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J. Biol. Chem., Vol. 283, Issue 41, 27688-27697, October 10, 2008

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Inactivation of UCP1 and the Glycerol Phosphate Cycle Synergistically Increases Energy Expenditure to Resist Diet-induced Obesity^*

From the Pennington Biomedical Research Center, Baton Rouge, Louisiana 70808

Our current paradigm for obesity assumes that reduced thermogenic capacity increases susceptibility to obesity, whereas enhanced thermogenic capacity protects against obesity. Here we report that elimination of two major thermogenic pathways encoded by the mitochondrial uncoupling protein (Ucp1) and mitochondrial glycerol-3-phosphate dehydrogenase (Gdm) result in mice with increased resistance to diet-induced obesity when housed at 28 °C, provided prior adaptation occurred at 20 °C. Obesity resistant Gdm^-/-·Ucp1^-/- mice maintained at 28 °C have increased energy expenditure, in part through conversion of white to brown adipocytes in inguinal fat. Increased oxygen consumption in inguinal fat cell suspensions and the up-regulation of genes of mitochondrial function and fat metabolism indicated increased thermogenic activity, despite the absence of UCP1, whereas liver and skeletal muscle showed no changes in gene expression. Additionally, comparisons of energy expenditure in UCP1-deficient and wild type mice fed an obesogenic diet indicates that UCP1-based brown fat-based thermogenesis plays no role in so-called diet-induced thermogenesis. Accordingly, a new paradigm for obesity emerges in which the inactivation of major thermogenic pathways force the induction of alternative pathways that increase metabolic inefficiency.

Received for publication, June 3, 2008 , and in revised form, July 8, 2008.

^* This work was supported, in whole or in part, by National Institutes of Health Grant R01-HD08431. This work was also supported by Clinical Nutrition Research Unit (CNRU) and COBRE Center Grants P-30 DK072476 and P20-RR021945, respectively. 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 Tables S1–S10 and Fig. S1.

¹ Present address: Institute of Experimental Endocrinology, Slovak Academy of Sciences, Vlarska 3, 833 06, Bratislava, Slovak Republic.

² To whom correspondence should be addressed: Pennington Biomedical Research Center, 6400 Perkins Rd., Baton Rouge, LA 70808. Tel.: 225-763-2771; Fax: 225-763-0273; E-mail: kozaklp{at}pbrc.edu.

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