Regulation of hepatic PPARgamma2 and lipogenic gene expression by melanocortin.
The central melanocortin system regulates hepatic lipid metabolism. Hepatic lipogenic gene expression is regulated by transcription factors including sterol regulatory element-binding protein 1c (SREBP-1c), carbohydrate responsive element-binding protein (ChREBP), and peroxisome proliferator-activated receptor gamma2 (PPARgamma2). However, it is unclear if central melanocortin signaling regulates hepatic lipogenic gene expression through the activation of these transcription factors. To delineate the molecular mechanisms by which the melanocortin system regulates hepatic lipid metabolism, we examined the effect of intracerebroventricular injection of SHU9119, a melanocortin receptor antagonist, on hepatic expression levels of genes involved in lipid metabolism in mice. SHU9119 treatment increased hepatic triglyceride content and mRNA levels of lipogenic genes, SREBP-1c, and PPARgamma2, whereas it did not cause any changes in hepatic ChREBP mRNA levels. These findings suggest that reduced central melanocortin signaling increases hepatic lipid deposition by stimulating hepatic lipogenic gene expression at least partly through the activation of SREBP-1c and PPARgamma2.
Poritsanos
Nicole J
NJ
Department of Physiology, University of Manitoba, 730 William Avenue, Winnipeg, MB, Canada R3E 3J7.
Wong
Davie
D
Vrontakis
Maria E
ME
Mizuno
Tooru M
TM
D052436:Adipose Tissue, White / Q000378:metabolism; D000818:Animals; D051778:Basic Helix-Loop-Helix Leucine Zipper Transcription Factors; D005786:Gene Expression Regulation; D050155:Lipogenesis / Q000187:drug effects / Q000235:genetics*; D008099:Liver / Q000187:drug effects / Q000378:metabolism*; D008297:Male; D053486:Melanocortins / Q000378:metabolism*; D009074:Melanocyte-Stimulating Hormones / Q000494:pharmacology; D051379:Mice; D008810:Mice, Inbred C57BL; D009687:Nuclear Proteins / Q000235:genetics / Q000378:metabolism; D047495:PPAR gamma / Q000235:genetics*; D044101:Receptors, Melanocortin / Q000037:antagonists & inhibitors / Q000378:metabolism; D015398:Signal Transduction; D051780:Sterol Regulatory Element Binding Protein 1 / Q000235:genetics / Q000378:metabolism; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism; D014280:Triglycerides
D051778:Basic Helix-Loop-Helix Leucine Zipper Transcription Factors; D053486:Melanocortins; C506001:Mlxipl protein, mouse; D009687:Nuclear Proteins; D047495:PPAR gamma; D044101:Receptors, Melanocortin; C497388:Srebf1 protein, mouse; D051780:Sterol Regulatory Element Binding Protein 1; D014157:Transcription Factors; D014280:Triglycerides; C103272:SHU 9119; D009074:Melanocyte-Stimulating Hormones