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J. Biol. Chem., Vol. 283, Issue 24, 16514-16524, June 13, 2008
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AMP-activated Protein Kinase Is Activated as a Consequence of Lipolysis in the Adipocyte
POTENTIAL MECHANISM AND PHYSIOLOGICAL RELEVANCE*
11
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From the
Diabetes and Metabolism Unit, Department of Medicine Section of Endocrinology, Boston University Medical Center, Boston, Massachusetts 02118, Jean Mayer United States Department of Agriculture Human Nutrition Research Center on Aging, Tufts University, Boston, Massachusetts 02111, ¶Hokkaido University Graduate School of Medicine, Sapporo 060-8638, Japan, ||Novartis Institutes for BioMedical Research, Cambridge, Massachusetts 02139, and the **Department of Pathology and Laboratory Medicine, Boston University School of Medicine, Boston, Massachusetts 02140
AMP-activated protein kinase (AMPK) is activated in adipocytes during exercise and other states in which lipolysis is stimulated. However, the mechanism(s) responsible for this effect and its physiological relevance are unclear. To examine these questions, 3T3-L1 adipocytes were treated with cAMP-inducing agents (isoproterenol, forskolin, and isobutylmethylxanthine), which stimulate lipolysis and activate AMPK. When lipolysis was partially inhibited with the general lipase inhibitor orlistat, AMPK activation by these agents was also partially reduced, but the increases in cAMP levels and cAMP-dependent protein kinase (PKA) activity were unaffected. Likewise, small hairpin RNA-mediated silencing of adipose tissue triglyceride lipase inhibited both forskolin-stimulated lipolysis and AMPK activation but not that of PKA. Forskolin treatment increased the AMP:ATP ratio, and this too was reduced by orlistat. When acyl-CoA synthetase, which catalyzes the conversion of fatty acids to fatty acyl-CoA, was inhibited with triacsin C, the increases in both AMPK activity and AMP:ATP ratio were blunted. Isoproterenol-stimulated lipolysis was accompanied by an increase in oxidative stress, an effect that was quintupled in cells incubated with the AMPK inhibitor compound C. The isoproterenol-induced increase in the AMP:ATP ratio was also much greater in these cells. In conclusion, the results indicate that activation of AMPK in adipocytes by cAMP-inducing agents is a consequence of lipolysis and not of PKA activation. They suggest that AMPK activation in this setting is caused by an increase in the AMP:ATP ratio that appears to be due, at least in part, to the acylation of fatty acids. Finally, this AMPK activation appears to restrain the energy depletion and oxidative stress caused by lipolysis.
Received for publication, October 2, 2007 , and in revised form, March 31, 2008.
* This work was supported, in whole or in part, by National Institutes of Health Grants RO1DK19514, RO1DK067509, PO1HL68758 (to N. B. R.), and RO1DK50647 (to A. S. G.). This work was also supported by United States Department of Agriculture Agriculture Research Service Co-operative Agreement Contract 58-1950-7-707 and a grant from the Robert C. and Veronica Atkins Foundation (to A. S. G.). 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 postdoctoral research fellowship from Fonds de la Recherche en Santé du Québec.
1 To whom correspondence should be addressed: Diabetes and Metabolism Research Unit, Boston University School of Medicine, 650 Albany St., Rm. 820, Boston, MA 02118. Tel.: 617-638-7191; Fax: 617-638-7094; E-mail: msgauth{at}bu.edu or ms.gauthier{at}gmail.com.
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