Prostaglandin F2α inhibits adipocyte differentiation via a Gαq-calcium-calcineurin-dependent signaling pathway

Abstract

Prostaglandin F2α (PGF2α) 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 PGF2α inhibits adipocyte differentiation via a signaling pathway that requires heterotrimeric G-protein Gαq 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/EBPβ. Instead, we find that PGF2α inhibits adipocyte differentiation via a calcineurin-dependent mechanism that acts to prevent the expression of the critical pro-adipogenic transcription factors PPARγ and C/EBPα. Furthermore, we demonstrate that the inhibitory effects of PGF2α on both the expression of PPARγ and C/EBPα and subsequent adipogenesis can be attenuated by treatment of preadipocytes with the histone deacetylase (HDAC) inhibitor trichostatin A. Taken together, these results indicate that PGF2α inhibits adipocyte differentiation via a Gαq-Ca2+-calcineurin-dependent signaling pathway that acts to block expression of PPARγ and C/EBPα by a mechanism that appears to involves an HDAC-sensitive step. © 2006 Wiley-Liss, Inc.