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J. Biol. Chem., Vol. 283, Issue 21, 14355-14365, May 23, 2008

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Fat-specific Protein 27 Regulates Storage of Triacylglycerol^*

Pernille Keller¹², John T. Petrie¹³, Paul De Rose, Isabelle Gerin, Wendy S. Wright, Shian-Huey Chiang, Anders R. Nielsen^¶, Christian P. Fischer^¶, Bente K. Pedersen^¶, and Ormond A. MacDougald⁴

From the Department of Molecular and Integrative Physiology and Life Sciences Institute, University of Michigan, Ann Arbor, Michigan 48109 and ^¶Centre for Inflammation and Metabolism, Rigshospitalet, University of Copenhagen, Copenhagen DK-2100, Denmark

FSP27 (fat-specific protein 27) is a member of the cell death-inducing DNA fragmentation factor--like effector (CIDE) family. Although Cidea and Cideb were initially characterized as activators of apoptosis, recent studies have demonstrated important metabolic roles for these proteins. In this study, we investigated the function of another member of this family, FSP27 (Cidec), in apoptosis and adipocyte metabolism. Although overexpression of FSP27 is sufficient to increase apoptosis of 293T and 3T3-L1 cells, more physiological levels of expression stimulate spontaneous lipid accumulation in several cell types without induction of adipocyte genes. Increased triacylglycerol is likely due to decreased β-oxidation of nonesterified fatty acids. Altered flux of fatty acids into triacylglycerol may be a direct effect of FSP27 function, which is localized to lipid droplets in 293T cells and 3T3-L1 adipocytes. Stable knockdown of FSP27 during adipogenesis of 3T3-L1 cells substantially decreases lipid droplet size, increases mitochondrial and lipid droplet number, and modestly increases glucose uptake and lipolysis. Expression of FSP27 in subcutaneous adipose tissue of a human diabetes cohort decreases with total fat mass but is not associated with measures of insulin resistance (e.g. homeostasis model assessment). Together, these data indicate that FSP27 binds to lipid droplets and regulates their enlargement.

Received for publication, October 5, 2007 , and in revised form, March 10, 2008.

^* This work was supported, in whole or in part, by National Institutes of Health Grant DK62876 (to O. A. M.). This work was also supported by the Michigan Metabolomics and Obesity Center and by Danish Medical Research Council Grants 22-01-009 and 22-03-0367. 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 Fig. 1.

¹ Both authors contributed equally to this work.

² Supported by the Lundbeck Foundation and the Novo Nordisk Foundation and recipient of a travel grant from The Danish Research Agency.

³ Maas Fellow and supported by a Systems and Integrative Biology training grant.

⁴ To whom correspondence should be addressed: 7620 Med. Sci. II, 1301 E. Catherine St., Ann Arbor, MI 48109-0622. E-mail: macdouga{at}umich.edu.

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