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

Lau, Patrick, Fitzsimmons, Rebecca L., Raichur, Suryaprakash, Wang, Shu-Ching M., Lechtken, Adriane and Muscat, George E. O. (2008) The orphan nuclear receptor, ROR alpha, regulates gene expression that controls lipid metabolism - Staggerer (sg/sg) mice are resistant to diet-induced obesity. The Journal of Biological Chemistry, 283 26: 18411-18421. doi:10.1074/jbc.M710526200

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Author Lau, Patrick
Fitzsimmons, Rebecca L.
Raichur, Suryaprakash
Wang, Shu-Ching M.
Lechtken, Adriane
Muscat, George E. O.
Title The orphan nuclear receptor, ROR alpha, regulates gene expression that controls lipid metabolism - Staggerer (sg/sg) mice are resistant to diet-induced obesity
Journal name The Journal of Biological Chemistry   Check publisher's open access policy
ISSN 0021-9258
Publication date 2008-06-27
Year available 2008
Sub-type Article (original research)
DOI 10.1074/jbc.M710526200
Open Access Status File (Publisher version)
Volume 283
Issue 26
Start page 18411
End page 18421
Total pages 10
Place of publication Bethesda, MD, USA
Publisher American Society for Biochemistry & Molecular Biology
Language eng
Subject C1
060405 Gene Expression (incl. Microarray and other genome-wide approaches)
060104 Cell Metabolism
920106 Endocrine Organs and Diseases (excl. Diabetes)
Abstract 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.
Keyword Biochemistry & Molecular Biology
Biochemistry & Molecular Biology
BIOCHEMISTRY & MOLECULAR BIOLOGY
Q-Index Code C1
Q-Index Status Confirmed Code
Institutional Status UQ

Document type: Journal Article
Sub-type: Article (original research)
Collections: 2009 Higher Education Research Data Collection
Institute for Molecular Bioscience - Publications
 
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Created: Tue, 14 Apr 2009, 21:08:33 EST by Cody Mudgway on behalf of Institute for Molecular Bioscience