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J. Biol. Chem., Vol. 281, Issue 36, 25956-25964, September 8, 2006

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5-Aminoimidazole-4-carboxamide-1--D-ribofuranoside-induced AMP-activated Protein Kinase Phosphorylation Inhibits Basal and Insulin-stimulated Glucose Uptake, Lipid Synthesis, and Fatty Acid Oxidation in Isolated Rat Adipocytes^*

From the School of Kinesiology and Health Science, York University, Toronto, Ontario M3J 1P3, Canada

The objective of this study was to investigate the effects of 5-aminoimidazole-4-carboxamide-1--D-ribofuranoside (AICAR)-induced AMP-activated protein kinase (AMPK) activation on basal and insulin-stimulated glucose and fatty acid metabolism in isolated rat adipocytes. AICAR-induced AMPK activation profoundly inhibited basal and insulin-stimulated glucose uptake, lipogenesis, glucose oxidation, and lactate production in fat cells. We also describe the novel findings that AICAR-induced AMPK phosphorylation significantly reduced palmitate (32%) and oleate uptake (41%), which was followed by a 50% reduction in palmitate oxidation despite a marked increase in AMPK and acetyl-CoA carboxylase phosphorylation. Compound C, a selective inhibitor of AMPK, not only completely prevented the inhibitory effect of AICAR on palmitate oxidation but actually caused a 2.2-fold increase in this variable. Compound C also significantly increased palmitate oxidation in the presence of inhibitory concentrations of malonyl-CoA and etomoxir indicating an increase in CPT1 activity. In contrast to skeletal muscle in which AMPK stimulates fatty acid oxidation to provide ATP as a fuel, we propose that AMPK activation inhibits lipogenesis and fatty acid oxidation in adipocytes. Inhibition of lipogenesis would conserve ATP under conditions of cellular stress, although suppression of intra-adipocyte oxidation would spare fatty acids for exportation to other tissues where their utilization is crucial for energy production. Additionally, the stimulatory effect of compound C on long chain fatty acid oxidation provides a novel pharmacological approach to promote energy dissipation in adipocytes, which may be of therapeutic importance for obesity and type II diabetes.

Received for publication, March 29, 2006 , and in revised form, June 28, 2006.

^* This work was supported in part by the National Science and Engineering Research Council via a Discovery grant (to R. B. C.). The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ Supported by a Canadian Institutes of Health Research Canada graduate scholarship, Master's award.

² Supported by a National Science and Engineering Research Council doctoral postgraduate scholarship.

³ To whom correspondence should be addressed. Tel.: 416-736-2100 (ext. 77204); Fax: 416-736-5774; E-mail: roceddia{at}yorku.ca.

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