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J. Biol. Chem., Vol. 279, Issue 33, 35017-35024, August 13, 2004

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Reduced Adiposity and Liver Steatosis by Stearoyl-CoA Desaturase Deficiency Are Independent of Peroxisome Proliferator-activated Receptor-^*

Makoto Miyazaki, Agnieszka Dobrzyn, Harini Sampath, Seong-Ho Lee, Weng Chi Man, Kiki Chu, Jeffrey M. Peters¶, Frank J. Gonzalez||, and James M. Ntambi**

From the Departments of Biochemistry and Nutritional Sciences, University of Wisconsin, Madison, Wisconsin 53706, the ^¶Department of Veterinary Science and Center for Molecular Toxicology and Carcinogenesis, The Pennsylvania State University, University Park, Pennsylvania 16802, and ^||Laboratory of Metabolism, NCI, National Institutes of Health, Bethesda, Maryland 20892

Stearoyl-CoA desaturase catalyzes the rate-limiting step in the biosynthesis of monounsaturated fatty acids, which are required for normal rates of synthesis of triglycerides, cholesterol esters, and phospholipids. Mice with a targeted disruption of the stearoyl-CoA desaturase 1 (SCD1) isoform are protected against diet and leptin deficiency-induced adiposity, have increased energy expenditure, and have up-regulated expression of hepatic genes encoding enzymes of fatty acid -oxidation. Because peroxisome proliferator-activated receptor- (PPAR) is a key transcription factor that induces the transcription of fatty acid -oxidation and thermogenic genes, we hypothesized that the increased fatty acid oxidation observed in SCD1 deficiency is dependent on activation of the PPAR pathway. Here we show that mice nullizygous for SCD1 and PPAR are still protected against adiposity, have increased energy expenditure, and maintain high expression of PPAR target genes in the liver and brown adipose tissue. The SCD1 deficiency rescued hepatic steatosis of the PPAR^-/- mice. The SCD1 mutation increased the phosphorylation of both AMP-activated protein kinase and acetyl-CoA carboxylase, thereby increasing CPT activity and stimulating the oxidation of liver palmitoyl-CoA in the PPAR null mice. The findings indicate that the reduced adiposity, reduced liver steatosis, increased energy expenditure, and increased expression of PPAR target genes associated with SCD1 deficiency are independent of activation of the PPAR pathway.

Received for publication, May 12, 2004

^* This work was supported in part by National Institute of Health Grants RO1-DK62388 (to J. M. N.) and American Heart Association Postdoctoral Fellowship 0420051Z (to A. D.). 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.

^** To whom correspondence should be addressed: Dept. of Biochemistry, University of Wisconsin, 433 Babcock Dr., Madison, WI 53706. Tel.: 608-265-3700; Fax: 608-265-3272; E-mail: ntambi{at}biochem.wisc.edu.

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