The orphan nuclear receptor, RORα, regulates gene expression that controls lipid metabolism -: Staggerer (sg/sg) mice are resistant to diet-induced obesity

被引:153
作者
Lau, Patrick [1 ]
Fitzsimmons, Rebecca L. [1 ]
Raichur, Suryaprakash [1 ]
Wang, Shu-Ching M. [1 ]
Lechtken, Adriane [1 ]
Muscat, George E. O. [1 ]
机构
[1] Univ Queensland, Inst Mol Biosci, Brisbane, Qld 4072, Australia
关键词
D O I
10.1074/jbc.M710526200
中图分类号
Q5 [生物化学]; Q7 [分子生物学];
学科分类号
071010 ; 081704 ;
摘要
Homozygous staggerer mice (sg/sg) display decreased and dysfunctional retinoic acid receptor-related orphan receptor alpha (ROR alpha) 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 alpha 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 alpha, PGC-1 alpha, 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 beta(2)-adrenergic receptor mRNA in brown adipose tissue. Finally, dysfunctional ROR alpha expression protects against diet-induced obesity. Following a 10-week high fat diet, wild-type but not sg/sg mice exhibited a similar to 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.
引用
收藏
页码:18411 / 18421
页数:11
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