title: Function of seipin: new insights from Bscl2/seipin knockout mouse models.
abstract: Mutations in BSCL2/seipin cause Berardinelli-Seip congenital lipodystrophy (BSCL), a rare recessive disorder characterized by near absence of adipose tissue and severe insulin resistance. Since the discovery of the gene in 2001, several cellular studies intended to unravel the biological function of seipin and revealed that seipin-deficiency alters adipocyte differentiation and lipid droplet morphology. However, the exact function of the protein remains unclear and the pathophysiology of BSCL in patients carrying BSCL2/seipin mutations is poorly understood. A major breakthrough in the field of seipin came recently, with the demonstration by three independent groups that Bscl2-deficient mice (Bscl2(-/-)) developed severe lipodystrophy with only residual white and brown fat pads, validating a critical role for seipin in adipose tissue homeostasis. Using in vivo, ex vivo and in vitro methods, these studies demonstrate that seipin plays a key role in adipogenesis, lipid droplet homeostasis and cellular triglyceride lipolysis. In addition to adipose tissue impairment, Bscl2(-/-) mice are diabetic and display severe hepatic steatosis. Treatment with thiazolidinediones (TZD) in Bscl2(-/-) mice increases adipose tissue mass and partially rescues the metabolic complications associated with BSCL, highlighting that lipoatrophy is the major cause of the BSCL phenotype. Except an unexpected hypotriglyceridemia, Bscl2(-/-) mice phenotype represents an almost perfect picture of the human disease. This review analyses how these studies using Bscl2(-/-) mice brought new insights into seipin function and the mechanisms involved in the pathophysiology of BSCL. We also analyse some of the human data in the light of the mouse phenotyping and discuss the validity of Bscl2(-/-) mice model to test pharmaceutical approaches for treating BSCL and its associated metabolic complications.
authors.affiliation: INSERM UMR 1087, IRS-UN, 8 quai Moncousu, BP 70721, 44007 Nantes Cedex 1, France.
authors.forename: Lucile
authors.initials: L
authors.lastname: Dollet
authors.forename: Jocelyne
authors.initials: J
authors.lastname: Magré
authors.forename: Bertrand
authors.initials: B
authors.lastname: Cariou
authors.forename: Xavier
authors.initials: X
authors.lastname: Prieur
mesh_terms: D017667:Adipocytes / Q000502:physiology; D000273:Adipose Tissue / Q000378:metabolism* / Q000473:pathology; D000818:Animals; D002454:Cell Differentiation; D044388:GTP-Binding Protein gamma Subunits; D020962:Heterotrimeric GTP-Binding Proteins / Q000235:genetics* / Q000378:metabolism; D006706:Homeostasis; D006801:Humans; D050356:Lipid Metabolism; D052497:Lipodystrophy, Congenital Generalized / Q000378:metabolism*; D051379:Mice; D018345:Mice, Knockout; D010641:Phenotype
chemical_list: C115783:Bscl2 protein, mouse; D044388:GTP-Binding Protein gamma Subunits; D020962:Heterotrimeric GTP-Binding Proteins
keywords: Adipocyte differentiation; Bscl2/seipin; Lipid droplet; Lipodystrophy; Mouse embryonic fibroblasts; Thiazolidinedione