Anandamide-derived Prostamide F2α Negatively Regulates Adipogenesis

Lipid mediators variedly affect adipocyte differentiation. Anandamide stimulates adipogenesis via CB 1 receptors and peroxisome proliferator-activated receptor γ. Anandamide may be converted by PTGS2 (COX2) and prostaglandin F synthases, such as prostamide/prostaglandin F synthase, to prostaglandin F 2α ethanolamide (PGF 2α EA), of which bimatoprost is a potent synthetic analog. PGF 2α EA/bimatoprost act via prostaglandin F 2α FP receptor/FP alt4 splicing variant heterodimers. We investigated whether prostamide signaling occurs in preadipocytes and controls adipogenesis. Exposure of mouse 3T3-L1 or human preadipocytes to PGF 2α EA/bimatoprost during early differentiation inhibits adipogenesis. PGF 2α EA is produced from anandamide in preadipocytes and much less so in differentiating adipocytes, which express much less PTGS2, FP, and its alt4 splicing variant. Selective antagonism of PGF 2α EA receptors counteracts prostamide effects on adipogenesis, as does inhibition of ERK1/2 phosphorylation. Selective inhibition of PGF 2α EA versus prostaglandin F 2α biosynthesis accelerates adipogenesis. PGF 2α EA levels are reduced in the white adipose tissue of high fat diet-fed mice where there is a high requirement for new adipocytes. Prostamides also inhibit zebrafish larval adipogenesis in vivo . We propose that prostamide signaling in preadipocytes is a novel anandamide-derived antiadipogenic mechanism. Background: Adipogenesis is the process by which adipocytes are formed to maintain or expand fat depots. Results: Prostaglandin F 2α ethanolamide (PGF 2α EA) is produced from anandamide in preadipocytes and inhibits adipogenesis. Conclusion: Conversion of proadipogenic anandamide to antiadipogenic PGF 2α EA is a novel mechanism for the regulation of adipogenesis. Significance: Discovering a PGF 2α EA-mediated negative regulatory mechanism over adipogenesis may lead to the development of antiobesity therapies.