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J. Biol. Chem., Vol. 283, Issue 5, 2906-2916, February 1, 2008

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Stearoyl-CoA Desaturase 2 Is Required for Peroxisome Proliferator-activated Receptor Expression and Adipogenesis in Cultured 3T3-L1 Cells^*

From the Program in Molecular Medicine, University of Massachusetts Medical School, Worcester, Massachusetts 01605

Based on recent evidence that fatty acid synthase and endogenously produced fatty acid derivatives are required for adipogenesis in 3T3-L1 adipocytes, we conducted a small interfering RNA-based screen to identify other fatty acid-metabolizing enzymes that may mediate this effect. Of 24 enzymes screened, stearoyl-CoA desaturase 2 (SCD2) was found to be uniquely and absolutely required for adipogenesis. Remarkably, SCD2 also controls the maintenance of adipocyte-specific gene expression in fully differentiated 3T3-L1 adipocytes, including the expression of SCD1. Despite the high sequence similarity between SCD2 and SCD1, silencing of SCD1 did not down-regulate 3T3-L1 cell differentiation or gene expression. SCD2 mRNA expression was also uniquely elevated 44-fold in adipose tissue upon feeding mice a high fat diet, whereas SCD1 showed little response. The inhibition of adipogenesis caused by SCD2 depletion was associated with a decrease in peroxisome proliferator-activated receptor (PPAR) mRNA and protein, whereas in mature adipocytes loss of SCD2 diminished PPAR protein levels, with little change in mRNA levels. In the latter case, SCD2 depletion did not change the degradation rate of PPAR protein but decreased the metabolic labeling of PPAR protein using [³⁵S]methionine/cysteine, indicating protein translation was decreased. This requirement of SCD2 for optimal protein synthesis in fully differentiated adipocytes was verified by polysome profile analysis, where a shift in the mRNA to monosomes was apparent in response to SCD2 silencing. These results reveal that SCD2 is required for the induction and maintenance of PPAR protein levels and adipogenesis in 3T3-L1 cells.

Received for publication, July 10, 2007 , and in revised form, October 26, 2007.

^* This work was supported by National Institutes of Health Grant DK30898, the Genomics and Bioinformatics Core Facilities of the University of Massachusetts Diabetes and Endocrinology Center (National Institutes of Health Grant DK32520), and the Diabetes Genome Anatomy Project (National Institutes of Health Grant DK60837). 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.

The on-line version of this article (available at http://www.jbc.org) contains supplemental Figs. 1 and 2 and Table 1.

¹ To whom correspondence should be addressed: Program in Molecular Medicine, University of Massachusetts Medical School, 373 Plantation St., Suite 100, Worcester, MA 01605. Tel.: 508-856-2254; Fax: 508-856-1617; E-mail: Michael.Czech{at}umassmed.edu.

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