGS Publications Warehouse

    Metcalf, Jessica L; Xu, Zhenjiang Zech; Weiss, Sophie; Lax, Simon; Van Treuren, Will; Hyde, Embriette R.; Song, Se Jin; Amir, Amnon; Larsen, Peter; Sangwan, Naseer; Haarmann, Daniel; Humphrey, Greg C; Ackermann, Gail; Thompson, Luke R; Lauber, Christian; Bibat, Alexander; Nicholas, Catherine; Gebert, Matthew J; Petrosino, Joseph F; Reed, Sasha C.; Gilbert, Jack A; Lynne, Aaron M; Bucheli, Sibyl R; Carter, David O; Knight, Rob

    2016-01-01

    Vertebrate corpse decomposition provides an important stage in nutrient cycling in most terrestrial habitats, yet microbially mediated processes are poorly understood. Here we combine deep microbial community characterization, community-level metabolic reconstruction, and soil biogeochemical assessment to understand the principles governing microbial community assembly during decomposition of mouse and human corpses on different soil substrates. We find a suite of bacterial and fungal groups that contribute to nitrogen cycling and a reproducible network of decomposers that emerge on predictable time scales. Our results show that this decomposer community is derived primarily from bulk soil, but key decomposers are ubiquitous in low abundance. Soil type was not a dominant factor driving community development, and the process of decomposition is sufficiently reproducible to offer new opportunities for forensic investigations.

  18. [Control of bone remodeling by nervous system. Regulation of bone metabolism by appetite regulating neuropeptides].

    PubMed

    Fukuda, Toru; Takeda, Shu

    2010-12-01

    The traditional view of bone metabolism as a primarily endocrine activity has been expanded in recent years following the identification of nervous system controlling bone metabolism by leptin studies. Especially, hypothalamic appetite regulating-peptides, such as NPY, CART and NMU have been demonstrated to be bone-regulating neuropeptides. Recently, other neuropeptides, such as serotonin and oxytocin, are reported to be associated with bone metabolism.

  19. Contextual Control by Function and Form of Transfer of Functions

    ERIC Educational Resources Information Center

    Perkins, David R.; Dougher, Michael J.; Greenway, David E.

    2007-01-01

    This study investigated conditions leading to contextual control by stimulus topography over transfer of functions. Three 4-member stimulus equivalence classes, each consisting of four (A, B, C, D) topographically distinct visual stimuli, were established for 5 college students. Across classes, designated A stimuli were open-ended linear figures,…

  20. Systems mapping of metabolic genes through control theory.

    PubMed

    Liu, Guodong; Kong, Lan; Wang, Zhong; Wang, Chenguang; Wu, Rongling

    2013-06-30

    The formation of any complex phenotype involves a web of metabolic pathways in which one chemical is transformed through the catalysis of enzymes into another. Traditional approaches for mapping quantitative trait loci (QTLs) are based on a direct association analysis between DNA marker genotypes and end-point phenotypes, neglecting the mechanistic processes of how a phenotype is formed biochemically. Here, we propose a new dynamic framework for mapping metabolic QTLs (mQTLs) responsible for phenotypic formation. By treating metabolic pathways as a biological system, robust differential equations have proven to be a powerful means of studying and predicting the dynamic behavior of biochemical reactions that cause a high-order phenotype. The new framework integrates these differential equations into a statistical mixture model for QTL mapping. Since the mathematical parameters that define the emergent properties of the metabolic system can be estimated and tested for different mQTL genotypes, the framework allows the dynamic pattern of genetic effects to be quantified on metabolic capacity and efficacy across a time-space scale. Based on a recent study of glycolysis in Saccharomyces cerevisiae, we design and perform a series of simulation studies to investigate the statistical properties of the framework and validate its usefulness and utilization in practice. This framework can be generalized to mapping QTLs for any other dynamic systems and may stimulate pharmacogenetic research toward personalized drug and treatment intervention.

  1. Systems mapping of metabolic genes through control theory☆

    PubMed Central

    Liu, Guodong; Kong, Lan; Wang, Zhong; Wang, Chenguang; Wu, Rongling

    2014-01-01

    The formation of any complex phenotype involves a web of metabolic pathways in which one chemical is transformed through the catalysis of enzymes into another. Traditional approaches for mapping quantitative trait loci (QTLs) are based on a direct association analysis between DNA marker genotypes and end-point phenotypes, neglecting the mechanistic processes of how a phenotype is formed biochemically. Here, we propose a new dynamic framework for mapping metabolic QTLs (mQTLs) responsible for phenotypic formation. By treating metabolic pathways as a biological system, robust differential equations have proven to be a powerful means of studying and predicting the dynamic behavior of biochemical reactions that cause a high-order phenotype. The new framework integrates these differential equations into a statistical mixture model for QTL mapping. Since the mathematical parameters that define the emergent properties of the metabolic system can be estimated and tested for different mQTL genotypes, the framework allows the dynamic pattern of genetic effects to be quantified on metabolic capacity and efficacy across a time-space scale. Based on a recent study of glycolysis in Saccharomyces cerevisiae, we design and perform a series of simulation studies to investigate the statistical properties of the framework and validate its usefulness and utilization in practice. This framework can be generalized to mapping QTLs for any other dynamic systems and may stimulate pharmacogenetic research toward personalized drug and treatment intervention. PMID:23603209

  2. Chronic Alcohol Ingestion in Rats Alters Lung Metabolism, Promotes Lipid Accumulation, and Impairs Alveolar Macrophage Functions

    PubMed Central

    Romero, Freddy; Shah, Dilip; Duong, Michelle; Stafstrom, William; Hoek, Jan B.; Kallen, Caleb B.; Lang, Charles H.

    2014-01-01

    Chronic alcoholism impairs pulmonary immune homeostasis and predisposes to inflammatory lung diseases, including infectious pneumonia and acute respiratory distress syndrome. Although alcoholism has been shown to alter hepatic metabolism, leading to lipid accumulation, hepatitis, and, eventually, cirrhosis, the effects of alcohol on pulmonary metabolism remain largely unknown. Because both the lung and the liver actively engage in lipid synthesis, we hypothesized that chronic alcoholism would impair pulmonary metabolic homeostasis in ways similar to its effects in the liver. We reasoned that perturbations in lipid metabolism might contribute to the impaired pulmonary immunity observed in people who chronically consume alcohol. We studied the metabolic consequences of chronic alcohol consumption in rat lungs in vivo and in alveolar epithelial type II cells and alveolar macrophages (AMs) in vitro. We found that chronic alcohol ingestion significantly alters lung metabolic homeostasis, inhibiting AMP-activated protein kinase, increasing lipid synthesis, and suppressing the expression of genes essential to metabolizing fatty acids (FAs). Furthermore, we show that these metabolic alterations promoted a lung phenotype that is reminiscent of alcoholic fatty liver and is characterized by marked accumulation of triglycerides and free FAs within distal airspaces, AMs, and, to a lesser extent, alveolar epithelial type II cells. We provide evidence that the metabolic alterations in alcohol-exposed rats are mechanistically linked to immune impairments in the alcoholic lung: the elevations in FAs alter AM phenotypes and suppress both phagocytic functions and agonist-induced inflammatory responses. In summary, our work demonstrates that chronic alcohol ingestion impairs lung metabolic homeostasis and promotes pulmonary immune dysfunction. These findings suggest that therapies aimed at reversing alcohol-related metabolic alterations might be effective for preventing and

  3. Locomotor Adaptation Improves Balance Control, Multitasking Ability and Reduces the Metabolic Cost of Postural Instability

    NASA Technical Reports Server (NTRS)

    Bloomberg, J. J.; Peters, B. T.; Mulavara, A. P.; Brady, R. A.; Batson, C. D.; Miller, C. A.; Ploutz-Snyder, R. J.; Guined, J. R.; Buxton, R. E.; Cohen, H. S.

    2011-01-01

    During exploration-class missions, sensorimotor disturbances may lead to disruption in the ability to ambulate and perform functional tasks during the initial introduction to a novel gravitational environment following a landing on a planetary surface. The overall goal of our current project is to develop a sensorimotor adaptability training program to facilitate rapid adaptation to these environments. We have developed a unique training system comprised of a treadmill placed on a motion-base facing a virtual visual scene. It provides an unstable walking surface combined with incongruent visual flow designed to enhance sensorimotor adaptability. Greater metabolic cost incurred during balance instability means more physical work is required during adaptation to new environments possibly affecting crewmembers? ability to perform mission critical tasks during early surface operations on planetary expeditions. The goal of this study was to characterize adaptation to a discordant sensory challenge across a number of performance modalities including locomotor stability, multi-tasking ability and metabolic cost. METHODS: Subjects (n=15) walked (4.0 km/h) on a treadmill for an 8 -minute baseline walking period followed by 20-minutes of walking (4.0 km/h) with support surface motion (0.3 Hz, sinusoidal lateral motion, peak amplitude 25.4 cm) provided by the treadmill/motion-base system. Stride frequency and auditory reaction time were collected as measures of locomotor stability and multi-tasking ability, respectively. Metabolic data (VO2) were collected via a portable metabolic gas analysis system. RESULTS: At the onset of lateral support surface motion, subj ects walking on our treadmill showed an increase in stride frequency and auditory reaction time indicating initial balance and multi-tasking disturbances. During the 20-minute adaptation period, balance control and multi-tasking performance improved. Similarly, throughout the 20-minute adaptation period, VO2 gradually

  4. Intestinal microbiota in metabolic diseases: from bacterial community structure and functions to species of pathophysiological relevance.

    PubMed

    Clavel, Thomas; Desmarchelier, Charles; Haller, Dirk; Gérard, Philippe; Rohn, Sascha; Lepage, Patricia; Daniel, Hannelore

    2014-07-01

    The trillions of bacterial cells that colonize the mammalian digestive tract influence both host physiology and the fate of dietary compounds. Gnotobionts and fecal transplantation have been instrumental in revealing the causal role of intestinal bacteria in energy homeostasis and metabolic dysfunctions such as type-2 diabetes. However, the exact contribution of gut bacterial metabolism to host energy balance is still unclear and knowledge about underlying molecular mechanisms is scant. We have previously characterized cecal bacterial community functions and host responses in diet-induced obese mice using omics approaches. Based on these studies, we here discuss issues on the relevance of mouse models, give evidence that the metabolism of cholesterol-derived compounds by gut bacteria is of particular importance in the context of metabolic disorders and that dominant species of the family Coriobacteriaceae are good models to study these functions.

  5. Macrophages and Mitochondria: A Critical Interplay Between Metabolism, Signaling, and the Functional Activity.

    PubMed

    Tur, J; Vico, T; Lloberas, J; Zorzano, A; Celada, A

    2017-01-01

    Macrophages are phagocytic cells that participate in a broad range of cellular functions and they are key regulators of innate immune responses and inflammation. Mitochondria are highly dynamic endosymbiotic organelles that play key roles in cellular metabolism and apoptosis. Mounting evidence suggests that mitochondria are involved in the interplay between metabolism and innate immune responses. The ability of these organelles to alter the metabolic profile of a cell, thereby allowing an appropriate response to each situation, is crucial for the correct establishment of immune responses. Furthermore, mitochondria act as scaffolds for many proteins involved in immune signaling pathways and as such they are able to modulate the function of these proteins. Finally, mitochondria release molecules, such as reactive oxygen species, which directly regulate the immune response. In summary, mitochondria can be considered as core components in the regulation of innate immune signaling. Here we discuss the intricate relationship between mitochondria, metabolism, intracellular signaling, and innate immune responses in macrophages.

  6. Hormonal control of the metabolic machinery of hepatocellular carcinoma.

    PubMed

    Wong, Carmen Chak-Lui; Wong, Chun-Ming; Ng, Irene Oi-Lin

    2016-06-01

    Hepatocellular carcinoma (HCC) is one of the most fatal malignancies worldwide. It is an aggressive cancer with low cure rate, frequent metastasis, and highly resistant to conventional chemotherapies. Better knowledge regarding the molecular and metabolic alterations in HCC will be instrumental to the development of novel therapeutic interventions against HCC. In the August 2015 issue of Hepatology, Nie et al. reports an important molecular pathway that contributes to the Warburg Effect in HCC. They have beautifully demonstrated that the loss of a component of a hormonal system, the mineralocorticoid receptor (MR), reprogrammed the metabolic machinery of HCC cells to aerobic glycolysis through the miR-338-3p-PKL/R axis. The implication could be that in addition to drugs that directly target the metabolic enzymes in cancer cells, more translational efforts could be focused on the development of drugs that involve the activation of the MR-aldosterone system or other hormonal systems to target the Warburg effect.

  7. A worm of one's own: how helminths modulate host adipose tissue function and metabolism.

    PubMed

    Guigas, Bruno; Molofsky, Ari B

    2015-09-01

    Parasitic helminths have coexisted with human beings throughout time. Success in eradicating helminths has limited helminth-induced morbidity and mortality but is also correlated with increasing rates of 'western' diseases, including metabolic syndrome and type 2 diabetes. Recent studies in mice describe how type 2 immune cells, traditionally associated with helminth infection, maintain adipose tissue homeostasis and promote adipose tissue beiging, protecting against obesity and metabolic dysfunction. Here, we review these studies and discuss how helminths and helminth-derived molecules may modulate these physiologic pathways to improve metabolic functions in specific tissues, such as adipose and liver, as well as at the whole-organism level.

  8. Gut-Brain Cross-Talk in Metabolic Control.

    PubMed

    Clemmensen, Christoffer; Müller, Timo D; Woods, Stephen C; Berthoud, Hans-Rudolf; Seeley, Randy J; Tschöp, Matthias H

    2017-02-23

    Because human energy metabolism evolved to favor adiposity over leanness, the availability of palatable, easily attainable, and calorically dense foods has led to unprecedented levels of obesity and its associated metabolic co-morbidities that appear resistant to traditional lifestyle interventions. However, recent progress identifying the molecular signaling pathways through which the brain and the gastrointestinal system communicate to govern energy homeostasis, combined with emerging insights on the molecular mechanisms underlying successful bariatric surgery, gives reason to be optimistic that novel precision medicines that mimic, enhance, and/or modulate gut-brain signaling can have unprecedented potential for stopping the obesity and type 2 diabetes pandemics.

  9. Circadian rhythms and the regulation of metabolic tissue function and energy homeostasis.

    PubMed

    Zvonic, Sanjin; Floyd, Z Elizabeth; Mynatt, Randall L; Gimble, Jeffrey M

    2007-03-01

    Circadian oscillators play an indispensable role in the coordination of physiological processes with the cyclic changes in the physical environment. A significant number of recent clinical and molecular studies suggest that circadian biology may play an important role in the regulation of adipose and other metabolic tissue functions. In this discussion, we present the hypothesis that circadian dysfunction may be involved in the pathogenesis of obesity, type 2 diabetes, and the metabolic syndrome.

  10. PTENα, a PTEN isoform translated through alternative initiation, regulates mitochondrial function and energy metabolism.

    PubMed

    Liang, Hui; He, Shiming; Yang, Jingyi; Jia, Xinying; Wang, Pan; Chen, Xi; Zhang, Zhong; Zou, Xiajuan; McNutt, Michael A; Shen, Wen Hong; Yin, Yuxin

    2014-05-06

    PTEN is one of the most frequently mutated genes in human cancer. It is known that PTEN has a wide range of biological functions beyond tumor suppression. Here, we report that PTENα, an N-terminally extended form of PTEN, functions in mitochondrial metabolism. Translation of PTENα is initiated from a CUG codon upstream of and in-frame with the coding region of canonical PTEN. Eukaryotic translation initiation factor 2A (eIF2A) controls PTENα translation, which requires a CUG-centered palindromic motif. We show that PTENα induces cytochrome c oxidase activity and ATP production in mitochondria. TALEN-mediated somatic deletion of PTENα impairs mitochondrial respiratory chain function. PTENα interacts with canonical PTEN to increase PINK1 protein levels and promote energy production. Our studies demonstrate the importance of eIF2A-mediated alternative translation for generation of protein diversity in eukaryotic systems and provide insights into the mechanism by which the PTEN family is involved in multiple cellular processes.

  11. Psychological and metabolic improvement after an outpatient teaching program for functional intensified insulin therapy (FIT).

    PubMed

    Langewitz, W; Wössmer, B; Iseli, J; Berger, W

    1997-09-01

    To be the master of their disease and not its slave is the ultimate goal of many patients with diabetes. Intensified functional insulin therapy (FIT) helps to establish this goal by an intensive patient education: each patient learns in five small-group sessions how s/he reacts to standardized challenges of glucose homeostasis (e.g. 24 h fasting; physical exercise; various carbohydrate loads). We investigated in 43 patients with long-standing diabetes type 1 (mean age: 33 +/- 10 years; mean duration of diabetes: 15 +/- 10 years) whether FIT improves quality of life, influences metabolic control and doctor-patient relationship. The following instruments were used: diabetes specific quality of life questionnaire (DQOL), hierarchical distance and cohesion between doctor and patient (FAST), anxiety and depression (HAD). Pre and post intervention values were compared with paired t-tests. HbA1c and number of hypoglycaemic episodes were also assessed 1 year after FIT and 1 year prior to FIT. Metabolic control was improved: HbA1c in the year before FIT: 6.72 +/- 1.35; 4 months before FIT: 6.61 +/- 1.46; 4 months after FIT: 6.29 +/- 1.09 (P < 0.05 compared to 4 months before FIT); 1 year after FIT: 6.46 +/- 1.12 (n.s. compared to 1 year before FIT). Dissatisfaction with life decreases from 33.3 +/- 8.0 to 28.5 +/- 7.7 (P < 0.001). Moments free of disease-specific strain increase from 74.3 +/- 13.9 to 78.1 +/- 16.1 (P = 0.07). Hierarchical distance between doctor and patient decreases from 1.1 +/- to 0.6 +/- 0.8 (P < 0.001), cohesion increases from 9.3 +/- 1.5 to 9.9 +/- 1.1 (P < 0.001). Anxiety and depression both decreases significantly: anxiety, 6.5 +/- 3.3-->4.6 +/- 3.2 (P < 0.001); depression, 2.7 +/- 2.5-->1.5 +/- 1.6 (P < 0.001). The number of patients with severe hypoglycaemic episodes (level 4) decreases from five (11.6%) to one (2.3%) after intervention (P < 0.05). In conclusion, FIT enhances quality of life in diabetic individuals. It helps to establish a less

  12. Proteomics-based metabolic modeling reveals that fatty acid oxidation (FAO) controls endothelial cell (EC) permeability.

    PubMed

    Patella, Francesca; Schug, Zachary T; Persi, Erez; Neilson, Lisa J; Erami, Zahra; Avanzato, Daniele; Maione, Federica; Hernandez-Fernaud, Juan R; Mackay, Gillian; Zheng, Liang; Reid, Steven; Frezza, Christian; Giraudo, Enrico; Fiorio Pla, Alessandra; Anderson, Kurt; Ruppin, Eytan; Gottlieb, Eyal; Zanivan, Sara

    2015-03-01

    Endothelial cells (ECs) play a key role to maintain the functionality of blood vessels. Altered EC permeability causes severe impairment in vessel stability and is a hallmark of pathologies such as cancer and thrombosis. Integrating label-free quantitative proteomics data into genome-wide metabolic modeling, we built up a model that predicts the metabolic fluxes in ECs when cultured on a tridimensional matrix and organize into a vascular-like network. We discovered how fatty acid oxidation increases when ECs are assembled into a fully formed network that can be disrupted by inhibiting CPT1A, the fatty acid oxidation rate-limiting enzyme. Acute CPT1A inhibition reduces cellular ATP levels and oxygen consumption, which are restored by replenishing the tricarboxylic acid cycle. Remarkably, global phosphoproteomic changes measured upon acute CPT1A inhibition pinpointed altered calcium signaling. Indeed, CPT1A inhibition increases intracellular calcium oscillations. Finally, inhibiting CPT1A induces hyperpermeability in vitro and leakage of blood vessel in vivo, which were restored blocking calcium influx or replenishing the tricarboxylic acid cycle. Fatty acid oxidation emerges as central regulator of endothelial functions and blood vessel stability and druggable pathway to control pathological vascular permeability.

  13. Exercise-stimulated interleukin-15 is controlled by AMPK and regulates skin metabolism and aging.

    PubMed

    Crane, Justin D; MacNeil, Lauren G; Lally, James S; Ford, Rebecca J; Bujak, Adam L; Brar, Ikdip K; Kemp, Bruce E; Raha, Sandeep; Steinberg, Gregory R; Tarnopolsky, Mark A

    2015-08-01

    Aging is commonly associated with a structural deterioration of skin that compromises its barrier function, healing, and susceptibility to disease. Several lines of evidence show that these changes are driven largely by impaired tissue mitochondrial metabolism. While exercise is associated with numerous health benefits, there is no evidence that it affects skin tissue or that endocrine muscle-to-skin signaling occurs. We demonstrate that endurance exercise attenuates age-associated changes to skin in humans and mice and identify exercise-induced IL-15 as a novel regulator of mitochondrial function in aging skin. We show that exercise controls IL-15 expression in part through skeletal muscle AMP-activated protein kinase (AMPK), a central regulator of metabolism, and that the elimination of muscle AMPK causes a deterioration of skin structure. Finally, we establish that daily IL-15 therapy mimics some of the anti-aging effects of exercise on muscle and skin in mice. Thus, we elucidate a mechanism by which exercise confers health benefits to skin and suggest that low-dose IL-15 therapy may prove to be a beneficial strategy to attenuate skin aging.

  14. Exercise-stimulated interleukin-15 is controlled by AMPK and regulates skin metabolism and aging

    PubMed Central

    Crane, Justin D; MacNeil, Lauren G; Lally, James S; Ford, Rebecca J; Bujak, Adam L; Brar, Ikdip K; Kemp, Bruce E; Raha, Sandeep; Steinberg, Gregory R; Tarnopolsky, Mark A

    2015-01-01

    Aging is commonly associated with a structural deterioration of skin that compromises its barrier function, healing, and susceptibility to disease. Several lines of evidence show that these changes are driven largely by impaired tissue mitochondrial metabolism. While exercise is associated with numerous health benefits, there is no evidence that it affects skin tissue or that endocrine muscle-to-skin signaling occurs. We demonstrate that endurance exercise attenuates age-associated changes to skin in humans and mice and identify exercise-induced IL-15 as a novel regulator of mitochondrial function in aging skin. We show that exercise controls IL-15 expression in part through skeletal muscle AMP-activated protein kinase (AMPK), a central regulator of metabolism, and that the elimination of muscle AMPK causes a deterioration of skin structure. Finally, we establish that daily IL-15 therapy mimics some of the anti-aging effects of exercise on muscle and skin in mice. Thus, we elucidate a mechanism by which exercise confers health benefits to skin and suggest that low-dose IL-15 therapy may prove to be a beneficial strategy to attenuate skin aging. PMID:25902870

  15. The heat shock factor HSF1 juggles protein quality control and metabolic regulation.

    PubMed

    Cantó, Carles

    2017-03-06

    Transcriptional regulators often act as central hubs to integrate multiple nutrient and stress signals. In this issue, Qiao et al. (2017. J. Cell Biol. https://doi.org/10.1083/jcb.201607091) demonstrate how heat shock factor 1 (HSF1) uncouples metabolic control from proteostatic regulation and unveils HSF1 as a critical transcriptional regulator of NAD(+) metabolism.

  16. Sensitive cells: enabling tools for static and dynamic control of microbial metabolic pathways.

    PubMed

    Cress, Brady F; Trantas, Emmanouil A; Ververidis, Filippos; Linhardt, Robert J; Koffas, Mattheos Ag

    2015-12-01

    Natural metabolic pathways are dynamically regulated at the transcriptional, translational, and protein levels. Despite this, traditional pathway engineering has relied on static control strategies to engender changes in metabolism, most likely due to ease of implementation and perceived predictability of design outcome. Increasingly in recent years, however, metabolic engineers have drawn inspiration from natural systems and have begun to harness dynamically controlled regulatory machinery to improve design of engineered microorganisms for production of specialty and commodity chemicals. Here, we review recent enabling technologies for engineering static control over pathway expression levels, and we discuss state-of-the-art dynamic control strategies that have yielded improved outcomes in the field of microbial metabolic engineering. Furthermore, we emphasize design of a novel class of genetically encoded controllers that will facilitate automatic, transient tuning of synthetic and endogenous pathways.

  17. Plasma protein regulation of platelet function and metabolism.

    PubMed

    Hansen, M S; Bang, N U

    1979-04-02

    This reviews summarizes our evidence suggesting that the plasma protein enviroment influences platelet aggregation potential and metabolic activity. Cationic proteins are capable of restoring the aggreation potential of washed human platelets. The aggregation restoring effect of gamma globulin is inhibited by more anionic proteins in subfractions of Cohn fraction IV and fractions V and VI. Artificial enhancement of the net negative charge of plasma proteins through acylation produces derivatives capable of inhibiting platelet rich plasma. The oxygen consumption of washed human platelets is lower than in platelet rich plasma while the lactate production is identical. Autologus plasma, albumin or IgG immunoglobulin restores the oxygen consumption of washed platelets to values comparable to those obtained for platelet rich plasma, while the lactate production is unaffected. Fibrinogen on IgA myeloma protein increases the lactate production, but not the oxygen consumption. Cyclic AMP levels are considerably lower in washed platelets than in platelet rich plasma. Gamma globulin and albumin causes a futher decrease, which is progressive with time. Fibrinogen causes no change in platelet cyclic AMP content. It is suggested that these observations may in part be explained by the equilibriun between anionic and cationic proteins in the platelet microenvironment. This hypothesis appears applicable in certain situations.

  18. Metabolic classification of microbial genomes using functional probes

    PubMed Central

    2012-01-01

    Background Microorganisms able to grow under artificial culture conditions comprise only a small proportion of the biosphere's total microbial community. Until recently, scientists have been unable to perform thorough analyses of difficult-to-culture microorganisms due to limitations in sequencing technology. As modern techniques have dramatically increased sequencing rates and rapidly expanded the number of sequenced genomes, in addition to traditional taxonomic classifications which focus on the evolutionary relationships of organisms, classifications of the genomes based on alternative points of view may help advance our understanding of the delicate relationships of organisms. Results We have developed a proteome-based method for classifying microbial species. This classification method uses a set of probes comprising short, highly conserved amino acid sequences. For each genome, in silico translation is performed to obtained its proteome, based on which a probe-set frequency pattern is generated. Then, the probe-set frequency patterns are used to cluster the proteomes/genomes. Conclusions Features of the proposed method include a high running speed in challenge of a large number of genomes, and high applicability for classifying organisms with incomplete genome sequences. Moreover, the probe-set clustering method is sensitive to the metabolic phenotypic similarities/differences among species and is thus supposed potential for the classification or differentiation of closely-related organisms. PMID:22537274

  19. L-carnitine--metabolic functions and meaning in humans life.

    PubMed

    Pekala, Jolanta; Patkowska-Sokoła, Bozena; Bodkowski, Robert; Jamroz, Dorota; Nowakowski, Piotr; Lochyński, Stanisław; Librowski, Tadeusz

    2011-09-01

    L-Carnitine is an endogenous molecule involved in fatty acid metabolism, biosynthesized within the human body using amino acids: L-lysine and L-methionine, as substrates. L-Carnitine can also be found in many foods, but red meats, such as beef and lamb, are the best choices for adding carnitine into the diet. Good carnitine sources also include fish, poultry and milk. Essentially, L-carnitine transports the chains of fatty acids into the mitochondrial matrix, thus allowing the cells to break down fat and get energy from the stored fat reserves. Recent studies have started to shed light on the beneficial effects of L-carnitine when used in various clinical therapies. Because L-carnitine and its esters help reduce oxidative stress, they have been proposed as a treatment for many conditions, i.e. heart failure, angina and weight loss. For other conditions, such as fatigue or improving exercise performance, L-carnitine appears safe but does not seem to have a significant effect. The presented review of the literature suggests that continued studies are required before L-carnitine administration could be recommended as a routine procedure in the noted disorders. Further research is warranted in order to evaluate the biochemical, pharmacological, and physiological determinants of the response to carnitine supplementation, as well as to determine the potential benefits of carnitine supplements in selected categories of individuals who do not have fatty acid oxidation defects.

  20. Simulated microgravity enhances oligodendrocyte mitochondrial function and lipid metabolism.

    PubMed

    Espinosa-Jeffrey, Araceli; Nguyen, Kevin; Kumar, Shalini; Toshimasa, Ochiai; Hirose, Ryuji; Reue, Karen; Vergnes, Laurent; Kinchen, Jason; Vellis, Jean de

    2016-12-01

    The primary energy sources of mammalian cells are proteins, fats, and sugars that are processed by well-known biochemical mechanisms that have been discovered and studied in 1G (terrestrial gravity). Here we sought to determine how simulated microgravity (sim-µG) impacts both energy and lipid metabolism in oligodendrocytes (OLs), the myelin-forming cells in the central nervous system. We report increased mitochondrial respiration and increased glycolysis 24 hr after exposure to sim-µG. Moreover, examination of the secretome after 3 days' exposure of OLs to sim-µG increased the Krebs cycle (Krebs and Weitzman, ) flux in sim-µG. The secretome study also revealed a significant increase in the synthesis of fatty acids and complex lipids such as 1,2-dipalmitoyl-GPC (5.67); lysolipids like 1-oleoyl-GPE (4.48) were also increased by microgravity. Although longer-chain lipids were not observed in this study, it is possible that at longer time points OLs would have continued moving forward toward the synthesis of lipids that constitute myelin. For centuries, basic developmental biology research has been the pillar of an array of discoveries that have led to clinical applications; we believe that studies using microgravity will open new avenues to our understanding of the brain in health and disease-in particular, to the discovery of new molecules and mechanisms impossible to unveil while in 1G. © 2016 Wiley Periodicals, Inc.

  1. Controlled functionalization of nanoparticles & practical applications

    NASA Astrophysics Data System (ADS)

    Rashwan, Khaled

    With the increasing use of nanoparticles in both science and industry, their chemical modification became a significant part of nanotechnology. Unfortunately, most commonly used procedures provide just randomly functionalized materials. The long-term objective of our work is site- and stoichiometrically-controlled functionalization of nanoparticles with the utilization of solid supports and other nanostructures. On the examples of silica nanoparticles and titanium dioxide nanorods, we have obtained results on the solid-phase chemistry, method development, and modeling, which advanced us toward this goal. At the same time, we explored several applications of nanoparticles that will benefit from the controlled functionalization: imaging of titanium-dioxide-based photocatalysts, bioimaging by fluorescent nanoparticles, drug delivery, assembling of bone implants, and dental compositions. Titanium dioxide-based catalysts are known for their catalytic activity and their application in solar energy utilization such as photosplitting of water. Functionalization of titanium dioxide is essential for enhancing bone-titanium dioxide nanotube adhesion, and, therefore, for its application as an interface between titanium implants and bones. Controlled functionalization of nanoparticles should enhance sensitivity and selectivity of nanoassemblies for imaging and drug delivery applications. Along those lines, we studied the relationship between morphology and surface chemistry of nanoparticles, and their affinity to organic molecules (salicylic and caffeic acid) using Langmuir adsorption isotherms, and toward material surfaces using SEM- and TEM-imaging. We focused on commercial samples of titanium dioxide, titanium dioxide nanorods with and without oleic acid ligands, and differently functionalized silica nanoparticles. My work included synthesis, functionalization, and characterization of several types of nanoparticles, exploring their application in imaging, dentistry, and bone

  2. Molecular changes in hepatic metabolism and transport in cirrhosis and their functional importance

    PubMed Central

    Dietrich, Christoph G; Götze, Oliver; Geier, Andreas

    2016-01-01

    Liver cirrhosis is the common endpoint of many hepatic diseases and represents a relevant risk for liver failure and hepatocellular carcinoma. The progress of liver fibrosis and cirrhosis is accompanied by deteriorating liver function. This review summarizes the regulatory and functional changes in phase I and phase II metabolic enzymes as well as transport proteins and provides an overview regarding lipid and glucose metabolism in cirrhotic patients. Interestingly, phase I enzymes are generally downregulated transcriptionally, while phase II enzymes are mostly preserved transcriptionally but are reduced in their function. Transport proteins are regulated in a specific way that resembles the molecular changes observed in obstructive cholestasis. Lipid and glucose metabolism are characterized by insulin resistance and catabolism, leading to the disturbance of energy expenditure and wasting. Possible non-invasive tests, especially breath tests, for components of liver metabolism are discussed. The heterogeneity and complexity of changes in hepatic metabolism complicate the assessment of liver function in individual patients. Additionally, studies in humans are rare, and species differences preclude the transferability of data from rodents to humans. In clinical practice, some established global scores or criteria form the basis for the functional evaluation of patients with liver cirrhosis, but difficult treatment decisions such as selection for transplantation or resection require further research regarding the application of existing non-invasive tests and the development of more specific tests. PMID:26755861

  3. Scopolamine impairs behavioural function and arginine metabolism in the rat dentate gyrus.

    PubMed

    Knox, Logan T; Jing, Yu; Fleete, Michael S; Collie, Nicola D; Zhang, Hu; Liu, Ping

    2011-12-01

    Alzheimer's disease (AD) is a neurodegenerative disorder with progressive memory loss. It has been shown that the cholinergic neurotransmission deficit is one of the neurochemical characteristics of AD, and that L-arginine and its metabolites also play a prominent role in AD pathogenesis. Scopolamine, a non-selective muscarinic receptor antagonist, blocks cholinergic neurotransmission and impairs behavioural function, including learning and memory. This study investigated the effects of scopolamine on animals' behavioural performance and L-arginine metabolism in the hippocampus and prefrontal cortex. Rats were given intraperitoneal injections of scopolamine (0.8 mg/kg) or saline (1 ml/kg) and tested in the Y-maze, open field, water maze and elevated plus maze 30 min post-treatment. After completion of the behavioural testing, the CA1, CA2/3 and dentate gyrus (DG) sub-regions of the hippocampus and the prefrontal cortex were harvested to measure the activity and protein expression of nitric oxide synthase (NOS) and arginase, and the levels of L-arginine, L-citrulline, L-ornithine, agmatine, putrescine, spermidine, spermine, glutamate and GABA. Scopolamine treated rats displayed reduced alternation and exploratory behaviour, increased swimming speed and impaired spatial learning and memory. There were significantly decreased NOS activity, increased arginase activity, and increased L-ornithine and putrescine levels in the DG, but not other regions examined, in the scopolamine treated rats as compared to the controls. These findings suggest that scopolamine impairs behavioural function and alters L-arginine metabolism in the DG sub-region of the hippocampus specifically. The underlying mechanisms of it remain to be explored further.

  4. Plasminogen activator inhibitor-1 is elevated in patients with COPD independent of metabolic and cardiovascular function

    PubMed Central

    Waschki, Benjamin; Watz, Henrik; Holz, Olaf; Magnussen, Helgo; Olejnicka, Beata; Welte, Tobias; Rabe, Klaus F; Janciauskiene, Sabina

    2017-01-01

    Introduction Plasminogen activator inhibitor-1 (PAI-1), a major inhibitor of fibrinolysis, is associated with thrombosis, obesity, insulin resistance, dyslipidemia, and premature aging, which all are coexisting conditions of chronic obstructive pulmonary disease (COPD). The role of PAI-1 in COPD with respect to metabolic and cardiovascular functions is unclear. Methods In this study, which was nested within a prospective cohort study, the serum levels of PAI-1 were cross-sectionally measured in 74 stable COPD patients (Global Initiative for Chronic Obstructive Lung Disease [GOLD] Stages I–IV) and 18 controls without lung disease. In addition, triglycerides, high-density lipoprotein cholesterol, fasting plasma glucose, waist circumference, blood pressure, smoking status, high-sensitive C-reactive protein (hs-CRP), adiponectin, ankle–brachial index, N-terminal pro-B-type natriuretic peptide, and history of comorbidities were also determined. Results The serum levels of PAI-1 were significantly higher in COPD patients than in controls, independent of a broad spectrum of possible confounders including metabolic and cardiovascular dysfunction. A multivariate regression analysis revealed triglyceride and hs-CRP levels to be the best predictors of PAI-1 within COPD. GOLD Stages II and III remained independently associated with higher PAI-1 levels in a final regression analysis. Conclusion The data from the present study showed that the serum levels of PAI-1 are higher in patients with COPD and that moderate-to-severe airflow limitation, hypertriglyceridemia, and systemic inflammation are independent predictors of an elevated PAI-1 level. PAI-1 may be a potential biomarker candidate for COPD-specific and extra-pulmonary manifestations. PMID:28356730

  5. Bidirectional electromagnetic control of the hypothalamus regulates feeding and metabolism

    PubMed Central

    Stanley, Sarah A.; Kelly, Leah; Latcha, Kaamashri N.; Schmidt, Sarah F.; Yu, Xiaofei; Nectow, Alexander R.; Sauer, Jeremy; Dyke, Jonathan P.; Dordick, Jonathan S.; Friedman, Jeffrey M.

    2016-01-01

    Targeted, temporally regulated neural modulation is invaluable in determining the physiological roles of specific neural populations or circuits. Here we describe a system for non-invasive, temporal activation or inhibition of neuronal activity in vivo and its use to study central nervous system control of glucose homeostasis and feeding in mice. We are able to induce neuronal activation remotely using radio waves or magnetic fields via Cre-dependent expression of a GFP-tagged ferritin fusion protein tethered to the cation-conducting transient receptor potential vanilloid 1 (TRPV1) by a camelid anti-GFP antibody (anti-GFP–TRPV1)1. Neuronal inhibition via the same stimuli is achieved by mutating the TRPV1 pore, rendering the channel chloride-permeable. These constructs were targeted to glucose-sensing neurons in the ventromedial hypothalamus in glucokinase–Cre mice, which express Cre in glucose-sensing neurons2. Acute activation of glucose-sensing neurons in this region increases plasma glucose and glucagon, lowers insulin levels and stimulates feeding, while inhibition reduces blood glucose, raises insulin levels and suppresses feeding. These results suggest that pancreatic hormones function as an effector mechanism of central nervous system circuits controlling blood glucose and behaviour. The method we employ obviates the need for permanent implants and could potentially be applied to study other neural processes or used to regulate other, even dispersed, cell types. PMID:27007848

  6. Metabolic Design and Control for Production in Prokaryotes

    SciTech Connect

    Chhabra, Swapnil R.; Keasling, J.D.

    2010-11-10

    Prokaryotic life on earth is manifested by its diversity and omnipresence. These microbes serve as natural sources of a large variety of compounds with the potential to serve the ever growing, medicinal, chemical and transportation needs of the human population. However, commercially viable production of these compounds can be realized only through significant improvement of the native production capacity of natural isolates. The most favorable way to achieve this goal is through the genetic manipulation of metabolic pathways that direct the production of these molecules. While random mutagenesis and screening have dominated the industrial production of such compounds in the past our increased understanding of microbial physiology over the last five decades has shifted this trend towards rational approaches for metabolic design. Major drivers of this trend include recombinant DNA technology, high throughput characterization of macromolecular cellular components, quantitative modeling for metabolic engine ring, targeted combinatorial engineering and synthetic biology. In this chapter we track the evolution of microbial engineering technologies from the black box era of random mutagenesis to the science and engineering-driven era of metabolic design.

  7. Emergence of Complexity in Protein Functions and Metabolic Networks

    NASA Technical Reports Server (NTRS)

    Pohorille, Andzej

    2009-01-01

    In modern organisms proteins perform a majority of cellular functions, such as chemical catalysis, energy transduction and transport of material across cell walls. Although great strides have been made towards understanding protein evolution, a meaningful extrapolation from contemporary proteins to their earliest ancestors is virtually impossible. In an alternative approach, the origin of water-soluble proteins was probed through the synthesis of very large libraries of random amino acid sequences and subsequently subjecting them to in vitro evolution. In combination with computer modeling and simulations, these experiments allow us to address a number of fundamental questions about the origins of proteins. Can functionality emerge from random sequences of proteins? How did the initial repertoire of functional proteins diversify to facilitate new functions? Did this diversification proceed primarily through drawing novel functionalities from random sequences or through evolution of already existing proto-enzymes? Did protein evolution start from a pool of proteins defined by a frozen accident and other collections of proteins could start a different evolutionary pathway? Although we do not have definitive answers to these questions, important clues have been uncovered. Considerable progress has been also achieved in understanding the origins of membrane proteins. We will address this issue in the example of ion channels - proteins that mediate transport of ions across cell walls. Remarkably, despite overall complexity of these proteins in contemporary cells, their structural motifs are quite simple, with -helices being most common. By combining results of experimental and computer simulation studies on synthetic models and simple, natural channels, I will show that, even though architectures of membrane proteins are not nearly as diverse as those of water-soluble proteins, they are sufficiently flexible to adapt readily to the functional demands arising during

  8. Energy metabolism of rabbit retina as related to function: high cost of Na+ transport.

    PubMed

    Ames, A; Li, Y Y; Heher, E C; Kimble, C R

    1992-03-01

    Experiments designed to examine the energy requirements of neurophysiological function were performed on isolated rabbit retina. Function was altered by photic stimulation or by function-specific drugs, and the response of energy metabolism was assessed by simultaneous measurements of O2 consumption and lactate production. In other experiments, the supply of O2 or glucose was reduced and the effect on energy metabolism and electrophysiological function was observed. Energy requirements under control conditions in darkness were high, with O2 consumption (per gm dry wt) at 11.3 mumol min-1, with lactate production at 14.8 mumol min-1, and with the derived value for glucose consumption at 9.3 mumol min-1 and for high-energy phosphate (approximately P) generation at 82.6 mumol min-1. Energy reserves were small. Removing glucose abolished the b-wave of the electroretinogram (ERG) with a t1/2 of 1 min, but did not immediately affect O2 consumption or the PIII of the ERG. Removing O2 caused increases of up to 2.7-fold in glycolysis (Pasteur effect) and caused both PIII and b-wave to fail, with a t1/2 of about 5 min. Neurotransmission through the inner retina was supported almost entirely by glycolysis, as evidenced by large increases in lactate production in response to flashing light and decreases in response to transmitter blockers (2.3-fold overall change), with no change in O2 consumption. Phototransduction, on the other hand, was normally supported by oxidative metabolism. The dark current accounted for 41% of the retina's O2 consumption. With O2 reduced, the dark current was partially supported by glycolysis, which accounts (at least in part) for the large Pasteur effect. Na+ transport by NaK ATPase accounted for about half of all energy used, as evidenced by the response to strophanthidin, that is, for 49% of the oxidative energy and 58% of the glycolytic energy. The t1/2 for the turnover of intracellular Na+ was calculated from these data to be less than 1 min

  9. Control of protein function through optochemical translocation.

    PubMed

    Engelke, Hanna; Chou, Chungjung; Uprety, Rajendra; Jess, Phillip; Deiters, Alexander

    2014-10-17

    Controlled manipulation of proteins and their function is important in almost all biological disciplines. Here, we demonstrate control of protein activity with light. We present two different applications-light-triggered transcription and light-triggered protease cleavage-both based on the same concept of protein mislocation, followed by optochemically triggered translocation to an active cellular compartment. In our approach, we genetically encode a photocaged lysine into the nuclear localization signal (NLS) of the transcription factor SATB1. This blocks nuclear import of the protein until illumination induces caging group removal and release of the protein into the nucleus. In the first application, prepending this NLS to the transcription factor FOXO3 allows us to optochemically switch on its transcription activity. The second application uses the developed light-activated NLS to control nuclear import of TEV protease and subsequent cleavage of nuclear proteins containing TEV cleavage sites. The small size of the light-controlled NLS (only 20 amino acids) minimizes impact of its insertion on protein function and promises a general approach to a wide range of optochemical applications. Since the light-activated NLS is genetically encoded and optically triggered, it will prove useful to address a variety of problems requiring spatial and temporal control of protein function, for example, in stem-cell, developmental, and cancer biology.

  10. Investigating neuronal function with optically controllable proteins

    PubMed Central

    Zhou, Xin X.; Pan, Michael; Lin, Michael Z.

    2015-01-01

    In the nervous system, protein activities are highly regulated in space and time. This regulation allows for fine modulation of neuronal structure and function during development and adaptive responses. For example, neurite extension and synaptogenesis both involve localized and transient activation of cytoskeletal and signaling proteins, allowing changes in microarchitecture to occur rapidly and in a localized manner. To investigate the role of specific protein regulation events in these processes, methods to optically control the activity of specific proteins have been developed. In this review, we focus on how photosensory domains enable optical control over protein activity and have been used in neuroscience applications. These tools have demonstrated versatility in controlling various proteins and thereby cellular functions, and possess enormous potential for future applications in nervous systems. Just as optogenetic control of neuronal firing using opsins has changed how we investigate the function of cellular circuits in vivo, optical control may yet yield another revolution in how we study the circuitry of intracellular signaling in the brain. PMID:26257603

  11. A Multifunctional Bread Rich in Beta Glucans and Low in Starch Improves Metabolic Control in Type 2 Diabetes: A Controlled Trial

    PubMed Central

    Tessari, Paolo; Lante, Anna

    2017-01-01

    Design: Functional foods may be useful for people with diabetes. The soluble fibers beta glucans can modify starch digestion and improve postprandial glucose response. We analyzed the metabolic effects of a specifically designed ‘functional’ bread, low in starch, rich in fibers (7 g/100 g), with a beta glucan/starch ratio of (7.6:100, g/g), in people with type 2 diabetes mellitus. Methods: Clinical and metabolic data from two groups of age-, sex- and glycated hemoglobin-matched diabetic subjects, taking either the functional bread or regular white bread, over a roughly six-month observation period, were retrieved. Results: Bread intake did not change during the trial. The functional bread reduced glycated hemoglobin by ~0.5% (absolute units) vs. pre-treatment values (p = 0.028), and by ~0.6% vs. the control group (p = 0.027). Post-prandial and mean plasma glucose was decreased in the treatment group too. Body weight, blood pressure and plasma lipids did not change. The acceptance of the functional bread was good in the majority of subjects, except for taste. Conclusions: A starch-restricted, fiber-rich functional bread, with an increased beta glucan/starch ratio, improved long term metabolic control, and may be indicated in the dietary treatment of type 2 diabetes. PMID:28304350

  12. Integration and control of circulatory function.

    PubMed

    Guyton, A C; Cowley, A W; Young, D B; Coleman, T G; Hall, J E; DeClue, J W

    1976-01-01

    In this chapter we have emphasized especially the intrinsic controls of the circulation, such as the autoregulation mechanism for control of local blood flow, automatic control of cardiac output, long-term control of arterial pressure, long-term control of blood volume, and automatic distribution of fluids between the circulation and the interstitial spaces. The reasons for emphasizing these mechanisms are several: first, many experiments have now shown that the intrinsic mechanisms can provide highly stable long-term control of the circulation. Second, the value of the nervous and hormonal controls have probably been greatly overemphasized in the past. And, third, there are special complexities of the intrinsic controls--such as nonlinearities, delay in responses, and other effects--that have made these difficult to understand; it is probably these difficulties that have led to their underemphasis. However, we have not meant to take from the nervous and hormonal systems their true importance in circulatory control. For instance, intrinsic mechanisms have almost no capability for acute arterial pressure control (only for long-term control), and they have no mechanism for providing the drive necessary to make the animal ingest water and electrolytes. These require the nervous controls. Also, nervous reflexes are important in enhancing the effectiveness of blood volume control and control of cardiac pumping. Among the hormonal mechanisms, the renin-angiotensin system can provide a modest degree of arterial pressure control when the pressure falls below normal by eliciting a vasoconstrictor response in the peripheral blood vessels. However, this system seems to have an even more important renal function, a direct effect on kidneys to cause fluid retention; this in turn increases the body fluid volume and in this way increases the arterial pressure. Finally, the roles of ADH and aldosterone in the control of blood volume have probably been greatly overemphasized. On

  13. Functional proteomic analysis of corticosteroid pharmacodynamics in rat liver: Relationship to hepatic stress, signaling, energy regulation, and drug metabolism.

    PubMed

    Ayyar, Vivaswath S; Almon, Richard R; DuBois, Debra C; Sukumaran, Siddharth; Qu, Jun; Jusko, William J

    2017-03-14

    Corticosteroids (CS) are anti-inflammatory agents that cause extensive pharmacogenomic and proteomic changes in multiple tissues. An understanding of the proteome-wide effects of CS in liver and its relationships to altered hepatic and systemic physiology remains incomplete. Here, we report the application of a functional pharmacoproteomic approach to gain integrated insight into the complex nature of CS responses in liver in vivo. An in-depth functional analysis was performed using rich pharmacodynamic (temporal-based) proteomic data measured over 66h in rat liver following a single dose of methylprednisolone (MPL). Data mining identified 451 differentially regulated proteins. These proteins were analyzed on the basis of temporal regulation, cellular localization, and literature-mined functional information. Of the 451 proteins, 378 were clustered into six functional groups based on major clinically-relevant effects of CS in liver. MPL-responsive proteins were highly localized in the mitochondria (20%) and cytosol (24%). Interestingly, several proteins were related to hepatic stress and signaling processes, which appear to be involved in secondary signaling cascades and in protecting the liver from CS-induced oxidative damage. Consistent with known adverse metabolic effects of CS, several rate-controlling enzymes involved in amino acid metabolism, gluconeogenesis, and fatty-acid metabolism were altered by MPL. In addition, proteins involved in the metabolism of endogenous compounds, xenobiotics, and therapeutic drugs including cytochrome P450 and Phase-II enzymes were differentially regulated. Proteins related to the inflammatory acute-phase response were up-regulated in response to MPL. Functionally-similar proteins showed large diversity in their temporal profiles, indicating complex mechanisms of regulation by CS.

  14. Evidence for compromised metabolic function and limited glucose uptake in spermatozoa from the teratospermic domestic cat (Felis catus) and cheetah (Acinonyx jubatus).

    PubMed

    Terrell, Kimberly A; Wildt, David E; Anthony, Nicola M; Bavister, Barry D; Leibo, Stanley P; Penfold, Linda M; Marker, Laurie L; Crosier, Adrienne E

    2010-11-01

    Cheetahs and certain other felids consistently ejaculate high proportions (≥ 60%) of malformed spermatozoa, a condition known as teratospermia, which is prevalent in humans. Even seemingly normal spermatozoa from domestic cat teratospermic ejaculates have reduced fertilizing capacity. To understand the role of sperm metabolism in this phenomenon, we conducted a comparative study in the normospermic domestic cat versus the teratospermic cat and cheetah with the general hypothesis that sperm metabolic function is impaired in males producing predominantly pleiomorphic spermatozoa. Washed ejaculates were incubated in chemically defined medium containing glucose and pyruvate. Uptake of glucose and pyruvate and production of lactate were assessed using enzyme-linked fluorescence assays. Spermatozoa from domestic cats and cheetahs exhibited similar metabolic profiles, with minimal glucose metabolism and approximately equimolar rates of pyruvate uptake and lactate production. Compared to normospermic counterparts, pyruvate and lactate metabolism were reduced in teratospermic cat and cheetah ejaculates, even when controlling for sperm motility. Rates of pyruvate and lactate (but not glucose) metabolism were correlated positively with sperm motility, acrosomal integrity, and normal morphology. Collectively, our findings reveal that pyruvate uptake and lactate production are reliable, quantitative indicators of sperm quality in these two felid species and that metabolic function is impaired in teratospermic ejaculates. Furthermore, patterns of substrate utilization are conserved between these species, including the unexpected lack of exogenous glucose metabolism. Because glycolysis is required to support sperm motility and capacitation in certain other mammals (including dogs), the activity of this pathway in felid spermatozoa is a target for future investigation.

  15. Translating the basic knowledge of mitochondrial functions to metabolic therapy: role of L-carnitine.

    PubMed

    Marcovina, Santica M; Sirtori, Cesare; Peracino, Andrea; Gheorghiade, Mihai; Borum, Peggy; Remuzzi, Giuseppe; Ardehali, Hossein

    2013-02-01

    Mitochondria play important roles in human physiological processes, and therefore, their dysfunction can lead to a constellation of metabolic and nonmetabolic abnormalities such as a defect in mitochondrial gene expression, imbalance in fuel and energy homeostasis, impairment in oxidative phosphorylation, enhancement of insulin resistance, and abnormalities in fatty acid metabolism. As a consequence, mitochondrial dysfunction contributes to the pathophysiology of insulin resistance, obesity, diabetes, vascular disease, and chronic heart failure. The increased knowledge on mitochondria and their role in cellular metabolism is providing new evidence that these disorders may benefit from mitochondrial-targeted therapies. We review the current knowledge of the contribution of mitochondrial dysfunction to chronic diseases, the outcomes of experimental studies on mitochondrial-targeted therapies, and explore the potential of metabolic modulators in the treatment of selected chronic conditions. As an example of such modulators, we evaluate the efficacy of the administration of L-carnitine and its analogues acetyl and propionyl L-carnitine in several chronic diseases. L-carnitine is intrinsically involved in mitochondrial metabolism and function as it plays a key role in fatty acid oxidation and energy metabolism. In addition to the transportation of free fatty acids across the inner mitochondrial membrane, L-carnitine modulates their oxidation rate and is involved in the regulation of vital cellular functions such as apoptosis. Thus, L-carnitine and its derivatives show promise in the treatment of chronic conditions and diseases associated with mitochondrial dysfunction but further translational studies are needed to fully explore their potential.

  16. Redox Control of Liver Function in Health and Disease

    PubMed Central

    Marí, Montserrat; Colell, Anna; Morales, Albert; von Montfort, Claudia; Garcia-Ruiz, Carmen

    2010-01-01

    Abstract Reactive oxygen species (ROS), a heterogeneous population of biologically active intermediates, are generated as by-products of the aerobic metabolism and exhibit a dual role in biology. When produced in controlled conditions and in limited quantities, ROS may function as signaling intermediates, contributing to critical cellular functions such as proliferation, differentiation, and cell survival. However, ROS overgeneration and, particularly, the formation of specific reactive species, inflicts cell death and tissue damage by targeting vital cellular components such as DNA, lipids, and proteins, thus arising as key players in disease pathogenesis. Given the predominant role of hepatocytes in biotransformation and metabolism of xenobiotics, ROS production constitutes an important burden in liver physiology and pathophysiology and hence in the progression of liver diseases. Despite the recognized role of ROS in disease pathogenesis, the efficacy of antioxidants as therapeutics has been limited. A better understanding of the mechanisms, nature, and location of ROS generation, as well as the optimization of cellular defense strategies, may pave the way for a brighter future for antioxidants and ROS scavengers in the therapy of liver diseases. Antioxid. Redox Signal. 12, 1295—1331. PMID:19803748

  17. AMP-activated protein kinase and metabolic control

    PubMed Central

    Viollet, Benoit; Andreelli, Fabrizio

    2011-01-01

    AMP-activated protein kinase (AMPK), a phylogenetically conserved serine/threonine protein kinase, is a major regulator of cellular and whole-body energy homeostasis that coordinates metabolic pathways in order to balance nutrient supply with energy demand. It is now recognized that pharmacological activation of AMPK improves blood glucose homeostasis, lipid profile and blood pressure in insulin-resistant rodents. Indeed, AMPK activation mimics the beneficial effects of physical activity or those of calorie restriction by acting on multiple cellular targets. In addition it is now demonstrated that AMPK is one of the probable (albeit indirect) targets of major antidiabetic drugs including, the biguanides (metformin) and thiazolidinediones, as well as of insulin sensitizing adipokines (e.g., adiponectin). Taken together, such findings highlight the logic underlying the concept of targeting the AMPK pathway for the treatment of metabolic syndrome and type 2 diabetes. PMID:21484577

  18. Circadian control of β-cell function and stress responses.

    PubMed

    Lee, J; Liu, R; de Jesus, D; Kim, B S; Ma, K; Moulik, M; Yechoor, V

    2015-09-01

    Circadian disruption is the bane of modern existence and its deleterious effects on health; in particular, diabetes and metabolic syndrome have been well recognized in shift workers. Recent human studies strongly implicate a 'dose-dependent' relationship between circadian disruption and diabetes. Genetic and environmental disruption of the circadian clock in rodents leads to diabetes secondary to β-cell failure. Deletion of Bmal1, a non-redundant core clock gene, leads to defects in β-cell stimulus-secretion coupling, decreased glucose-stimulated ATP production, uncoupling of OXPHOS and impaired glucose-stimulated insulin secretion. Both genetic and environmental circadian disruptions are sufficient to induce oxidative stress and this is mediated by a disruption of the direct transcriptional control of the core molecular clock and Bmal1 on Nrf2, the master antioxidant transcription factor in the β-cell. In addition, circadian disruption also leads to a dysregulation of the unfolded protein response and leads to endoplasmic reticulum stress in β-cells. Both the oxidative and endoplasmic reticulum (ER) stress contribute to an impairment of mitochondrial function and β-cell failure. Understanding the basis of the circadian control of these adaptive stress responses offers hope to target them for pharmacological modulation to prevent and mitigate the deleterious metabolic consequences of circadian disruption.

  19. Medium-chain fatty acids: functional lipids for the prevention and treatment of the metabolic syndrome.

    PubMed

    Nagao, Koji; Yanagita, Teruyoshi

    2010-03-01

    Metabolic syndrome is a cluster of metabolic disorders, such as abdominal obesity, dyslipidemia, hypertension and impaired fasting glucose, that contribute to increased cardiovascular morbidity and mortality. Although the pathogenesis of metabolic syndrome is complicated and the precise mechanisms have not been elucidated, dietary lipids have been recognized as contributory factors in the development and the prevention of cardiovascular risk clustering. This review explores the physiological functions and molecular actions of medium-chain fatty acids (MCFAs) and medium-chain triglycerides (MCTs) in the development of metabolic syndrome. Experimental studies demonstrate that dietary MCFAs/MCTs suppress fat deposition through enhanced thermogenesis and fat oxidation in animal and human subjects. Additionally, several reports suggest that MCFAs/MCTs offer the therapeutic advantage of preserving insulin sensitivity in animal models and patients with type 2 diabetes.

  20. Hormonal control of the metabolic machinery of hepatocellular carcinoma

    PubMed Central

    Wong, Carmen Chak-Lui; Wong, Chun-Ming

    2016-01-01

    Hepatocellular carcinoma (HCC) is one of the most fatal malignancies worldwide. It is an aggressive cancer with low cure rate, frequent metastasis, and highly resistant to conventional chemotherapies. Better knowledge regarding the molecular and metabolic alterations in HCC will be instrumental to the development of novel therapeutic interventions against HCC. In the August 2015 issue of Hepatology, Nie et al. reports an important molecular pathway that contributes to the Warburg Effect in HCC. They have beautifully demonstrated that the loss of a component of a hormonal system, the mineralocorticoid receptor (MR), reprogrammed the metabolic machinery of HCC cells to aerobic glycolysis through the miR-338-3p-PKL/R axis. The implication could be that in addition to drugs that directly target the metabolic enzymes in cancer cells, more translational efforts could be focused on the development of drugs that involve the activation of the MR-aldosterone system or other hormonal systems to target the Warburg effect. PMID:27275458

  1. Retinoic Acid-Related Orphan Receptors (RORs): Regulatory Functions in Immunity, Development, Circadian Rhythm, and Metabolism

    PubMed Central

    Cook, Donald N.; Kang, Hong Soon; Jetten, Anton M.

    2015-01-01

    In this overview, we provide an update on recent progress made in understanding the mechanisms of action, physiological functions, and roles in disease of retinoic acid related orphan receptors (RORs). We are particularly focusing on their roles in the regulation of adaptive and innate immunity, brain function, retinal development, cancer, glucose and lipid metabolism, circadian rhythm, metabolic and inflammatory diseases and neuropsychiatric disorders. We also summarize the current status of ROR agonists and inverse agonists, including their regulation of ROR activity and their therapeutic potential for management of various diseases in which RORs have been implicated. PMID:26878025

  2. Calcium and ATP control multiple vital functions.

    PubMed

    Petersen, Ole H; Verkhratsky, Alexei

    2016-08-05

    Life on Planet Earth, as we know it, revolves around adenosine triphosphate (ATP) as a universal energy storing molecule. The metabolism of ATP requires a low cytosolic Ca(2+) concentration, and hence tethers these two molecules together. The exceedingly low cytosolic Ca(2+) concentration (which in all life forms is kept around 50-100 nM) forms the basis for a universal intracellular signalling system in which Ca(2+) acts as a second messenger. Maintenance of transmembrane Ca(2+) gradients, in turn, requires ATP-dependent Ca(2+) transport, thus further emphasizing the inseparable links between these two substances. Ca(2+) signalling controls the most fundamental processes in the living organism, from heartbeat and neurotransmission to cell energetics and secretion. The versatility and plasticity of Ca(2+) signalling relies on cell specific Ca(2+) signalling toolkits, remodelling of which underlies adaptive cellular responses. Alterations of these Ca(2+) signalling toolkits lead to aberrant Ca(2+) signalling which is fundamental for the pathophysiology of numerous diseases from acute pancreatitis to neurodegeneration. This paper introduces a theme issue on this topic, which arose from a Royal Society Theo Murphy scientific meeting held in March 2016.This article is part of the themed issue 'Evolution brings Ca(2+) and ATP together to control life and death'.

  3. Metabolic modeling of Saccharomyces cerevisiae using the optimal control of homeostasis: a cybernetic model definition.

    PubMed

    Giuseppin, M L; van Riel, N A

    2000-01-01

    A model is presented to describe the observed behavior of microorganisms that aim at metabolic homeostasis while growing and adapting to their environment in an optimal way. The cellular metabolism is seen as a network with a multiple controller system with both feedback and feedforward control, i.e., a model based on a dynamic optimal metabolic control. The dynamic network consists of aggregated pathways, each having a control setpoint for the metabolic states at a given growth rate. This set of strategies of the cell forms a true cybernetic model with a minimal number of assumptions. The cellular strategies and constraints were derived from metabolic flux analysis using an identified, biochemically relevant, stoichiometry matrix derived from experimental data on the cellular composition of continuous cultures of Saccharomyces cerevisiae. Based on these data a cybernetic model was developed to study its dynamic behavior. The growth rate of the cell is determined by the structural compounds and fluxes of compounds related to central metabolism. In contrast to many other cybernetic models, the minimal model does not consist of any assumed internal kinetic parameters or interactions. This necessitates the use of a stepwise integration with an optimization of the fluxes at every time interval. Some examples of the behavior of this model are given with respect to steady states and pulse responses. This model is very suitable for describing semiquantitatively dynamics of global cellular metabolism and may form a useful framework for including structured and more detailed kinetic models.

  4. Functional Operons in Secondary Metabolic Gene Clusters in Glarea lozoyensis (Fungi, Ascomycota, Leotiomycetes)

    PubMed Central

    Yue, Qun; Chen, Li; Li, Yan; Bills, Gerald F.; Zhang, Xinyu; Xiang, Meichun; Li, Shaojie; Che, Yongsheng; Niu, Xuemei

    2015-01-01

    ABSTRACT Operons are multigene transcriptional units which occur mostly in prokaryotes but rarely in eukaryotes. Protein-coding operons have not been reported in the Fungi even though they represent a very diverse kingdom of organisms. Here, we report a functional operon involved in the secondary metabolism of the fungus Glarea lozoyensis belonging to Leotiomycetes (Ascomycota). Two contiguous genes, glpks3 and glnrps7, encoding polyketide synthase and nonribosomal peptide synthetase, respectively, are cotranscribed into one dicistronic mRNA under the control of the same promoter, and the mRNA is then translated into two individual proteins, GLPKS3 and GLNRPS7. Heterologous expression in Aspergillus nidulans shows that the GLPKS3-GLNRPS7 enzyme complex catalyzes the biosynthesis of a novel pyrrolidinedione-containing compound, xenolozoyenone (compound 1), which indicates the operon is functional. Although it is structurally similar to prokaryotic operons, the glpks3-glnrps7 operon locus has a monophylogenic origin from fungi rather than having been horizontally transferred from prokaryotes. Moreover, two additional operons, glpks28-glnrps8 and glpks29-glnrps9, were verified at the transcriptional level in the same fungus. This is the first report of protein-coding operons in a member of the Fungi. PMID:26081635

  5. T Cell Receptor Signaling in the Control of Regulatory T Cell Differentiation and Function

    PubMed Central

    Li, Ming O.; Rudensky, Alexander Y.

    2016-01-01

    Regulatory T cells (TReg cells), a specialized T cell lineage, have a pivotal function in the control of self-tolerance and inflammatory responses. Recent studies have revealed a discrete mode of TCR signaling that regulates Treg cell differentiation, maintenance and function and that impacts on gene expression, metabolism, cell adhesion and migration of these cells. Here, we discuss the emerging understanding of TCR-guided differentiation of Treg cells in the context of their function in health and disease. PMID:27026074

  6. The post-transcriptional regulatory system CSR controls the balance of metabolic pools in upper glycolysis of Escherichia coli.

    PubMed

    Morin, Manon; Ropers, Delphine; Letisse, Fabien; Laguerre, Sandrine; Portais, Jean-Charles; Cocaign-Bousquet, Muriel; Enjalbert, Brice

    2016-05-01

    Metabolic control in Escherichia coli is a complex process involving multilevel regulatory systems but the involvement of post-transcriptional regulation is uncertain. The post-transcriptional factor CsrA is stated as being the only regulator essential for the use of glycolytic substrates. A dozen enzymes in the central carbon metabolism (CCM) have been reported as potentially controlled by CsrA, but its impact on the CCM functioning has not been demonstrated. Here, a multiscale analysis was performed in a wild-type strain and its isogenic mutant attenuated for CsrA (including growth parameters, gene expression levels, metabolite pools, abundance of enzymes and fluxes). Data integration and regulation analysis showed a coordinated control of the expression of glycolytic enzymes. This also revealed the imbalance of metabolite pools in the csrA mutant upper glycolysis, before the phosphofructokinase PfkA step. This imbalance is associated with a glucose-phosphate stress. Restoring PfkA activity in the csrA mutant strain suppressed this stress and increased the mutant growth rate on glucose. Thus, the carbon storage regulator system is essential for the effective functioning of the upper glycolysis mainly through its control of PfkA. This work demonstrates the pivotal role of post-transcriptional regulation to shape the carbon metabolism.

  7. Oral administration of nano-titanium dioxide particle disrupts hepatic metabolic functions in a mouse model.

    PubMed

    Yang, Julin; Luo, Min; Tan, Zhen; Dai, Manyun; Xie, Minzhu; Lin, Jiao; Hua, Huiying; Ma, Qing; Zhao, Jinshun; Liu, Aiming

    2017-01-01

    TiO2 nano-particle (TiO2 NP) is widely used in industrial, household necessities, as well as medicinal products. However, the effect of TiO2 NP on liver metabolic function has not been reported. In this study, after mice were orally administered TiO2 NP (21nm) for 14days, the serum and liver tissues were assayed by biochemical analysis, real time quantitative polymerase chain reaction, western blot and transmission electron microscopy. The serum bilirubin was increased in a dose dependent manner. Deposition of TiO2 NP in hepatocytes and the abnormality of microstructures was observed. Expression of metabolic genes involved in the endogenous and exogenous metabolism was modified, supporting the toxic phenotype. Collectively, oral administration of TiO2 NP (21nm) led to deposition of particles in hepatocytes, mitochondrial edema, and the disturbance of liver metabolism function. These data suggested oral administration disrupts liver metabolic functions, which was more sensitive than regular approaches to detect material hepatotoxicity. This study provided useful information for risk analysis and regulation of TiO2 NPs by administration agencies.

  8. Non-invasive evaluation of vasomotor and metabolic functions of microvascular endothelium in human skin.

    PubMed

    Fedorovich, Andrey A

    2012-07-01

    Correlation between metabolic and microhemodynamic processes in skin was assessed through acute pharmacological test with metabolically active Actovegin in 28 healthy volunteers. Laser Doppler flowmetry in combination with wavelet analysis of blood flow oscillations was used to identify functional state of arteriolar-venular areas of microvascular bed in the right forearm skin; capillary blood flow parameters were assessed through computer capillaroscopy in the nail bed of the right hand on the 4th finger. The metabolic effect (improved oxygen uptake and glucose disposal by tissues) was accompanied by significant increase in endothelial rhythm amplitude by 98% (p<0.00006), neurogenic rhythm amplitude by 50% (p<0.003) and myogenic rhythm amplitude by 54% (p<0.03), with capillary blood flow rate increasing by 90μm/s (p<0.04), pericapillary zone reducing by 15μm (p<0.0001) and diastolic blood pressure dropping by 4mm Hg (p<0.02). These results show close correlation between metabolic and microhemodynamic processes, which suggests that the amplitude activity within the range of endothelial rhythm (0.0095-0.021Hz) during laser Doppler flowmetry reflects not only solely vasomotor function but also metabolic function of microvascular endothelium.

  9. Functional Neuroanatomy for Posture and Gait Control.

    PubMed

    Takakusaki, Kaoru

    2017-01-01

    Here we argue functional neuroanatomy for posture-gait control. Multi-sensory information such as somatosensory, visual and vestibular sensation act on various areas of the brain so that adaptable posture-gait control can be achieved. Automatic process of gait, which is steady-state stepping movements associating with postural reflexes including headeye coordination accompanied by appropriate alignment of body segments and optimal level of postural muscle tone, is mediated by the descending pathways from the brainstem to the spinal cord. Particularly, reticulospinal pathways arising from the lateral part of the mesopontine tegmentum and spinal locomotor network contribute to this process. On the other hand, walking in unfamiliar circumstance requires cognitive process of postural control, which depends on knowledges of self-body, such as body schema and body motion in space. The cognitive information is produced at the temporoparietal association cortex, and is fundamental to sustention of vertical posture and construction of motor programs. The programs in the motor cortical areas run to execute anticipatory postural adjustment that is optimal for achievement of goal-directed movements. The basal ganglia and cerebellum may affect both the automatic and cognitive processes of posturegait control through reciprocal connections with the brainstem and cerebral cortex, respectively. Consequently, impairments in cognitive function by damages in the cerebral cortex, basal ganglia and cerebellum may disturb posture-gait control, resulting in falling.

  10. Functional Neuroanatomy for Posture and Gait Control

    PubMed Central

    Takakusaki, Kaoru

    2017-01-01

    Here we argue functional neuroanatomy for posture-gait control. Multi-sensory information such as somatosensory, visual and vestibular sensation act on various areas of the brain so that adaptable posture-gait control can be achieved. Automatic process of gait, which is steady-state stepping movements associating with postural reflexes including headeye coordination accompanied by appropriate alignment of body segments and optimal level of postural muscle tone, is mediated by the descending pathways from the brainstem to the spinal cord. Particularly, reticulospinal pathways arising from the lateral part of the mesopontine tegmentum and spinal locomotor network contribute to this process. On the other hand, walking in unfamiliar circumstance requires cognitive process of postural control, which depends on knowledges of self-body, such as body schema and body motion in space. The cognitive information is produced at the temporoparietal association cortex, and is fundamental to sustention of vertical posture and construction of motor programs. The programs in the motor cortical areas run to execute anticipatory postural adjustment that is optimal for achievement of goal-directed movements. The basal ganglia and cerebellum may affect both the automatic and cognitive processes of posturegait control through reciprocal connections with the brainstem and cerebral cortex, respectively. Consequently, impairments in cognitive function by damages in the cerebral cortex, basal ganglia and cerebellum may disturb posture-gait control, resulting in falling. PMID:28122432

  11. Absorption, metabolism, and functions of β-cryptoxanthin

    PubMed Central

    La Frano, Michael R.; Zhu, Chenghao

    2016-01-01

    β-Cryptoxanthin, a carotenoid found in fruits and vegetables such as tangerines, red peppers, and pumpkin, has several functions important for human health. Most evidence from observational, in vitro, animal model, and human studies suggests that β-cryptoxanthin has relatively high bioavailability from its common food sources, to the extent that some β-cryptoxanthin–rich foods might be equivalent to β-carotene–rich foods as sources of retinol. β-Cryptoxanthin is an antioxidant in vitro and appears to be associated with decreased risk of some cancers and degenerative diseases. In addition, many in vitro, animal model, and human studies suggest that β-cryptoxanthin–rich foods may have an anabolic effect on bone and, thus, may help delay osteoporosis. PMID:26747887

  12. Intrinsic and Tumor Microenvironment-Induced Metabolism Adaptations of T Cells and Impact on Their Differentiation and Function

    PubMed Central

    Kouidhi, Soumaya; Noman, Muhammad Zaeem; Kieda, Claudine; Elgaaied, Amel Benammar; Chouaib, Salem

    2016-01-01

    It is well recognized that the immune system and metabolism are highly integrated. In this context, multilevel interactions between metabolic system and T lymphocyte signaling and fate exist. This review will discuss different potential cell metabolism pathways involved in shaping T lymphocyte function and differentiation. We will also provide a general framework for understanding how tumor microenvironmental metabolism, associated with hypoxic stress, interferes with T-cell priming and expansion. How T-cell metabolism drives T-cell-mediated immunity and how the manipulation of metabolic programing for therapeutic purposes will be also discussed. PMID:27066006

  13. Dietary Proteins as Determinants of Metabolic and Physiologic Functions of the Gastrointestinal Tract

    PubMed Central

    Jahan-Mihan, Alireza; Luhovyy, Bohdan L.; Khoury, Dalia El; Anderson, G. Harvey

    2011-01-01

    Dietary proteins elicit a wide range of nutritional and biological functions. Beyond their nutritional role as the source of amino acids for protein synthesis, they are instrumental in the regulation of food intake, glucose and lipid metabolism, blood pressure, bone metabolism and immune function. The interaction of dietary proteins and their products of digestion with the regulatory functions of the gastrointestinal (GI) tract plays a dominant role in determining the physiological properties of proteins. The site of interaction is widespread, from the oral cavity to the colon. The characteristics of proteins that influence their interaction with the GI tract in a source-dependent manner include their physico-chemical properties, their amino acid composition and sequence, their bioactive peptides, their digestion kinetics and also the non-protein bioactive components conjugated with them. Within the GI tract, these products affect several regulatory functions by interacting with receptors releasing hormones, affecting stomach emptying and GI transport and absorption, transmitting neural signals to the brain, and modifying the microflora. This review discusses the interaction of dietary proteins during digestion and absorption with the physiological and metabolic functions of the GI tract, and illustrates the importance of this interaction in the regulation of amino acid, glucose, lipid metabolism, and food intake. PMID:22254112

  14. Dietary proteins as determinants of metabolic and physiologic functions of the gastrointestinal tract.

    PubMed

    Jahan-Mihan, Alireza; Luhovyy, Bohdan L; El Khoury, Dalia; Anderson, G Harvey

    2011-05-01

    Dietary proteins elicit a wide range of nutritional and biological functions. Beyond their nutritional role as the source of amino acids for protein synthesis, they are instrumental in the regulation of food intake, glucose and lipid metabolism, blood pressure, bone metabolism and immune function. The interaction of dietary proteins and their products of digestion with the regulatory functions of the gastrointestinal (GI) tract plays a dominant role in determining the physiological properties of proteins. The site of interaction is widespread, from the oral cavity to the colon. The characteristics of proteins that influence their interaction with the GI tract in a source-dependent manner include their physico-chemical properties, their amino acid composition and sequence, their bioactive peptides, their digestion kinetics and also the non-protein bioactive components conjugated with them. Within the GI tract, these products affect several regulatory functions by interacting with receptors releasing hormones, affecting stomach emptying and GI transport and absorption, transmitting neural signals to the brain, and modifying the microflora. This review discusses the interaction of dietary proteins during digestion and absorption with the physiological and metabolic functions of the GI tract, and illustrates the importance of this interaction in the regulation of amino acid, glucose, lipid metabolism, and food intake.

  15. Sex-Specific Effects of Organophosphate Diazinon on the Gut Microbiome and Its Metabolic Functions

    PubMed Central

    Gao, Bei; Bian, Xiaoming; Mahbub, Ridwan; Lu, Kun

    2016-01-01

    Background: There is growing recognition of the significance of the gut microbiome to human health, and the association between a perturbed gut microbiome with human diseases has been established. Previous studies also show the role of environmental toxicants in perturbing the gut microbiome and its metabolic functions. The wide agricultural use of diazinon, an organophosphate insecticide, has raised serious environmental health concerns since it is a potent neurotoxicant. With studies demonstrating the presence of a microbiome–gut–brain axis, it is possible that gut microbiome perturbation may also contribute to diazinon toxicity. Objectives: We investigated the impact of diazinon exposure on the gut microbiome composition and its metabolic functions in C57BL/6 mice. Methods: We used a combination of 16S rRNA gene sequencing, metagenomics sequencing, and mass spectrometry–based metabolomics profiling in a mouse model to examine the functional impact of diazinon on the gut microbiome. Results: 16S rRNA gene sequencing revealed that diazinon exposure significantly perturbed the gut microbiome, and metagenomic sequencing found that diazinon exposure altered the functional metagenome. Moreover, metabolomics profiling revealed an altered metabolic profile arising from exposure. Of particular significance, these changes were more pronounced for male mice than for female mice. Conclusions: Diazinon exposure perturbed the gut microbiome community structure, functional metagenome, and associated metabolic profiles in a sex-specific manner. These findings may provide novel insights regarding perturbations of the gut microbiome and its functions as a potential new mechanism contributing to diazinon neurotoxicity and, in particular, its sex-selective effects. Citation: Gao B, Bian X, Mahbub R, Lu K. 2017. Sex-specific effects of organophosphate diazinon on the gut microbiome and its metabolic functions. Environ Health Perspect 125:198–206; http://dx.doi.org/10

  16. Divergent Expression and Metabolic Functions of Human Glucuronosyltransferases through Alternative Splicing.

    PubMed

    Rouleau, Michèle; Tourancheau, Alan; Girard-Bock, Camille; Villeneuve, Lyne; Vaucher, Jonathan; Duperré, Anne-Marie; Audet-Delage, Yannick; Gilbert, Isabelle; Popa, Ion; Droit, Arnaud; Guillemette, Chantal

    2016-09-27

    Maintenance of cellular homeostasis and xenobiotic detoxification is mediated by 19 human UDP-glucuronosyltransferase enzymes (UGTs) encoded by ten genes that comprise the glucuronidation pathway. Deep RNA sequencing of major metabolic organs exposes a substantial expansion of the UGT transcriptome by alternative splicing, with variants representing 20% to 60% of canonical transcript expression. Nearly a fifth of expressed variants comprise in-frame sequences that may create distinct structural and functional features. Follow-up cell-based assays reveal biological functions for these alternative UGT proteins. Some isoforms were found to inhibit or induce inactivation of drugs and steroids in addition to perturbing global cell metabolism (energy, amino acids, nucleotides), cell adhesion, and proliferation. This work highlights the biological relevance of alternative UGT expression, which we propose increases protein diversity through the evolution of metabolic regulators from specific enzymes.

  17. Metabolic control of resting hemispheric cerebral blood flow is oxidative, not glycolytic.

    PubMed

    Powers, William J; Videen, Tom O; Markham, Joanne; Walter, Vonn; Perlmutter, Joel S

    2011-05-01

    Although the close regional coupling of resting cerebral blood flow (CBF) with both cerebral metabolic rate of oxygen (CMRO(2)) and cerebral metabolic rate of glucose (CMRglc) within individuals is well documented, there are few data regarding the coupling between whole brain flow and metabolism among different subjects. To investigate the metabolic control of resting whole brain CBF, we performed multivariate analysis of hemispheric CMRO(2), CMRglc, and other covariates as predictors of resting CBF among 23 normal humans. The univariate analysis showed that only CMRO(2) was a significant predictor of CBF. The final multivariate model contained two additional terms in addition to CMRO(2): arterial oxygen content and oxygen extraction fraction. Notably, arterial plasma glucose concentration and CMRglc were not included in the final model. Our data demonstrate that the metabolic factor controlling hemispheric CBF in the normal resting brain is CMRO(2) and that CMRglc does not make a contribution. Our findings provide evidence for compartmentalization of brain metabolism into a basal component in which CBF is coupled to oxygen metabolism and an activation component in which CBF is controlled by another mechanism.

  18. Improving fatty acids production by engineering dynamic pathway regulation and metabolic control

    PubMed Central

    Xu, Peng; Li, Lingyun; Zhang, Fuming; Stephanopoulos, Gregory; Koffas, Mattheos

    2014-01-01

    Global energy demand and environmental concerns have stimulated increasing efforts to produce carbon-neutral fuels directly from renewable resources. Microbially derived aliphatic hydrocarbons, the petroleum-replica fuels, have emerged as promising alternatives to meet this goal. However, engineering metabolic pathways with high productivity and yield requires dynamic redistribution of cellular resources and optimal control of pathway expression. Here we report a genetically encoded metabolic switch that enables dynamic regulation of fatty acids (FA) biosynthesis in Escherichia coli. The engineered strains were able to dynamically compensate the critical enzymes involved in the supply and consumption of malonyl-CoA and efficiently redirect carbon flux toward FA biosynthesis. Implementation of this metabolic control resulted in an oscillatory malonyl-CoA pattern and a balanced metabolism between cell growth and product formation, yielding 15.7- and 2.1-fold improvement in FA titer compared with the wild-type strain and the strain carrying the uncontrolled metabolic pathway. This study provides a new paradigm in metabolic engineering to control and optimize metabolic pathways facilitating the high-yield production of other malonyl-CoA–derived compounds. PMID:25049420

  19. Working memory dysfunction associated with brain functional deficits and cellular metabolic changes in patients with generalized anxiety disorder.

    PubMed

    Moon, Chung-Man; Sundaram, Thirunavukkarasu; Choi, Nam-Gil; Jeong, Gwang-Woo

    2016-08-30

    Generalized anxiety disorder (GAD) is associated with brain functional and morphological changes in connected with emotional dysregulation and cognitive deficit. This study dealt with the neural functional deficits and metabolic abnormalities in working memory (WM) task with emotion-inducing distractors in patients with GAD. Fourteen patients with GAD and 14 healthy controls underwent functional magnetic resonance imaging (fMRI) and proton magnetic resonance spectroscopy ((1)H-MRS) at 3T. In response to the emotional distractors in WM tasks, the patients concurrently showed higher activity in the hippocampus and lower activities in the superior occipital gyrus, superior parietal gyrus, dorsolateral prefrontal cortex (DLPFC) and precentral gyrus compared to the controls. MRS revealed significantly lower choline/creatine (Cho/Cr) and choline/N-acetylaspartate (Cho/NAA) ratios in the DLPFC. In particular, the Cho ratios were positively correlated with the brain activities based on blood oxygenation level-dependent signal change in the DLPFC. This study provides the first evidence for the association between the metabolic alterations and functional deficit in WM processing with emotion-inducing distractors in GAD. These findings will be helpful to understand the neural dysfunction in connection with WM impairment in GAD.

  20. Control of YAP/TAZ Activity by Metabolic and Nutrient-Sensing Pathways.

    PubMed

    Santinon, Giulia; Pocaterra, Arianna; Dupont, Sirio

    2016-04-01

    Metabolism is a fundamental cellular function that can be reprogrammed by signaling pathways and oncogenes to meet cellular requirements. An emerging paradigm is that signaling and transcriptional networks can be in turn regulated by metabolism, allowing cells to coordinate their metabolism and behavior in an integrated manner. The activity of the YAP/TAZ transcriptional coactivators, downstream transducers of the Hippo cascade and powerful pro-oncogenic factors, was recently found to be regulated by metabolic pathways, such as aerobic glycolysis and mevalonate synthesis, and by the nutrient-sensing LKB1-AMPK and TSC-mTOR pathways. We discuss here current data linking YAP/TAZ to metabolism and suggest how this coupling might coordinate nutrient availability with genetic programs that sustain tissue growth, neoplastic cell proliferation, and tumor malignancy.

  1. Rb and p53 Liver Functions Are Essential for Xenobiotic Metabolism and Tumor Suppression.

    PubMed

    Nantasanti, Sathidpak; Toussaint, Mathilda J M; Youssef, Sameh A; Tooten, Peter C J; de Bruin, Alain

    2016-01-01

    The tumor suppressors Retinoblastoma (Rb) and p53 are frequently inactivated in liver diseases, such as hepatocellular carcinomas (HCC) or infections with Hepatitis B or C viruses. Here, we discovered a novel role for Rb and p53 in xenobiotic metabolism, which represent a key function of the liver for metabolizing therapeutic drugs or toxins. We demonstrate that Rb and p53 cooperate to metabolize the xenobiotic 3,5-diethoxycarbonyl-1,4-dihydrocollidine (DDC). DDC is metabolized mainly by cytochrome P450 (Cyp)3a enzymes resulting in inhibition of heme synthesis and accumulation of protoporphyrin, an intermediate of heme pathway. Protoporphyrin accumulation causes bile injury and ductular reaction. We show that loss of Rb and p53 resulted in reduced Cyp3a expression decreased accumulation of protoporphyrin and consequently less ductular reaction in livers of mice fed with DDC for 3 weeks. These findings provide strong evidence that synergistic functions of Rb and p53 are essential for metabolism of DDC. Because Rb and p53 functions are frequently disabled in liver diseases, our results suggest that liver patients might have altered ability to remove toxins or properly metabolize therapeutic drugs. Strikingly the reduced biliary injury towards the oxidative stress inducer DCC was accompanied by enhanced hepatocellular injury and formation of HCCs in Rb and p53 deficient livers. The increase in hepatocellular injury might be related to reduce protoporphyrin accumulation, because protoporphrin is well known for its anti-oxidative activity. Furthermore our results indicate that Rb and p53 not only function as tumor suppressors in response to carcinogenic injury, but also in response to non-carcinogenic injury such as DDC.

  2. A tryptophan derivative, ITE, enhances liver cell metabolic functions in vitro.

    PubMed

    Zhang, Xiaoqian; Lu, Juan; He, Bin; Tang, Lingling; Liu, Xiaoli; Zhu, Danhua; Cao, Hongcui; Wang, Yingjie; Li, Lanjuan

    2017-01-01

    Cell encapsulation provides a three-dimensional support by incorporating isolated cells into microcapsules with the goal of simultaneously maintaining cell survival and function, as well as providing active transport for a bioreactor in vitro similarly to that observed in vivo. However, the biotra-nsformation and metabolic functions of the encapsulated cells are not satisfactory for clinical applications. For this purpose, in this study, hepatoma-derived Huh7 cells/C3A cells were treated with 2-(1'H-indole-3'-carbonyl)-thiazole-4-carboxylic acid methyl ester (ITE), an endogenous non-toxic ligand for aryl hydrocarbon receptor, in monolayer cultures and on microspheres. The mRNA and protein levels, as well as the metabolic activities of drug metabolizing enzymes, albumin secretion and urea synthesis were determined. When the Huh7 and C3A cells cultured in a monolayer on two‑dimensional surfaces, ITE enhanced the protein levels and the metabolic activities of the major cytochrome P450 (CYP450) enzymes, CYP1A1, CYP1A2, CYP3A4 and CYP1B1, and slightly increased albumin secretion and urea synthesis. Moreover, when cultured on microspheres, ITE also substantially increased the protein levels and metabolic activities of CYP1A1, CYP1A2, CYP3A4 and CYP1B1 in both liver cell lines. On the whole, our findings indicate that ITE enhances the enzymatic activities of major CYP450 enzymes and the metabolic functions of liver cells cultured in monolayer or on microspheres, indicating that it may be utilized to improve the functions of hepatocytes. Thus, it may be used in the future for the treatment of liver diseases.

  3. A tryptophan derivative, ITE, enhances liver cell metabolic functions in vitro

    PubMed Central

    Zhang, Xiaoqian; Lu, Juan; He, Bin; Tang, Lingling; Liu, Xiaoli; Zhu, Danhua; Cao, Hongcui; Wang, Yingjie; Li, Lanjuan

    2017-01-01

    Cell encapsulation provides a three-dimensional support by incorporating isolated cells into microcapsules with the goal of simultaneously maintaining cell survival and function, as well as providing active transport for a bioreactor in vitro similarly to that observed in vivo. However, the biotransformation and metabolic functions of the encapsulated cells are not satisfactory for clinical applications. For this purpose, in this study, hepatoma-derived Huh7 cells/C3A cells were treated with 2-(1′H-indole-3′-carbonyl)-thiazole-4-carboxylic acid methyl ester (ITE), an endogenous non-toxic ligand for aryl hydrocarbon receptor, in monolayer cultures and on microspheres. The mRNA and protein levels, as well as the metabolic activities of drug metabolizing enzymes, albumin secretion and urea synthesis were determined. When the Huh7 and C3A cells cultured in a monolayer on two-dimensional surfaces, ITE enhanced the protein levels and the metabolic activities of the major cytochrome P450 (CYP450) enzymes, CYP1A1, CYP1A2, CYP3A4 and CYP1B1, and slightly increased albumin secretion and urea synthesis. Moreover, when cultured on microspheres, ITE also substantially increased the protein levels and metabolic activities of CYP1A1, CYP1A2, CYP3A4 and CYP1B1 in both liver cell lines. On the whole, our findings indicate that ITE enhances the enzymatic activities of major CYP450 enzymes and the metabolic functions of liver cells cultured in monolayer or on microspheres, indicating that it may be utilized to improve the functions of hepatocytes. Thus, it may be used in the future for the treatment of liver diseases. PMID:27959388

  4. Functional genomics identifies negative regulatory nodes controlling phagocyte oxidative burst

    PubMed Central

    Graham, Daniel B.; Becker, Christine E.; Doan, Aivi; Goel, Gautam; Villablanca, Eduardo J.; Knights, Dan; Mok, Amanda; Ng, Aylwin C.Y.; Doench, John G.; Root, David E.; Clish, Clary B.; Xavier, Ramnik J.

    2015-01-01

    The phagocyte oxidative burst, mediated by Nox2 NADPH oxidase-derived reactive oxygen species, confers host defense against a broad spectrum of bacterial and fungal pathogens. Loss-of-function mutations that impair function of the Nox2 complex result in a life-threatening immunodeficiency, and genetic variants of Nox2 subunits have been implicated in pathogenesis of inflammatory bowel disease (IBD). Thus, alterations in the oxidative burst can profoundly impact host defense, yet little is known about regulatory mechanisms that fine-tune this response. Here we report the discovery of regulatory nodes controlling oxidative burst by functional screening of genes within loci linked to human inflammatory disease. Implementing a multi-omics approach, we define transcriptional, metabolic and ubiquitin-cycling nodes controlled by Rbpj, Pfkl and Rnf145, respectively. Furthermore, we implicate Rnf145 in proteostasis of the Nox2 complex by endoplasmic reticulum-associated degradation. Consequently, ablation of Rnf145 in murine macrophages enhances bacterial clearance, and rescues the oxidative burst defects associated with Ncf4 haploinsufficiency. PMID:26194095

  5. The Functional Connectome of Speech Control

    PubMed Central

    Fuertinger, Stefan; Horwitz, Barry; Simonyan, Kristina

    2015-01-01

    In the past few years, several studies have been directed to understanding the complexity of functional interactions between different brain regions during various human behaviors. Among these, neuroimaging research installed the notion that speech and language require an orchestration of brain regions for comprehension, planning, and integration of a heard sound with a spoken word. However, these studies have been largely limited to mapping the neural correlates of separate speech elements and examining distinct cortical or subcortical circuits involved in different aspects of speech control. As a result, the complexity of the brain network machinery controlling speech and language remained largely unknown. Using graph theoretical analysis of functional MRI (fMRI) data in healthy subjects, we quantified the large-scale speech network topology by constructing functional brain networks of increasing hierarchy from the resting state to motor output of meaningless syllables to complex production of real-life speech as well as compared to non-speech-related sequential finger tapping and pure tone discrimination networks. We identified a segregated network of highly connected local neural communities (hubs) in the primary sensorimotor and parietal regions, which formed a commonly shared core hub network across the examined conditions, with the left area 4p playing an important role in speech network organization. These sensorimotor core hubs exhibited features of flexible hubs based on their participation in several functional domains across different networks and ability to adaptively switch long-range functional connectivity depending on task content, resulting in a distinct community structure of each examined network. Specifically, compared to other tasks, speech production was characterized by the formation of six distinct neural communities with specialized recruitment of the prefrontal cortex, insula, putamen, and thalamus, which collectively forged the formation

  6. Towards stable kinetics of large metabolic networks: Nonequilibrium potential function approach

    NASA Astrophysics Data System (ADS)

    Chen, Yong-Cong; Yuan, Ruo-Shi; Ao, Ping; Xu, Min-Juan; Zhu, Xiao-Mei

    2016-06-01

    While the biochemistry of metabolism in many organisms is well studied, details of the metabolic dynamics are not fully explored yet. Acquiring adequate in vivo kinetic parameters experimentally has always been an obstacle. Unless the parameters of a vast number of enzyme-catalyzed reactions happened to fall into very special ranges, a kinetic model for a large metabolic network would fail to reach a steady state. In this work we show that a stable metabolic network can be systematically established via a biologically motivated regulatory process. The regulation is constructed in terms of a potential landscape description of stochastic and nongradient systems. The constructed process draws enzymatic parameters towards stable metabolism by reducing the change in the Lyapunov function tied to the stochastic fluctuations. Biologically it can be viewed as interplay between the flux balance and the spread of workloads on the network. Our approach allows further constraints such as thermodynamics and optimal efficiency. We choose the central metabolism of Methylobacterium extorquens AM1 as a case study to demonstrate the effectiveness of the approach. Growth efficiency on carbon conversion rate versus cell viability and futile cycles is investigated in depth.

  7. Autonomous benthic algal cultivator under feedback control of ecosystem metabolism

    Technology Transfer Automated Retrieval System (TEKTRAN)

    An autonomous and internally-controlled techno-ecological hybrid was developed that controls primary production of algae in a laboratory-scale cultivator. The technoecosystem is based on an algal turf scrubber (ATS) system that combines engineered feedback control programming with internal feedback...

  8. Hyperkalemia after acute metabolic decompensation in two children with vitamin B12-unresponsive methylmalonic acidemia and normal renal function.

    PubMed

    Pela, I; Gasperini, S; Pasquini, E; Donati, M A

    2006-07-01

    The patients affected by vitamin B12-unresponsive methylmalonic acidemia (MMA) on the long run develop chronic renal disease with interstitial nephropathy and progressive renal insufficiency. The mechanism of nephrotoxicity in vitamin B12-unresponsive MMA is not yet known. Chronic hyporeninemic hypoaldosteronism has been found in many cases of methylmalonic acidemia, hyperkalemia and renal tubular acidosis type 4. We report 2 patients affected by B12-unresponsive methylmalonic acidemia diagnosed at the age of 23 months and 5 years, respectively, with normal glomerular filtration and function. They showed hyporeninemic hypoaldosteronism and significant hyperkalemia requiring sodium potassium exchange resin (Kayexalate) therapy after an episode of metabolic decompensation leading to diagnosis of MMA. In both children, hyporeninemic hypoaldosteronism and hyperkalemia disappeared after 6 months of good metabolic control.

  9. Regulation and Function of Versatile Aerobic and Anaerobic Respiratory Metabolism in Pseudomonas aeruginosa

    PubMed Central

    Arai, Hiroyuki

    2011-01-01

    Pseudomonas aeruginosa is a ubiquitously distributed opportunistic pathogen that inhabits soil and water as well as animal-, human-, and plant-host-associated environments. The ubiquity would be attributed to its very versatile energy metabolism. P. aeruginosa has a highly branched respiratory chain terminated by multiple terminal oxidases and denitrification enzymes. Five terminal oxidases for aerobic respiration have been identified in the P. aeruginosa cells. Three of them, the cbb3-1 oxidase, the cbb3-2 oxidase, and the aa3 oxidase, are cytochrome c oxidases and the other two, the bo3 oxidase and the cyanide-insensitive oxidase, are quinol oxidases. Each oxidase has a specific affinity for oxygen, efficiency of energy coupling, and tolerance to various stresses such as cyanide and reactive nitrogen species. These terminal oxidases are used differentially according to the environmental conditions. P. aeruginosa also has a complete set of the denitrification enzymes that reduce nitrate to molecular nitrogen via nitrite, nitric oxide (NO), and nitrous oxide. These nitrogen oxides function as alternative electron acceptors and enable P. aeruginosa to grow under anaerobic conditions. One of the denitrification enzymes, NO reductase, is also expected to function for detoxification of NO produced by the host immune defense system. The control of the expression of these aerobic and anaerobic respiratory enzymes would contribute to the adaptation of P. aeruginosa to a wide range of environmental conditions including in the infected hosts. Characteristics of these respiratory enzymes and the regulatory system that controls the expression of the respiratory genes in the P. aeruginosa cells are overviewed in this article. PMID:21833336

  10. Genomic islands link secondary metabolism to functional adaptation in marine Actinobacteria

    PubMed Central

    Penn, Kevin; Jenkins, Caroline; Nett, Markus; Udwary, Daniel W.; Gontang, Erin A.; McGlinchey, Ryan P.; Foster, Brian; Lapidus, Alla; Podell, Sheila; Allen, Eric E.; Moore, Bradley S.; Jensen, Paul R.

    2009-01-01

    Genomic islands have been shown to harbor functional traits that differentiate ecologically distinct populations of environmental bacteria. A comparative analysis of the complete genome sequences of the marine Actinobacteria Salinispora tropica and S. arenicola reveals that 75% of the species-specific genes are located in 21 genomic islands. These islands are enriched in genes associated with secondary metabolite biosynthesis providing evidence that secondary metabolism is linked to functional adaptation. Secondary metabolism accounts for 8.8% and 10.9% of the genes in the S. tropica and S. arenicola genomes, respectively, and represents the major functional category of annotated genes that differentiates the two species. Genomic islands harbor all 25 of the species-specific biosynthetic pathways, the majority of which occur in S. arenicola and may contribute to the cosmopolitan distribution of this species. Genome evolution is dominated by gene duplication and acquisition, which in the case of secondary metabolism provide immediate opportunities for the production of new bioactive products. Evidence that secondary metabolic pathways are exchanged horizontally, coupled with prior evidence for fixation among globally distributed populations, supports a functional role and suggests that the acquisition of natural product biosynthetic gene clusters represents a previously unrecognized force driving bacterial diversification. Species-specific differences observed in CRISPR (clustered regularly interspaced short palindromic repeat) sequences suggest that S. arenicola may possess a higher level of phage immunity, while a highly duplicated family of polymorphic membrane proteins provides evidence of a new mechanism of marine adaptation in Gram-positive bacteria. PMID:19474814

  11. Beyond Leptin: Emerging Candidates for the Integration of Metabolic and Reproductive Function during Negative Energy Balance.

    PubMed

    True, Cadence; Grove, Kevin L; Smith, M Susan

    2011-01-01

    Reproductive status is tightly coupled to metabolic state in females, and ovarian cycling in mammals is halted when energy output exceeds energy input, a metabolic condition known as negative energy balance. This inhibition of reproductive function during negative energy balance occurs due to suppression of gonadotropin-releasing hormone (GnRH) release in the hypothalamus. The GnRH secretagogue kisspeptin is also inhibited during negative energy balance, indicating that inhibition of reproductive neuroendocrine circuits may occur upstream of GnRH itself. Understanding the metabolic signals responsible for the inhibition of reproductive pathways has been a compelling research focus for many years. A predominant theory in the field is that the status of energy balance is conveyed to reproductive neuroendocrine circuits via the adipocyte hormone leptin. Leptin is stimulatory for GnRH release and lower levels of leptin during negative energy balance are believed to result in decreased stimulatory drive for GnRH cells. However, recent evidence found that restoring leptin to physiological levels did not restore GnRH function in three different models of negative energy balance. This suggests that although leptin may be an important permissive signal for reproductive function as indicated by many years of research, factors other than leptin must critically contribute to negative energy balance-induced reproductive inhibition. This review will focus on emerging candidates for the integration of metabolic status and reproductive function during negative energy balance.

  12. Metabolic status, gonadotropin secretion, and ovarian function during acute nutrient restriction of beef heifers

    Technology Transfer Automated Retrieval System (TEKTRAN)

    The effect of acute nutritional restriction on metabolic status, gonadotropin secretion, and ovarian function of heifers was determined in 2 experiments. In Exp. 1, 14-mo-old heifers were fed a diet supplying 1.2 × maintenance energy requirements (1.2M). After 10 d, heifers were fed 1.2M or were res...

  13. Beyond Leptin: Emerging Candidates for the Integration of Metabolic and Reproductive Function during Negative Energy Balance

    PubMed Central

    True, Cadence; Grove, Kevin L.; Smith, M. Susan

    2011-01-01

    Reproductive status is tightly coupled to metabolic state in females, and ovarian cycling in mammals is halted when energy output exceeds energy input, a metabolic condition known as negative energy balance. This inhibition of reproductive function during negative energy balance occurs due to suppression of gonadotropin-releasing hormone (GnRH) release in the hypothalamus. The GnRH secretagogue kisspeptin is also inhibited during negative energy balance, indicating that inhibition of reproductive neuroendocrine circuits may occur upstream of GnRH itself. Understanding the metabolic signals responsible for the inhibition of reproductive pathways has been a compelling research focus for many years. A predominant theory in the field is that the status of energy balance is conveyed to reproductive neuroendocrine circuits via the adipocyte hormone leptin. Leptin is stimulatory for GnRH release and lower levels of leptin during negative energy balance are believed to result in decreased stimulatory drive for GnRH cells. However, recent evidence found that restoring leptin to physiological levels did not restore GnRH function in three different models of negative energy balance. This suggests that although leptin may be an important permissive signal for reproductive function as indicated by many years of research, factors other than leptin must critically contribute to negative energy balance-induced reproductive inhibition. This review will focus on emerging candidates for the integration of metabolic status and reproductive function during negative energy balance. PMID:22645510

  14. Plastoglobuli: Plastid Microcompartments with Integrated Functions in Metabolism, Plastid Developmental Transitions, and Environmental Adaptation.

    PubMed

    van Wijk, Klaas J; Kessler, Felix

    2017-01-25

    Plastoglobuli (PGs) are plastid lipoprotein particles surrounded by a membrane lipid monolayer. PGs contain small specialized proteomes and metabolomes. They are present in different plastid types (e.g., chloroplasts, chromoplasts, and elaioplasts) and are dynamic in size and shape in response to abiotic stress or developmental transitions. PGs in chromoplasts are highly enriched in carotenoid esters and enzymes involved in carotenoid metabolism. PGs in chloroplasts are associated with thylakoids and contain ∼30 core proteins (including six ABC1 kinases) as well as additional proteins recruited under specific conditions. Systems analysis has suggested that chloroplast PGs function in metabolism of prenyl lipids (e.g., tocopherols, plastoquinone, and phylloquinone); redox and photosynthetic regulation; plastid biogenesis; and senescence, including recycling of phytol, remobilization of thylakoid lipids, and metabolism of jasmonate. These functionalities contribute to chloroplast PGs' role in responses to stresses such as high light and nitrogen starvation. PGs are thus lipid microcompartments with multiple functions integrated into plastid metabolism, developmental transitions, and environmental adaptation. This review provides an in-depth overview of PG experimental observations, summarizes the present understanding of PG features and functions, and provides a conceptual framework for PG research and the realization of opportunities for crop improvement. Expected final online publication date for the Annual Review of Plant Biology Volume 68 is April 29, 2017. Please see http://www.annualreviews.org/page/journal/pubdates for revised estimates.

  15. Circadian rhythms in myocardial metabolism and contractile function; influence of workload and oleate

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Multiple extra-cardiac stimuli, such as workload and circulating nutrients (e.g., fatty acids), known to influence myocardial metabolism and contractile function exhibit marked circadian rhythms. The aim of the present study was to investigate whether the rat heart exhibits circadian rhythms in its ...

  16. Hydrodynamics-Based Functional Forms of Activity Metabolism: A Case for the Power-Law Polynomial Function in Animal Swimming Energetics

    PubMed Central

    Papadopoulos, Anthony

    2009-01-01

    The first-degree power-law polynomial function is frequently used to describe activity metabolism for steady swimming animals. This function has been used in hydrodynamics-based metabolic studies to evaluate important parameters of energetic costs, such as the standard metabolic rate and the drag power indices. In theory, however, the power-law polynomial function of any degree greater than one can be used to describe activity metabolism for steady swimming animals. In fact, activity metabolism has been described by the conventional exponential function and the cubic polynomial function, although only the power-law polynomial function models drag power since it conforms to hydrodynamic laws. Consequently, the first-degree power-law polynomial function yields incorrect parameter values of energetic costs if activity metabolism is governed by the power-law polynomial function of any degree greater than one. This issue is important in bioenergetics because correct comparisons of energetic costs among different steady swimming animals cannot be made unless the degree of the power-law polynomial function derives from activity metabolism. In other words, a hydrodynamics-based functional form of activity metabolism is a power-law polynomial function of any degree greater than or equal to one. Therefore, the degree of the power-law polynomial function should be treated as a parameter, not as a constant. This new treatment not only conforms to hydrodynamic laws, but also ensures correct comparisons of energetic costs among different steady swimming animals. Furthermore, the exponential power-law function, which is a new hydrodynamics-based functional form of activity metabolism, is a special case of the power-law polynomial function. Hence, the link between the hydrodynamics of steady swimming and the exponential-based metabolic model is defined. PMID:19333397

  17. Impact of perinatal exposure to acetaminophen on hepatocellular metabolic function in offspring

    PubMed Central

    Wu, Ka; Guo, Chao; Lu, Xiuli; Wu, Xinmou; Pan, Hongmei; Su, Min

    2016-01-01

    Acetaminophen (APAP), an over the counter (OTC) medication, is widely used in antipyretic treatment. Although the risk of dose-dependent cytotoxicity has been known, the potential effect of perinatal exposure to acetaminophen on metabolic function in offspring remains uninvestigated. Therefore, we established a prenatally APAP-exposed pregnancy mouse model to assess the possible adverse effect on liver metabolic function in offspring. Biochemical assays were applied in analysis of basic metabolic parameters in postnatal mice. Further, immunoblotting assay was used to assess the expressions of insulin receptor β (IRβ), insulin receptor substrate 1 (IRS1), phospho-Akt and phospho-GSK-3β proteins in liver cells. In addition, hepatic glucose transporter 2 (GLUT2) immunoactivity was determined by using immunohistochemistry staining. Compared with untreated postnatal mice, APAP-exposed offspring induced impaired glucose metabolism, increased plasma insulin level, and reduced liver glycogen content. In addition, APAP exposure decreased the expressions of IRS1 and phospho-GSK-3β, phospho-AKT proteins and down-regulated the level of glucose-import regulator GLUT2 in the liver. Taken together, our preliminary findings indicate that perinatal APAP exposure-impaired hepatic glucose metabolism in offspring may be associated with disturbance of insulin-dependent AKT signaling in the liver. PMID:28078035

  18. Functional coupling as a basic mechanism of feedback regulation of cardiac energy metabolism.

    PubMed

    Saks, V A; Kuznetsov, A V; Vendelin, M; Guerrero, K; Kay, L; Seppet, E K

    2004-01-01

    In this review we analyze the concepts and the experimental data on the mechanisms of the regulation of energy metabolism in muscle cells. Muscular energetics is based on the force-length relationship, which in the whole heart is expressed as a Frank-Starling law, by which the alterations of left ventricle diastolic volume change linearly both the cardiac work and oxygen consumption. The second basic characteristics of the heart is the metabolic stability--almost constant levels of high energy phosphates, ATP and phosphocreatine, which are practically independent of the workload and the rate of oxygen consumption, in contrast to the fast-twitch skeletal muscle with no metabolic stability and rapid fatigue. Analysis of the literature shows that an increase in the rate of oxygen consumption by order of magnitude, due to Frank-Starling law, is observed without any significant changes in the intracellular calcium transients. Therefore, parallel activation of contraction and mitochondrial respiration by calcium ions may play only a minor role in regulation of respiration in the cells. The effective regulation of the respiration under the effect of Frank-Starling law and metabolic stability of the heart are explained by the mechanisms of functional coupling within supramolecular complexes in mitochondria, and at the subcellular level within the intracellular energetic units. Such a complex structural and functional organisation of heart energy metabolism can be described quantitatively by mathematical models.

  19. Proteomic analysis uncovers a metabolic phenotype in C. elegans after nhr-40 reduction of function

    SciTech Connect

    Pohludka, Michal; Simeckova, Katerina; Vohanka, Jaroslav; Yilma, Petr; Novak, Petr; Krause, Michael W.; Kostrouchova, Marta; Kostrouch, Zdenek

    2008-09-12

    Caenorhabditis elegans has an unexpectedly large number (284) of genes encoding nuclear hormone receptors, most of which are nematode-specific and are of unknown function. We have exploited comparative two-dimensional chromatography of synchronized cultures of wild type C. elegans larvae and a mutant in nhr-40 to determine if proteomic approaches will provide additional insight into gene function. Chromatofocusing, followed by reversed-phase chromatography and mass spectrometry, identified altered chromatographic patterns for a set of proteins, many of which function in muscle and metabolism. Prompted by the proteomic analysis, we find that the penetrance of the developmental phenotypes in the mutant is enhanced at low temperatures and by food restriction. The combination of our phenotypic and proteomic analysis strongly suggests that NHR-40 provides a link between metabolism and muscle development. Our results highlight the utility of comparative two-dimensional chromatography to provide a relatively rapid method to gain insight into gene function.

  20. Investigation into the role of catabolite control protein A in the metabolic regulation of Streptococcus suis serotype 2 using gene expression profile analysis.

    PubMed

    Lang, Xulong; Wan, Zhonghai; Pan, Ying; Wang, Xiuran; Wang, Xiaoxu; Bu, Zhaoyang; Qian, Jing; Zeng, Huazong; Wang, Xinglong

    2015-07-01

    Catabolite control protein A (CcpA) serves a key function in the catabolism of Streptococcus suis serotype 2 (S. suis 2) by affecting the biological function and metabolic regulatory mechanisms of this bacterium. The aim of the present study was to identify variations in CcpA expression in S. suis 2 using gene expression profile analysis. Using sequencing and functional analysis, CcpA was demonstrated to play a regulatory role in the expression and regulation of virulence genes, carbon metabolism and immunoregulation in S. suis 2. Gene Ontology and Kyto Encyclopedia of Genes and Genomes analyses indicated that CcpA in S. suis 2 is involved in the regulation of multiple metabolic processes. Furthermore, combined analysis of the transcriptome and metabolite data suggested that metabolites varied due to the modulation of gene expression levels under the influence of CcpA regulation. In addition, metabolic network analysis indicated that CcpA impacted carbon metabolism to a certain extent. Therefore, the present study has provided a more comprehensive analysis of the role of CcpA in the metabolic regulation of S. suis 2, which may facilitate future investigation into this mechanism. Furthermore, the results of the present study provide a foundation for further research into the regulatory function of CcpA and associated metabolic pathways in S. suis 2.

  1. Multiple controls of oxidative metabolism in living tissues as studied by phosphorus magnetic resonance.

    PubMed Central

    Chance, B; Leigh, J S; Kent, J; McCully, K; Nioka, S; Clark, B J; Maris, J M; Graham, T

    1986-01-01

    Three types of metabolic control of oxidative metabolism are observed in the various tissues that have been studied by phosphorous magnetic resonance spectroscopy. The principal control of oxidative metabolism in skeletal muscle is by ADP (or Pi/phosphocreatine). This conclusion is based upon studies of arm muscles of humans during steady-state exercise. A work-cost (Vm vs. Pi/phosphocreatine) relationship follows a Michaelis-Menten rectangular hyperbola, where Km values from 0.5 to 0.6 and Vmax values from 50 to 200 (at nearly constant pH) are found in linearized plots of the equation V/Vmax = 1/(1 + 0.6 phosphocreatine/Pi) where V is work level (which is equal to the velocity of the enzymatic reaction) and Vmax is the maximal work capacity that is a measure of the enzyme activity (E) of oxidative metabolism. Adaptation to exercise enhances the slope of the work-cost relationship and causes large changes in Vmax or E. A second metabolic control may enhance the slope of the work-cost relationship but not Vmax. For example, the initiation of exercise can lead to an improved characteristic that can be explained by 2-fold increased substrate delivery, for example, increased oxygen delivery by microcirculatory control. Cardiac tissue of the adult dog affords an example of optimal endurance performance adaptation and exhibits the steepest work-cost relationship observed and is attributed to a coordinated control of substrate delivery that may involve Ca2+ and inorganic phosphate control of NADH; control of O2 delivery may also be involved. The calculated work-cost relationship is similar to that observed in the beagle heart. The theoretical curve illustrates that the liability of multiple controls is a sharp break point in metabolic control at the end of the multiple control range--a possible cause of instability of cardiac performance at high V/Vmax. PMID:3467315

  2. Farnesoid X Receptor Signaling Shapes the Gut Microbiota and Controls Hepatic Lipid Metabolism

    PubMed Central

    Zhang, Limin; Xie, Cen; Nichols, Robert G.; Chan, Siu H. J.; Jiang, Changtao; Hao, Ruixin; Smith, Philip B.; Cai, Jingwei; Simons, Margaret N.; Hatzakis, Emmanuel; Maranas, Costas D.; Gonzalez, Frank J.

    2016-01-01

    ABSTRACT The gut microbiota modulates obesity and associated metabolic phenotypes in part through intestinal farnesoid X receptor (FXR) signaling. Glycine-β-muricholic acid (Gly-MCA), an intestinal FXR antagonist, has been reported to prevent or reverse high-fat diet (HFD)-induced and genetic obesity, insulin resistance, and fatty liver; however, the mechanism by which these phenotypes are improved is not fully understood. The current study investigated the influence of FXR activity on the gut microbiota community structure and function and its impact on hepatic lipid metabolism. Predictions about the metabolic contribution of the gut microbiota to the host were made using 16S rRNA-based PICRUSt (phylogenetic investigation of communities by reconstruction of unobserved states), then validated using 1H nuclear magnetic resonance-based metabolomics, and results were summarized by using genome-scale metabolic models. Oral Gly-MCA administration altered the gut microbial community structure, notably reducing the ratio of Firmicutes to Bacteroidetes and its PICRUSt-predicted metabolic function, including reduced production of short-chain fatty acids (substrates for hepatic gluconeogenesis and de novo lipogenesis) in the ceca of HFD-fed mice. Metabolic improvement was intestinal FXR dependent, as revealed by the lack of changes in HFD-fed intestine-specific Fxr-null (FxrΔIE) mice treated with Gly-MCA. Integrative analyses based on genome-scale metabolic models demonstrated an important link between Lactobacillus and Clostridia bile salt hydrolase activity and bacterial fermentation. Hepatic metabolite levels after Gly-MCA treatment correlated with altered levels of gut bacterial species. In conclusion, modulation of the gut microbiota by inhibition of intestinal FXR signaling alters host liver lipid metabolism and improves obesity-related metabolic dysfunction. IMPORTANCE The farnesoid X receptor (FXR) plays an important role in mediating the dialog between the host

  3. NF-κB controls energy homeostasis and metabolic adaptation by upregulating mitochondrial respiration.

    PubMed

    Mauro, Claudio; Leow, Shi Chi; Anso, Elena; Rocha, Sonia; Thotakura, Anil K; Tornatore, Laura; Moretti, Marta; De Smaele, Enrico; Beg, Amer A; Tergaonkar, Vinay; Chandel, Navdeep S; Franzoso, Guido

    2011-08-28

    Cell proliferation is a metabolically demanding process. It requires active reprogramming of cellular bioenergetic pathways towards glucose metabolism to support anabolic growth. NF-κB/Rel transcription factors coordinate many of the signals that drive proliferation during immunity, inflammation and oncogenesis, but whether NF-κB regulates the metabolic reprogramming required for cell division during these processes is unknown. Here, we report that NF-κB organizes energy metabolism networks by controlling the balance between the utilization of glycolysis and mitochondrial respiration. NF-κB inhibition causes cellular reprogramming to aerobic glycolysis under basal conditions and induces necrosis on glucose starvation. The metabolic reorganization that results from NF-κB inhibition overcomes the requirement for tumour suppressor mutation in oncogenic transformation and impairs metabolic adaptation in cancer in vivo. This NF-κB-dependent metabolic pathway involves stimulation of oxidative phosphorylation through upregulation of mitochondrial synthesis of cytochrome c oxidase 2 (SCO2; ref. ). Our findings identify NF-κB as a physiological regulator of mitochondrial respiration and establish a role for NF-κB in metabolic adaptation in normal cells and cancer.

  4. Optimizing human hepatocyte models for metabolic phenotype and function: effects of treatment with dimethyl sulfoxide (DMSO).

    PubMed

    Nikolaou, Nikolaos; Green, Charlotte J; Gunn, Pippa J; Hodson, Leanne; Tomlinson, Jeremy W

    2016-11-01

    Primary human hepatocytes are considered to be the "gold standard" cellular model for studying hepatic fatty acid and glucose metabolism; however, they come with limitations. Although the HepG2 cell line retains many of the primary hepatocyte metabolic functions they have a malignant origin and low rates of triglyceride secretion. The aim of this study was to investigate whether dimethyl sulfoxide supplementation in the media of HepG2 cells would enhance metabolic functionality leading to the development of an improved in vitro cell model that closely recapitulates primary human hepatocyte metabolism. HepG2 cells were cultured in media containing 1% dimethyl sulfoxide for 2, 4, 7, 14, and 21 days. Gene expression, protein levels, intracellular triglyceride, and media concentrations of triglyceride, urea, and 3-hydroxybutyrate concentrations were measured. Dimethyl sulfoxide treatment altered the expression of genes involved in lipid (FAS, ACC1, ACC2, DGAT1, DGAT2, SCD) and glucose (PEPCK, G6Pase) metabolism as well as liver functionality (albumin, alpha-1-antitrypsin, AFP). mRNA changes were paralleled by alterations at the protein level. DMSO treatment decreased intracellular triglyceride content and lactate production and increased triglyceride and 3-hydroxybutyrate concentrations in the media in a time-dependent manner. We have demonstrated that the addition of 1% dimethyl sulfoxide to culture media changes the metabolic phenotype of HepG2 cells toward a more primary human hepatocyte phenotype. This will enhance the currently available in vitro model systems for the study of hepatocyte biology related to pathological processes that contribute to disease and their response to specific therapeutic interventions.

  5. Sex steroids do not affect muscle weight, oxidative metabolism or cytosolic androgen reception binding of functionally overloaded rat Plantaris muscles

    NASA Technical Reports Server (NTRS)

    Max, S. R.; Rance, N.

    1983-01-01

    The effects of sex steroids on muscle weight and oxidative capacity of rat planaris muscles subjected to functional overload by removal of synergistic muscles were investigated. Ten weeks after bilateral synergist removal, plantaris muscles were significantly hypertrophic compared with unoperated controls. After this period, the ability of the muscles to oxide three substrates of oxidative metabolism was assessed. Experimental procedures are discussed and results are presented herein. Results suggest a lack of beneficial effect of sex hormone status on the process of hypertrophy and on biochemical changes in overloaded muscle. Such findings are not consistent with the idea of synergistic effects of sex steroids and muscle usage.

  6. Phylogenetic and Functional Analysis of Metagenome Sequence from High-Temperature Archaeal Habitats Demonstrate Linkages between Metabolic Potential and Geochemistry

    PubMed Central

    Inskeep, William P.; Jay, Zackary J.; Herrgard, Markus J.; Kozubal, Mark A.; Rusch, Douglas B.; Tringe, Susannah G.; Macur, Richard E.; Jennings, Ryan deM.; Boyd, Eric S.; Spear, John R.; Roberto, Francisco F.

    2013-01-01

    Geothermal habitats in Yellowstone National Park (YNP) provide an unparalleled opportunity to understand the environmental factors that control the distribution of archaea in thermal habitats. Here we describe, analyze, and synthesize metagenomic and geochemical data collected from seven high-temperature sites that contain microbial communities dominated by archaea relative to bacteria. The specific objectives of the study were to use metagenome sequencing to determine the structure and functional capacity of thermophilic archaeal-dominated microbial communities across a pH range from 2.5 to 6.4 and to discuss specific examples where the metabolic potential correlated with measured environmental parameters and geochemical processes occurring in situ. Random shotgun metagenome sequence (∼40–45 Mb Sanger sequencing per site) was obtained from environmental DNA extracted from high-temperature sediments and/or microbial mats and subjected to numerous phylogenetic and functional analyses. Analysis of individual sequences (e.g., MEGAN and G + C content) and assemblies from each habitat type revealed the presence of dominant archaeal populations in all environments, 10 of whose genomes were largely reconstructed from the sequence data. Analysis of protein family occurrence, particularly of those involved in energy conservation, electron transport, and autotrophic metabolism, revealed significant differences in metabolic strategies across sites consistent with differences in major geochemical attributes (e.g., sulfide, oxygen, pH). These observations provide an ecological basis for understanding the distribution of indigenous archaeal lineages across high-temperature systems of YNP. PMID:23720654

  7. The hypothalamus and metabolism: integrating signals to control energy and glucose homeostasis.

    PubMed

    Coll, Anthony P; Yeo, Giles S H

    2013-12-01

    Molecules acting in the central nervous system play a critical role in the control of both energy and glucose homeostasis. The hypothalamus consists of a highly diverse collection of interconnected neurons and supporting glial cells that allow this region of the brain to sense and respond to a diverse range of hormonal and metabolic signals. We review recent advances in our understanding of the anatomical architecture and molecular mechanisms within the hypothalamus and how these facilitate the orchestration of systemic metabolic processes.

  8. Structure and function of sphingosine-1-phosphate lyase, a key enzyme of sphingolipid metabolism.

    PubMed

    Bourquin, Florence; Riezman, Howard; Capitani, Guido; Grütter, Markus G

    2010-08-11

    Sphingosine-1-phosphate lyase (SPL), a key enzyme of sphingolipid metabolism, catalyzes the irreversible degradation of sphingoid base phosphates. Its main substrate sphingosine-1-phosphate (S1P) acts both extracellularly, by binding G protein-coupled receptors of the lysophospholipid receptor family, and inside the cell, as a second messenger. There, S1P takes part in regulating various cellular processes and its levels are tightly regulated. SPL is a pivotal enzyme regulating S1P intracellular concentrations and a promising drug target for the design of immunosuppressants. We structurally and functionally characterized yeast SPL (Dpl1p) and its first prokaryotic homolog, from Symbiobacterium thermophilum. The Dpl1p structure served as a basis for a very reliable model of Homo sapiens SPL. The above results, together with in vitro and in vivo studies of SPL mutants, reveal which residues are involved in activity and substrate binding and pave the way to studies aimed at controlling the activity of this pivotal enzyme.

  9. Relationships between years of education and gray matter volume, metabolism and functional connectivity in healthy elders.

    PubMed

    Arenaza-Urquijo, Eider M; Landeau, Brigitte; La Joie, Renaud; Mevel, Katell; Mézenge, Florence; Perrotin, Audrey; Desgranges, Béatrice; Bartrés-Faz, David; Eustache, Francis; Chételat, Gaël

    2013-12-01

    More educated elders are less susceptible to age-related or pathological cognitive changes. We aimed at providing a comprehensive contribution to the neural mechanism underlying this effect thanks to a multimodal approach. Thirty-six healthy elders were selected based on neuropsychological assessments and cerebral amyloid imaging, i.e. as presenting normal cognition and a negative florbetapir-PET scan. All subjects underwent structural MRI, FDG-PET and resting-state functional MRI scans. We assessed the relationships between years of education and i) gray matter volume, ii) gray matter metabolism and iii) functional connectivity in the brain areas showing associations with both volume and metabolism. Higher years of education were related to greater volume in the superior temporal gyrus, insula and anterior cingulate cortex and to greater metabolism in the anterior cingulate cortex. The latter thus showed both volume and metabolism increases with education. Seed connectivity analyses based on this region showed that education was positively related to the functional connectivity between the anterior cingulate cortex and the hippocampus as well as the inferior frontal lobe, posterior cingulate cortex and angular gyrus. Increased connectivity was in turn related with improved cognitive performances. Reinforcement of the connectivity of the anterior cingulate cortex with distant cortical areas of the frontal, temporal and parietal lobes appears as one of the mechanisms underlying education-related reserve in healthy elders.

  10. Fatty aldehyde and fatty alcohol metabolism: review and importance for epidermal structure and function.

    PubMed

    Rizzo, William B

    2014-03-01

    Normal fatty aldehyde and alcohol metabolism is essential for epidermal differentiation and function. Long-chain aldehydes are produced by catabolism of several lipids including fatty alcohols, sphingolipids, ether glycerolipids, isoprenoid alcohols and certain aliphatic lipids that undergo α- or ω-oxidation. The fatty aldehyde generated by these pathways is chiefly metabolized to fatty acid by fatty aldehyde dehydrogenase (FALDH, alternately known as ALDH3A2), which also functions to oxidize fatty alcohols as a component of the fatty alcohol:NAD oxidoreductase (FAO) enzyme complex. Genetic deficiency of FALDH/FAO in patients with Sjögren-Larsson syndrome (SLS) results in accumulation of fatty aldehydes, fatty alcohols and related lipids (ether glycerolipids, wax esters) in cultured keratinocytes. These biochemical changes are associated with abnormalities in formation of lamellar bodies in the stratum granulosum and impaired delivery of their precursor membranes to the stratum corneum (SC). The defective extracellular SC membranes are responsible for a leaky epidermal water barrier and ichthyosis. Although lamellar bodies appear to be the pathogenic target for abnormal fatty aldehyde/alcohol metabolism in SLS, the precise biochemical mechanisms are yet to be elucidated. Nevertheless, studies in SLS highlight the critical importance of FALDH and normal fatty aldehyde/alcohol metabolism for epidermal function. This article is part of a Special Issue entitled The Important Role of Lipids in the Epidermis and their Role in the Formation and Maintenance of the Cutaneous Barrier. Guest Editors: Kenneth R. Feingold and Peter Elias.

  11. 2009 Plant Lipids: Structure, Metabolism & Function Gordon Research Conference - February 1- 6 ,2009

    SciTech Connect

    Kent D. Chapman

    2009-02-06

    The Gordon Research Conference on 'Plant Lipids: Structure, Metabolism and Function' has been instituted to accelerate research productivity in the field of plant lipids. This conference will facilitate wide dissemination of research breakthroughs, support recruitment of young scientists to the field of plant lipid metabolism and encourage broad participation of the plant lipid community in guiding future directions for research in plant lipids. This conference will build upon the strengths of the successful, previous biannual meetings of the National Plant Lipid Cooperative (www.plantlipids.org) that began in 1993, but will reflect a broader scope of topics to include the biochemistry, cell biology, metabolic regulation, and signaling functions of plant acyl lipids. Most importantly, this conference also will serve as a physical focal point for the interaction of the plant lipid research community. Applications to attend this conference will be open to all researchers interested in plant lipids and will provide a venue for the presentation of the latest research results, networking opportunities for young scientists, and a forum for the development and exchange of useful lipid resources and new ideas. By bringing together senior- and junior-level scientists involved in plant lipid metabolism, a broad range of insights will be shared and the community of plant lipid researchers will function more as a network of vested partners. This is important for the vitality of the research community and for the perceived value that will encourage conference attendance into the future.

  12. Fatty Aldehyde and Fatty Alcohol Metabolism: Review and Importance for Epidermal Structure and Function

    PubMed Central

    Rizzo, William B.

    2014-01-01

    Normal fatty aldehyde and alcohol metabolism is essential for epidermal differentiation and function. Long-chain aldehydes are produced by catabolism of several lipids including fatty alcohols, sphingolipids, ether glycerolipids, isoprenoid alcohols and certain aliphatic lipids that undergo α- or ω-oxidation. The fatty aldehyde generated by these pathways is chiefly metabolized to fatty acid by fatty aldehyde dehydrogenase (FALDH, alternately known as ALDH3A2), which also functions to oxidize fatty alcohols as a component of the fatty alcohol:NAD oxidoreductase (FAO) enzyme complex. Genetic deficiency of FALDH/FAO in patients with Sjögren-Larsson syndrome (SLS) results in accumulation of fatty aldehydes, fatty alcohols and related lipids (ether glycerolipids, wax esters) in cultured keratinocytes. These biochemical changes are associated with abnormalities in formation of lamellar bodies in the stratum granulosum and impaired delivery of their precursor membranes to the stratum corneum (SC). The defective extracellular SC membranes are responsible for a leaky epidermal water barrier and ichthyosis. Although lamellar bodies appear to be the pathogenic target for abnormal fatty aldehyde/alcohol metabolism in SLS, the precise biochemical mechanisms are yet to be elucidated. Nevertheless, studies in SLS highlight the critical importance of FALDH and normal fatty aldehyde/alcohol metabolism for epidermal function. PMID:24036493

  13. Neuroendocrinology: Electromagnetogenetic Control over Feeding and Glucose Metabolism.

    PubMed

    Ruud, Johan; Brüning, Jens C

    2016-06-06

    Cutting-edge experiments show a new means to control the activity of specifically genetically targeted neurons in the hypothalamus using electromagnetic force. At the flip of a switch, the system bidirectionally regulates feeding behavior and glucose homeostasis, demonstrating wireless control over deep brain regions and their strong influence over energy balance.

  14. Effects of Temperature and Controlled Atmospheres on Codling Moth Metabolism

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Although controlled atmosphere temperature treatments are effective in controlling codling moth in fruit, the mechanism by which this combination treatment kills the larvae is unknown. Differential scanning calorimetry was used to determine the effects of elevated temperatures, low oxygen, and high ...

  15. Octopamine controls starvation resistance, life span and metabolic traits in Drosophila

    PubMed Central

    Li, Yong; Hoffmann, Julia; Li, Yang; Stephano, Flora; Bruchhaus, Iris; Fink, Christine; Roeder, Thomas

    2016-01-01

    The monoamines octopamine (OA) and tyramine (TA) modulate numerous behaviours and physiological processes in invertebrates. Nevertheless, it is not clear whether these invertebrate counterparts of norepinephrine are important regulators of metabolic and life history traits. We show that flies (Drosophila melanogaster) lacking OA are more resistant to starvation, while their overall life span is substantially reduced compared with control flies. In addition, these animals have increased body fat deposits, reduced physical activity and a reduced metabolic resting rate. Increasing the release of OA from internal stores induced the opposite effects. Flies devoid of both OA and TA had normal body fat and metabolic rates, suggesting that OA and TA act antagonistically. Moreover, OA-deficient flies show increased insulin release rates. We inferred that the OA-mediated control of insulin release accounts for a substantial proportion of the alterations observed in these flies. Apparently, OA levels control the balance between thrifty and expenditure metabolic modes. Thus, changes in OA levels in response to external and internal signals orchestrate behaviour and metabolic processes to meet physiological needs. Moreover, chronic deregulation of the corresponding signalling systems in humans may be associated with metabolic disorders, such as obesity or diabetes. PMID:27759117

  16. Control and Functions of Fixational Eye Movements

    PubMed Central

    Rucci, Michele; Poletti, Martina

    2016-01-01

    Humans and other species explore a visual scene by rapidly shifting their gaze 2-3 times every second. Although the eyes may appear immobile in the brief intervals in between saccades, microscopic (fixational) eye movements are always present, even when attending to a single point. These movements occur during the very periods in which visual information is acquired and processed and their functions have long been debated. Recent technical advances in controlling retinal stimulation during normal oculomotor activity have shed new light on the visual contributions of fixational eye movements and their degree of control. The emerging body of evidence, reviewed in this article, indicates that fixational eye movements are important components of the strategy by which the visual system processes fine spatial details, enabling both precise positioning of the stimulus on the retina and encoding of spatial information into the joint space-time domain. PMID:27795997

  17. Regulatory and Functional Aspects of Indolic Metabolism in Plant Systemic Acquired Resistance.

    PubMed

    Stahl, Elia; Bellwon, Patricia; Huber, Stefan; Schlaeppi, Klaus; Bernsdorff, Friederike; Vallat-Michel, Armelle; Mauch, Felix; Zeier, Jürgen

    2016-05-02

    Tryptophan-derived, indolic metabolites possess diverse functions in Arabidopsis innate immunity to microbial pathogen infection. Here, we investigate the functional role and regulatory characteristics of indolic metabolism in Arabidopsis systemic acquired resistance (SAR) triggered by the bacterial pathogen Pseudomonas syringae. Indolic metabolism is broadly activated in both P. syringae-inoculated and distant, non-inoculated leaves. At inoculation sites, camalexin, indol-3-ylmethylamine (I3A), and indole-3-carboxylic acid (ICA) are the major accumulating compounds. Camalexin accumulation is positively affected by MYB122, and the cytochrome P450 genes CYP81F1 and CYP81F2. Local I3A production, by contrast, occurs via indole glucosinolate breakdown by PEN2- dependent and independent pathways. Moreover, exogenous application of the defense hormone salicylic acid stimulates I3A generation at the expense of its precursor indol-3-ylmethylglucosinolate (I3M), and the SAR regulator pipecolic acid primes plants for enhanced P. syringae-induced activation of distinct branches of indolic metabolism. In uninfected systemic tissue, the metabolic response is more specific and associated with enhanced levels of the indolics I3A, ICA, and indole-3-carbaldehyde (ICC). Systemic indole accumulation fully depends on functional CYP79B2/3, PEN2, and MYB34/51/122, and requires functional SAR signaling. Genetic analyses suggest that systemically elevated indoles are dispensable for SAR and associated systemic increases of salicylic acid. However, soil-grown but not hydroponically -cultivated cyp79b2/3 and pen2 plants, both defective in indolic secondary metabolism, exhibit pre-induced immunity, which abrogates their intrinsic ability to induce SAR.

  18. Metabolomic strategies for the identification of new enzyme functions and metabolic pathways

    PubMed Central

    Prosser, Gareth A; Larrouy-Maumus, Gerald; de Carvalho, Luiz Pedro S

    2014-01-01

    Recent technological advances in accurate mass spectrometry and data analysis have revolutionized metabolomics experimentation. Activity-based and global metabolomic profiling methods allow simultaneous and rapid screening of hundreds of metabolites from a variety of chemical classes, making them useful tools for the discovery of novel enzymatic activities and metabolic pathways. By using the metabolome of the relevant organism or close species, these methods capitalize on biological relevance, avoiding the assignment of artificial and non-physiological functions. This review discusses state-of-the-art metabolomic approaches and highlights recent examples of their use for enzyme annotation, discovery of new metabolic pathways, and gene assignment of orphan metabolic activities across diverse biological sources. PMID:24829223

  19. Structure to function of an α-glucan metabolic pathway that promotes Listeria monocytogenes pathogenesis.

    PubMed

    Light, Samuel H; Cahoon, Laty A; Halavaty, Andrei S; Freitag, Nancy E; Anderson, Wayne F

    2016-11-07

    Here we employ a 'systems structural biology' approach to functionally characterize an unconventional α-glucan metabolic pathway from the food-borne pathogen Listeria monocytogenes (Lm). Crystal structure determination coupled with basic biochemical and biophysical assays allowed for the identification of anabolic, transport, catabolic and regulatory portions of the cycloalternan pathway. These findings provide numerous insights into cycloalternan pathway function and reveal the mechanism of repressor, open reading frame, kinase (ROK) transcription regulators. Moreover, by developing a structural overview we were able to anticipate the cycloalternan pathway's role in the metabolism of partially hydrolysed starch derivatives and demonstrate its involvement in Lm pathogenesis. These findings suggest that the cycloalternan pathway plays a role in interspecies resource competition-potentially within the host gastrointestinal tract-and establish the methodological framework for characterizing bacterial systems of unknown function.

  20. Multiple genetic imaging study of the association between cholesterol metabolism and brain functional alterations in individuals with risk factors for Alzheimer's disease

    PubMed Central

    Bai, Feng; Yuan, Yonggui; Shi, Yongmei; Zhang, Zhijun

    2016-01-01

    Alzheimer's disease (AD) is a clinically and genetically heterogeneous neurodegenerative disease. Genes involved in cholesterol metabolism may play a role in the pathological changes of AD. However, the imaging genetics-based endophenotypes derived from polymorphisms in multiple functionally related genes are unclear in individuals with risk factors for AD. Forty-three amnestic mild cognitive impairment (aMCI) subjects and 30 healthy controls underwent resting-state functional magnetic resonance imaging (fMRI) measurements of brain topological organization. Thirty-three previously suggested tagging single nucleotide polymorphisms (SNPs) from 12 candidate genes in the cholesterol metabolism pathway were further investigated. A cholesterol metabolism pathway gene-based imaging genetics approach was then utilized to investigate disease-related differences between the groups based on genotype-by-aMCI interactions. The cholesterol metabolism pathway genes exerted widespread effects on the cortico-subcortical-cerebellar spontaneous brain activity. Meanwhile, left lateralization of global brain connectivity was associated with cholesterol metabolism pathway genes. The APOE rs429358 variation significantly influenced the brain network characteristics, affecting the activation of nodes as well as the connectivity of edges in aMCI subjects. The cholesterol metabolism pathway gene-based imaging genetics approach may provide new opportunities to understand the mechanisms underlying AD and suggested that APOE rs429358 is a core genetic variation that is associated with disease-related differences in brain function. PMID:26985771

  1. Bridging Between Proline Structure, Functions, Metabolism, and Involvement in Organism Physiology.

    PubMed

    Saibi, Walid; Feki, Kaouthar; Yacoubi, Ines; Brini, Faiçal

    2015-08-01

    Much is now known about proline multifunctionality and metabolism; some aspects of its biological functions are still unclear. Here, we discuss some cases in the proline, structure, definition, metabolism, compartmentalization, accumulation, plausible functions and also its implication in homeostasis and organism physiology. Indeed, we report the role of proline in cellular homeostasis, including redox balance and energy status and their implication as biocatalyst for aldolase activity. Proline can act as a signaling molecule to modulate mitochondrial functions, influence cell proliferation or cell death, and trigger specific gene expression, which can be essential for plant recovery from stresses. Although, the regulation and the function of proline accumulation, during abiotic stresses, are not yet completely understood. The engineering of proline metabolism could lead to new opportunities to improve plant tolerance against environmental stresses. This atypical amino acid has a potential role in the toxicity during growth of some microorganism, vegetal, and mammalian species. Furthermore, we note that the purpose through the work is to provide a rich, concise, and mostly cohesive source on proline, considered as a platform and an anchor between several disciplines and biological functions.

  2. Black Beans, Fiber, and Antioxidant Capacity Pilot Study: Examination of Whole Foods vs. Functional Components on Postprandial Metabolic, Oxidative Stress, and Inflammation in Adults with Metabolic Syndrome.

    PubMed

    Reverri, Elizabeth J; Randolph, Jody M; Steinberg, Francene M; Kappagoda, C Tissa; Edirisinghe, Indika; Burton-Freeman, Britt M

    2015-07-27

    Beans (Phaseolus vulgaris) contain bioactive components with functional properties that may modify cardiovascular risk. The aims of this pilot study were to evaluate the ability of black beans to attenuate postprandial metabolic, oxidative stress, and inflammatory responses and determine relative contribution of dietary fiber and antioxidant capacity of beans to the overall effect. In this randomized, controlled, crossover trial, 12 adults with metabolic syndrome (MetS) consumed one of three meals (black bean (BB), fiber matched (FM), and antioxidant capacity matched (AM)) on three occasions that included blood collection before (fasting) and five hours postprandially. Insulin was lower after the BB meal, compared to the FM or AM meals (p < 0.0001). A significant meal × time interaction was observed for plasma antioxidant capacity (p = 0.002) revealing differences over time: AM > BB > FM. Oxidized LDL (oxLDL) was not different by meal, although a trend for declining oxLDL was observed after the BB and AM meals at five hours compared to the FM meal. Triglycerides and interleukin-6 (IL-6) increased in response to meals (p < 0.0001). Inclusion of black beans with a typical Western-style meal attenuates postprandial insulin and moderately enhances postprandial antioxidant endpoints in adults with MetS, which could only be partly explained by fiber content and properties of antioxidant capacity.

  3. Black Beans, Fiber, and Antioxidant Capacity Pilot Study: Examination of Whole Foods vs. Functional Components on Postprandial Metabolic, Oxidative Stress, and Inflammation in Adults with Metabolic Syndrome

    PubMed Central

    Reverri, Elizabeth J.; Randolph, Jody M.; Steinberg, Francene M.; Kappagoda, C. Tissa; Edirisinghe, Indika; Burton-Freeman, Britt M.

    2015-01-01

    Beans (Phaseolus vulgaris) contain bioactive components with functional properties that may modify cardiovascular risk. The aims of this pilot study were to evaluate the ability of black beans to attenuate postprandial metabolic, oxidative stress, and inflammatory responses and determine relative contribution of dietary fiber and antioxidant capacity of beans to the overall effect. In this randomized, controlled, crossover trial, 12 adults with metabolic syndrome (MetS) consumed one of three meals (black bean (BB), fiber matched (FM), and antioxidant capacity matched (AM)) on three occasions that included blood collection before (fasting) and five hours postprandially. Insulin was lower after the BB meal, compared to the FM or AM meals (p < 0.0001). A significant meal × time interaction was observed for plasma antioxidant capacity (p = 0.002) revealing differences over time: AM > BB > FM. Oxidized LDL (oxLDL) was not different by meal, although a trend for declining oxLDL was observed after the BB and AM meals at five hours compared to the FM meal. Triglycerides and interleukin-6 (IL-6) increased in response to meals (p < 0.0001). Inclusion of black beans with a typical Western-style meal attenuates postprandial insulin and moderately enhances postprandial antioxidant endpoints in adults with MetS, which could only be partly explained by fiber content and properties of antioxidant capacity. PMID:26225995

  4. μ-Crystallin controls muscle function through thyroid hormone action.

    PubMed

    Seko, Daiki; Ogawa, Shizuka; Li, Tao-Sheng; Taimura, Akihiro; Ono, Yusuke

    2016-05-01

    μ-Crystallin (Crym), a thyroid hormone-binding protein, is abnormally up-regulated in the muscles of patients with facioscapulohumeral muscular dystrophy, a dominantly inherited progressive myopathy. However, the physiologic function of Crym in skeletal muscle remains to be elucidated. In this study, Crym was preferentially expressed in skeletal muscle throughout the body. Crym-knockout mice exhibited a significant hypertrophy of fast-twitch glycolytic type IIb fibers, causing an increase in grip strength and high intensity running ability in Crym-null mice. Genetic inactivation of Crym or blockade of Crym by siRNA-mediated knockdown up-regulated the gene expression of fast-glycolytic contractile fibers in satellite cell-derived myotubes in vitro These alterations in Crym-inactivated muscle were rescued by inhibition of thyroid hormone, even though Crym is a positive regulator of thyroid hormone action in nonmuscle cells. The results demonstrated that Crym is a crucial regulator of muscle plasticity, controlling metabolic and contractile properties of myofibers, and thus the selective inactivation of Crym may be a potential therapeutic target for muscle-wasting diseases, such as muscular dystrophies and age-related sarcopenia.-Seko, D., Ogawa, S., Li, T.-S., Taimura, A., Ono, Y. μ-Crystallin controls muscle function through thyroid hormone action.

  5. Changes in functional metabolism in the rat central nervous system following spaceflight

    NASA Technical Reports Server (NTRS)

    Murakami, D. M.; Miller, J. D.; Fuller, C. A.

    1985-01-01

    The neuronal metabolism and soma size of neurons within the paraventricular nucleus (PVN) and the supraoptic nucleus of rats are analyzed. Five male Sprague-Dawley rats were flown on Spacelab 3 for 7 days under a 12:12 light/dark cycle and unlimited food and water, and a control group was kept on the ground under similar conditions. The preparation of the hypothalamus of the rats for microscopic examination using thionin or the cytochrome oxidase (CYOX) technique is described. CYOX activity and soma size within the PVN are evaluated. The effects of water drinking pattern and space flight on CYOX activity and soma size are investigated. The data reveal that the flight rats with normal drinking patterns display a decrease in neuronal metabolism within the vasopressin-containing neurons of the hypothalamus and this metabolic change may reflect fluid shifts caused by microgravity.

  6. Dietary Iron Controls Circadian Hepatic Glucose Metabolism Through Heme Synthesis

    PubMed Central

    Simcox, Judith A.; Mitchell, Thomas Creighton; Gao, Yan; Just, Steven F.; Cooksey, Robert; Cox, James; Ajioka, Richard; Jones, Deborah; Lee, Soh-hyun; King, Daniel; Huang, Jingyu

    2015-01-01

    The circadian rhythm of the liver maintains glucose homeostasis, and disruption of this rhythm is associated with type 2 diabetes. Feeding is one factor that sets the circadian clock in peripheral tissues, but relatively little is known about the role of specific dietary components in that regard. We assessed the effects of dietary iron on circadian gluconeogenesis. Dietary iron affects circadian glucose metabolism through heme-mediated regulation of the interaction of nuclear receptor subfamily 1 group d member 1 (Rev-Erbα) with its cosuppressor nuclear receptor corepressor 1 (NCOR). Loss of regulated heme synthesis was achieved by aminolevulinic acid (ALA) treatment of mice or cultured cells to bypass the rate-limiting enzyme in hepatic heme synthesis, ALA synthase 1 (ALAS1). ALA treatment abolishes differences in hepatic glucose production and in the expression of gluconeogenic enzymes seen with variation of dietary iron. The differences among diets are also lost with inhibition of heme synthesis with isonicotinylhydrazine. Dietary iron modulates levels of peroxisome proliferator–activated receptor γ coactivator 1α (PGC-1α), a transcriptional activator of ALAS1, to affect hepatic heme. Treatment of mice with the antioxidant N-acetylcysteine diminishes PGC-1α variation observed among the iron diets, suggesting that iron is acting through reactive oxygen species signaling. PMID:25315005

  7. The function of the aerenchyma in arborescent lycopsids: evidence of an unfamiliar metabolic strategy.

    PubMed

    Green, W A

    2010-08-07

    Most species of the modern family Isoëtaceae (Quillworts) some other modern hydrophytes, use a metabolic pathway for carbon fixation that involves uptake of sedimentary carbon and enrichment of CO(2) in internal gas spaces as a carbon-concentrating mechanism. This metabolism, which is related to 'aquatic CAM', is characterized by morphological, physiological and biochemical adaptations for decreasing photorespirative loss, aerating roots and maintaining high growth rates in anoxic, oligotrophic, stressed environments. Some of the closest relatives of the Isoëtaceae were the 'arborescent lycopsids', which were among the dominant taxa in the coal swamps found in lowland ecosystems during the Carboniferous and Permian periods (approx. 300 Ma). Morphological, ecological and geochemical evidence supports the hypothesis that the arborescent lycopsids had an unusual metabolism similar to that of modern Isoëtaceae and processed a biogeochemically significant proportion of organically fixed carbon over a period of about 100 million years in the late Palaeozoic. The temporal coincidence between the dominance of plants with this metabolism and an anomalous global atmosphere (high O(2); low CO(2)) supports the idea that biosphere feedbacks are important in regulating global climatic homeostasis. The potential influence of this metabolism on the global carbon cycle and its specific adaptive function suggest that it should perhaps be considered a fourth major photosynthetic pathway.

  8. Comparative Functional Genomic Analysis of Two Vibrio Phages Reveals Complex Metabolic Interactions with the Host Cell

    PubMed Central

    Skliros, Dimitrios; Kalatzis, Panos G.; Katharios, Pantelis; Flemetakis, Emmanouil

    2016-01-01

    Sequencing and annotation was performed for two large double stranded DNA bacteriophages, φGrn1 and φSt2 of the Myoviridae family, considered to be of great interest for phage therapy against Vibrios in aquaculture live feeds. In addition, phage–host metabolic interactions and exploitation was studied by transcript profiling of selected viral and host genes. Comparative genomic analysis with other large Vibrio phages was also performed to establish the presence and location of homing endonucleases highlighting distinct features for both phages. Phylogenetic analysis revealed that they belong to the “schizoT4like” clade. Although many reports of newly sequenced viruses have provided a large set of information, basic research related to the shift of the bacterial metabolism during infection remains stagnant. The function of many viral protein products in the process of infection is still unknown. Genome annotation identified the presence of several viral open reading frames (ORFs) participating in metabolism, including a Sir2/cobB (sirtuin) protein and a number of genes involved in auxiliary NAD+ and nucleotide biosynthesis, necessary for phage DNA replication. Key genes were subsequently selected for detail study of their expression levels during infection. This work suggests a complex metabolic interaction and exploitation of the host metabolic pathways and biochemical processes, including a possible post-translational protein modification, by the virus during infection. PMID:27895630

  9. Comparative Functional Genomic Analysis of Two Vibrio Phages Reveals Complex Metabolic Interactions with the Host Cell.

    PubMed

    Skliros, Dimitrios; Kalatzis, Panos G; Katharios, Pantelis; Flemetakis, Emmanouil

    2016-01-01

    Sequencing and annotation was performed for two large double stranded DNA bacteriophages, φGrn1 and φSt2 of the Myoviridae family, considered to be of great interest for phage therapy against Vibrios in aquaculture live feeds. In addition, phage-host metabolic interactions and exploitation was studied by transcript profiling of selected viral and host genes. Comparative genomic analysis with other large Vibrio phages was also performed to establish the presence and location of homing endonucleases highlighting distinct features for both phages. Phylogenetic analysis revealed that they belong to the "schizoT4like" clade. Although many reports of newly sequenced viruses have provided a large set of information, basic research related to the shift of the bacterial metabolism during infection remains stagnant. The function of many viral protein products in the process of infection is still unknown. Genome annotation identified the presence of several viral open reading frames (ORFs) participating in metabolism, including a Sir2/cobB (sirtuin) protein and a number of genes involved in auxiliary NAD(+) and nucleotide biosynthesis, necessary for phage DNA replication. Key genes were subsequently selected for detail study of their expression levels during infection. This work suggests a complex metabolic interaction and exploitation of the host metabolic pathways and biochemical processes, including a possible post-translational protein modification, by the virus during infection.

  10. Metabolic disorders and the risk of nasopharyngeal carcinoma: a case-control study in Italy.

    PubMed

    Zucchetto, Antonella; Taborelli, Martina; Bosetti, Cristina; Montella, Maurizio; La Vecchia, Carlo; Franchin, Gianni; Libra, Massimo; Serraino, Diego; Polesel, Jerry

    2016-07-29

    The aim of this study is to evaluate the association between metabolic disorders and the risk of nasopharyngeal carcinoma, considering different histological subtypes. Between 1992 and 2008, we carried out a multicentre case-control study in Italy. One-hundred and ninety-seven White patients with histologically confirmed nasopharyngeal carcinoma were enrolled as cases. The control group included 592 cancer-free patients, frequency matched by study centre, area of residence, sex, age and period of interview. Odds ratios (OR) and corresponding 95% confidence intervals (CI), for nasopharyngeal carcinoma according to obesity and self-reported history of other metabolic disorders, were calculated through logistic regression models adjusted for matching variables and tobacco smoking and drinking habits. Obesity (OR=1.44; 95% CI: 0.88-2.36), diabetes mellitus (OR=0.91; 95% CI: 0.42-1.98), hypertension (OR=0.79; 95% CI: 0.48-1.32), hypercholesterolaemia (OR=1.41; 95% CI: 0.84-2.35) and metabolic syndrome (i.e. at least three among the four previously cited metabolic disorders; OR=1.11; 95% CI: 0.86-1.43) were not significantly associated with the overall risk of nasopharyngeal carcinoma. However, the associations observed for diabetes mellitus, hypercholesterolaemia and metabolic syndrome were stronger among differentiated nasopharyngeal carcinomas than among undifferentiated ones. In particular, 21.7% of differentiated nasopharyngeal carcinoma cases and 7.8% of controls reported a history of metabolic syndrome (OR=3.37; 95% CI: 1.05-10.81). The results of the study indicated no overall association between metabolic disorders and nasopharyngeal carcinoma. Nonetheless, although the small sample size calls for caution in interpretation, metabolic disorders could increase the risk of differentiated nasopharyngeal carcinoma. This finding further supports a different aetiology of the two histological subtypes.

  11. Stability and control of functional differential equations

    NASA Astrophysics Data System (ADS)

    Peet, Matthew Monnig

    This thesis addresses the question of stability of systems defined by differential equations which contain nonlinearity and delay. In particular, we analyze the stability of a well-known delayed nonlinear implementation of a certain Internet congestion control protocol. We also describe a generalized methodology for proving stability of time-delay systems through the use of semidefinite programming. In Chapters 4 and 5, we consider an Internet congestion control protocol based on the decentralized gradient projection algorithm. For a certain class of utility function, this algorithm was shown to be globally convergent for some sufficiently small value of a gain parameter. Later work gave an explicit bound on this gain for a linearized version of the system. This thesis proves that this bound also implies stability of the original system. The proof is constructed within a generalized passivity framework. The dynamics of the system are separated into a linear, delayed component and a system defined by a nonlinear differential equation with discontinuity in the dynamics. Frequency-domain analysis is performed on the linear component and time-domain analysis is performed on the nonlinear discontinuous system. In Chapter 7, we describe a general methodology for proving stability of linear time-delay systems by computing solutions to an operator-theoretic version of the Lyapunov inequality via semidefinite programming. The result is stated in terms of a nested sequence of sufficient conditions which are of increasing accuracy. This approach is generalized to the case of parametric uncertainty by considering parameter-dependent Lyapunov functionals. Numerical examples are given to demonstrate convergence of the algorithm. In Chapter 8, this approach is generalized to nonlinear time-delay systems through the use of non-quadratic Lyapunov functionals.

  12. Interferon Control of the Sterol Metabolic Network: Bidirectional Molecular Circuitry-Mediating Host Protection

    PubMed Central

    Robertson, Kevin A.; Ghazal, Peter

    2016-01-01

    The sterol metabolic network is emerging center stage in inflammation and immunity. Historically, observational clinical studies show that hypocholesterolemia is a common side effect of interferon (IFN) treatment. More recently, comprehensive systems-wide investigations of the macrophage IFN response reveal a direct molecular link between cholesterol metabolism and infection. Upon infection, flux through the sterol metabolic network is acutely moderated by the IFN response at multiple regulatory levels. The precise mechanisms by which IFN regulates the mevalonate-sterol pathway—the spine of the network—are beginning to be unraveled. In this review, we discuss our current understanding of the multifactorial mechanisms by which IFN regulates the sterol pathway. We also consider bidirectional communications resulting in sterol metabolism regulation of immunity. Finally, we deliberate on how this fundamental interaction functions as an integral element of host protective responses to infection and harmful inflammation. PMID:28066443

  13. Metabolic risk factors and long-term graft function after paediatric renal transplantation.

    PubMed

    Tainio, Juuso; Qvist, Erik; Hölttä, Tuula; Pakarinen, Mikko; Jahnukainen, Timo; Jalanko, Hannu

    2014-06-01

    The aim of this study was to evaluate metabolic risk factors and their impact on long-term allograft function in paediatric renal transplant (RTx) patients. We reviewed the medical records of 210 RTx patients who underwent transplantation at a median age of 4.5 years (range 0.7-18.2) and a median follow-up of 7.0 years (range 1.5-18.0). Data on lipid and glucose metabolism, uric acid levels, weight and blood pressure were collected up to 13 years post-RTx, and the findings were correlated with the measured glomerular filtration rate (GFR). Beyond the first year, GFR showed gradual deterioration with a mean decline of 2.4 ml/min/1.73 m(2)/year. Metabolic syndrome, overweight, hypertension and type 2 diabetes were diagnosed in 14-19%, 20-23%, 62-87% and 3-5% of the patients, respectively. These entities showed only mild association with the concomitant or long-term GFR values. Dyslipidaemia was common and hypertriglyceridaemia associated with a lower GFR at 1.5 and 5 years post-RTx (P = 0.008 and P = 0.017, respectively). Similarly, hyperuricaemia was frequent and associated significantly with GFR (P < 0.001). Except for hyperuricaemia and hypertriglyceridaemia, metabolic risk factors beyond the first postoperative year associated modestly with the long-term kidney graft function in paediatric RTx patients.

  14. Microbial structures, functions, and metabolic pathways in wastewater treatment bioreactors revealed using high-throughput sequencing.

    PubMed

    Ye, Lin; Zhang, Tong; Wang, Taitao; Fang, Zhiwei

    2012-12-18

    The objective of this study was to explore microbial community structures, functional profiles, and metabolic pathways in a lab-scale and a full-scale wastewater treatment bioreactors. In order to do this, over 12 gigabases of metagenomic sequence data and 600,000 paired-end sequences of bacterial 16S rRNA gene were generated with the Illumina HiSeq 2000 platform, using DNA extracted from activated sludge in the two bioreactors. Three kinds of sequences (16S rRNA gene amplicons, 16S rRNA gene sequences obtained from metagenomic sequencing, and predicted proteins) were used to conduct taxonomic assignments. Specially, relative abundances of ammonia-oxidizing archaea (AOA) and ammonia-oxidizing bacteria (AOB) were analyzed. Compared with quantitative real-time PCR (qPCR), metagenomic sequencing was demonstrated to be a better approach to quantify AOA and AOB in activated sludge samples. It was found that AOB were more abundant than AOA in both reactors. Furthermore, the analysis of the metabolic profiles indicated that the overall patterns of metabolic pathways in the two reactors were quite similar (73.3% of functions shared). However, for some pathways (such as carbohydrate metabolism and membrane transport), the two reactors differed in the number of pathway-specific genes.

  15. Respiratory, metabolic and cardiac functions are altered by disinhibition of subregions of the medial prefrontal cortex

    PubMed Central

    Hassan, Sarah F; Cornish, Jennifer L; Goodchild, Ann K

    2013-01-01

    The prefrontal cortex (PFC) is referred to as the visceral motor cortex; however, little is known about whether this region influences respiratory or metabolic outflows. The aim of this study was to describe simultaneous changes in respiratory, metabolic and cardiovascular functions evoked by disinhibition of the medial PFC (mPFC) and adjacent lateral septal nucleus (LSN). In urethane-anaesthetized rats, bicuculline methiodide was microinjected (2 mm; GABA-A receptor antagonist) into 90 sites in the mPFC at 0.72–4.00 mm from bregma. Phrenic nerve amplitude and frequency, arterial pressure, heart rate, splanchnic and lumbar sympathetic nerve activities (SNA), expired CO2, and core and brown adipose tissue temperatures were measured. Novel findings included disturbances to respiratory rhythm evoked from all subregions of the mPFC. Injections into the cingulate cortex evoked reductions in central respiratory function exclusively, whereas in ventral sites, particularly the infralimbic region, increases in respiratory drive and frequency, and metabolic and cardiac outflows were evoked. Disinhibition of sites in surrounding regions revealed that the LSN could evoke cardiovascular changes accompanied by distinct oscillations in SNA, as well as increases in respiratory amplitude. We show that activation of neurons within the mPFC and LSN influence respiratory, metabolic and cardiac outflows in a site-dependent manner. This study has implications with respect to the altered PFC neuronal activity seen in stress-related and mental health disorders, and suggests how basic physiological systems may be affected. PMID:24042503

  16. Interplay between metabolic identities in the intestinal crypt supports stem cell function.

    PubMed

    Rodríguez-Colman, Maria J; Schewe, Matthias; Meerlo, Maaike; Stigter, Edwin; Gerrits, Johan; Pras-Raves, Mia; Sacchetti, Andrea; Hornsveld, Marten; Oost, Koen C; Snippert, Hugo J; Verhoeven-Duif, Nanda; Fodde, Riccardo; Burgering, Boudewijn M T

    2017-03-16

    The small intestinal epithelium self-renews every four or five days. Intestinal stem cells (Lgr5(+) crypt base columnar cells (CBCs)) sustain this renewal and reside between terminally differentiated Paneth cells at the bottom of the intestinal crypt. Whereas the signalling requirements for maintaining stem cell function and crypt homeostasis have been well studied, little is known about how metabolism contributes to epithelial homeostasis. Here we show that freshly isolated Lgr5(+) CBCs and Paneth cells from the mouse small intestine display different metabolic programs. Compared to Paneth cells, Lgr5(+) CBCs display high mitochondrial activity. Inhibition of mitochondrial activity in Lgr5(+) CBCs or inhibition of glycolysis in Paneth cells strongly affects stem cell function, as indicated by impaired organoid formation. In addition, Paneth cells support stem cell function by providing lactate to sustain the enhanced mitochondrial oxidative phosphorylation in the Lgr5(+) CBCs. Mechanistically, we show that oxidative phosphorylation stimulates p38 MAPK activation by mitochondrial reactive oxygen species signalling, thereby establishing the mature crypt phenotype. Together, our results reveal a critical role for the metabolic identity of Lgr5(+) CBCs and Paneth cells in supporting optimal stem cell function, and we identify mitochondria and reactive oxygen species signalling as a driving force of cellular differentiation.

  17. Tristetraprolin disables prostate cancer maintenance by impairing proliferation and metabolic function

    PubMed Central

    Li, Weimin; Yang, Chunying; Fernandez, Mario R.; Schaub, Franz X.; Cleveland, John L.; Rounbehler, Robert J.

    2016-01-01

    Tristetraprolin (TTP) is an RNA-binding protein that post-transcriptionally suppresses gene expression by delivering mRNA cargo to processing bodies (P-bodies) where the mRNA is degraded. TTP functions as a tumor suppressor in a mouse model of B cell lymphoma, and in some human malignancies low TTP expression correlates with reduced survival. Here we report important prognostic and functional roles for TTP in human prostate cancer. First, gene expression analysis of prostate tumors revealed low TTP expression correlates with patients having high-risk Gleason scores and increased biochemical recurrence. Second, in prostate cancer cells with low levels of endogenous TTP, inducible TTP expression inhibits their growth and proliferation, as well as their clonogenic growth. Third, TTP functions as a tumor suppressor in prostate cancer, as forced TTP expression markedly impairs the tumorigenic potential of prostate cancer cells in a mouse xenograft model. Finally, pathway analysis of gene expression data suggested metabolism is altered by TTP expression in prostate tumor cells, and metabolic analyses revealed that such processes are impaired by TTP, including mitochondrial respiration. Collectively, these findings suggest that TTP is an important prognostic indicator for prostate cancer, and augmenting TTP function would effectively disable the metabolism and proliferation of aggressive prostate tumors. PMID:27825143

  18. The effect of metal oxide nanoparticles on functional bacteria and metabolic profiles in agricultural soil.

    PubMed

    Chai, Hankui; Yao, Jun; Sun, Jingjing; Zhang, Chi; Liu, Wenjuan; Zhu, Mijia; Ceccanti, Brunello

    2015-04-01

    A significant knowledge gap in nanotechnology is the absence of standardized protocols for examining the effect of engineered nanoparticles on soil microorganisms. In this study, agricultural soil was exposed to ZnO, SiO2, TiO2 and CeO2 nanoparticles at 1 mg g(-1). The toxicity effect was evaluated by thermal metabolism, the abundance of functional bacteria and enzymatic activity. ZnO and CeO2 nanoparticles were observed to hinder thermogenic metabolism, reduce numbers of soil Azotobacter, P-solubilizing and K-solubilizing bacteria and inhibit enzymatic activities. TiO2 nanoparticles reduced the abundance of functional bacteria and enzymatic activity. SiO2 nanoparticles slightly boosted the soil microbial activity. Pearson's correlation analysis showed that thermodynamic parameters had a strong correlation with abundance of functional bacteria and enzymatic activity. These findings demonstrated that the combined approach of monitoring thermal metabolism, functional bacteria and enzymatic activity is feasible for testing the ecotoxicity of nanoparticles on agricultural soil.

  19. Diet and Gut Microbial Function in Metabolic and Cardiovascular Disease Risk

    PubMed Central

    Meyer, Katie A.; Bennett, Brian J.

    2017-01-01

    Over the past decade, the gut microbiome has emerged as a novel and largely untapped source of variability for metabolic and cardiovascular disease risk, including diabetes. Animal and human studies support several possible pathways through which the gut microbiome may impact health, including the production of health-related metabolites from dietary sources. Diet is considered important to shaping the gut microbiota; in addition, gut microbiota influence the metabolism of many dietary components. In the present paper, we address the distinction between compositional and functional analysis of the gut microbiota. We focus on literature that highlights the value of moving beyond surveys of microbial composition to measuring gut microbial functioning to delineate mechanisms related to the interplay between diet and gut microbiota in cardiometabolic health. PMID:27541295

  20. Diet and Gut Microbial Function in Metabolic and Cardiovascular Disease Risk.

    PubMed

    Meyer, Katie A; Bennett, Brian J

    2016-10-01

    Over the past decade, the gut microbiome has emerged as a novel and largely unexplored source of variability for metabolic and cardiovascular disease risk, including diabetes. Animal and human studies support several possible pathways through which the gut microbiome may impact health, including the production of health-related metabolites from dietary sources. Diet is considered important to shaping the gut microbiota; in addition, gut microbiota influence the metabolism of many dietary components. In the present paper, we address the distinction between compositional and functional analysis of the gut microbiota. We focus on literature that highlights the value of moving beyond surveys of microbial composition to measuring gut microbial functioning to delineate mechanisms related to the interplay between diet and gut microbiota in cardiometabolic health.

  1. Iron regulatory proteins and their role in controlling iron metabolism.

    PubMed

    Kühn, Lukas C

    2015-02-01

    Cellular iron homeostasis is regulated by post-transcriptional feedback mechanisms, which control the expression of proteins involved in iron uptake, release and storage. Two cytoplasmic proteins with mRNA-binding properties, iron regulatory proteins 1 and 2 (IRP1 and IRP2) play a central role in this regulation. Foremost, IRPs regulate ferritin H and ferritin L translation and thus iron storage, as well as transferrin receptor 1 (TfR1) mRNA stability, thereby adjusting receptor expression and iron uptake via receptor-mediated endocytosis of iron-loaded transferrin. In addition splice variants of iron transporters for import and export at the plasma-membrane, divalent metal transporter 1 (DMT1) and ferroportin are regulated by IRPs. These mechanisms have probably evolved to maintain the cytoplasmic labile iron pool (LIP) at an appropriate level. In certain tissues, the regulation exerted by IRPs influences iron homeostasis and utilization of the entire organism. In intestine, the control of ferritin expression limits intestinal iron absorption and, thus, whole body iron levels. In bone marrow, erythroid heme biosynthesis is coordinated with iron availability through IRP-mediated translational control of erythroid 5-aminolevulinate synthase mRNA. Moreover, the translational control of HIF2α mRNA in kidney by IRP1 coordinates erythropoietin synthesis with iron and oxygen supply. Besides IRPs, body iron absorption is negatively regulated by hepcidin. This peptide hormone, synthesized and secreted by the liver in response to high serum iron, downregulates ferroportin at the protein level and thereby limits iron absorption from the diet. Hepcidin will not be discussed in further detail here.

  2. Modified metabolic syndrome and second cancers in women: A case control study

    PubMed Central

    Ortiz-Mendoza, Carlos-Manuel; Pérez-Chávez, Ernesto; Fuente-Vera, Tania-Angélica De-la

    2016-01-01

    Background: According to some studies, the metabolic syndrome causes diverse primary cancers; however, there is no evidence about metabolic syndrome impact on second cancers development in women. Aim: To find out the implication of the modified metabolic syndrome in women with second cancers. Materials and Methods: This was a case–control study, at a general hospital in Mexico City, in women with second cancers (cases) and age-matched women with only one neoplasm (controls). The analysis comprised: Tumor (s), anthropometric features, and body mass index (BMI); moreover, presence of diabetes mellitus, hypertension, and fasting serum levels of total cholesterol, triglycerides and glucose. Results: The sample was of nine cases and 27 controls. In cases, the metabolic syndrome (diabetes mellitus or glucose > 99 mg/dL + hypertension or blood pressure ≥ 135/85 mm Hg + triglycerides > 149 mg/dL or BMI ≥ 30 kg/m2) was more frequent (odds ratio 20.8, 95% confidence interval: 1.9–227.1). Conclusion: Our results suggest that in women, the modified metabolic syndrome may be a risk factor for second cancers. PMID:28032086

  3. Redox Control of Renal Function and Hypertension

    PubMed Central

    Whaley-Connell, Adam; Sowers, James R.

    2008-01-01

    Abstract Loss of redox homeostasis and formation of excessive free radicals play an important role in the pathogenesis of kidney disease and hypertension. Free radicals such as reactive oxygen species (ROS) are necessary in physiologic processes. However, loss of redox homeostasis contributes to proinflammatory and profibrotic pathways in the kidney, which in turn lead to reduced vascular compliance and proteinuria. The kidney is susceptible to the influence of various extracellular and intracellular cues, including the renin–angiotensin–aldosterone system (RAAS), hyperglycemia, lipid peroxidation, inflammatory cytokines, and growth factors. Redox control of kidney function is a dynamic process with reversible pro– and anti-free radical processes. The imbalance of redox homeostasis within the kidney is integral in hypertension and the progression of kidney disease. An emerging paradigm exists for renal redox contribution to hypertension. Antioxid. Redox Signal. 11, 2047–2089. PMID:18821850

  4. Regioselectivity control of graphene functionalization by ripples.

    PubMed

    Gao, Xingfa; Wang, Ying; Liu, Xin; Chan, T-L; Irle, Stephan; Zhao, Yuliang; Zhang, Shengbai B

    2011-11-21

    Ripples naturally occur in graphene sheets. First-principles calculations reveal that, by altering the pyramidalization angles of the carbon atoms, these ripples can be used to direct the chemical reactivity of graphene towards hydrogenation. A fraction of the carbon atoms of a rippled graphene, located around the crests and troughs, show significantly increased reactivity. The remaining carbon atoms have comparable reactivity to those in a flat graphene. To illustrate the increased reactivity, we show that hydrogenation becomes exothermic when the characteristic ratio between the amplitude and wavelength reaches ~0.55. This finding offers a practical chemical venue for regioselectivity control of graphene functionalization. While the rippling does not directly affect the band gap of the graphene, the rippling-induced hydrogenation does.

  5. Metabolic Activity and Functional Diversity Changes in Sediment Prokaryotic Communities Organically Enriched with Mussel Biodeposits

    PubMed Central

    Pollet, Thomas; Cloutier, Olivier; Nozais, Christian; McKindsey, Christopher W.; Archambault, Philippe

    2015-01-01

    This experimental microcosm study reports the influence of organic enrichments by mussel biodeposits on the metabolic activity and functional diversity of benthic prokaryotic communities. The different biodeposit enrichment regimes created, which mimicked the quantity of faeces and pseudo-faeces potentially deposited below mussel farms, show a clear stimulatory effect of this organic enrichment on prokaryotic metabolic activity. This effect was detected once a certain level of biodeposition was attained with a tipping point estimated between 3.25 and 10 g day-1 m-2. Prokaryotic communities recovered their initial metabolic activity by 11 days after the cessation of biodeposit additions. However, their functional diversity remained greater than prior to the disturbance suggesting that mussel biodeposit enrichment may disturb the functioning and perhaps the role of prokaryotic communities in benthic ecosystems. This manipulative approach provided new information on the influence of mussel biodeposition on benthic prokaryotic communities and dose-response relationships and may support the development of carrying capacity models for bivalve culture. PMID:25923715

  6. Metabolic activity and functional diversity changes in sediment prokaryotic communities organically enriched with mussel biodeposits.

    PubMed

    Pollet, Thomas; Cloutier, Olivier; Nozais, Christian; McKindsey, Christopher W; Archambault, Philippe

    2015-01-01

    This experimental microcosm study reports the influence of organic enrichments by mussel biodeposits on the metabolic activity and functional diversity of benthic prokaryotic communities. The different biodeposit enrichment regimes created, which mimicked the quantity of faeces and pseudo-faeces potentially deposited below mussel farms, show a clear stimulatory effect of this organic enrichment on prokaryotic metabolic activity. This effect was detected once a certain level of biodeposition was attained with a tipping point estimated between 3.25 and 10 g day-1 m-2. Prokaryotic communities recovered their initial metabolic activity by 11 days after the cessation of biodeposit additions. However, their functional diversity remained greater than prior to the disturbance suggesting that mussel biodeposit enrichment may disturb the functioning and perhaps the role of prokaryotic communities in benthic ecosystems. This manipulative approach provided new information on the influence of mussel biodeposition on benthic prokaryotic communities and dose-response relationships and may support the development of carrying capacity models for bivalve culture.

  7. Diurnal Changes in Mitochondrial Function Reveal Daily Optimization of Light and Dark Respiratory Metabolism in Arabidopsis*

    PubMed Central

    Lee, Chun Pong; Eubel, Holger; Millar, A. Harvey

    2010-01-01

    Biomass production by plants is often negatively correlated with respiratory rate, but the value of this rate changes dramatically during diurnal cycles, and hence, biomass is the cumulative result of complex environment-dependent metabolic processes. Mitochondria in photosynthetic plant tissues undertake substantially different metabolic roles during light and dark periods that are dictated by substrate availability and the functional capacity of mitochondria defined by their protein composition. We surveyed the heterogeneity of the mitochondrial proteome and its function during a typical night and day cycle in Arabidopsis shoots. This used a staged, quantitative analysis of the proteome across 10 time points covering 24 h of the life of 3-week-old Arabidopsis shoots grown under 12-h dark and 12-h light conditions. Detailed analysis of enzyme capacities and substrate-dependent respiratory processes of isolated mitochondria were also undertaken during the same time course. Together these data reveal a range of dynamic changes in mitochondrial capacity and uncover day- and night-enhanced protein components. Clear diurnal changes were evident in mitochondrial capacities to drive the TCA cycle and to undertake functions associated with nitrogen and sulfur metabolism, redox poise, and mitochondrial antioxidant defense. These data quantify the nature and nuances of a daily rhythm in Arabidopsis mitochondrial respiratory capacity. PMID:20601493

  8. Large-scale functional analysis of the roles of phosphorylation in yeast metabolic pathways.

    PubMed

    Schulz, Juliane Caroline; Zampieri, Mattia; Wanka, Stefanie; von Mering, Christian; Sauer, Uwe

    2014-11-25

    Protein phosphorylation is a widespread posttranslational modification that regulates almost all cellular functions. To investigate the large number of phosphorylation events with unknown functions, we monitored the concentrations of several hundred intracellular metabolites in Saccharomyces cerevisiae yeast strains with deletions of 118 kinases or phosphatases. Whereas most deletion strains had no detectable difference in growth compared to wild-type yeast, two-thirds of deletion strains had alterations in metabolic profiles. For about half of the kinases and phosphatases encoded by the deleted genes, we inferred specific regulatory roles on the basis of knowledge about the affected metabolic pathways. We demonstrated that the phosphatase Ppq1 was required for metal homeostasis. Combining metabolomic data with published phosphoproteomic data in a stoichiometric model enabled us to predict functions for phosphorylation in the regulation of 47 enzymes. Overall, we provided insights and testable predictions covering greater than twice the number of known phosphorylated enzymes in yeast, suggesting extensive phosphorylation-dependent regulation of yeast metabolism.

  9. Functional analysis of free fatty acid receptor GPR120 in human eosinophils: implications in metabolic homeostasis.

    PubMed

    Konno, Yasunori; Ueki, Shigeharu; Takeda, Masahide; Kobayashi, Yoshiki; Tamaki, Mami; Moritoki, Yuki; Oyamada, Hajime; Itoga, Masamichi; Kayaba, Hiroyuki; Omokawa, Ayumi; Hirokawa, Makoto

    2015-01-01

    Recent evidence has shown that eosinophils play an important role in metabolic homeostasis through Th2 cytokine production. GPR120 (FFA4) is a G protein-coupled receptor (GPCR) for long-chain fatty acids that functions as a regulator of physiological energy metabolism. In the present study, we aimed to investigate whether human eosinophils express GPR120 and, if present, whether it possesses a functional capacity on eosinophils. Eosinophils isolated from peripheral venous blood expressed GPR120 at both the mRNA and protein levels. Stimulation with a synthetic GPR120 agonist, GW9508, induced rapid down-regulation of cell surface expression of GPR120, suggesting ligand-dependent receptor internalization. Although GPR120 activation did not induce eosinophil chemotactic response and degranulation, we found that GW9508 inhibited eosinophil spontaneous apoptosis and Fas receptor expression. The anti-apoptotic effect was attenuated by phosphoinositide 3-kinase (PI3K) inhibitors and was associated with inhibition of caspase-3 activity. Eosinophil response investigated using ELISpot assay indicated that stimulation with a GPR120 agonist induced IL-4 secretion. These findings demonstrate the novel functional properties of fatty acid sensor GPR120 on human eosinophils and indicate the previously unrecognized link between nutrient metabolism and the immune system.

  10. Air Pollution Exposure During Pregnancy and Fetal Markers of Metabolic function: The MIREC Study.

    PubMed

    Lavigne, Eric; Ashley-Martin, Jillian; Dodds, Linda; Arbuckle, Tye E; Hystad, Perry; Johnson, Markey; Crouse, Dan L; Ettinger, Adrienne S; Shapiro, Gabriel D; Fisher, Mandy; Morisset, Anne-Sophie; Taback, Shayne; Bouchard, Maryse F; Sun, Liu; Monnier, Patricia; Dallaire, Renée; Fraser, William D

    2016-05-01

    Previous evidence suggests that exposure to outdoor air pollution during pregnancy could alter fetal metabolic function, which could increase the risk of obesity in childhood. However, to our knowledge, no epidemiologic study has investigated the association between prenatal exposure to air pollution and indicators of fetal metabolic function. We investigated the association between maternal exposure to nitrogen dioxide and fine particulate matter (aerodynamic diameter ≤2.5 µm) and umbilical cord blood leptin and adiponectin levels with mixed-effects linear regression models among 1,257 mother-infant pairs from the Maternal-Infant Research on Environmental Chemicals (MIREC) Study, conducted in Canada (2008-2011). We observed that an interquartile-range increase in average exposure to fine particulate matter (3.2 µg/m(3)) during pregnancy was associated with an 11% (95% confidence interval: 4, 17) increase in adiponectin levels. We also observed 13% (95% confidence interval: 6, 20) higher adiponectin levels per interquartile-range increase in average exposure to nitrogen dioxide (13.6 parts per billion) during pregnancy. Significant associations were seen between air pollution markers and cord blood leptin levels in models that adjusted for birth weight z score but not in models that did not adjust for birth weight z score. The roles of prenatal exposure to air pollution and fetal metabolic function in the potential development of childhood obesity should be further explored.

  11. The functional gene composition and metabolic potential of coral-associated microbial communities

    PubMed Central

    Zhang, Yanying; Ling, Juan; Yang, Qingsong; Wen, Chongqing; Yan, Qingyun; Sun, Hongyan; Van Nostrand, Joy D.; Shi, Zhou; Zhou, Jizhong; Dong, Junde

    2015-01-01

    The phylogenetic diversity of coral-associated microbes has been extensively examined, but some contention remains regarding whether coral-associated microbial communities are species-specific or site-specific. It is suggested that corals may associate with microbes in terms of function, although little is known about the differences in coral-associated microbial functional gene composition and metabolic potential among coral species. Here, 16S rRNA Illumina sequencing and functional gene array (GeoChip 5.0) were used to assess coral-associated microbial communities. Our results indicate that both host species and environmental variables significantly correlate with shifts in the microbial community structure and functional potential. Functional genes related to key biogeochemical cycles including carbon, nitrogen, sulfur and phosphorus cycling, metal homeostasis, organic remediation, antibiotic resistance and secondary metabolism were shown to significantly vary between and among the four study corals (Galaxea astreata, Porites lutea, Porites andrewsi and Pavona decussata). Genes specific for anammox were also detected for the first time in the coral holobiont and positively correlated with ammonium. This study reveals that variability in the functional potential of coral-associated microbial communities is largely driven by changes in environmental factors and further demonstrates the importance of linking environmental parameters with genomic data in complex environmental systems. PMID:26536917

  12. Cerebral energy metabolism and the brain's functional network architecture: an integrative review

    PubMed Central

    Lord, Louis-David; Expert, Paul; Huckins, Jeremy F; Turkheimer, Federico E

    2013-01-01

    Recent functional magnetic resonance imaging (fMRI) studies have emphasized the contributions of synchronized activity in distributed brain networks to cognitive processes in both health and disease. The brain's ‘functional connectivity' is typically estimated from correlations in the activity time series of anatomically remote areas, and postulated to reflect information flow between neuronal populations. Although the topological properties of functional brain networks have been studied extensively, considerably less is known regarding the neurophysiological and biochemical factors underlying the temporal coordination of large neuronal ensembles. In this review, we highlight the critical contributions of high-frequency electrical oscillations in the γ-band (30 to 100 Hz) to the emergence of functional brain networks. After describing the neurobiological substrates of γ-band dynamics, we specifically discuss the elevated energy requirements of high-frequency neural oscillations, which represent a mechanistic link between the functional connectivity of brain regions and their respective metabolic demands. Experimental evidence is presented for the high oxygen and glucose consumption, and strong mitochondrial performance required to support rhythmic cortical activity in the γ-band. Finally, the implications of mitochondrial impairments and deficits in glucose metabolism for cognition and behavior are discussed in the context of neuropsychiatric and neurodegenerative syndromes characterized by large-scale changes in the organization of functional brain networks. PMID:23756687

  13. Diabetes, impaired glucose tolerance, and metabolic biomarkers in individuals with normal glucose tolerance are inversely associated with lung function: the Jackson Heart Study.

    PubMed

    Hickson, DeMarc A; Burchfiel, Cecil M; Liu, Jiankang; Petrini, Marcy F; Harrison, Kimystian; White, Wendy B; Sarpong, Daniel F

    2011-08-01

    The objectives of this study were to test the hypothesis that diabetes and impaired glucose tolerance (IGT), diabetes control and diabetes duration, and metabolic biomarkers in adults with normal glucose tolerance (NGT) are inversely associated with spirometry-measured lung function. We conducted a cross-sectional observational cohort study that included nonsmoking African American adults (n = 2,945; mean age = 52.5 ± 12.6 years; 69.2% female), who were free of cardiovascular disease, from the Jackson Heart Study. The interventions were diabetes, metabolic biomarkers and lung function. We measured the associations of glycemia with forced expiratory volume (FEV) in 1 s, FEV in 6 s, and vital capacity. Multivariable adjusted mean lung function values were lower among adults with diabetes and IGT (in women only, but not after adjustment for waist circumference) than adults with NGT. Among adults with diabetes, no associations were observed between lung function and diabetes control or duration. In women with NGT, lower lung function was consistently associated with higher glucose levels and less consistently with higher insulin levels and insulin resistance. Lower lung function was consistently associated with higher insulin levels and insulin resistance and less consistently associated with insulin and hemoglobin A1c in men with NGT. Overall, our findings generally support the hypothesis that diabetes, IGT, and increased levels of metabolic biomarkers in individuals with NGT are inversely associated with lung function in African Americans, independent of adiposity.

  14. The Control of Calcium Metabolism in Zebrafish (Danio rerio)

    PubMed Central

    Lin, Chia-Hao; Hwang, Pung-Pung

    2016-01-01

    Zebrafish is an emerging model for the research of body fluid ionic homeostasis. In this review, we focus on current progress on the regulation of Ca2+ uptake in the context of Ca2+ sensing and hormonal regulation in zebrafish. Na+-K+-ATPase-rich cells (NaRCs), the specialized ionocytes in the embryonic skin and adult gills, play a dominant role in Ca2+ uptake in zebrafish. Transepithelial Ca2+ transport in NaRC, through apical epithelial Ca2+ channels (ECaC), basolateral plasma membrane Ca2+-ATPase (PMCA), and Na+/Ca2+ exchanger (NCX), is analogous to mammalian renal and intestinal Ca2+-absorption cells. Several hormones were demonstrated to differentially regulate Ca2+ uptake through modulating the expression of Ca2+ transporters and/or the proliferation/differentiation of NaRC in zebrafish. In addition, the counterbalance among these hormones is associated with the maintenance of body fluid Ca2+ homeostasis. Calcium-sensing receptor (CaSR) is expressed in several hormone-secreting tissues in zebrafish, and activated CaSR differentially controls calciotropic hormones. The major principles of Ca2+ transport and the hormonal control appear to be conserved from zebrafish to other vertebrates including mammals. The new knowledge gained from zebrafish studies provides new insights into the related issues in vertebrates. PMID:27792163

  15. Canonical and non-canonical Hedgehog signalling and the control of metabolism

    PubMed Central

    Teperino, Raffaele; Aberger, Fritz; Esterbauer, Harald; Riobo, Natalia; Pospisilik, John Andrew

    2014-01-01

    Obesity and diabetes represent key healthcare challenges of our day, affecting upwards of one billion people worldwide. These individuals are at higher risk for cancer, stroke, blindness, heart and cardiovascular disease, and to date, have no effective long-term treatment options available. Recent and accumulating evidence has implicated the developmental morphogen Hedgehog and its downstream signalling in metabolic control. Generally thought to be quiescent in adults, Hedgehog is associated with several human cancers, and as such, has already emerged as a therapeutic target in oncology. Here, we attempt to give a comprehensive overview of the key signalling events associated with both canonical and non-canonical Hedgehog signalling, and highlight the increasingly complex regulatory modalities that appear to link Hedgehog and control metabolism. We highlight these key findings and discuss their impact for therapeutic development, cancer and metabolic disease. PMID:24862854

  16. A dual control mechanism synchronizes riboflavin and sulphur metabolism in Bacillus subtilis.

    PubMed

    Pedrolli, Danielle Biscaro; Kühm, Christian; Sévin, Daniel C; Vockenhuber, Michael P; Sauer, Uwe; Suess, Beatrix; Mack, Matthias

    2015-11-10

    Flavin mononucleotide (FMN) riboswitches are genetic elements, which in many bacteria control genes responsible for biosynthesis and/or transport of riboflavin (rib genes). Cytoplasmic riboflavin is rapidly and almost completely converted to FMN by flavokinases. When cytoplasmic levels of FMN are sufficient ("high levels"), FMN binding to FMN riboswitches leads to a reduction of rib gene expression. We report here that the protein RibR counteracts the FMN-induced "turn-off" activities of both FMN riboswitches in Bacillus subtilis, allowing rib gene expression even in the presence of high levels of FMN. The reason for this secondary metabolic control by RibR is to couple sulfur metabolism with riboflavin metabolism.

  17. Functional imaging using the retinal function imager: direct imaging of blood velocity, achieving fluorescein angiography-like images without any contrast agent, qualitative oximetry, and functional metabolic signals.

    PubMed

    Izhaky, David; Nelson, Darin A; Burgansky-Eliash, Zvia; Grinvald, Amiram

    2009-07-01

    The Retinal Function Imager (RFI; Optical Imaging, Rehovot, Israel) is a unique, noninvasive multiparameter functional imaging instrument that directly measures hemodynamic parameters such as retinal blood-flow velocity, oximetric state, and metabolic responses to photic activation. In addition, it allows capillary perfusion mapping without any contrast agent. These parameters of retinal function are degraded by retinal abnormalities. This review delineates the development of these parameters and demonstrates their clinical applicability for noninvasive detection of retinal function in several modalities. The results suggest multiple clinical applications for early diagnosis of retinal diseases and possible critical guidance of their treatment.

  18. Development of an Objective Space Suit Mobility Performance Metric Using Metabolic Cost and Functional Tasks

    NASA Technical Reports Server (NTRS)

    McFarland, Shane M.; Norcross, Jason

    2016-01-01

    Existing methods for evaluating EVA suit performance and mobility have historically concentrated on isolated joint range of motion and torque. However, these techniques do little to evaluate how well a suited crewmember can actually perform during an EVA. An alternative method of characterizing suited mobility through measurement of metabolic cost to the wearer has been evaluated at Johnson Space Center over the past several years. The most recent study involved six test subjects completing multiple trials of various functional tasks in each of three different space suits; the results indicated it was often possible to discern between different suit designs on the basis of metabolic cost alone. However, other variables may have an effect on real-world suited performance; namely, completion time of the task, the gravity field in which the task is completed, etc. While previous results have analyzed completion time, metabolic cost, and metabolic cost normalized to system mass individually, it is desirable to develop a single metric comprising these (and potentially other) performance metrics. This paper outlines the background upon which this single-score metric is determined to be feasible, and initial efforts to develop such a metric. Forward work includes variable coefficient determination and verification of the metric through repeated testing.

  19. Regulation of mitochondrial function by voltage dependent anion channels in ethanol metabolism and the Warburg effect.

    PubMed

    Lemasters, John J; Holmuhamedov, Ekhson L; Czerny, Christoph; Zhong, Zhi; Maldonado, Eduardo N

    2012-06-01

    Voltage dependent anion channels (VDAC) are highly conserved proteins that are responsible for permeability of the mitochondrial outer membrane to hydrophilic metabolites like ATP, ADP and respiratory substrates. Although previously assumed to remain open, VDAC closure is emerging as an important mechanism for regulation of global mitochondrial metabolism in apoptotic cells and also in cells that are not dying. During hepatic ethanol oxidation to acetaldehyde, VDAC closure suppresses exchange of mitochondrial metabolites, resulting in inhibition of ureagenesis. In vivo, VDAC closure after ethanol occurs coordinately with mitochondrial uncoupling. Since acetaldehyde passes through membranes independently of channels and transporters, VDAC closure and uncoupling together foster selective and more rapid oxidative metabolism of toxic acetaldehyde to nontoxic acetate by mitochondrial aldehyde dehydrogenase. In single reconstituted VDAC, tubulin decreases VDAC conductance, and in HepG2 hepatoma cells, free tubulin negatively modulates mitochondrial membrane potential, an effect enhanced by protein kinase A. Tubulin-dependent closure of VDAC in cancer cells contributes to suppression of mitochondrial metabolism and may underlie the Warburg phenomenon of aerobic glycolysis. This article is part of a Special Issue entitled: VDAC structure, function, and regulation of mitochondrial metabolism.

  20. Metabolic functions of Pseudomonas fluorescens strains from Populus deltoides depend on rhizosphere or endosphere isolation compartment

    PubMed Central

    Timm, Collin M.; Campbell, Alisha G.; Utturkar, Sagar M.; Jun, Se-Ran; Parales, Rebecca E.; Tan, Watumesa A.; Robeson, Michael S.; Lu, Tse-Yuan S.; Jawdy, Sara; Brown, Steven D.; Ussery, David W.; Schadt, Christopher W.; Tuskan, Gerald A.; Doktycz, Mitchel J.; Weston, David J.; Pelletier, Dale A.

    2015-01-01

    The bacterial microbiota of plants is diverse, with 1000s of operational taxonomic units (OTUs) associated with any individual plant. In this work, we used phenotypic analysis, comparative genomics, and metabolic models to investigate the differences between 19 sequenced Pseudomonas fluorescens strains. These isolates represent a single OTU and were collected from the rhizosphere and endosphere of Populus deltoides. While no traits were exclusive to either endosphere or rhizosphere P. fluorescens isolates, multiple pathways relevant for plant-bacterial interactions are enriched in endosphere isolate genomes. Further, growth phenotypes such as phosphate solubilization, protease activity, denitrification and root growth promotion are biased toward endosphere isolates. Endosphere isolates have significantly more metabolic pathways for plant signaling compounds and an increased metabolic range that includes utilization of energy rich nucleotides and sugars, consistent with endosphere colonization. Rhizosphere P. fluorescens have fewer pathways representative of plant-bacterial interactions but show metabolic bias toward chemical substrates often found in root exudates. This work reveals the diverse functions that may contribute to colonization of the endosphere by bacteria and are enriched among closely related isolates. PMID:26528266

  1. Metabolic profiling indicates impaired pyruvate dehydrogenase function in myalgic encephalopathy/chronic fatigue syndrome

    PubMed Central

    Mella, Olav; Bruland, Ove; Risa, Kristin; Dyrstad, Sissel E.; Alme, Kine; Rekeland, Ingrid G.; Sapkota, Dipak; Røsland, Gro V.; Fosså, Alexander; Ktoridou-Valen, Irini; Lunde, Sigrid; Sørland, Kari; Lien, Katarina; Herder, Ingrid; Thürmer, Hanne; Gotaas, Merete E.; Baranowska, Katarzyna A.; Bohnen, Louis M.L.J.; Schäfer, Christoph; McCann, Adrian; Sommerfelt, Kristian; Helgeland, Lars; Ueland, Per M.; Dahl, Olav

    2016-01-01

    Myalgic encephalopathy/chronic fatigue syndrome (ME/CFS) is a debilitating disease of unknown etiology, with hallmark symptoms including postexertional malaise and poor recovery. Metabolic dysfunction is a plausible contributing factor. We hypothesized that changes in serum amino acids may disclose specific defects in energy metabolism in ME/CFS. Analysis in 200 ME/CFS patients and 102 healthy individuals showed a specific reduction of amino acids that fuel oxidative metabolism via the TCA cycle, mainly in female ME/CFS patients. Serum 3-methylhistidine, a marker of endogenous protein catabolism, was significantly increased in male patients. The amino acid pattern suggested functional impairment of pyruvate dehydrogenase (PDH), supported by increased mRNA expression of the inhibitory PDH kinases 1, 2, and 4; sirtuin 4; and PPARδ in peripheral blood mononuclear cells from both sexes. Myoblasts grown in presence of serum from patients with severe ME/CFS showed metabolic adaptations, including increased mitochondrial respiration and excessive lactate secretion. The amino acid changes could not be explained by symptom severity, disease duration, age, BMI, or physical activity level among patients. These findings are in agreement with the clinical disease presentation of ME/CFS, with inadequate ATP generation by oxidative phosphorylation and excessive lactate generation upon exertion. PMID:28018972

  2. Metabolic functions of Pseudomonas fluorescens strains from Populus deltoides depend on rhizosphere or endosphere isolation compartment

    SciTech Connect

    Timm, Collin M.; Campbell, Alicia G.; Utturkar, Sagar M.; Jun, Se Ran; Parales, Rebecca E.; Tan, Mesa; Robeson, Michael S.; Lu, Tse-Yuan S.; Jawdy, Sara; Schadt, Christopher Warren; Doktycz, Mitchel John; Weston, David; Pelletier, Dale A.

    2015-10-14

    The bacterial microbiota of plants is diverse, with ~1000s of operational taxonomic units (OTUs) associated with any individual plant. In this work we investigate how 19 sequenced Pseudomonas fluorescens strains representing a single OTU isolated from Populus deltoides rhizosphere and endosphere differ using phenotypic analysis, comparative genomics, and metabolic models. While no traits were exclusive to either endosphere or rhizosphere P. fluorescens isolates, multiple pathways relevant for bacterial-plant interactions are enriched in endosphere isolate genomes and growth phenotypes such as phosphate solubilization, protease activity, denitrification and root growth promotion are biased towards endosphere isolates. Endosphere isolates have more metabolic pathways for plant signaling compounds and an increased metabolic range that includes utilization of energy rich nucleotides and sugars, consistent with endosphere colonization. Rhizosphere P. fluorescens have fewer pathways important for bacterial-plant interactions but show metabolic bias towards chemical substrates often found in root exudates. This work reveals the diverse functions that may contribute to colonization of the endosphere by bacteria that are enriched in event he most closely related isolates.

  3. Metabolic functions of Pseudomonas fluorescens strains from Populus deltoides depend on rhizosphere or endosphere isolation compartment

    DOE PAGES

    Timm, Collin M.; Campbell, Alicia G.; Utturkar, Sagar M.; ...

    2015-10-14

    The bacterial microbiota of plants is diverse, with ~1000s of operational taxonomic units (OTUs) associated with any individual plant. In this work we investigate how 19 sequenced Pseudomonas fluorescens strains representing a single OTU isolated from Populus deltoides rhizosphere and endosphere differ using phenotypic analysis, comparative genomics, and metabolic models. While no traits were exclusive to either endosphere or rhizosphere P. fluorescens isolates, multiple pathways relevant for bacterial-plant interactions are enriched in endosphere isolate genomes and growth phenotypes such as phosphate solubilization, protease activity, denitrification and root growth promotion are biased towards endosphere isolates. Endosphere isolates have more metabolic pathwaysmore » for plant signaling compounds and an increased metabolic range that includes utilization of energy rich nucleotides and sugars, consistent with endosphere colonization. Rhizosphere P. fluorescens have fewer pathways important for bacterial-plant interactions but show metabolic bias towards chemical substrates often found in root exudates. This work reveals the diverse functions that may contribute to colonization of the endosphere by bacteria that are enriched in event he most closely related isolates.« less

  4. Metabolism of eicosanoids and their action on renal function during ischaemia and reperfusion: the effect of alprostadil.

    PubMed

    Dołegowska, B; Pikuła, E; Safranow, K; Olszewska, M; Jakubowska, K; Chlubek, D; Gutowski, P

    2006-12-01

    Eicosanoids, active metabolites of arachidonic acid (AA), play an important role in the regulation of renal haemodynamics and glomerular filtration. Our study verified the hypothesis on the positive action of exogenously administered PGE(1) on renal function during an operation with temporary ischaemia of the lower half of the body. Also the effect of alprostadil (prostaglandin E(1) analogue) administered during the operation of an abdominal aorta aneurysm on the postoperative systemic metabolism of AA and the glomerular filtration rate (GFR) was investigated. The study included 42 patients with a diagnosed abdominal aorta aneurysm who have been qualified for the operation of implantation of the aortic prosthesis. The patients were randomly assigned to two groups: the study group (I) receiving alprostadil and the control group (II) without alprostadil. The levels of hydroxyeicosatetraenoic acids (15-HETE, 12-HETE, 5-HETE) were determined by RP-HPLC and the level of thromboxane B(2) (TxB(2)) was determined by ELISA in the plasma of the blood drawn from vena cava superior immediately before aortic clamping (A) and 5 min after aortic declamping (B). The administration of PGE(1) affects the metabolism of 15-HETE in a manner dependent on the baseline value of GFR but does not significantly change the postoperative renal function. The metabolism of 15-HETE is affected by the baseline value of GFR1 and a longer period of ischaemia is correlated with lower concentrations of 5-HETE during reperfusion. The results of our studies indicate that TxB(2) influences the postoperative function of kidneys.

  5. Urea and Ammonia Metabolism and the Control of Renal Nitrogen Excretion.

    PubMed

    Weiner, I David; Mitch, William E; Sands, Jeff M

    2015-08-07

    Renal nitrogen metabolism primarily involves urea and ammonia metabolism, and is essential to normal health. Urea is the largest circulating pool of nitrogen, excluding nitrogen in circulating proteins, and its production changes in parallel to the degradation of dietary and endogenous proteins. In addition to serving as a way to excrete nitrogen, urea transport, mediated through specific urea transport proteins, mediates a central role in the urine concentrating mechanism. Renal ammonia excretion, although often considered only in the context of acid-base homeostasis, accounts for approximately 10% of total renal nitrogen excretion under basal conditions, but can increase substantially in a variety of clinical conditions. Because renal ammonia metabolism requires intrarenal ammoniagenesis from glutamine, changes in factors regulating renal ammonia metabolism can have important effects on glutamine in addition to nitrogen balance. This review covers aspects of protein metabolism and the control of the two major molecules involved in renal nitrogen excretion: urea and ammonia. Both urea and ammonia transport can be altered by glucocorticoids and hypokalemia, two conditions that also affect protein metabolism. Clinical conditions associated with altered urine concentrating ability or water homeostasis can result in changes in urea excretion and urea transporters. Clinical conditions associated with altered ammonia excretion can have important effects on nitrogen balance.

  6. Thyroid Function in Obese Children and Adolescents and Its Association with Anthropometric and Metabolic Parameters.

    PubMed

    Rumińska, Małgorzata; Witkowska-Sędek, Ewelina; Majcher, Anna; Pyrżak, Beata

    2016-01-01

    Fat accumulation leads to dysfunction of hypothalamic-pituitary-thyroid axis and to changes in thyroid function. A higher serum level of thyroid stimulating hormone (TSH), with normal levels of thyroid hormones, suggesting subclinical hypothyroidism, is often found in obese individuals. The influence on lipid and glucose metabolism of thyroid dysfunction in obese patients remains unclear. This retrospective study encompassed 110 obese children and 38 healthy non-obese children aged 5-18. Anthropometric measurements, including bioelectrical impedance, were taken in all children. Fasting TSH, fT4, glucose, lipid profile, and a glucose tolerance test in case of the obese individuals, were evaluated. The obese children demonstrated a significantly higher mean concentration of TSH compared with their peers with proper body weight: 2.1 ± 1.0 μIU/ml vs. 1.5 ± 0.6 μIU/ml, p = 0.001. The fT4 was not different between the two groups. In the obese children, TSH correlated with body mass index (BMI) and waist circumference after controlling for age and gender. A multivariate regression analysis showed a relationship of TSH with total cholesterol, LDL cholesterol, triglycerides, and non-HDL after adjusting for BMI. None of these relationships were revealed for fT4. The level of TSH correlated with the degree of abdominal obesity. We conclude that the serum TSH concentration, even remaining within the norm, could adversely affect the lipid profile, irrespective of obesity.

  7. Beneficial effects of herbs, spices and medicinal plants on the metabolic syndrome, brain and cognitive function.

    PubMed

    Panickar, Kiran S

    2013-03-01

    Herbs and spices have been used since ancient times to not only improve the flavor of edible food but also to prevent and treat chronic health maladies. While the scientific evidence for the use of such common herbs and medicinal plants then had been scarce or lacking, the beneficial effects observed from such use were generally encouraging. It is, therefore, not surprising that the tradition of using such herbs, perhaps even after the advent of modern medicine, has continued. More recently, due to an increased interest in understanding the nutritional effects of herbs/spices more comprehensively, several studies have examined the cellular and molecular modes of action of the active chemical components in herbs and their biological properties. Beneficial actions of herbs/spices include anti-inflammatory, antioxidant, anti-hypertensive, gluco-regulatory, and anti-thrombotic effects. One major component of herbs and spices is the polyphenols. Some of the aforementioned properties are attributed to the polyphenols and they are associated with attenuating the metabolic syndrome. Detrimental changes associated with the metabolic syndrome over time affect brain and cognitive function. Metabolic syndrome and type-2 diabetes are also risk factors for Alzheimer's disease and stroke. In addition, the neuroprotective effects of herbs and spices have been demonstrated and, whether directly or indirectly, such beneficial effects may also contribute to an improvement in cognitive function. This review evaluates the current evidence available for herbs/spices in potentially improving the metabolic syndrome, as well as their neuroprotective effects on the brain, and cognitive function in animal and human studies.

  8. Maternal high-fat diet impairs cardiac function in offspring of diabetic pregnancy through metabolic stress and mitochondrial dysfunction

    PubMed Central

    Mdaki, Kennedy S.; Larsen, Tricia D.; Wachal, Angela L.; Schimelpfenig, Michelle D.; Weaver, Lucinda J.; Dooyema, Samuel D. R.; Louwagie, Eli J.

    2016-01-01

    Offspring of diabetic pregnancies are at risk of cardiovascular disease at birth and throughout life, purportedly through fuel-mediated influences on the developing heart. Preventative measures focus on glycemic control, but the contribution of additional offenders, including lipids, is not understood. Cellular bioenergetics can be influenced by both diabetes and hyperlipidemia and play a pivotal role in the pathophysiology of adult cardiovascular disease. This study investigated whether a maternal high-fat diet, independently or additively with diabetes, could impair fuel metabolism, mitochondrial function, and cardiac physiology in the developing offspring's heart. Sprague-Dawley rats fed a control or high-fat diet were administered placebo or streptozotocin to induce diabetes during pregnancy and then delivered offspring from four groups: control, diabetes exposed, diet exposed, and combination exposed. Cardiac function, cellular bioenergetics (mitochondrial stress test, glycolytic stress test, and palmitate oxidation assay), lipid peroxidation, mitochondrial histology, and copy number were determined. Diabetes-exposed offspring had impaired glycolytic and respiratory capacity and a reduced proton leak. High-fat diet-exposed offspring had increased mitochondrial copy number, increased lipid peroxidation, and evidence of mitochondrial dysfunction. Combination-exposed pups were most severely affected and demonstrated cardiac lipid droplet accumulation and diastolic/systolic cardiac dysfunction that mimics that of adult diabetic cardiomyopathy. This study is the first to demonstrate that a maternal high-fat diet impairs cardiac function in offspring of diabetic pregnancies through metabolic stress and serves as a critical step in understanding the role of cellular bioenergetics in developmentally programmed cardiac disease. PMID:26801311

  9. Physiology and genetics of metabolic flux control in Zymomonas mobilis. Progress report

    SciTech Connect

    Conway, T.

    1992-08-01

    This work seeks to understand the role of gene expression in regulating glycolytic enzyme synthesis in a balance that allows proper glycoltic flux control. The seven genes targeted for study in this laboratory have been cloned and sequenced, and molecular details of regulation have been investigated. Clear that glycolytic enzyme synthesis is coordinated to prevent the build up of toxic metabolic intermediates. The genetic mechanisms responsible for regulating balanced expression of the EntnerDoudoroff and glycolytic genes in Z. mobilis are beginning to be understood. Several layers of genetic control, perhaps in a hierarchal arrangement act in concert to determine the relative abundance of the glycolytic enzymes. These genetic controls involve differential translational efficiency, highly conserved promoter sequences, transcription factors, differential mRNA stabilities, and nucleolytic mRNA processing. The serendipitous cloning of the glucose facilitator, glf, as a result of linkage to several other genes of interest will have a significant impact on the study of Z. mobilis metabolism. The glucose facilitator is being characterized in a genetically reconstituted system in E. coli. Molecular genetic studies indicate that the ratio of glf expression to that of glk, zmf, and edd is carefully regulated, and suggests a critical role in metabolic control. Regulation of glycolytic gene expression is now sufficiently well understood to allow use of the glycolytic genes as tools to manipulate specified enzyme levels for the purpose of analyzing metabolic flux control. The critical genes have been subcloned for stable expression in Z. mobilis and placed under control of a regulated promoter system involving the tac promoter, the lacI repressor, and gene induction in by IPTG. HPLC methods have been developed that allow quantitation of virtually all of the metabolic intermediates in the cell pool.

  10. [Stages of grief in diabetes and metabolic control].

    PubMed

    Rodríguez-Moctezuma, José Raymundo; López-Delgado, María Elisa; Ortiz-Aguirre, Alma Rosa; Jiménez-Luna, Jorge; López-Ocaña, Luis Rafael; Chacón-Sánchez, Jesús

    2015-01-01

    Introducción: el objetivo de este artículo es identificar las etapas del duelo y su asociación con el control metabólico en pacientes diabéticos tipo 2. Métodos: se incluyeron 186 sujetos diabéticos, de ambos sexos, sin pérdida reciente de un ser querido ni enfermedades terminales. Se les aplicó un instrumento validado que exploró las etapas del duelo (negación, ira/incredulidad, negociación, depresión, y aceptación). Se midió: IMC, perímetro de cintura, niveles promedio de glucosa, colesterol y triglicéridos en los últimos 6 meses. Resultados: las asociaciones entre las etapas del duelo y las variables clínicas mostraron que en la negación, el IMC es mayor 33.1 ± 6.2 contra 28.9 ± 4.6 con p = 0.001; en etapa de incredulidad, la glucemia es mayor 190 ± 67 frente a 16 ± 51 con p < 0.05; la etapa de negociación se asocia a mayor edad 65.6 ± 10 contra 59.1 ± 11 años con p = 0.001 y con nivel de colesterol mayor de 229.4 ± 39.1 frente a 206.6 ± 40 con p < 0.05; la etapa de depresión se asoció con mayor tiempo de diagnóstico 13.3 ± 8.9 frente a 9.4 ± 7.1 años, con p < 0.05 y con el nivel de glucemia de 198.9 ± 60 frente a 164 ± 51 mg/dL con p = 0.001. Conclusiones: existen asociaciones lógicas entre variables clínicas y etapas del duelo. Se debe identificar el duelo como un elemento adicional en la evaluación de pacientes con diabetes y establecer estrategias que mejoren la adherencia al tratamiento y el control metabólico.

  11. Cognitive Maturity, Stressful Events and Metabolic Control in Adolescents with Diabetes.

    ERIC Educational Resources Information Center

    Ingersoll, Gary M.; And Others

    Management of insulin dependent diabetes mellitus (IDDM) is a complex task that requires the adolescent with IDDM recognize the interaction between diet, exercise, stress, emotions, and insulin dosage. With regularity, however, adolescents with IDDM are shown to be in less good metabolic control than younger children or young adults. The study…

  12. Herbal Medicines for Treating Metabolic Syndrome: A Systematic Review of Randomized Controlled Trials.

    PubMed

    Jang, Soobin; Jang, Bo-Hyoung; Ko, Youme; Sasaki, Yui; Park, Jeong-Su; Hwang, Eui-Hyoung; Song, Yun-Kyung; Shin, Yong-Cheol; Ko, Seong-Gyu

    2016-01-01

    Objective. The aim of this systematic review is to evaluate the efficacy and safety of herbal medicines in the management of metabolic syndrome. Materials and Methods. On December 9, 2015, we searched PubMed, EMBASE, Cochrane Library, SCOPUS, AMED, CNKI, KoreaMed, KMBASE, OASIS, and J-STAGE with no restriction on language or published year. We selected randomized controlled trials that involved patients with metabolic syndrome being treated with herbal medicines as intervention. The main keywords were "Chinese herbal medicines", "metabolic syndrome", and "randomized controlled trials". Herbal substances which were not based on East Asian medical theory, combination therapy with western medicines, and concurrent diseases other than metabolic syndrome were excluded. The risk of bias was assessed by Cochrane's "Risk of Bias" tool. The protocol or review was registered in PROSPERO (an international prospective register of systematic reviews) (CRD42014006842). Results. From 1,098 articles, 12 RCTs were included in this review: five trials studied herbal medicines versus a placebo or no treatment, and seven trials studied herbal medicines versus western medicines. Herbal medicines were effective on decreasing waist circumference, blood glucose, blood lipids, and blood pressure. Conclusion. This study suggests the possibility that herbal medicines can be complementary and alternative medicines for metabolic syndrome.

  13. Herbal Medicines for Treating Metabolic Syndrome: A Systematic Review of Randomized Controlled Trials

    PubMed Central

    Ko, Youme; Sasaki, Yui; Hwang, Eui-Hyoung; Song, Yun-Kyung; Shin, Yong-Cheol

    2016-01-01

    Objective. The aim of this systematic review is to evaluate the efficacy and safety of herbal medicines in the management of metabolic syndrome. Materials and Methods. On December 9, 2015, we searched PubMed, EMBASE, Cochrane Library, SCOPUS, AMED, CNKI, KoreaMed, KMBASE, OASIS, and J-STAGE with no restriction on language or published year. We selected randomized controlled trials that involved patients with metabolic syndrome being treated with herbal medicines as intervention. The main keywords were “Chinese herbal medicines”, “metabolic syndrome”, and “randomized controlled trials”. Herbal substances which were not based on East Asian medical theory, combination therapy with western medicines, and concurrent diseases other than metabolic syndrome were excluded. The risk of bias was assessed by Cochrane's “Risk of Bias” tool. The protocol or review was registered in PROSPERO (an international prospective register of systematic reviews) (CRD42014006842). Results. From 1,098 articles, 12 RCTs were included in this review: five trials studied herbal medicines versus a placebo or no treatment, and seven trials studied herbal medicines versus western medicines. Herbal medicines were effective on decreasing waist circumference, blood glucose, blood lipids, and blood pressure. Conclusion. This study suggests the possibility that herbal medicines can be complementary and alternative medicines for metabolic syndrome. PMID:27413388

  14. The interplay between genotype, metabolic state and cofactor treatment governs phenylalanine hydroxylase function and drug response.

    PubMed

    Staudigl, Michael; Gersting, Søren W; Danecka, Marta K; Messing, Dunja D; Woidy, Mathias; Pinkas, Daniel; Kemter, Kristina F; Blau, Nenad; Muntau, Ania C

    2011-07-01

    The discovery of a pharmacological treatment for phenylketonuria (PKU) raised new questions about function and dysfunction of phenylalanine hydroxylase (PAH), the enzyme deficient in this disease. To investigate the interdependence of the genotype, the metabolic state (phenylalanine substrate) and treatment (BH(4) cofactor) in the context of enzyme function in vitro and in vivo, we (i) used a fluorescence-based method for fast enzyme kinetic analyses at an expanded range of phenylalanine and BH(4) concentrations, (ii) depicted PAH function as activity landscapes, (iii) retraced the analyses in eukaryotic cells, and (iv) translated this into the human system by analyzing the outcome of oral BH(4) loading tests. PAH activity landscapes uncovered the optimal working range of recombinant wild-type PAH and provided new insights into PAH kinetics. They demonstrated how mutations might alter enzyme function in the space of varying substrate and cofactor concentrations. Experiments in eukaryotic cells revealed that the availability of the active PAH enzyme depends on the phenylalanine-to-BH(4) ratio. Finally, evaluation of data from BH(4) loading tests indicated that the patient's genotype influences the impact of the metabolic state on drug response. The results allowed for visualization and a better understanding of PAH function in the physiological and pathological state as well as in the therapeutic context of cofactor treatment. Moreover, our data underscore the need for more personalized procedures to safely identify and treat patients with BH(4)-responsive PAH deficiency.

  15. Uranyl Precipitation by Pseudomonas aeruginosa via Controlled Polyphosphate Metabolism

    PubMed Central

    Renninger, Neil; Knopp, Roger; Nitsche, Heino; Clark, Douglas S.; Keasling, Jay D.

    2004-01-01

    The polyphosphate kinase gene from Pseudomonas aeruginosa was overexpressed in its native host, resulting in the accumulation of 100 times the polyphosphate seen with control strains. Degradation of this polyphosphate was induced by carbon starvation conditions, resulting in phosphate release into the medium. The mechanism of polyphosphate degradation is not clearly understood, but it appears to be associated with glycogen degradation. Upon suspension of the cells in 1 mM uranyl nitrate, nearly all polyphosphate that had accumulated was degraded within 48 h, resulting in the removal of nearly 80% of the uranyl ion and >95% of lesser-concentrated solutions. Electron microscopy, energy-dispersive X-ray spectroscopy, and time-resolved laser-induced fluorescence spectroscopy (TRLFS) suggest that this removal was due to the precipitation of uranyl phosphate at the cell membrane. TRLFS also indicated that uranyl was initially sorbed to the cell as uranyl hydroxide and was then precipitated as uranyl phosphate as phosphate was released from the cell. Lethal doses of radiation did not halt phosphate secretion from polyphosphate-filled cells under carbon starvation conditions. PMID:15574942

  16. Effects of ammonia-N stress on metabolic and immune function via the neuroendocrine system in Litopenaeus vannamei.

    PubMed

    Cui, Yanting; Ren, Xianyun; Li, Jian; Zhai, Qianqian; Feng, Yanyan; Xu, Yang; Ma, Li

    2017-03-16

    The purpose of this study was to evaluate the immunological responses, such as phenoloxidase (PO), antibacterial, and bacteriolytic activities, and metabolic variables, such as oxyhemocyanin, lactate, and glucose levels, of Litopenaeus vannamei exposed to ambient ammonia-N at 0, 2.5, 5, 7.5, and 10 mg/L for 0, 3, 6, 12, 24, and 48 h, and determine the effects of the eyestalk hormone on the metabolic and immune functions of unilateral eyestalk-ablated L. vannamei exposed to ambient ammonia-N at 10 mg/L. The actual concentrations of the control and test solutions were 0.04, 2.77, 6.01, 8.30, and 11.36 mg/L for ammonia-N and 0.01, 0.15, 0.32, 0.44, and 0.60 mg/L for NH3-N (unionized ammonia). The results showed a significant decrease in the PO, antibacterial, and bacteriolytic activities in the plasma as well as a significant increase in the glucose and lactate levels and decreased oxyhemocyanin levels in the hemolymph of L. vannamei exposed to elevated ammonia-N levels. These findings indicated that L. vannamei exposed to ammonia-N might demonstrate weakened metabolic and immunological responses. Moreover, eyestalk removal caused a dramatic decrease in PO, antibacterial, and bacteriolytic activities, which indicated that the eyestalk hormone in L. vannamei exhibited a higher immune response due to the induction of protective mechanisms against ammonia-N stress. Eyestalk removal also caused a dramatic decrease in glucose and lactate levels, suggesting that the eyestalk hormone is involved in glucose metabolism to meet the energy requirements under ammonia-N stress conditions.

  17. Early maternal undernutrition programs increased feed intake, altered glucose metabolism and insulin secretion, and liver function in aged female offspring

    PubMed Central

    George, Lindsey A.; Zhang, Liren; Tuersunjiang, Nuermaimaiti; Ma, Yan; Long, Nathan M.; Uthlaut, Adam B.; Smith, Derek T.; Nathanielsz, Peter W.

    2012-01-01

    Insulin resistance and obesity are components of the metabolic syndrome that includes development of cardiovascular disease and diabetes with advancing age. The thrifty phenotype hypothesis suggests that offspring of poorly nourished mothers are predisposed to the various components of the metabolic syndrome due to adaptations made during fetal development. We assessed the effects of maternal nutrient restriction in early gestation on feeding behavior, insulin and glucose dynamics, body composition, and liver function in aged female offspring of ewes fed either a nutrient-restricted [NR 50% National Research Council (NRC) recommendations] or control (C: 100% NRC) diet from 28 to 78 days of gestation, after which both groups were fed at 100% of NRC from day 79 to lambing and through lactation. Female lambs born to NR and C dams were reared as a single group from weaning, and thereafter, they were fed 100% NRC recommendations until assigned to this study at 6 yr of age. These female offspring were evaluated by a frequently sampled intravenous glucose tolerance test, followed by dual-energy X-ray absorptiometry for body composition analysis prior to and after ad libitum feeding of a highly palatable pelleted diet for 11 wk with automated monitoring of feed intake (GrowSafe Systems). Aged female offspring born to NR ewes demonstrated greater and more rapid feed intake, greater body weight gain, and efficiency of gain, lower insulin sensitivity, higher insulin secretion, and greater hepatic lipid and glycogen content than offspring from C ewes. These data confirm an increased metabolic “thriftiness” of offspring born to NR mothers, which continues into advanced age, possibly predisposing these offspring to metabolic disease. PMID:22277936

  18. [Dynamic variance of intracellular metabolic energies under rhythmical control for dissolved oxygen in PHB mixed cultivation].

    PubMed

    Qian, Z W; Tohyama, M; Hua, Q; Shimizu, K

    2001-07-01

    The mixed cultivation using cheaper carbon source-wasted food material contained glucose and lactate at the same time was conducted in 5L fermentor, within which glucose was converted to lactate by L. delbrueckii in anaerobic condition and the lactate was converted to PHB by R. eutropha in aerobic condition. Considering dissolved oxygen concentration may affect the level of intracellular ATP and NADPH of the metabolic pathways for R. eutropha in lactate under autotrophy or heterotrophy, rhythmical oscillated control for DO based on chaos control method was consequently presented. This method was employed to satisfy two strains for opposite oxygen preferences, moreover, excite the intracellular metabolic energy simultaneously. The values examined through spectrophotofluorimetry represented that both ATP and NADPH exhibited fluctuations in accordance with the DO rhythm. By means of this control design, the concentration of PHB can be doubled than the usual under stable DO control.

  19. Alterations in mitochondrial respiratory functions, redox metabolism and apoptosis by oxidant 4-hydroxynonenal and antioxidants curcumin and melatonin in PC12 cells

    SciTech Connect

    Raza, Haider John, Annie; Brown, Eric M.; Benedict, Sheela; Kambal, Amr

    2008-01-15

    Cellular oxidative stress and alterations in redox metabolisms have been implicated in the etiology and pathology of many diseases including cancer. Antioxidant treatments have been proven beneficial in controlling these diseases. We have recently shown that 4-hydroxynonenal (4-HNE), a by-product of lipid peroxidation, induces oxidative stress in PC12 cells by compromising the mitochondrial redox metabolism. In this study, we have further investigated the deleterious effects of 4-HNE on mitochondrial respiratory functions and apoptosis using the same cell line. In addition, we have also compared the effects of two antioxidants, curcumin and melatonin, used as chemopreventive agents, on mitochondrial redox metabolism and respiratory functions in these cells. 4-HNE treatment has been shown to cause a reduction in glutathione (GSH) pool, an increase in reactive oxygen species (ROS), protein carbonylation and apoptosis. A marked inhibition in the activities of the mitochondrial respiratory enzymes, cytochrome c oxidase and aconitase was observed after 4-HNE treatment. Increased nuclear translocation of NF-kB/p65 protein was also observed after 4-HNE treatment. Curcumin and melatonin treatments, on the other hand, maintained the mitochondrial redox and respiratory functions without a marked effect on ROS production and cell viability. These results suggest that 4-HNE-induced cytotoxicity may be associated, at least in part, with the altered mitochondrial redox and respiratory functions. The alterations in mitochondrial energy metabolism and redox functions may therefore be critical in determining the difference between cell death and survival.

  20. 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.

  1. A Wearable Hip Assist Robot Can Improve Gait Function and Cardiopulmonary Metabolic Efficiency in Elderly Adults.

    PubMed

    Lee, Hwang-Jae; Lee, Suhyun; Chang, Won Hyuk; Seo, Keehong; Shim, Youngbo; Choi, Byung-Ok; Ryu, Gyu-Ha; Kim, Yun-Hee

    2017-02-06

    The aims of this study were to investigate the effectiveness of a newly developed wearable hip assist robot that uses an active assist algorithm to improve gait function, muscle effort, and cardiopulmonary metabolic efficiency in elderly adults. Thirty elderly adults (15 males/15 females) participated in this study. The experimental protocol consisted of overground gait at comfortable speed under three different conditions: free gait without robot assistance, robot-assisted gait with zero torque (RAG-Z), and full robot-assisted gait (RAG). Under all conditions, muscle effort was analyzed using a 12-channel surface electromyography system. Spatio-temporal data were collected at 120 Hz using a 3D motion capture system with six infrared cameras. Metabolic cost parameters were collected as oxygen consumption per unit (ml/min/kg) and aerobic energy expenditure (Kcal/min). In the RAG condition, participants demonstrated improved gait function, decreased muscle effort, and reduced metabolic cost. Although the hip assist robot only provides assistance at the hip joint, our results demonstrated a clear reduction in knee and ankle muscle activity in addition to decreased hip flexor and extensor activity. Our findings suggest that this robot has the potential to improve stabilization of the trunk during walking in elderly adults.

  2. Novel metabolic and physiological functions of branched chain amino acids: a review.

    PubMed

    Zhang, Shihai; Zeng, Xiangfang; Ren, Man; Mao, Xiangbing; Qiao, Shiyan

    2017-01-01

    It is widely known that branched chain amino acids (BCAA) are not only elementary components for building muscle tissue but also participate in increasing protein synthesis in animals and humans. BCAA (isoleucine, leucine and valine) regulate many key signaling pathways, the most classic of which is the activation of the mTOR signaling pathway. This signaling pathway connects many diverse physiological and metabolic roles. Recent years have witnessed many striking developments in determining the novel functions of BCAA including: (1) Insufficient or excessive levels of BCAA in the diet enhances lipolysis. (2) BCAA, especially isoleucine, play a major role in enhancing glucose consumption and utilization by up-regulating intestinal and muscular glucose transporters. (3) Supplementation of leucine in the diet enhances meat quality in finishing pigs. (4) BCAA are beneficial for mammary health, milk quality and embryo growth. (5) BCAA enhance intestinal development, intestinal amino acid transportation and mucin production. (6) BCAA participate in up-regulating innate and adaptive immune responses. In addition, abnormally elevated BCAA levels in the blood (decreased BCAA catabolism) are a good biomarker for the early detection of obesity, diabetes and other metabolic diseases. This review will provide some insights into these novel metabolic and physiological functions of BCAA.

  3. Sequence divergence and diversity suggests ongoing functional diversification of vertebrate NAD metabolism.

    PubMed

    Gossmann, Toni I; Ziegler, Mathias

    2014-11-01

    NAD is not only an important cofactor in redox reactions but has also received attention in recent years because of its physiological importance in metabolic regulation, DNA repair and signaling. In contrast to the redox reactions, these regulatory processes involve degradation of NAD and therefore necessitate a constant replenishment of its cellular pool. NAD biosynthetic enzymes are common to almost all species in all clades, but the number of NAD degrading enzymes varies substantially across taxa. In particular, vertebrates, including humans, have a manifold of NAD degrading enzymes which require a high turnover of NAD. As there is currently a lack of a systematic study of how natural selection has shaped enzymes involved in NAD metabolism we conducted a comprehensive evolutionary analysis based on intraspecific variation and interspecific divergence. We compare NAD biosynthetic and degrading enzymes in four eukaryotic model species and subsequently focus on human NAD metabolic enzymes and their orthologs in other vertebrates. We find that the majority of enzymes involved in NAD metabolism are subject to varying levels of purifying selection. While NAD biosynthetic enzymes appear to experience a rather high level of evolutionary constraint, there is evidence for positive selection among enzymes mediating NAD-dependent signaling. This is particularly evident for members of the PARP family, a diverse protein family involved in DNA damage repair and programmed cell death. Based on haplotype information and substitution rate analysis we pinpoint sites that are potential targets of positive selection. We also link our findings to a three dimensional structure, which suggests that positive selection occurs in domains responsible for DNA binding and polymerization rather than the NAD catalytic domain. Taken together, our results indicate that vertebrate NAD metabolism is still undergoing functional diversification.

  4. New inducible genetic method reveals critical roles of GABA in the control of feeding and metabolism.

    PubMed

    Meng, Fantao; Han, Yong; Srisai, Dollada; Belakhov, Valery; Farias, Monica; Xu, Yong; Palmiter, Richard D; Baasov, Timor; Wu, Qi

    2016-03-29

    Currently available inducible Cre/loxP systems, despite their considerable utility in gene manipulation, have pitfalls in certain scenarios, such as unsatisfactory recombination rates and deleterious effects on physiology and behavior. To overcome these limitations, we designed a new, inducible gene-targeting system by introducing an in-frame nonsense mutation into the coding sequence of Cre recombinase (nsCre). Mutant mRNAs transcribed from nsCre transgene can be efficiently translated into full-length, functional Cre recombinase in the presence of nonsense suppressors such as aminoglycosides. In a proof-of-concept model, GABA signaling from hypothalamic neurons expressing agouti-related peptide (AgRP) was genetically inactivated within 4 d after treatment with a synthetic aminoglycoside. Disruption of GABA synthesis in AgRP neurons in young adult mice led to a dramatic loss of body weight due to reduced food intake and elevated energy expenditure; they also manifested glucose intolerance. In contrast, older mice with genetic inactivation of GABA signaling by AgRP neurons had only transient reduction of feeding and body weight; their energy expenditure and glucose tolerance were unaffected. These results indicate that GABAergic signaling from AgRP neurons plays a key role in the control of feeding and metabolism through an age-dependent mechanism. This new genetic technique will augment current tools used to elucidate mechanisms underlying many physiological and neurological processes.

  5. New inducible genetic method reveals critical roles of GABA in the control of feeding and metabolism

    PubMed Central

    Meng, Fantao; Han, Yong; Srisai, Dollada; Belakhov, Valery; Farias, Monica; Xu, Yong; Palmiter, Richard D.; Baasov, Timor; Wu, Qi

    2016-01-01

    Currently available inducible Cre/loxP systems, despite their considerable utility in gene manipulation, have pitfalls in certain scenarios, such as unsatisfactory recombination rates and deleterious effects on physiology and behavior. To overcome these limitations, we designed a new, inducible gene-targeting system by introducing an in-frame nonsense mutation into the coding sequence of Cre recombinase (nsCre). Mutant mRNAs transcribed from nsCre transgene can be efficiently translated into full-length, functional Cre recombinase in the presence of nonsense suppressors such as aminoglycosides. In a proof-of-concept model, GABA signaling from hypothalamic neurons expressing agouti-related peptide (AgRP) was genetically inactivated within 4 d after treatment with a synthetic aminoglycoside. Disruption of GABA synthesis in AgRP neurons in young adult mice led to a dramatic loss of body weight due to reduced food intake and elevated energy expenditure; they also manifested glucose intolerance. In contrast, older mice with genetic inactivation of GABA signaling by AgRP neurons had only transient reduction of feeding and body weight; their energy expenditure and glucose tolerance were unaffected. These results indicate that GABAergic signaling from AgRP neurons plays a key role in the control of feeding and metabolism through an age-dependent mechanism. This new genetic technique will augment current tools used to elucidate mechanisms underlying many physiological and neurological processes. PMID:26976589

  6. Bidirectional Control of Blood Flow by Astrocytes: A Role for Tissue Oxygen and Other Metabolic Factors.

    PubMed

    Gordon, Grant R J; Howarth, Clare; MacVicar, Brian A

    2016-01-01

    Altering cerebral blood flow through the control of cerebral vessel diameter is critical so that the delivery of molecules important for proper brain functioning is matched to the activity level of neurons. Although the close relationship of brain glia known as astrocytes with cerebral blood vessels has long been recognized, it is only recently that these cells have been demonstrated to translate information on the activity level and energy demands of neurons to the vasculature. In particular, astrocytes respond to elevations in extracellular glutamate as a consequence of synaptic transmission through the activation of group 1 metabotropic glutamate receptors. These Gq-protein coupled receptors elevate intracellular calcium via IP3 signaling. A close examination of astrocyte endfeet calcium signals has been shown to cause either vasoconstriction or vasodilation. Common to both vasomotor responses is the generation of arachidonic acid in astrocytes by calcium sensitive phospholipase A2. Vasoconstriction ensues from the conversion of arachidonic acid to 20-hydroxyeicosatetraenoic acid, while vasodilation ensues from the production of epoxyeicosatrienoic acids or prostaglandins. Factors that determine whether constrictor or dilatory pathways predominate include brain oxygen, lactate, adenosine as well as nitric oxide. Changing the oxygen level itself leads to many downstream changes that facilitate the switch from vasoconstriction at high oxygen to vasodilation at low oxygen. These findings highlight the importance of astrocytes as sensors of neural activity and metabolism to coordinate the delivery of essential nutrients via the blood to the working cells.

  7. Glucosinolate metabolism, functionality and breeding for the improvement of Brassicaceae vegetables

    PubMed Central

    Ishida, Masahiko; Hara, Masakazu; Fukino, Nobuko; Kakizaki, Tomohiro; Morimitsu, Yasujiro

    2014-01-01

    Unique secondary metabolites, glucosinolates (S-glucopyranosyl thiohydroximates), are naturally occurring S-linked glucosides found mainly in Brassicaceae plants. They are enzymatically hydrolyzed to produce sulfate ions, D-glucose, and characteristic degradation products such as isothiocyanates. The functions of glucosinolates in the plants remain unclear, but isothiocyanates possessing a pungent or irritating taste and odor might be associated with plant defense from microbes. Isothiocyanates have been studied extensively in experimental in vitro and in vivo carcinogenesis models for their cancer chemopreventive properties. The beneficial isothiocyanates, glucosinolates that are functional for supporting human health, have received attention from many scientists studying plant breeding, plant physiology, plant genetics, and food functionality. This review presents a summary of recent topics related with glucosinolates in the Brassica family, along with a summary of the chemicals, metabolism, and genes of glucosinolates in Brassicaceae. The bioavailabilities of isothiocyanates from certain functional glucosinolates and the importance of breeding will be described with emphasis on glucosinolates. PMID:24987290

  8. Effects of acute and chronic systemic methamphetamine on respiratory, cardiovascular and metabolic function, and cardiorespiratory reflexes

    PubMed Central

    Hassan, Sarah F.; Wearne, Travis A.; Cornish, Jennifer L.

    2016-01-01

    Key points Methamphetamine (METH) abuse is escalating worldwide, with the most common cause of death resulting from cardiovascular failure and hyperthermia; however, the underlying physiological mechanisms are poorly understood.Systemic administration of METH in anaesthetised rats reduced the effectiveness of some protective cardiorespiratory reflexes, increased central respiratory activity independently of metabolic function, and increased heart rate, metabolism and respiration in a pattern indicating that non‐shivering thermogenesis contributes to the well‐described hyperthermia.In animals that showed METH‐induced behavioural sensitisation following chronic METH treatment, no changes were evident in baseline cardiovascular, respiratory and metabolic measures and the METH‐evoked effects in these parameters were similar to those seen in saline‐treated or drug naïve animals.Physiological effects evoked by METH were retained but were neither facilitated nor depressed following chronic treatment with METH.These data highlight and identify potential mechanisms for targeted intervention in patients vulnerable to METH overdose. Abstract Methamphetamine (METH) is known to promote cardiovascular failure or life‐threatening hyperthermia; however, there is still limited understanding of the mechanisms responsible for evoking the physiological changes. In this study, we systematically determined the effects on both autonomic and respiratory outflows, as well as reflex function, following acute and repeated administration of METH, which enhances behavioural responses. Arterial pressure, heart rate, phrenic nerve discharge amplitude and frequency, lumbar and splanchnic sympathetic nerve discharge, interscapular brown adipose tissue and core temperatures, and expired CO2 were measured in urethane‐anaesthetised male Sprague‐Dawley rats. Novel findings include potent increases in central inspiratory drive and frequency that are not dependent on METH

  9. Feeding, evaluating, and controlling rumen function

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Optimal rumen function is pivotal to health, production, and profit in dairy systems. Achieving that function requires an understanding of feeds and systems of nutritional evaluation. A key influence on optimal rumen function includes dry matter intake. The function of feeds in the rumen depends on ...

  10. Structure-Function of CD36 and Importance of Fatty Acid Signal Transduction in Fat Metabolism

    PubMed Central

    Pepino, Marta Yanina; Kuda, Ondrej; Samovski, Dmitri; Abumrad, Nada A

    2015-01-01

    CD36 is a scavenger receptor that functions in high affinity tissue uptake of long chain fatty acids (FA) and contributes under excessive fat supply to lipid accumulation and metabolic dysfunction. This review describes recent evidence regarding the CD36 FA binding site and a potential mechanism for FA transfer. It also presents the view that CD36 and FA signaling coordinate fat utilization based on newly identified CD36 actions that involve oral fat perception, intestinal fat absorption, secretion of the peptides cholecystokinin and secretin, regulation of hepatic lipoprotein output, activation of beta oxidation by muscle and regulation of the production of the FA derived bioactive eicosanoids. Thus abnormalities of fat metabolism and the associated pathology might involve dysfunction of CD36-mediated signal transduction in addition to the changes of FA uptake. PMID:24850384

  11. Metabolic rate of carrying added mass: a function of walking speed, carried mass and mass location.

    PubMed

    Schertzer, Eliran; Riemer, Raziel

    2014-11-01

    The effort of carrying additional mass at different body locations is important in ergonomics and in designing wearable robotics. We investigate the metabolic rate of carrying a load as a function of its mass, its location on the body and the subject's walking speed. Novel metabolic rate prediction equations for walking while carrying loads at the ankle, knees and back were developed based on experiments where subjects walked on a treadmill at 4, 5 or 6km/h bearing different amounts of added mass (up to 2kg per leg and 22kg for back). Compared to previously reported equations, ours are 7-69% more accurate. Results also show that relative cost for carrying a mass at a distal versus a proximal location changes with speed and mass. Contrary to mass carried on the back, mass attached to the leg cannot be modeled as an increase in body mass.

  12. Effect of the acute crowding stress on the rat brown adipose tissue metabolic function.

    PubMed

    Djordjevic, Jelena; Cvijic, Gordana; Petrovic, Natasa; Davidovic, Vukosava

    2005-12-01

    Our previous results have shown that metabolic and thermal stressors influence interscapular brown adipose tissue (IBAT) metabolic activity by increasing oxygen consumption and, consequently, altering the toxic reactive oxygen species (ROS) production and the antioxidative system activity. Since there is not enough evidence about the effect of psychosocial stressors on these processes, we studied the effect of acute crowding stress on the IBAT and hypothalamic monoamine oxidase (MAO) activity as well as IBAT antioxidative enzymes, manganese (MnSOD), copper-zinc superoxide dismutase (CuZnSOD) and catalase (CAT), as the relevant indicators of IBAT metabolic alternations under the stress exposure and the returning of animals to control conditions. The results indicated that acute crowding stress did not change the hypothalamic and IBAT MAO activities, the generation of ROS and, consequently, the IBAT CuZnSOD and CAT activities. However, all three antioxidative enzymes were affected only after the recovery period. It seems that peripheral overheating of rats during acute crowding changes the stress nature, by becoming more thermal than psychosocial and by suppression the hypothalamic efferent pathways involved in the IBAT thermogenesis regulation. However, it seems that returning of the animals to the control conditions after the stress termination causes the reactivation of IBAT thermogenesis with tendency to normalise the body temperature.

  13. Metaboloepigenetics: Interrelationships between energy metabolism and epigenetic control of gene expression

    PubMed Central

    Donohoe, Dallas R.; Bultman, Scott J.

    2012-01-01

    Diet and energy metabolism affect gene expression, which influences human health and disease. Here, we discuss the role of epigenetics as a mechanistic link between energy metabolism and control of gene expression. A number of key energy metabolites including SAM, acetyl-CoA, NAD+, and ATP serve as essential co-factors for many, perhaps most, epigenetic enzymes that regulate DNA methylation, posttranslational histone modifications, and nucleosome position. The relative abundance of these energy metabolites allows a cell to sense its energetic state. And as co-factors, energy metabolites act as rheostats to modulate the activity of epigenetic enzymes and upregulate/downregulate transcription as appropriate to maintain homeostasis. PMID:22261928

  14. Metabolic control of cell division in α-proteobacteria by a NAD-dependent glutamate dehydrogenase

    PubMed Central

    Beaufay, François; De Bolle, Xavier; Hallez, Régis

    2016-01-01

    ABSTRACT Prior to initiate energy-consuming processes, such as DNA replication or cell division, cells need to evaluate their metabolic status. We have recently identified and characterized a new connection between metabolism and cell division in the α-proteobacterium Caulobacter crescentus. We showed that an NAD-dependent glutamate dehydrogenase (GdhZ) coordinates growth with cell division according to its enzymatic activity. Here we report the conserved role of GdhZ in controlling cell division in another α-proteobacterium, the facultative intracellular pathogen Brucella abortus. We also discuss the importance of amino acids as a main carbon source for α-proteobacteria. PMID:27066186

  15. Genome-Enabled Modeling of Biogeochemical Processes Predicts Metabolic Dependencies that Connect the Relative Fitness of Microbial Functional Guilds

    NASA Astrophysics Data System (ADS)

    Brodie, E.; King, E.; Molins, S.; Karaoz, U.; Steefel, C. I.; Banfield, J. F.; Beller, H. R.; Anantharaman, K.; Ligocki, T. J.; Trebotich, D.

    2015-12-01

    Pore-scale processes mediated by microorganisms underlie a range of critical ecosystem services, regulating carbon stability, nutrient flux, and the purification of water. Advances in cultivation-independent approaches now provide us with the ability to reconstruct thousands of genomes from microbial populations from which functional roles may be assigned. With this capability to reveal microbial metabolic potential, the next step is to put these microbes back where they belong to interact with their natural environment, i.e. the pore scale. At this scale, microorganisms communicate, cooperate and compete across their fitness landscapes with communities emerging that feedback on the physical and chemical properties of their environment, ultimately altering the fitness landscape and selecting for new microbial communities with new properties and so on. We have developed a trait-based model of microbial activity that simulates coupled functional guilds that are parameterized with unique combinations of traits that govern fitness under dynamic conditions. Using a reactive transport framework, we simulate the thermodynamics of coupled electron donor-acceptor reactions to predict energy available for cellular maintenance, respiration, biomass development, and enzyme production. From metagenomics, we directly estimate some trait values related to growth and identify the linkage of key traits associated with respiration and fermentation, macromolecule depolymerizing enzymes, and other key functions such as nitrogen fixation. Our simulations were carried out to explore abiotic controls on community emergence such as seasonally fluctuating water table regimes across floodplain organic matter hotspots. Simulations and metagenomic/metatranscriptomic observations highlighted the many dependencies connecting the relative fitness of functional guilds and the importance of chemolithoautotrophic lifestyles. Using an X-Ray microCT-derived soil microaggregate physical model combined

  16. Autonomic and endocrine control of cardiovascular function

    PubMed Central

    Gordan, Richard; Gwathmey, Judith K; Xie, Lai-Hua

    2015-01-01

    The function of the heart is to contract and pump oxygenated blood to the body and deoxygenated blood to the lungs. To achieve this goal, a normal human heart must beat regularly and continuously for one’s entire life. Heartbeats originate from the rhythmic pacing discharge from the sinoatrial (SA) node within the heart itself. In the absence of extrinsic neural or hormonal influences, the SA node pacing rate would be about 100 beats per minute. Heart rate and cardiac output, however, must vary in response to the needs of the body’s cells for oxygen and nutrients under varying conditions. In order to respond rapidly to the changing requirements of the body’s tissues, the heart rate and contractility are regulated by the nervous system, hormones, and other factors. Here we review how the cardiovascular system is controlled and influenced by not only a unique intrinsic system, but is also heavily influenced by the autonomic nervous system as well as the endocrine system. PMID:25914789

  17. Functional aspects of redox control during neuroinflammation.

    PubMed

    Rosales-Corral, Sergio; Reiter, Russel J; Tan, Dun-Xian; Ortiz, Genaro G; Lopez-Armas, Gabriela

    2010-07-15

    Neuroinflammation is a CNS reaction to injury in which some severe pathologies, regardless of their origin, converge. The phenomenon emphasizes crosstalk between neurons and glia and reveals a complex interaction with oxidizing agents through redox sensors localized in enzymes, receptors, and transcription factors. When oxidizing pressures cause reversible molecular changes, such as minimal or transitory proinflammatory cytokine overproduction, redox couples provide a means of translating the presence of reactive oxygen or nitrogen species into useful signals in the cell. Additionally, thiol-based redox sensors convey information about localized changes in redox potential induced by physiologic or pathologic situations. They are susceptible to oxidative changes and become key events during neuroinflammation, altering the course of a signaling response or the behavior of specific transcription factors. When oxidative stress augments the pressure on the intracellular environment, the effective reduction potential of redox pairs diminishes, and cell signaling shifts toward proinflammatory and proapoptotic signals, creating a vicious cycle between oxidative stress and neuroinflammation. In addition, electrophilic compounds derived from the oxidative cascade react with key protein thiols and interfere with redox signaling. This article reviews the relevant functional aspects of redox control during the neuroinflammatory process.

  18. Systematic analysis of the regulatory functions of microRNAs in chicken hepatic lipid metabolism

    PubMed Central

    Li, Hong; Ma, Zheng; Jia, Lijuan; Li, Yanmin; Xu, Chunlin; Wang, Taian; Han, Ruili; Jiang, Ruirui; Li, Zhuanjian; Sun, Guirong; Kang, Xiangtao; Liu, Xiaojun

    2016-01-01

    Laying performance is an important economic trait in hens, and this physiological process is largely influenced by the liver function. The livers of hens at 20- and 30-week-old stages were investigated using the next generation sequencing to identify the differences of microRNA expression profiles. Compared with the 20-week-old hens, 67 down- and 13 up-regulated microRNAs were verified to be significant differentially expressed (false discovery rate, FDR ≤ 0.05) (SDE) in the 30-week-old. We also identified 13 down- and 6 up-regulated novel differentially expressed (DE) microRNAs. miR-22-3p and miR-146b-5p, which exhibit critical roles in mammalian lipid metabolism, showed the most abundant expression and the highest fold-change, respectively. A total of 648 potential target genes of the SDE microRNAs were identified through an integrated analysis of microRNAs and the DE genes obtained in previous RNA-sequencing, including FADS1, FADS2, ELOVL6 and ACSL5, which are critical lipid metabolism-related regulators. Bioinformatic analyses revealed that target genes were mainly enriched in lipid-related metabolism processes. This work provides the first study of the expression patterns of hepatic microRNAs between 20- and 30-week old hens. The findings may serve as a fundamental resource for understanding the detailed functions of microRNAs in the molecular regulatory systems of lipid metabolism. PMID:27535581

  19. Apolipoprotein E: structure and function in lipid metabolism, neurobiology, and Alzheimer's diseases.

    PubMed

    Huang, Yadong; Mahley, Robert W

    2014-12-01

    Apolipoprotein (apo) E is a multifunctional protein with central roles in lipid metabolism, neurobiology, and neurodegenerative diseases. It has three major isoforms (apoE2, apoE3, and apoE4) with different effects on lipid and neuronal homeostasis. A major function of apoE is to mediate the binding of lipoproteins or lipid complexes in the plasma or interstitial fluids to specific cell-surface receptors. These receptors internalize apoE-containing lipoprotein particles; thus, apoE participates in the distribution/redistribution of lipids among various tissues and cells of the body. In addition, intracellular apoE may modulate various cellular processes physiologically or pathophysiologically, including cytoskeletal assembly and stability, mitochondrial integrity and function, and dendritic morphology and function. Elucidation of the functional domains within this protein and of the three-dimensional structure of the major isoforms of apoE has contributed significantly to our understanding of its physiological and pathophysiological roles at a molecular level. It is likely that apoE, with its multiple cellular origins and multiple structural and biophysical properties, is involved widely in processes of lipid metabolism and neurobiology, possibly encompassing a variety of disorders of neuronal repair, remodeling, and degeneration by interacting with different factors through various pathways.

  20. Functional gains in energy and cell metabolism after TSPO gene insertion.

    PubMed

    Liu, Guo-Jun; Middleton, Ryan J; Kam, Winnie Wai-Ying; Chin, David Y; Hatty, Claire R; Chan, Ronald H Y; Banati, Richard B

    2017-03-04

    Recent loss-of-function studies in tissue-specific as well as global Tspo (Translocator Protein 18 kDa) knockout mice have not confirmed its long assumed indispensability for the translocation of cholesterol across the mitochondrial inter-membrane space, a rate-limiting step in steroid biosynthesis. Instead, recent studies in global Tspo knockout mice indicate that TSPO may play a more fundamental role in cellular bioenergetics, which may include the indirect down-stream regulation of transport or metabolic functions. To examine whether overexpression of the TSPO protein alters the cellular bioenergetic profile, Jurkat cells with low to absent endogenous expression were transfected with a TSPO construct to create a stable cell line with de novo expression of exogenous TSPO protein. Expression of TSPO was confirmed by RT-qPCR, radioligand binding with [3H]PK11195 and immunocytochemistry with a TSPO antibody. We demonstrate that TSPO gene insertion causes increased transcription of genes involved in the mitochondrial electron transport chain. Furthermore, TSPO insertion increased mitochondrial ATP production as well as cell excitability, reflected in a decrease in patch clamp recorded rectified K channel currents. These functional changes were accompanied by an increase in cell proliferation and motility, which were inhibited by PK11195, a selective ligand for TSPO. We suggest that TSPO may serve a range of functions that can be viewed as downstream regulatory effects of its primary, evolutionary conserved role in cell metabolism and energy production.

  1. Functional coupling of simultaneous electrical and metabolic activity in the human brain.

    PubMed

    Oakes, Terrence R; Pizzagalli, Diego A; Hendrick, Andrew M; Horras, Katherine A; Larson, Christine L; Abercrombie, Heather C; Schaefer, Stacey M; Koger, John V; Davidson, Richard J

    2004-04-01

    The relationships between brain electrical and metabolic activity are being uncovered currently in animal models using invasive methods; however, in the human brain this relationship remains not well understood. In particular, the relationship between noninvasive measurements of electrical activity and metabolism remains largely undefined. To understand better these relations, cerebral activity was measured simultaneously with electroencephalography (EEG) and positron emission tomography using [(18)f]-fluoro-2-deoxy-D-glucose (PET-FDG) in 12 normal human subjects during rest. Intracerebral distributions of current density were estimated, yielding tomographic maps for seven standard EEG frequency bands. The PET and EEG data were registered to the same space and voxel dimensions, and correlational maps were created on a voxel-by-voxel basis across all subjects. For each band, significant positive and negative correlations were found that are generally consistent with extant understanding of EEG band power function. With increasing EEG frequency, there was an increase in the number of positively correlated voxels, whereas the lower alpha band (8.5-10.0 Hz) was associated with the highest number of negative correlations. This work presents a method for comparing EEG signals with other more traditionally tomographic functional imaging data on a 3-D basis. This method will be useful in the future when it is applied to functional imaging methods with faster time resolution, such as short half-life PET blood flow tracers and functional magnetic resonance imaging.

  2. Functional gains in energy and cell metabolism after TSPO gene insertion

    PubMed Central

    Chin, David Y.; Hatty, Claire R.; Chan, Ronald H. Y.

    2017-01-01

    ABSTRACT Recent loss-of-function studies in tissue-specific as well as global Tspo (Translocator Protein 18 kDa) knockout mice have not confirmed its long assumed indispensability for the translocation of cholesterol across the mitochondrial inter-membrane space, a rate-limiting step in steroid biosynthesis. Instead, recent studies in global Tspo knockout mice indicate that TSPO may play a more fundamental role in cellular bioenergetics, which may include the indirect down-stream regulation of transport or metabolic functions. To examine whether overexpression of the TSPO protein alters the cellular bioenergetic profile, Jurkat cells with low to absent endogenous expression were transfected with a TSPO construct to create a stable cell line with de novo expression of exogenous TSPO protein. Expression of TSPO was confirmed by RT-qPCR, radioligand binding with [3H]PK11195 and immunocytochemistry with a TSPO antibody. We demonstrate that TSPO gene insertion causes increased transcription of genes involved in the mitochondrial electron transport chain. Furthermore, TSPO insertion increased mitochondrial ATP production as well as cell excitability, reflected in a decrease in patch clamp recorded rectified K channel currents. These functional changes were accompanied by an increase in cell proliferation and motility, which were inhibited by PK11195, a selective ligand for TSPO. We suggest that TSPO may serve a range of functions that can be viewed as downstream regulatory effects of its primary, evolutionary conserved role in cell metabolism and energy production. PMID:28103132

  3. Single-walled carbon nanotubes disturbed the immune and metabolic regulation function 13-weeks after a single intratracheal instillation.

    PubMed

    Park, Eun-Jung; Hong, Young-Shick; Lee, Byoung-Seok; Yoon, Cheolho; Jeong, Uiseok; Kim, Younghun

    2016-07-01

    Due to their unique physicochemical properties, the potential health effects of single-walled carbon nanotubes (SWCNTs) have attracted continuous attention together with their extensive application. In this study, we aimed to identify local and systemic health effects following pulmonary persistence of SWCNTs. As expected, SWCNTs remained in the lung for 13 weeks after a single intratracheal instillation (50, 100, and 200μg/kg). In the lung, the total number of cells and the percentages of lymphocytes and neutrophils significantly increased at 200μg/kg compared to the control, and the Th1-polarized immune response was induced accompanying enhanced expression of tissue damage-related genes and increased release of chemokines. Additionally, SWCNTs enhanced the expression of antigen presentation-related proteins on the surface of antigen-presenting cells, however, maturation of dendritic cells was inhibited by their persistence. As compared to the control, a significant increase in the percentage of neutrophils and a remarkable decrease of BUN and potassium level were observed in the blood of mice treated with the highest dose. This was accompanied by the down-regulation of the expression of antigen presentation-related proteins on splenocytes. Moreover, protein and glucose metabolism were disturbed with an up-regulation of fatty acid β-oxidation. Taken together, we conclude that SWCNTs may induce adverse health effects by disturbing immune and metabolic regulation functions in the body. Therefore, careful application of SWCNTs is necessary for the enforcement of safety in nano-industries.

  4. Renal transplantation promptly restores excretory function but disturbed L-arginine metabolism persists in patients during the early period after surgery.

    PubMed

    Žunić, Gordana; Vučević, Dragana; Tomić, Aleksandar; Drašković-Pavlović, Biljana; Majstorović, Ivana; Spasić, Slavica

    2015-01-30

    The synthesis and whole body metabolism of L-arginine (Arg) are disturbed in renal diseases. Renal transplantation represents the best therapy in the end-stage of these diseases. In the present we compared alterations of plasma Arg and related compounds with renal excretory function in patients with end-stage renal disease, before and after kidney transplantation. Arg, asymmetric dimethylarginine (ADMA), citrulline (Cit), glutamine (Gln), ornithine (Orn), phenylalanine (Phe), tyrosine (Tyr), urea, creatinine, albumin, and nitrate were analyzed in patients before, immediately after (0-time) and 1, 2, 3, 7 and 14 days following living donors kidney transplantation. Healthy subjects were controls. Glomerular filtration rate (GFR) and amino acid molar ratios were calculated. Before transplantation creatinine, urea, Cit, Gln, ADMA, and nitrate were above, while GFR and Arg were below controls, confirming disturbed excretory and metabolic renal functions in patients with renal disease. Renal transplantation promptly normalized creatinine, urea, GFR, Cit, and nitrate. However, regardless of increased molar Phe/Tyr ratios, indicating increased net protein catabolism in peripheral tissues, low Arg and elevated ADMA concentrations persisted throughout the examined period. Alterations of other amino acids also suggest similarly disturbed Arg metabolism in patients after kidney transplantation. In conclusion, renal transplant promptly restored its excretory function, but increased net protein catabolism, disturbed Arg metabolism and endothelial dysfunction in entire body of these patients were not improved throughout the early period after the operation. That has to be considered in their therapy.

  5. [Biological activities of exogenous polysaccharides via controlling endogenous proteoglycan metabolism in vascular endothelial cells].

    PubMed

    Sato, Tomoko; Yamamoto, Chika; Fujiwara, Yasuyuki; Kaji, Toshiyuki

    2008-05-01

    Proteoglycan contains glycosmainoglycans, which are endogenous sulfated polysaccharides, in the molecule. The metabolism of proteoglycans regulates cell behavior and cellular events. It is possible that exogenous polysaccharide-related molecules exhibit their biological activities by two mechanisms. One is the interaction with cells and the other is the interaction with growth factors/cytokines that regulate proteoglycans. In this review, we describe sodium spirulan, a sulfated polysaccharide obtained from a hot-water extract of the blue-green alga Spirulina platensis, as an exogenous polysaccharide that stimulates the release of proteoglycans from vascular endothelial cells. Factors that regulate endothelial proteoglycan metabolism are also being described as possible target molecules of exogenous polysaccharides. Further research is required to obtain exogenous polysaccharide-related molecules that exhibit useful biological activities through controlling endothelial proteoglycan metabolism for protection against vascular lesions such as atheroslcerosis.

  6. The lysosome as a command-and-control center for cellular metabolism

    PubMed Central

    2016-01-01

    Lysosomes are membrane-bound organelles found in every eukaryotic cell. They are widely known as terminal catabolic stations that rid cells of waste products and scavenge metabolic building blocks that sustain essential biosynthetic reactions during starvation. In recent years, this classical view has been dramatically expanded by the discovery of new roles of the lysosome in nutrient sensing, transcriptional regulation, and metabolic homeostasis. These discoveries have elevated the lysosome to a decision-making center involved in the control of cellular growth and survival. Here we review these recently discovered properties of the lysosome, with a focus on how lysosomal signaling pathways respond to external and internal cues and how they ultimately enable metabolic homeostasis and cellular adaptation. PMID:27621362

  7. Myocardial VHL-HIF Signaling Controls an Embryonic Metabolic Switch Essential for Cardiac Maturation.

    PubMed

    Menendez-Montes, Ivan; Escobar, Beatriz; Palacios, Beatriz; Gómez, Manuel Jose; Izquierdo-Garcia, Jose Luis; Flores, Lorena; Jiménez-Borreguero, Luis Jesus; Aragones, Julian; Ruiz-Cabello, Jesus; Torres, Miguel; Martin-Puig, Silvia

    2016-12-19

    While gene regulatory networks involved in cardiogenesis have been characterized, the role of bioenergetics remains less studied. Here we show that until midgestation, myocardial metabolism is compartmentalized, with a glycolytic signature restricted to compact myocardium contrasting with increased mitochondrial oxidative activity in the trabeculae. HIF1α regulation mirrors this pattern, with expression predominating in compact myocardium and scarce in trabeculae. By midgestation, the compact myocardium downregulates HIF1α and switches toward oxidative metabolism. Deletion of the E3 ubiquitin ligase Vhl results in HIF1α hyperactivation, blocking the midgestational metabolic shift and impairing cardiac maturation and function. Moreover, the altered glycolytic signature induced by HIF1 trabecular activation precludes regulation of genes essential for establishment of the cardiac conduction system. Our findings reveal VHL-HIF-mediated metabolic compartmentalization in the developing heart and the connection between metabolism and myocardial differentiation. These results highlight the importance of bioenergetics in ventricular myocardium specialization and its potential relevance to congenital heart disease.

  8. Successful control of dyslipidemia in patients with metabolic syndrome: focus on lifestyle changes.

    PubMed

    Stone, Neil J

    2006-01-01

    Approaches to controlling dyslipidemia in patients with metabolic syndrome must take into consideration a patient's individual characteristics and underlying lipid disorder. Some patients will require pharmacologic therapy, whereas others can be controlled with lifestyle changes alone. The National Cholesterol Education Program (NCEP) Adult Treatment Panel III (ATP III) guidelines recommend that patients with at least 3 of the following clinical variables be designated as having metabolic syndrome: abdominal obesity as reflected in increased waist circumference; a low high-density lipoprotein cholesterol (HDL-C) level; an elevated triglyceride level; elevated blood pressure or treatment with antihypertensive medications; and/or elevated fasting plasma glucose or treatment with antidiabetic medications. Unless patients with metabolic syndrome change their lifestyle, existing cardiovascular and metabolic risk factors will worsen or new risk factors will develop. This helps explain why these patients are at increased risk for developing type 2 diabetes mellitus (DM) and coronary heart disease (CHD). The lifestyle changes recommended by NCEP ATP III for controlling dyslipidemia (i.e., elevated levels of triglycerides and decreased levels of HDL-C) in patients with metabolic syndrome or type 2 DM include (1) reduced intake of saturated fats and dietary cholesterol, (2) intake of dietary options to enhance lowering of low-density lipoprotein cholesterol, (3) weight control, and (4) increased physical activity. If lifestyle changes are not successful for individuals at high risk of developing CHD, or for those who currently have CHD, a CHD risk equivalent, or persistent atherogenic dyslipidemia, then pharmacotherapy may be necessary as defined by NCEP ATP III guidelines.

  9. Alcohol decreases baseline brain glucose metabolism more in heavy drinkers than controls but has no effect on stimulation-induced metabolic increases

    DOE PAGES

    Volkow, Nora D.; Fowler, Joanna S.; Wang, Gene-Jack; ...

    2015-02-18

    During alcohol intoxication the human brain increases metabolism of acetate and decreases metabolism of glucose as energy substrate. Here we hypothesized that chronic heavy drinking facilitates this energy substrate shift both for baseline and stimulation conditions. To test this hypothesis we compared the effects of alcohol intoxication (0.75g/kg alcohol versus placebo) on brain glucose metabolism during video-stimulation (VS) versus when given with no-stimulation (NS), in 25 heavy drinkers (HD) and 23 healthy controls each of whom underwent four PET-¹⁸FDG scans. We showed that resting whole-brain glucose metabolism (placebo-NS) was lower in HD than controls (13%, p=0.04); that alcohol (compared tomore » placebo) decreased metabolism more in HD (20±13%) than controls (9±11%, p=0.005) and in proportion to daily alcohol consumption (r=0.36, p=0.01) but found that alcohol did not reduce the metabolic increases in visual cortex from VS in either group. Instead, VS reduced alcohol-induced decreases in whole-brain glucose metabolism (10±12%) compared to NS in both groups (15±13%, p=0.04), consistent with stimulation-related glucose metabolism enhancement. These findings corroborate our hypothesis that heavy alcohol consumption facilitates use of alternative energy substrates (i.e. acetate) for resting activity during intoxication, which might persist through early sobriety, but indicate that glucose is still favored as energy substrate during brain stimulation. Our findings are consistent with reduced reliance on glucose as the main energy substrate for resting brain metabolism during intoxication (presumably shifting to acetate or other ketones) and a priming of this shift in heavy drinkers, which might make them vulnerable to energy deficits during withdrawal.« less

  10. Alcohol decreases baseline brain glucose metabolism more in heavy drinkers than controls but has no effect on stimulation-induced metabolic increases

    SciTech Connect

    Volkow, Nora D.; Fowler, Joanna S.; Wang, Gene-Jack; Kojori, Eshan Shokri; Benveniste, Helene; Tomasi, Dardo

    2015-02-18

    During alcohol intoxication the human brain increases metabolism of acetate and decreases metabolism of glucose as energy substrate. Here we hypothesized that chronic heavy drinking facilitates this energy substrate shift both for baseline and stimulation conditions. To test this hypothesis we compared the effects of alcohol intoxication (0.75g/kg alcohol versus placebo) on brain glucose metabolism during video-stimulation (VS) versus when given with no-stimulation (NS), in 25 heavy drinkers (HD) and 23 healthy controls each of whom underwent four PET-¹⁸FDG scans. We showed that resting whole-brain glucose metabolism (placebo-NS) was lower in HD than controls (13%, p=0.04); that alcohol (compared to placebo) decreased metabolism more in HD (20±13%) than controls (9±11%, p=0.005) and in proportion to daily alcohol consumption (r=0.36, p=0.01) but found that alcohol did not reduce the metabolic increases in visual cortex from VS in either group. Instead, VS reduced alcohol-induced decreases in whole-brain glucose metabolism (10±12%) compared to NS in both groups (15±13%, p=0.04), consistent with stimulation-related glucose metabolism enhancement. These findings corroborate our hypothesis that heavy alcohol consumption facilitates use of alternative energy substrates (i.e. acetate) for resting activity during intoxication, which might persist through early sobriety, but indicate that glucose is still favored as energy substrate during brain stimulation. Our findings are consistent with reduced reliance on glucose as the main energy substrate for resting brain metabolism during intoxication (presumably shifting to acetate or other ketones) and a priming of this shift in heavy drinkers, which might make them vulnerable to energy deficits during withdrawal.

  11. Alcohol decreases baseline brain glucose metabolism more in heavy drinkers than controls but has no effect on stimulation-induced metabolic increases.

    PubMed

    Volkow, Nora D; Wang, Gene-Jack; Shokri Kojori, Ehsan; Fowler, Joanna S; Benveniste, Helene; Tomasi, Dardo

    2015-02-18

    During alcohol intoxication, the human brain increases metabolism of acetate and decreases metabolism of glucose as energy substrate. Here we hypothesized that chronic heavy drinking facilitates this energy substrate shift both for baseline and stimulation conditions. To test this hypothesis, we compared the effects of alcohol intoxication (0.75 g/kg alcohol vs placebo) on brain glucose metabolism during video stimulation (VS) versus when given with no stimulation (NS), in 25 heavy drinkers (HDs) and 23 healthy controls, each of whom underwent four PET-(18)FDG scans. We showed that resting whole-brain glucose metabolism (placebo-NS) was lower in HD than controls (13%, p = 0.04); that alcohol (compared with placebo) decreased metabolism more in HD (20 ± 13%) than controls (9 ± 11%, p = 0.005) and in proportion to daily alcohol consumption (r = 0.36, p = 0.01) but found that alcohol did not reduce the metabolic increases in visual cortex from VS in either group. Instead, VS reduced alcohol-induced decreases in whole-brain glucose metabolism (10 ± 12%) compared with NS in both groups (15 ± 13%, p = 0.04), consistent with stimulation-related glucose metabolism enhancement. These findings corroborate our hypothesis that heavy alcohol consumption facilitates use of alternative energy substrates (i.e., acetate) for resting activity during intoxication, which might persist through early sobriety, but indicate that glucose is still favored as energy substrate during brain stimulation. Our findings are consistent with reduced reliance on glucose as the main energy substrate for resting brain metabolism during intoxication (presumably shifting to acetate or other ketones) and a priming of this shift in HDs, which might make them vulnerable to energy deficits during withdrawal.

  12. Alcohol Decreases Baseline Brain Glucose Metabolism More in Heavy Drinkers Than Controls But Has No Effect on Stimulation-Induced Metabolic Increases

    PubMed Central

    Wang, Gene-Jack; Shokri Kojori, Ehsan; Fowler, Joanna S.; Benveniste, Helene; Tomasi, Dardo

    2015-01-01

    During alcohol intoxication, the human brain increases metabolism of acetate and decreases metabolism of glucose as energy substrate. Here we hypothesized that chronic heavy drinking facilitates this energy substrate shift both for baseline and stimulation conditions. To test this hypothesis, we compared the effects of alcohol intoxication (0.75 g/kg alcohol vs placebo) on brain glucose metabolism during video stimulation (VS) versus when given with no stimulation (NS), in 25 heavy drinkers (HDs) and 23 healthy controls, each of whom underwent four PET-18FDG scans. We showed that resting whole-brain glucose metabolism (placebo-NS) was lower in HD than controls (13%, p = 0.04); that alcohol (compared with placebo) decreased metabolism more in HD (20 ± 13%) than controls (9 ± 11%, p = 0.005) and in proportion to daily alcohol consumption (r = 0.36, p = 0.01) but found that alcohol did not reduce the metabolic increases in visual cortex from VS in either group. Instead, VS reduced alcohol-induced decreases in whole-brain glucose metabolism (10 ± 12%) compared with NS in both groups (15 ± 13%, p = 0.04), consistent with stimulation-related glucose metabolism enhancement. These findings corroborate our hypothesis that heavy alcohol consumption facilitates use of alternative energy substrates (i.e., acetate) for resting activity during intoxication, which might persist through early sobriety, but indicate that glucose is still favored as energy substrate during brain stimulation. Our findings are consistent with reduced reliance on glucose as the main energy substrate for resting brain metabolism during intoxication (presumably shifting to acetate or other ketones) and a priming of this shift in HDs, which might make them vulnerable to energy deficits during withdrawal. PMID:25698759

  13. Metabolism and the Control of Cell Fate Decisions and Stem Cell Renewal

    PubMed Central

    Ito, Kyoko; Ito, Keisuke

    2016-01-01

    Although the stem cells of various tissues remain in the quiescent state to maintain their undifferentiated state, they also undergo cell divisions as required, and if necessary, even a single stem cell is able to provide for lifelong tissue homeostasis. Stem cell populations are precisely controlled by the balance between their symmetric and asymmetric divisions, with their division patterns determined by whether the daughter cells involved retain their self-renewal capacities. Recent studies have reported that metabolic pathways and the distribution of mitochondria are regulators of the division balance of stem cells and that metabolic defects can shift division balance toward symmetric commitment, which leads to stem cell exhaustion. It has also been observed that in asymmetric division, old mitochondria, which are central metabolic organelles, are segregated to the daughter cell fated to cell differentiation, whereas in symmetric division, young and old mitochondria are equally distributed between both daughter cells. Thus, metabolism and mitochondrial biology play important roles in stem cell fate decisions. As these decisions directly affect tissue homeostasis, understanding their regulatory mechanisms in the context of cellular metabolism is critical. PMID:27482603

  14. The Anti-Oxidant Drug Tempol Promotes Functional Metabolic Changes in the Gut Microbiota

    PubMed Central

    Cai, Jingwei; Zhang, Limin; Jones, Richard A.; Correll, Jared B.; Hatzakis, Emmanuel; Smith, Philip B.; Gonzalez, Frank J.; Patterson, Andrew D.

    2016-01-01

    Recent studies have identified the important role of the gut microbiota in the pathogenesis and progression of obesity and related metabolic disorders. The antioxidant tempol was shown to prevent or reduce weight gain and modulate the gut microbiota community in mice; however, the mechanism by which tempol modulates weight gain/loss with respect to the host and gut microbiota has not been clearly established. Here we show that tempol (0, 1, 10, and 50 mg/kg p.o. f