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Diabetes 54:1331-1339, 2005
© 2005 by the American Diabetes Association, Inc.
Short-Term Overexpression of a Constitutively Active Form of AMP-Activated Protein Kinase in the Liver Leads to Mild Hypoglycemia and Fatty Liver
1 Département de Génétique, Développement et Pathologie Moléculaire, Institut Cochin, Université René Descartes Paris 5, Institut National de la Santé et de la Recherche Medicale U567, Centre National de la Recherchè Scientifique UMR8104, Paris, France
2 GlaxoSmithKline, Les Ulis, France
3 Institute of Physiology, University of Lausanne, Lausanne, Switzerland
AMP-activated protein kinase (AMPK) is a major therapeutic target for the treatment of diabetes. We investigated the effect of a short-term overexpression of AMPK specifically in the liver by adenovirus-mediated transfer of a gene encoding a constitutively active form of AMPK
2 (AMPK2-CA). Hepatic AMPK2-CA expression significantly decreased blood glucose levels and gluconeogenic gene expression. Hepatic expression of AMPK2-CA in streptozotocin-induced and ob/ob diabetic mice abolished hyperglycemia and decreased gluconeogenic gene expression. In normal mouse liver, AMPK2-CA considerably decreased the refeeding-induced transcriptional activation of genes encoding proteins involved in glycolysis and lipogenesis and their upstream regulators, SREBP-1 (sterol regulatory element–binding protein-1) and ChREBP (carbohydrate response element–binding protein). This resulted in decreases in hepatic glycogen synthesis and circulating lipid levels. Surprisingly, despite the inhibition of hepatic lipogenesis, expression of AMPK2-CA led to fatty liver due to the accumulation of lipids released from adipose tissue. The relative scarcity of glucose due to AMPK2-CA expression led to an increase in hepatic fatty acid oxidation and ketone bodies production as an alternative source of energy for peripheral tissues. Thus, short-term AMPK activation in the liver reduces blood glucose levels and results in a switch from glucose to fatty acid utilization to supply energy needs.
Address correspondence and reprint requests to Benoît Viollet, Institut Cochin, Département de Génétique, Développement et Pathologie Moléculaire, 24 rue du faubourg Saint Jacques, 75014 Paris, France. E-mail: viollet{at}cochin.inserm.fr
Abbreviations: ACC, acetyl-CoA carboxylase; Ad, adenovirus; AICAR, 5-aminoimidazole-4-carboxamide ribonucleoside; AMPK, AMP-activated protein kinase; FFA, free fatty acid; G6Pase, glucose-6-phosphatase; HC, high-carbohydrate/low-fat; LPL, lipoprotein lipase; STZ, streptozotocin; UCP-2, uncoupling protein 2
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