SEIPIN regulates lipid droplet expansion and adipocyte development by modulating the activity of glycerol-3-phosphate acyltransferase

Summary Berardinelli-Seip congenital lipodystrophy2 ( BSCL2) is caused by loss-of-function mutations in SEIPIN, a protein implicated in both adipogenesisand lipid dropletexpansion but whose molecular function remains obscure. Here, we identify physical and functional interactions between SEIPINand microsomal isoforms of glycerol-3-phosphate acyltransferase(GPAT) in multiple organisms. Compared to controls, GPAT activity was elevated in SEIPIN-deficient cells and tissues and GPAT kinetic values were altered. Increased GPAT activity appears to underpin the block in adipogenesisand abnormal lipid dropletmorphology associated with SEIPINloss. Overexpression of Gpat3 blocked adipogenesis, and Gpat3 knockdown in SEIPIN-deficient preadipocytes partially restored differentiation. GPAT overexpression in yeast, preadipocytes, and fly salivary glands also formed supersized lipid droplets. Finally, pharmacological inhibition of GPAT in Seipin−/− mouse preadipocytes partially restored adipogenesis. These data identify SEIPINas an evolutionarily conserved regulator of microsomal GPAT and suggest that GPAT inhibitors might be useful for the treatment of human BSCL2patients.