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J. Biol. Chem., Vol. 280, Issue 24, 23024-23031, June 17, 2005

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LXR Is Required for Adipocyte Growth, Glucose Homeostasis, and Cell Function^*

Isabelle Gerin, Vernon W. Dolinsky, Jonathan G. Shackman¶, Robert T. Kennedy¶, Shian-Huey Chiang, Charles F. Burant||, Knut R. Steffensen**, Jan-Åke Gustafsson**, and Ormond A. MacDougald||

From the Departments of Molecular and Integrative Physiology, of ^¶Chemistry, and of ^||Internal Medicine, University of Michigan, Ann Arbor, Michigan 48109, Laboratoire de Chimie Physiologique, Université Catholique de Louvain, B-1200 Brussels, Belgium, and the ^**Department of Medical Nutrition and Biosciences, Karolinska Institutet, S-14157 Huddinge, Sweden

Liver X receptors (LXR) and are nuclear oxysterol receptors with established roles in cholesterol, lipid, and carbohydrate metabolism. Although LXRs have been extensively studied in liver and macrophages, the importance for development and metabolism of other tissues and cell types is not as well characterized. We demonstrate here that although LXR and LXR are not required for adipocyte development per se, LXR is required for the increase in adipocyte size that normally occurs with aging and diet-induced obesity. Similar food intake and oxygen consumption in LXR–/– mice suggests that reduced storage of lipid in adipose tissue is not due to altered energy balance. Despite reduced amounts of adipose tissue, LXR–/– mice on a chow diet have insulin sensitivity and levels of adipocyte hormones similar to wild type mice. However, these mice are glucose-intolerant due to impaired glucose-induced insulin secretion. Lipid droplets in pancreatic islets may result from accumulation of cholesterol esters as analysis of islet gene expression reveals that LXR is required for expression of the cholesterol transporters, ABCA1 and ABCG1. Our data establish novel roles for LXR in adipocyte growth, glucose homeostasis, and cell function.

Received for publication, November 8, 2004 , and in revised form, March 28, 2005.

^* This work was supported by grants from the National Institutes of Health to O.A.M. (DK51563 and DK62876) and to R.T.K (DK046960). Other support was from the Diabetes Research and Training Center (P60 DK20572), the Nathan Shock Mutant and Transgenic Rodent Core, the Swedish Research Council, and KaroBio AB. Fellowships were from Tissue Engineering and Regeneration Training Grant, Center for Organogenesis, a mentor-based postdoctoral fellowship from the American Diabetes Association, Eli Lilly Foundation, and the Belgian Fonds National de la Recherche Scientifique. 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 a supplemental figure showing that LXR–/– mice have increased blood glucose upon pyruvate challenge.

To whom correspondence should be addressed: Dept. of Molecular and Integrative Physiology, 7620 Medical Science II, 1301 E. Catherine Dr., Ann Arbor, MI 48109-0622. Tel.: 734-647-4880; Fax: 734-936-8813; E-mail: macdouga{at}umich.edu.

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