The Experts below are selected from a list of 360 Experts worldwide ranked by ideXlab platform
Michael N Sack - One of the best experts on this subject based on the ideXlab platform.
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prolonged fasting identifies heat shock protein 10 as a sirtuin 3 substrate elucidating a new mechanism linking mitochondrial protein acetylation to fatty acid oxidation enzyme folding and function
Journal of Biological Chemistry, 2015Co-Authors: Zhongping Lu, Yong Chen, Angel Aponte, Valentina Battaglia, Marjan Gucek, Michael N SackAbstract:Although Sirtuin 3 (SIRT3), a mitochondrially enriched deacetylase and activator of fat oxidation, is down-regulated in response to high fat feeding, the rate of fatty acid oxidation and mitochondrial protein acetylation are invariably enhanced in this dietary milieu. These paradoxical data implicate that additional acetylation modification-dependent levels of regulation may be operational under Nutrient Excess conditions. Because the heat shock protein (Hsp) Hsp10-Hsp60 chaperone complex mediates folding of the fatty acid oxidation enzyme medium-chain acyl-CoA dehydrogenase, we tested whether acetylation-dependent mitochondrial protein folding contributes to this regulatory discrepancy. We demonstrate that Hsp10 is a functional SIRT3 substrate and that, in response to prolonged fasting, SIRT3 levels modulate mitochondrial protein folding. Acetyl mutagenesis of Hsp10 lysine 56 alters Hsp10-Hsp60 binding, conformation, and protein folding. Consistent with Hsp10-Hsp60 regulation of fatty acid oxidation enzyme integrity, medium-chain acyl-CoA dehydrogenase activity and fat oxidation are elevated by Hsp10 acetylation. These data identify acetyl modification of Hsp10 as a Nutrient-sensing regulatory node controlling mitochondrial protein folding and metabolic function.
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sirt3 is regulated by Nutrient Excess and modulates hepatic susceptibility to lipotoxicity
Free Radical Biology and Medicine, 2010Co-Authors: Iain Scott, Zhongping Lu, Liyan Pang, Christopher C Dimond, David Gius, Michael N SackAbstract:SIRT3 is the primary mitochondrial deacetylase that modulates mitochondrial metabolic and oxidative stress regulatory pathways. However, its role in response to Nutrient Excess remains unknown. Thus, we investigated SIRT3 regulation of the electron transfer chain and evaluated the role of SIRT3 in hepatic lipotoxic stress. SIRT3-depleted HepG2 cells show diffuse disruption in mitochondrial electron transfer chain functioning, a concurrent reduction in the mitochondrial membrane potential, and Excess basal reactive oxygen species levels. As this phenotype may predispose to increased lipotoxic hepatic susceptibility we evaluated the expression of SIRT3 in murine liver after chronic high-fat feeding. In this Nutrient-Excess model SIRT3 transcript and protein levels are downregulated in parallel with increased hepatic fat storage and oxidative stress. Palmitate was used to investigate lipotoxic susceptibility in SIRT3 knockout mouse primary hepatocytes and SIRT3-siRNA-transfected HepG2 cells. Under SIRT3-deficient conditions palmitate enhances reactive oxygen species and increases hepatocyte death. Reconstitution of SIRT3 levels and/or treatment with N-acetylcysteine ameliorates these adverse effects. In conclusion SIRT3 functions to ameliorate hepatic lipotoxicity, although paradoxically, exposure to high fat downregulates this adaptive program in the liver. This SIRT3-dependent lipotoxic susceptibility is possibly modulated, in part, by SIRT3-mediated control of electron transfer chain flux.
Michael E. Symonds - One of the best experts on this subject based on the ideXlab platform.
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Interscapular and Perivascular Brown Adipose Tissue Respond Differently to a Short-Term High-Fat Diet.
Nutrients, 2019Co-Authors: Peter Aldiss, Jo E. Lewis, David J. Boocock, Amanda K. Miles, Ian Bloor, Francis J. P. Ebling, Helen Budge, Michael E. SymondsAbstract:Brown adipose tissue (BAT) function may depend on its anatomical location and developmental origin. Interscapular BAT (iBAT) regulates acute macroNutrient metabolism, whilst perivascular BAT (PVAT) regulates vascular function. Although phenotypically similar, whether these depots respond differently to acute Nutrient Excess is unclear. Given their distinct anatomical locations and developmental origins and we hypothesised that iBAT and PVAT would respond differently to brief period of Nutrient Excess. Sprague-Dawley rats aged 12 weeks (n=12) were fed either a standard (10% fat, n=6) or high fat diet (HFD: 45% fat, n=6) for 72h and housed at thermoneutrality. Following an assessment of whole body physiology, fat was collected from both depots for analysis of gene expression and the proteome. HFD consumption for 72h induced rapid weight gain (c. 2.6%) and reduced serum non-esterified fatty acids (NEFA) with no change in either total adipose or depot mass. In iBAT, an upregulation of genes involved in insulin signalling and lipid metabolism was accompanied by enrichment of lipid-related processes and functions, plus glucagon and peroxisome proliferator-activated receptor (PPAR) signalling pathways. In PVAT, HFD induced a pronounced down-regulation of multiple metabolic pathways which was accompanied with increased abundance of proteins involved in apoptosis (e.g., Hdgf and Ywaq) and toll-like receptor signalling (Ube2n). There was also an enrichment of DNA-related processes and functions (e.g., nucleosome assembly and histone exchange) and RNA degradation and cell adhesion pathways. In conclusion, we show that iBAT and PVAT elicit divergent responses to short-term Nutrient Excess highlighting early adaptations in these depots before changes in fat mass.
Asish K Saha - One of the best experts on this subject based on the ideXlab platform.
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Nutrient Excess and ampk downregulation in incubated skeletal muscle and muscle of glucose infused rats
PLOS ONE, 2015Co-Authors: Kimberly A Coughlan, Rudy J Valentine, Neil B Ruderman, T W Balon, Amanda E Brandon, Edward W Kraegen, Robert Petrocelli, Vera Schultz, Gregory J Cooney, Asish K SahaAbstract:We have previously shown that incubation for 1h with Excess glucose or leucine causes insulin resistance in rat extensor digitorum longus (EDL) muscle by inhibiting AMP-activated protein kinase (AMPK). To examine the events that precede and follow these changes, studies were performed in rat EDL incubated with elevated levels of glucose or leucine for 30min-2h. Incubation in high glucose (25mM) or leucine (100μM) significantly diminished AMPK activity by 50% within 30min, with further decreases occurring at 1 and 2h. The initial decrease in activity at 30min coincided with a significant increase in muscle glycogen. The subsequent decreases at 1h were accompanied by phosphorylation of αAMPK at Ser485/491, and at 2h by decreased SIRT1 expression and increased PP2A activity, all of which have previously been shown to diminish AMPK activity. Glucose infusion in vivo, which caused several fold increases in plasma glucose and insulin, produced similar changes but with different timing. Thus, the initial decrease in AMPK activity observed at 3h was associated with changes in Ser485/491 phosphorylation and SIRT1 expression and increased PP2A activity was a later event. These findings suggest that both ex vivo and in vivo, multiple factors contribute to fuel-induced decreases in AMPK activity in skeletal muscle and the insulin resistance that accompanies it.
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Nutrient Excess in ampk downregulation and insulin resistance
Journal of endocrinology diabetes & obesity, 2013Co-Authors: Kimberly A Coughlan, Rudy J Valentine, Neil B Ruderman, Asish K SahaAbstract:It is well established that chronic exposure to Excess Nutrients leads to insulin resistance (IR) in skeletal muscle. Since skeletal muscle is responsible for 70-80% of insulin-stimulated glucose uptake, skeletal muscle IR is a key pathological component of type 2 diabetes (T2D). Recent evidence suggests that inhibition of the Nutrient-sensing enzyme AMP-activated protein kinase (AMPK) is an early event in the development of IR in response to high glucose, branched chain amino acids (BCAA), or fatty acids (FA). Whether the decrease in AMPK activity is causal to the events leading to insulin resistance (increased mTOR/p70S6K signaling) remains to be determined. Interestingly, pharmacological activation of AMPK can prevent activation of mTOR/p70S6K and insulin resistance, while inhibition of mTOR with rapamycin prevents insulin resistance, but not AMPK downregulation. AMPK can be inhibited by increased energy state (reduced AMP/ATP ratio), decreased phosphorylation of its activation site (αThr172) (by decreased upstream kinase activity or increased phosphatase activity), increased inhibitory phosphorylation at αSer485/491, changes in redox state or hormone levels, or other yet to be identified mechanisms. Excess Nutrients also lead to an accumulation of the toxic lipid intermediates diacylglycerol (DAG) and ceramides, both of which can activate various protein kinase C (PKC) isoforms, and contribute to IR. The mechanism responsible for the initial downregulation of AMPK in response to Excess Nutrients, and whether glucose, BCAA, and FA act through similar or different pathways requires further study. Identification of this mechanism and the relative importance of other events would be beneficial for designing novel pharmacological interventions to prevent and/or reverse IR. This review will focus on the some of the mechanisms responsible for AMPK downregulation and the relative sequence and importance of these events.
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insulin resistance due to Nutrient Excess is it a consequence of ampk downregulation
Cell Cycle, 2011Co-Authors: Asish K Saha, T W Balon, Amanda E Brandon, Edward W Kraegen, Neil B RudermanAbstract:It has long been known that Excesses of glucose and branched chain amino acids, such as leucine, lead to insulin resistance in skeletal muscle. A recent study in incubated rat muscle suggests that both molecules may do so by virtue of their ability to downregulate the fuel sensing and signaling enzyme AMP-activated protein kinase (AMPK) and activate mTOR/p70S6 kinase (p70S6K) signaling. The results also demonstrated that inhibition of mTOR/p70S6K with rapamycin prevented the development of insulin resistance but had no effect on AMPK activity (Thr172 phosphorylation of its catalytic subunit). In contrast, activation of AMPK by both AICAR and α-lipoic acid led to the phosphorylation of specific molecules that diminished both mTOR/p70S6K signaling and insulin resistance. These findings suggest that downregulation of AMPK precedes mTOR/p70S6K activation in mediating glucose and leucine-induced insulin resistance, although the mechanism by which it does so remains to be determined. Also requiring study is how an Excess of the two Nutrients leads to AMPK downregulation.
Vincent Poitout - One of the best experts on this subject based on the ideXlab platform.
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epidermal growth factor receptor signaling promotes pancreatic β cell proliferation in response to Nutrient Excess in rats through mtor and foxm1
Diabetes, 2014Co-Authors: Bader Zarrouki, Isma Benterki, Ghislaine Fontes, Marieline Peyot, Ondrej Seda, Marc Prentki, Vincent PoitoutAbstract:The cellular and molecular mechanisms underpinning the compensatory increase in β-cell mass in response to insulin resistance are essentially unknown. We previously reported that a 72-h coinfusion of glucose and Intralipid (GLU+IL) induces insulin resistance and a marked increase in β-cell proliferation in 6-month-old, but not in 2-month-old, Wistar rats. The aim of the current study was to identify the mechanisms underlying Nutrient-induced β-cell proliferation in this model. A transcriptomic analysis identified a central role for the forkhead transcription factor FOXM1 and its targets, and for heparin-binding epidermal growth factor (EGF)-like growth factor (HB-EGF), a ligand of the EGF receptor (EGFR), in Nutrient-induced β-cell proliferation. Phosphorylation of ribosomal S6 kinase, a mammalian target of rapamycin (mTOR) target, was increased in islets from GLU+IL–infused 6-month-old rats. HB-EGF induced proliferation of insulin-secreting MIN6 cells and isolated rat islets, and this effect was blocked in MIN6 cells by the EGFR inhibitor AG1478 or the mTOR inhibitor rapamycin. Coinfusion of either AG1478 or rapamycin blocked the increase in FOXM1 signaling, β-cell proliferation, and β-cell mass and size in response to GLU+IL infusion in 6-month-old rats. We conclude that chronic Nutrient Excess promotes β-cell mass expansion via a pathway that involves EGFR signaling, mTOR activation, and FOXM1-mediated cell proliferation.
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epidermal growth factor signalling promotes pancreatic beta cell proliferation in response to Nutrient Excess tn rats through mtor and foxm1
Canadian Journal of Diabetes, 2013Co-Authors: Bader Zarrouki, Isma Benterki, Ghislaine Fontes, Marieline Peyot, Ondrej Seda, Marc Prentki, Vincent PoitoutAbstract:s / Can J Diabetes 37 (2013) S6eS11 S8 showed systolicddiastolic dysfunctions and a development of aortic stenosis in IGF-II mice compared to WT mice. Gene expression was consistent with LV hypertrophy revealed by up-regulation of ANP, BNP, b-MHC mRNA in IGF-II mice. Osteogenic gene expression (Runx2, SPP1, BGLAP) was significantly increased in aorta of IGF-II mice. After 2 months of treatment, 2thio-UTP injected IGF-II mice showed a reduction of peak aortic jet velocity (Vpeak [ 6.6%]) and pressure gradient (PG [ 12.5%]) compared to baseline (p<0.05). In contrast, saline-injected IGF-II mice showed an augmentation of Vpeak (+7.4%) and LV PG (+17.1%) during the same period. Conclusion: These results indicate for the first time that 2thio-UTP induces regression of calcific aortic stenosis and associated LV dysfunction in this new model of obese diabetic animals.
Marc Prentki - One of the best experts on this subject based on the ideXlab platform.
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Nutrient induced metabolic stress adaptation detoxification and toxicity in the pancreatic β cell
Diabetes, 2020Co-Authors: Marc Prentki, Marieline Peyot, Pellegrino Masiello, S Murthy R MadirajuAbstract:Paraphrasing the Swiss physician and father of toxicology Paracelsus (1493-1541) on chemical agents used as therapeutics, "the dose makes the poison," it is now realized that this aptly applies to the calorigenic Nutrients. The case here is the pancreatic islet β-cell presented with Excessive levels of Nutrients such as glucose, lipids, and amino acids. The short-term effects these Nutrients exert on the β-cell are enhanced insulin biosynthesis and secretion and changes in glucose sensitivity. However, chronic fuel surfeit triggers additional compensatory and adaptive mechanisms by β-cells to cope with the increased insulin demand or to protect itself. When these mechanisms fail, toxicity due to the Nutrient surplus ensues, leading to β-cell dysfunction, dedifferentiation, and apoptosis. The terms glucotoxicity, lipotoxicity, and glucolipotoxicity have been widely used, but there is some confusion as to what they mean precisely and which is most appropriate for a given situation. Here we address the gluco-, lipo-, and glucolipo-toxicities in β-cells by assessing the evidence both for and against each of them. We also discuss potential mechanisms and defend the view that many of the identified "toxic" effects of Nutrient Excess, which may also include amino acids, are in fact beneficial adaptive processes. In addition, candidate fuel-Excess detoxification pathways are evaluated. Finally, we propose that a more general term should be used for the in vivo situation of overweight-associated type 2 diabetes reflecting both the adaptive and toxic processes to mixed calorigenic Nutrients Excess: "Nutrient-induced metabolic stress" or, in brief, "nutri-stress."
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epidermal growth factor receptor signaling promotes pancreatic β cell proliferation in response to Nutrient Excess in rats through mtor and foxm1
Diabetes, 2014Co-Authors: Bader Zarrouki, Isma Benterki, Ghislaine Fontes, Marieline Peyot, Ondrej Seda, Marc Prentki, Vincent PoitoutAbstract:The cellular and molecular mechanisms underpinning the compensatory increase in β-cell mass in response to insulin resistance are essentially unknown. We previously reported that a 72-h coinfusion of glucose and Intralipid (GLU+IL) induces insulin resistance and a marked increase in β-cell proliferation in 6-month-old, but not in 2-month-old, Wistar rats. The aim of the current study was to identify the mechanisms underlying Nutrient-induced β-cell proliferation in this model. A transcriptomic analysis identified a central role for the forkhead transcription factor FOXM1 and its targets, and for heparin-binding epidermal growth factor (EGF)-like growth factor (HB-EGF), a ligand of the EGF receptor (EGFR), in Nutrient-induced β-cell proliferation. Phosphorylation of ribosomal S6 kinase, a mammalian target of rapamycin (mTOR) target, was increased in islets from GLU+IL–infused 6-month-old rats. HB-EGF induced proliferation of insulin-secreting MIN6 cells and isolated rat islets, and this effect was blocked in MIN6 cells by the EGFR inhibitor AG1478 or the mTOR inhibitor rapamycin. Coinfusion of either AG1478 or rapamycin blocked the increase in FOXM1 signaling, β-cell proliferation, and β-cell mass and size in response to GLU+IL infusion in 6-month-old rats. We conclude that chronic Nutrient Excess promotes β-cell mass expansion via a pathway that involves EGFR signaling, mTOR activation, and FOXM1-mediated cell proliferation.
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epidermal growth factor signalling promotes pancreatic beta cell proliferation in response to Nutrient Excess tn rats through mtor and foxm1
Canadian Journal of Diabetes, 2013Co-Authors: Bader Zarrouki, Isma Benterki, Ghislaine Fontes, Marieline Peyot, Ondrej Seda, Marc Prentki, Vincent PoitoutAbstract:s / Can J Diabetes 37 (2013) S6eS11 S8 showed systolicddiastolic dysfunctions and a development of aortic stenosis in IGF-II mice compared to WT mice. Gene expression was consistent with LV hypertrophy revealed by up-regulation of ANP, BNP, b-MHC mRNA in IGF-II mice. Osteogenic gene expression (Runx2, SPP1, BGLAP) was significantly increased in aorta of IGF-II mice. After 2 months of treatment, 2thio-UTP injected IGF-II mice showed a reduction of peak aortic jet velocity (Vpeak [ 6.6%]) and pressure gradient (PG [ 12.5%]) compared to baseline (p<0.05). In contrast, saline-injected IGF-II mice showed an augmentation of Vpeak (+7.4%) and LV PG (+17.1%) during the same period. Conclusion: These results indicate for the first time that 2thio-UTP induces regression of calcific aortic stenosis and associated LV dysfunction in this new model of obese diabetic animals.
