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Liver Adenosine Monophosphate-Activated Kinase-2 Catalytic Subunit Is a Key Target for the Control of Hepatic Glucose Production by Adiponectin and Leptin But Not Insulin

Institut National de la Santé et de la Recherche Médicale Unité 567 (F.A., M.F., S.V., B.V.), Centre National de la Recherche Scientifique Unité Mixte de Recherche 8104, Université René Descartes Paris 5, Institut Fédératif de Recherche Alfred Jost, Institut Cochin, Department of Endocrinology, Metabolism and Cancer, 75014 Paris, France; Unité Mixte de Recherche 5018 (C.K., P.D.C., C.P., M.A.I., R.B.), Centre National de la Recherche Scientifique, Université Paul Sabatier and Institut Fédératif de Recherche 31 Louis Bugnard, Hôpital Rangueil, 31932 Toulouse, France; Institut National de la Santé et de la Recherche Médicale, Unité 449 (B.P., G.M.), 69372 Lyon, France; Institut National de la Santé et de la Recherche Médicale Unité 683 (A.B.), Institut Fédératif de Recherche 02 Claude Bernard, Faculté de Médecine Xavier Bichat, 75018 Paris, France; and Collège de France (F.T.), Centre National de la Recherche Scientifique Formation de Recherche en Evolution 2401, 75231 Paris, France

Address all correspondence and requests for reprints to: Professor Rémy Burcelin, UMR5018, Centre National de la Recherche Scientifique, Université Paul Sabatier and Institut Fédératif de Recherche 31, Hôpital Rangueil, Batiment L1, BP 84225, 31432 Toulouse Cedex 4, France. E-mail: burcelin{at}toulouse.inserm.fr.

The AMP-activated kinase (AMPK) is a serine threonine kinase that functions as a fuel sensor to regulate energy balance at both cellular and whole-body levels. Here we studied how hepatic AMPK2 isoform affects hepatic glucose production and peripheral glucose uptake in vivo. We generated mice deleted for the AMPK2 gene specifically in the liver (liver2KO). Liver2KO mice were glucose intolerant and hyperglycemic in the fasted state. Hyperglycemia was associated with a 50% higher endogenous glucose production than in controls as assessed in vivo. We then investigated whether this increased glucose production was sensitive to insulin. Insulin, when infused at a rate inducing physiological hyperinsulinemia, totally inhibited endogenous glucose production in liver2KO mice, showing that they had normal insulin sensitivity. This was confirmed in vivo by normal insulin-induced phosphorylation of Akt and transcriptional regulation of the phosphoenolpyruvate carboxykinase, glucose-6 phosphatase, and pyruvate kinase in liver during the fasted/fed transition. Leptin and adiponectin regulate hepatic glucose production, so we then infused these adipokines into liver2KO mice. Neither of these adipokines regulated hepatic glucose production in mice lacking hepatic AMPK2, whereas both did so in control mice. In conclusion, we show that the hepatic AMPK2 isoform is essential for suppressing hepatic glucose production and maintaining fasting blood glucose levels in the physiological range. We also demonstrate that regulation of hepatic glucose production by leptin and adiponectin, but not insulin, requires hepatic AMPK2 activity.

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