Seipin differentially regulates lipogenesis and adipogenesis through a conserved core sequence and an evolutionarily acquired C-terminus

Homozygous mutations in BSCL2/seipin cause congenital generalized lipodystrophy type 2 (CGL2). Recent data suggest that seipin regulates lipid droplet (LD) 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 orthologs, 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 non-adipocytes, 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 controls lipid homeostasis by restricting lipogenesis and LD accumulation in non-adipocytes, while promoting adipogenesis to accommodate excess energy storage.

Source: BJ Cell - March 4, 2013 Category: Biochemistry Authors: W Yang, S Thein, X Guo, F Xu, B Venkatesh, S Sugii, G K. Radda, W Han Tags: BJ Cell Source Type: research