Role of AMP-activated protein kinase in mechanism of metformin action
Gaochao Zhou,Robert W. Myers,Ying Li,Yuli Chen,Xiaolan Shen,Judy Fenyk-Melody,Margaret Wu,John Ventre,Thomas W. Doebber,Nobuharu Fujii,Nicolas Musi,Michael F. Hirshman,Laurie J. Goodyear,David E. Moller +13 more
TLDR
It is reported that metformin activates AMPK in hepatocytes; as a result, acetyl-CoA carboxylase (ACC) activity is reduced, fatty acid oxidation is induced, and expression of lipogenic enzymes is suppressed.Abstract:
Metformin is a widely used drug for treatment of type 2 diabetes with no defined cellular mechanism of action. Its glucose-lowering effect results from decreased hepatic glucose production and increased glucose utilization. Metformin's beneficial effects on circulating lipids have been linked to reduced fatty liver. AMP-activated protein kinase (AMPK) is a major cellular regulator of lipid and glucose metabolism. Here we report that metformin activates AMPK in hepatocytes; as a result, acetyl-CoA carboxylase (ACC) activity is reduced, fatty acid oxidation is induced, and expression of lipogenic enzymes is suppressed. Activation of AMPK by metformin or an adenosine analogue suppresses expression of SREBP-1, a key lipogenic transcription factor. In metformin-treated rats, hepatic expression of SREBP-1 (and other lipogenic) mRNAs and protein is reduced; activity of the AMPK target, ACC, is also reduced. Using a novel AMPK inhibitor, we find that AMPK activation is required for metformin's inhibitory effect on glucose production by hepatocytes. In isolated rat skeletal muscles, metformin stimulates glucose uptake coincident with AMPK activation. Activation of AMPK provides a unified explanation for the pleiotropic beneficial effects of this drug; these results also suggest that alternative means of modulating AMPK should be useful for the treatment of metabolic disorders.read more
Citations
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BMP8B Increases Brown Adipose Tissue Thermogenesis through Both Central and Peripheral Actions
Andrew J. Whittle,Stefania Carobbio,Luís Martins,Marc Slawik,Marc Slawik,Elayne Hondares,María Jesús Vázquez,Donald A. Morgan,Robert I. Csikasz,Rosalía Gallego,Sergio Rodriguez-Cuenca,Martin Dale,Samuel Virtue,Francesc Villarroya,Barbara Cannon,Barbara Cannon,Kamal Rahmouni,Miguel López,Antonio Vidal-Puig +18 more
TL;DR: The results indicate that BMP8B is a thermogenic protein that regulates energy balance in partnership with hypothalamic AMPK, and may offer a mechanism to specifically increase energy dissipation by BAT.
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AMPK activators: mechanisms of action and physiological activities
TL;DR: This review provides a comprehensive summary of both indirect and direct AMPK activators and their modes of action in relation to the structure of AMPK.
Journal ArticleDOI
New perspectives in the regulation of hepatic glycolytic and lipogenic genes by insulin and glucose: a role for the transcription factor sterol regulatory element binding protein-1c.
Fabienne Foufelle,Pascal Ferré +1 more
TL;DR: The role of the transcription factors forkhead and sterol regulatory element bindingprotein-1c in the inductive and repressive effects of insulin on hepatic gene expression are reviewed, and the pathway that leads from glucose to gene regulation with the recently discovered carbohydrate response element binding protein is reviewed.
Journal ArticleDOI
Crucial role of a long-chain fatty acid elongase, Elovl6, in obesity-induced insulin resistance
Takashi Matsuzaka,Hitoshi Shimano,Naoya Yahagi,Naoya Yahagi,Toyonori Kato,Ayaka Atsumi,Takashi Yamamoto,Noriyuki Inoue,Mayumi Ishikawa,Sumiyo Okada,Naomi Ishigaki,Hitoshi Iwasaki,Yuko Iwasaki,Tadayoshi Karasawa,Shin Kumadaki,Toshiyuki Matsui,Motohiro Sekiya,Ken Ohashi,Alyssa H. Hasty,Yoshimi Nakagawa,Akimitsu Takahashi,Hiroaki Suzuki,Sigeru Yatoh,Hirohito Sone,Hideo Toyoshima,Jun-ichi Osuga,Nobuhiro Yamada +26 more
TL;DR: Hepatic fatty acid composition is a new determinant for insulin sensitivity that acts independently of cellular energy balance and stress and could be a new therapeutic approach for ameliorating insulin resistance, diabetes and cardiovascular risks, even in the presence of a continuing state of obesity.
Journal ArticleDOI
Activation of the AMP-activated Protein Kinase by the Anti-diabetic Drug Metformin in Vivo ROLE OF MITOCHONDRIAL REACTIVE NITROGEN SPECIES
Ming-Hui Zou,Stacy S. Kirkpatrick,Bradley J. Davis,John S. Nelson,Walter G. Wiles,Uwe Schlattner,Dietbert Neumann,Michael Brownlee,Michael B. Freeman,M.H. Goldman +9 more
TL;DR: It is concluded that activation of AMPK by metformin might be mediated by mitochondria-derived RNS, and activation of the c-Src/PI3K pathway might generate a metabolite or other molecule inside the cell to promote AMPK activation by the LKB1 complex.
References
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Journal ArticleDOI
Evidence that metformin exerts its anti-diabetic effects through inhibition of complex 1 of the mitochondrial respiratory chain
TL;DR: It is concluded that the drug's pharmacological effects are mediated, at least in part, through a time-dependent, self-limiting inhibition of the respiratory chain that restrains hepatic gluconeogenesis while increasing glucose utilization in peripheral tissues.
Journal ArticleDOI
The mitochondrial carnitine palmitoyltransferase system. From concept to molecular analysis.
J. Denis McGarry,N. F. Brown +1 more
TL;DR: Key developments of the last 20 years that have led to the current understanding of the physiology of the CPT system, the structure of theCPT isoforms, the chromosomal localization of their respective genes, and the identification of mutations in the human population are reviewed.
Journal ArticleDOI
The AMP‐Activated Protein Kinase
D. Grahame Hardie,David Carling +1 more
TL;DR: The central hypothesis is that the AMP-activated protein kinase cascade appears to be an ancient system which evolved to protect cells against the effects of nutritional or environmental stress, and protects the cell by switching off ATP-consuming pathways and switching on alternative pathways for ATP generation.
Journal ArticleDOI
Dimethylbiguanide inhibits cell respiration via an indirect effect targeted on the respiratory chain complex I.
Mohamad Y. El-Mir,Véronique Nogueira,Eric Fontaine,Nicole Avéret,Michel Rigoulet,Xavier Leverve +5 more
TL;DR: The results suggest the existence of a new cell-signaling pathway targeted to the respiratory chain complex I with a persistent effect after cessation of the signaling process.
Journal ArticleDOI
Metabolic effects of metformin in non-insulin-dependent diabetes mellitus.
TL;DR: Metformin acts primarily by decreasing hepatic glucose output, largely by inhibiting gluconeogenesis, and also seems to induce weight loss, preferentially involving adipose tissue.