title: Seipin differentially regulates lipogenesis and adipogenesis through a conserved core sequence and an evolutionarily acquired C-terminus.
abstract: Homozygous mutations in BSCL2 (Berardinelli-Seip congenital lipodystrophy)/seipin cause CGL2 (congenital generalized lipodystrophy type 2). Recent data suggest that seipin regulates LD (lipid droplet) dynamics and adipocyte differentiation, but whether these roles are mechanistically linked remains unclear. To understand how seipin regulates these processes, we investigated the evolutionary changes of seipin orthologues, and studied individual domains in regulating lipid accumulation in non-adipocytes and adipocytes. Mammalian seipins comprise at least two distinct functional domains, a conserved core sequence and an evolutionarily acquired C-terminus. Despite its requirement for adipocyte formation, seipin overexpression inhibited oleate-induced LD formation and accumulation in nonadipocytes, which was mediated by the core sequence. In contrast, seipin overexpression did not inhibit LD accumulation during adipocyte differentiation or the adipogenic process in 3T3-L1 cells. However, adipogenesis and LD accumulation were impaired in 3T3-L1 cells expressing a seipin mutant lacking the C-terminus. Furthermore, expression of the same mutant without the C-terminus failed to rescue the adipogenic defects in seipin-knockdown cells, demonstrating the importance of the C-terminus for seipin's function in adipocyte development. We propose that seipin is involved in lipid homoeostasis by restricting lipogenesis and LD accumulation in non-adipocytes, while promoting adipogenesis to accommodate excess energy storage.
authors: Laboratory of Metabolic Medicine, Singapore Bioimaging Consortium, 11 Biopolis Way, Singapore 138667.
authors: Wulin
authors: W
authors: Yang
authors: Shermaine
authors: S
authors: Thein
authors: Xiangxiang
authors: X
authors: Guo
authors: Feng
authors: F
authors: Xu
authors: Byrappa
authors: B
authors: Venkatesh
authors: Shigeki
authors: S
authors: Sugii
authors: George K
authors: GK
authors: Radda
authors: Weiping
authors: W
authors: Han
mesh_terms: D041721:3T3-L1 Cells; D017667:Adipocytes / Q000737:chemistry / Q000378:metabolism / Q000502:physiology; D050156:Adipogenesis / Q000502:physiology*; D000818:Animals; D017124:Conserved Sequence / Q000502:physiology*; D019143:Evolution, Molecular; D044388:GTP-Binding Protein gamma Subunits; D057809:HEK293 Cells; D020962:Heterotrimeric GTP-Binding Proteins / Q000502:physiology*; D006801:Humans; D050356:Lipid Metabolism / Q000502:physiology*; D008055:Lipids / Q000037:antagonists & inhibitors / Q000096:biosynthesis; D050155:Lipogenesis / Q000502:physiology*; D051379:Mice; D017434:Protein Structure, Tertiary / Q000502:physiology
chemical_list: C115783:Bscl2 protein, mouse; D044388:GTP-Binding Protein gamma Subunits; D008055:Lipids; D020962:Heterotrimeric GTP-Binding Proteins