Prostaglandin F2alpha inhibits adipocyte differentiation via a G alpha q-calcium-calcineurin-dependent signaling pathway.
Prostaglandin F2alpha (PGF2alpha) is a potent physiological inhibitor of adipocyte differentiation, however the specific signaling pathways and molecular mechanisms involved in mediating its anti-adipogenic effects are not well understood. In the current study, we now provide evidence that PGF2alpha inhibits adipocyte differentiation via a signaling pathway that requires heterotrimeric G-protein G alpha q subunits, the elevation of the intracellular calcium concentration ([Ca2+]i), and the activation of the Ca2+/calmodulin-regulated serine/threonine phosphatase calcineurin. We show that while this pathway acts to inhibit an early step in the adipogenic cascade, it does not interfere with the initial mitotic clonal expansion phase of adipogenesis, nor does it affect either the expression, DNA binding activity or differentiation-induced phosphorylation of the early transcription factor C/EBPbeta. Instead, we find that PGF2alpha inhibits adipocyte differentiation via a calcineurin-dependent mechanism that acts to prevent the expression of the critical pro-adipogenic transcription factors PPARgamma and C/EBPalpha. Furthermore, we demonstrate that the inhibitory effects of PGF2alpha on both the expression of PPARgamma and C/EBPalpha and subsequent adipogenesis can be attenuated by treatment of preadipocytes with the histone deacetylase (HDAC) inhibitor trichostatin A. Taken together, these results indicate that PGF2alpha inhibits adipocyte differentiation via a G alpha q-Ca2+-calcineurin-dependent signaling pathway that acts to block expression of PPARgamma and C/EBPalpha by a mechanism that appears to involves an HDAC-sensitive step.
Liu
Li
L
Department of Microbiology-Immunology, Feinberg School of Medicine, Northwestern University, 303 East Chicago Avenue, Chicago, Illinois 60611, USA.
Clipstone
Neil A
NA
D041721:3T3-L1 Cells; D017667:Adipocytes / Q000166:cytology* / Q000378:metabolism; D000818:Animals; D022763:CCAAT-Enhancer-Binding Protein-alpha / Q000378:metabolism; D022782:CCAAT-Enhancer-Binding Protein-beta / Q000378:metabolism; D019703:Calcineurin / Q000502:physiology*; D002118:Calcium / Q000502:physiology*; D002454:Cell Differentiation; D015237:Dinoprost / Q000502:physiology*; D043802:GTP-Binding Protein alpha Subunits, Gq-G11 / Q000502:physiology*; D056572:Histone Deacetylase Inhibitors; D006655:Histone Deacetylases / Q000378:metabolism; D006877:Hydroxamic Acids / Q000378:metabolism; D051379:Mice; D047495:PPAR gamma / Q000378:metabolism; D010766:Phosphorylation; D015398:Signal Transduction
D022763:CCAAT-Enhancer-Binding Protein-alpha; D022782:CCAAT-Enhancer-Binding Protein-beta; D056572:Histone Deacetylase Inhibitors; D006877:Hydroxamic Acids; D047495:PPAR gamma; C012589:trichostatin A; D015237:Dinoprost; D019703:Calcineurin; D006655:Histone Deacetylases; D043802:GTP-Binding Protein alpha Subunits, Gq-G11; D002118:Calcium