The 5′‐AMP‐activated protein kinase inhibits the transcriptional stimulation by glucose in liver cells, acting through the glucose response complex

Leclerc, Isabelle; Kahn, Axel; Doiron, Bruno

doi:10.1016/s0014-5793(98)00745-5

Cited by 132 publications

(103 citation statements)

References 47 publications

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“…In the present study, we have found that hypothalamic FAS and SREBP1c genes are significantly induced by both insulin and glucose, suggesting that insulin and glucose regulate FAS gene expression via a SREBP-1c dependent pathway in the hypothalamus. In contrast, the expression of both FAS and SREBP1c is repressed by AICAR, which is consistent with the results shown in hepatocytes and pancreatic islets [4,12].…”

Section: Discussionsupporting

confidence: 92%

Fatty acid synthase gene regulation in primary hypothalamic neurons

Kim

Kleman

Ronnett

2007

Neuroscience Letters

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Understanding the mechanisms that regulate feeding is critical to the development of therapeutic interventions for obesity. Many studies indicate that enzymes within fatty acid metabolic pathways may serve as targets for pharmacological tools to treat this epidemic. We, and others have previously demonstrated that C75, a fatty acid synthase (FAS) inhibitor, induced significant anorexia and weight loss by both central and peripheral mechanisms. Because the hypothalamus is important in the regulation of homeostatic processes for feeding control, we have identified pathways that alter the gene expression of FAS in primary hypothalamic neuronal cultures. Insulin, glucose and AICAR (an activator of AMP-activated protein kinase) affected changes in hypothalamic FAS mRNA, which may be regulated via the SREBP1c dependent or independent pathway.

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Section: Discussionsupporting

confidence: 92%

Fatty acid synthase gene regulation in primary hypothalamic neurons

Kim

Kleman

Ronnett

2007

Neuroscience Letters

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“…A similar reduction in glucose-activated FAS gene expression is obtained by incubation with 5-amino-imidazolecarboxamide riboside, a cell-permeable activator of the AMP-activated protein kinase (AMPK; Foretz et al 1998). Expression of the S14 and L-pyruvate kinase genes is also down-regulated when AMPK is activated (Leclerc et al 1998). AMPK phosphorylates and inactivates acetyl-CoA carboxylase (EC 6.4.1.2) and 3-hydroxy-3-methylglutarylCoA reductase (EC 1.1.1.34), resulting in the inhibition of both lipogenesis and cholesterol synthesis.…”

Section: The Glucose Effect Can Be Antagonized By a Specific Kinasementioning

confidence: 74%

Regulation of gene expression by glucose

Ferré¹

1999

Proc. Nutr. Soc.

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Fatty acid synthase (EC 2.3.1.85) is an enzyme involved in the lipogenic pathway allowing fatty acid synthesis from glucose. Glucose up-regulates the transcription of the fatty acid synthase gene in both adipocytes and hepatocytes, with insulin having only an indirect role. The signal metabolite could be glucose-6-phosphate rather than glucose itself. The glucose response element of the fatty acid synthase gene has not yet been precisely identified, although a −2 kb region of the fatty acid synthase promoter is sufficient to confer nutritional responsiveness to a reporter gene. ADD1/SREBP1, a b-HLH-LZ transcription factor belonging to the sterol regulatory element-binding protein family might be involved in the transduction of the glucose effect. Finally, the stimulatory effect of glucose on the expression of the fatty acid synthase gene is inhibited by the activation of AMP-activated protein kinase. Interestingly enough, AMP-activated protein kinase is structurally and functionally related to the yeast SNF1 protein kinase complex which is essential for the transcriptional activation of glucose-repressed genes in Saccharomyces cerevisiae.

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“…AMPK may also be regulated through the glycogenbinding domain on the β subunit by the content and structure of intracellular glycogen [9]. When stimulated, AMPK acts to restore cellular energy balance by stimulating ATP-producing pathways (glucose uptake, fatty acid oxidation and mitochondrial biogenesis) [10][11][12][13] and inhibiting ATP-consuming pathways (fatty acid synthesis, glycogen synthesis and protein synthesis) [14][15][16][17].…”

Section: Introductionmentioning

confidence: 99%

Naturally occurring R225W mutation of the gene encoding AMP-activated protein kinase (AMPK)γ3 results in increased oxidative capacity and glucose uptake in human primary myotubes

et al. 2010

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Aims/hypothesis AMP-activated protein kinase (AMPK) has a broad role in the regulation of glucose and lipid metabolism making it a promising target in the treatment of type 2 diabetes mellitus. We therefore sought to characterise for the first time the effects of chronic AMPK activation on skeletal muscle carbohydrate metabolism in carriers of the rare gain-of-function mutation of the gene encoding AMPKγ 3 subunit, PRKAG3 R225W.Methods Aspects of fuel metabolism were studied in vitro in myocytes isolated from vastus lateralis of PRKAG3 R225W carriers and matched control participants. In vivo, muscular strength and fatigue were evaluated by isokinetic dynamometer and surface electromyography, respectively. Glucose uptake in exercising quadriceps was determined using [ 18 F]fluorodeoxyglucose and positron emission tomography. Results Myotubes from PRKAG3 R225W carriers had threefold higher mitochondrial content (p < 0.01) and oxidative capacity, higher leak-dependent respiration (1.6-fold, p<0.05), higher basal glucose uptake (twofold, p<0.01) and higher glycogen synthesis rates (twofold, p<0.05) than control myotubes. They also had higher levels of intracellular glycogen (p<0.01) and a trend for lower intramuscular triacylglycerol stores. R225W carriers showed remarkable resistance to muscular fatigue and a trend for increased glucose uptake in exercising muscle in vivo. Conclusions/interpretation Through the enhancement of skeletal muscle glucose uptake and increased mitochondrial content, the R225W mutation may significantly enhance exercise performance. These findings are also consistent with the hypothesis that the γ 3 subunit of AMPK is a promising tissue-specific target for the treatment of type 2 diabetes mellitus, a condition in which glucose uptake and mitochondrial function are impaired.

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The 5′‐AMP‐activated protein kinase inhibits the transcriptional stimulation by glucose in liver cells, acting through the glucose response complex

Cited by 132 publications

References 47 publications

Fatty acid synthase gene regulation in primary hypothalamic neurons

Fatty acid synthase gene regulation in primary hypothalamic neurons

Regulation of gene expression by glucose

Naturally occurring R225W mutation of the gene encoding AMP-activated protein kinase (AMPK)γ3 results in increased oxidative capacity and glucose uptake in human primary myotubes

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