The Orphan Nuclear Receptor, RORα, Regulates Gene Expression That Controls Lipid Metabolism
STAGGERER (SG/SG) MICE ARE RESISTANT TO DIET-INDUCED OBESITY*
- Patrick Lau1,
- Rebecca L. Fitzsimmons1,
- Suryaprakash Raichur2,
- Shu-Ching M. Wang,
- Adriane Lechtken and
- George E. O. Muscat3
- 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.
Abstract
Homozygous staggerer mice (sg/sg) display decreased and dysfunctional retinoic acid receptor-related orphan receptor α (RORα) 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 RORα 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-1α, 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 RORα 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.
Footnotes
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↵4 The abbreviations used are: sg, staggerer; RORα, retinoic acid receptor-related orphan receptor α; HDL, high density lipoprotein; HDL-c, HCL-cholesterol; ABCA1, ATP-binding cassette, subfamily A, member 1; ABCG1, ATP-binding cassette, subfamily G, member 1; SREBP-1c, sterol regulatory element-binding transcription factor 1, isoform c; FAS, fatty acid synthase; ChIP, chromatin immunoprecipitation; PGC-1β, peroxisome proliferator-activated receptor-γ, coactivator 1β; wt, wild type; ChREBP, carbohydrate response element-binding protein; LXR, liver X receptor; NR, nuclear receptor; NR4A, nuclear receptor subfamily 4, group A; LPL, lipoprotein lipase; ATGL, adipose triglyceride lipase; LUC, luciferase.
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↵* 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.
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↵1 Both authors contributed equally to this work.
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↵2 A recipient of an International Postgraduate Research Scholarship, Australia.
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- Received December 26, 2007.
- Revision received April 4, 2008.
- The American Society for Biochemistry and Molecular Biology, Inc.
