Critical roles of the p160 transcriptional coactivators p/CIP and SRC-1 in energy balance.
Several transcriptional coactivators have been implicated in modulating the transcriptional activities of nuclear hormone receptors in vitro. Potential roles of these cofactors in important physiological processes such as energy homeostasis remain unknown. We report here that a developmental arrest in interscapular brown fat and defective adaptive thermogenesis occur in mice lacking both the p160 family transcriptional coactivators SRC-1 and p/CIP due to a failure in induction of selective PPARgamma target genes involved in adipogenesis and mitochondrial uncoupling. In the absence of p/CIP and SRC-1, mice eat more food on both regular chow and a high-fat diet because of decreased blood leptin levels. However, the p/CIP(-/-)/SRC-1(-/-) mice are lean and resistant to high-fat-diet-induced obesity. They exhibit increased basal metabolic rates and heightened levels of physical activity. Therefore, p/CIP and SRC-1 play critical roles in energy balance by controlling both energy intake and energy expenditure.
Wang
Zhiyong
Z
Molecular and Cell Biology Laboratory, Salk Institute for Biological Studies, La Jolla, California 92037, USA. zwang@salk.edu
Qi
Chao
C
Krones
Anna
A
Woodring
Pamela
P
Zhu
Xiaoyan
X
Reddy
Janardan K
JK
Evans
Ronald M
RM
Rosenfeld
Michael G
MG
Hunter
Tony
T
D050156:Adipogenesis / Q000235:genetics; D002001:Adipose Tissue, Brown / Q000254:growth & development; D000818:Animals; D001481:Basal Metabolism / Q000235:genetics; D015152:Blotting, Northern; D047369:Chromatin Immunoprecipitation; D017931:DNA Primers; D004435:Eating / Q000235:genetics; D004734:Energy Metabolism / Q000235:genetics* / Q000502:physiology; D004797:Enzyme-Linked Immunosorbent Assay; D005786:Gene Expression Regulation / Q000235:genetics*; D051548:Histone Acetyltransferases / Q000235:genetics*; D006706:Homeostasis / Q000235:genetics* / Q000502:physiology; D020738:Leptin / Q000097:blood; D051379:Mice; D018345:Mice, Knockout; D009043:Motor Activity / Q000235:genetics; D056920:Nuclear Receptor Coactivator 1; D056921:Nuclear Receptor Coactivator 3; D022722:Thermogenesis / Q000235:genetics; D015534:Trans-Activators / Q000235:genetics*; D014157:Transcription Factors / Q000235:genetics*; D014280:Triglycerides / Q000097:blood
D017931:DNA Primers; D020738:Leptin; D015534:Trans-Activators; D014157:Transcription Factors; D014280:Triglycerides; D051548:Histone Acetyltransferases; C538861:Ncoa1 protein, mouse; C538867:Ncoa3 protein, mouse; D056920:Nuclear Receptor Coactivator 1; D056921:Nuclear Receptor Coactivator 3