Prostaglandins promote and block adipogenesis through opposing effects on peroxisome proliferator-activated receptor gamma.
Fat cell differentiation is a critical aspect of obesity and diabetes. Dietary fatty acids are converted to arachidonic acid, which serves as precursor of prostaglandins (PGs). PGJ2 derivatives function as activating ligands for peroxisome proliferator-activated receptor gamma (PPAR gamma), a nuclear hormone receptor that is central to adipogenic determination. We report here that PGF2 alpha blocks adipogenesis through activation of mitogen-activated protein kinase, resulting in inhibitory phosphorylation of PPAR gamma. Both mitogen-activated protein kinase activation and PPAR gamma phosphorylation are required for the anti-adipogenic effects of PGF2 alpha. Thus, PG signals generated at a cell surface receptor regulate the program of gene expression required for adipogenesis by modulating the activity of a nuclear hormone receptor that is directly activated by other PG signals. The balance between PGF2 alpha and PGJ2 signaling may thus be central to the development of obesity and diabetes.
Reginato
M J
MJ
Department of Medicine, University of Pennsylvania Medical Center, Philadelphia 19104, USA.
Krakow
S L
SL
Bailey
S T
ST
Lazar
M A
MA
D016475:3T3 Cells; D017667:Adipocytes / Q000166:cytology*; D000818:Animals; D017871:Calcium-Calmodulin-Dependent Protein Kinases / Q000378:metabolism; D002454:Cell Differentiation / Q000187:drug effects; D015237:Dinoprost / Q000494:pharmacology*; D004789:Enzyme Activation; D051379:Mice; D008830:Microbodies / Q000378:metabolism*; D009687:Nuclear Proteins / Q000378:metabolism*; D010766:Phosphorylation; D015230:Prostaglandin D2 / Q000031:analogs & derivatives / Q000494:pharmacology; D011465:Prostaglandins, Synthetic / Q000494:pharmacology; D018160:Receptors, Cytoplasmic and Nuclear / Q000378:metabolism*; D014157:Transcription Factors / Q000378:metabolism*
D009687:Nuclear Proteins; D011465:Prostaglandins, Synthetic; D018160:Receptors, Cytoplasmic and Nuclear; D014157:Transcription Factors; C037112:9-deoxy-delta-9-prostaglandin D2; D015237:Dinoprost; D017871:Calcium-Calmodulin-Dependent Protein Kinases; D015230:Prostaglandin D2