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J. Biol. Chem., Vol. 283, Issue 26, 18411-18421, June 27, 2008

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The Orphan Nuclear Receptor, ROR, Regulates Gene Expression That Controls Lipid Metabolism

STAGGERER (SG/SG) MICE ARE RESISTANT TO DIET-INDUCED OBESITY^*

From the Institute for Molecular Bioscience, University of Queensland, Queensland 4072, Australia

Homozygous staggerer mice (sg/sg) display decreased and dysfunctional retinoic acid receptor-related orphan receptor (ROR) expression. We observed decreases in serum (and liver) triglycerides and total and high density lipoprotein serum cholesterol in sg/sg mice. Moreover, the sg/sg mice were characterized by reduced adiposity (associated with decreased fat pad mass and adipocyte size). Candidate-based expression profiling demonstrated that the dyslipidemia in sg/sg mice is associated with decreased hepatic expression of SREBP-1c, and the reverse cholesterol transporters, ABCA1 and ABCG1. This is consistent with the reduced serum lipids. The molecular mechanism did not involve aberrant expression of LXR and/or ChREBP. However, ChIP and transfection analyses revealed that ROR is recruited to and regulates the activity of the SREBP-1c promoter. Furthermore, the lean phenotype in sg/sg mice is also characterized by significantly increased expression of PGC-1, PGC-1β, and lipin1 mRNA in liver and white and brown adipose tissue from sg/sg mice. In addition, we observed a significant 4-fold increase in β₂-adrenergic receptor mRNA in brown adipose tissue. Finally, dysfunctional ROR expression protects against diet-induced obesity. Following a 10-week high fat diet, wild-type but not sg/sg mice exhibited a 20% weight gain, increased hepatic triglycerides, and notable white and brown adipose tissue accumulation. In summary, these changes in gene expression (that modulate lipid homeostasis) in metabolic tissues are involved in decreased adiposity and resistance to diet-induced obesity in the sg/sg mice, despite hyperphagia. In conclusion, we suggest this orphan nuclear receptor is a key modulator of fat accumulation and that selective ROR modulators may have utility in the treatment of obesity.

Received for publication, December 26, 2007 , and in revised form, April 4, 2008.

^* This work was supported in part by a National Health and Medical Research Council (NHMRC) project grant. 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.

¹ Both authors contributed equally to this work.

² A recipient of an International Postgraduate Research Scholarship, Australia.

³ A Principal Research Fellow of the NHMRC of Australia. To whom correspondence should be addressed. Tel.: 61-7-3346-2222; Fax: 61-7-3346-2101; E-mail: g.muscat{at}imb.uq.edu.au.

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