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Science 12 July 2002:
Vol. 297. no. 5579, pp. 240 - 243
DOI: 10.1126/science.1071527
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Reports

Role for Stearoyl-CoA Desaturase-1 in Leptin-Mediated Weight Loss

Paul Cohen,1 Makoto Miyazaki,5 Nicholas D. Socci,12 Aaron Hagge-Greenberg,1 Wolfgang Liedtke,1 Alexander A. Soukas,1 Ratnendra Sharma,1 Lisa C. Hudgins,3 James M. Ntambi,56 Jeffrey M. Friedman14*

Leptin elicits a metabolic response that cannot be explained by its anorectic effects alone. To examine the mechanism underlying leptin's metabolic actions, we used transcription profiling to identify leptin-regulated genes in ob/ob liver. Leptin was found to specifically repress RNA levels and enzymatic activity of hepatic stearoyl-CoA desaturase-1 (SCD-1), which catalyzes the biosynthesis of monounsaturated fatty acids. Mice lacking SCD-1 were lean and hypermetabolic. ob/ob mice with mutations in SCD-1 were significantly less obese than ob/ob controls and had markedly increased energy expenditure. ob/ob mice with mutations in SCD-1 had histologically normal livers with significantly reduced triglyceride storage and VLDL (very low density lipoprotein) production. These findings suggest that down-regulation of SCD-1 is an important component of leptin's metabolic actions.

1 Laboratory of Molecular Genetics,
2 Center for Studies in Physics and Biology,
3 Rogosin Institute,
4 Howard Hughes Medical Institute, The Rockefeller University, 1230 York Avenue, New York, NY 10021, USA.
5 Department of Biochemistry and
6 Department of Nutritional Sciences, University of Wisconsin, Madison, WI 53706, USA.
*   To whom correspondence should be addressed. E-mail: friedj{at}rockvax.rockefeller.edu

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Dwarfism and Impaired Gut Development in Insulin-Like Growth Factor II mRNA-Binding Protein 1-Deficient Mice.
T. V. O. Hansen, N. A. Hammer, J. Nielsen, M. Madsen, C. Dalbaeck, U. M. Wewer, J. Christiansen, and F. C. Nielsen (2004)
Mol. Cell. Biol. 24, 4448-4464
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Stearoyl-CoA desaturase 1 deficiency increases fatty acid oxidation by activating AMP-activated protein kinase in liver.
P. Dobrzyn, A. Dobrzyn, M. Miyazaki, P. Cohen, E. Asilmaz, D. G. Hardie, J. M. Friedman, and J. M. Ntambi (2004)
PNAS 101, 6409-6414
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Efficacy of Recombinant Methionyl Human Leptin Therapy for the Extreme Insulin Resistance of the Rabson-Mendenhall Syndrome.
E. Cochran, J. R. Young, N. Sebring, A. DePaoli, E. A. Oral, and P. Gorden (2004)
J. Clin. Endocrinol. Metab. 89, 1548-1554
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Defective uptake of triglyceride-associated fatty acids in adipose tissue causes the SREBP-1c-mediated induction of lipogenesis.
E. M. Wagner, D. Kratky, G. Haemmerle, A. Hrzenjak, G. M. Kostner, E. Steyrer, and R. Zechner (2004)
J. Lipid Res. 45, 356-365
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Update on Adipocyte Hormones: Regulation of Energy Balance and Carbohydrate/Lipid Metabolism.
P. J. Havel (2004)
Diabetes 53, S143-151
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