title: The human lipodystrophy gene BSCL2/seipin may be essential for normal adipocyte differentiation.
abstract: OBJECTIVE
  Berardinelli-Seip congenital lipodystrophy type 2 (BSCL2) is a recessive disorder featuring near complete absence of adipose tissue. Remarkably, although the causative gene, BSCL2, has been known for several years, its molecular function and its role in adipose tissue development have not been elucidated. Therefore, we examined whether BSCL2 is involved in the regulation of adipocyte differentiation and the mechanism whereby pathogenic mutations in BSCL2 cause lipodystrophy.
  
  
  METHODS
  Following the characterization of BSCL2 expression in developing adipocytes, C3H10T1/2 mesenchymal stem cells were generated in which BSCL2 expression was knocked down using short hairpin RNA (shRNA). These cells were used to investigate whether BSCL2 is required for adipogenesis. BSCL2 constructs harboring pathogenic mutations known to cause lipodystrophy were also generated and characterized.
  
  
  RESULTS
  BSCL2 expression was strongly induced during adipocyte differentiation, and the induction of BSCL2 expression was essential for adipogenesis to occur. The initial induction of key adipogenic transcription factors, including peroxisome proliferator-activated receptor (PPAR)gamma and CAAT/enhancer-binding protein-alpha, was preserved in cells lacking BSCL2. However, the expression of these critical factors was not sustained, suggesting that the activity of PPARgamma was impaired. Moreover, expression of key genes mediating triglyceride synthesis, including AGPAT2, lipin 1, and DGAT2, was persistently reduced and lipid accumulation was inhibited. Analysis of pathogenic missense mutants of BSCL2 revealed that the amino acid substitution A212P causes aberrant targeting of BSCL2 within the cell, suggesting that subcellular localization of BSCL2 may be critical to its function.
  
  
  CONCLUSIONS
  This study demonstrates that BSCL2 is an essential, cell-autonomous regulator of adipogenesis.
authors.affiliation: University of Cambridge Metabolic Research Laboratories, Institute of Metabolic Science, Addenbrooke's Hospital, Cambridge, UK.
authors.forename: Victoria A
authors.initials: VA
authors.lastname: Payne
authors.forename: Neil
authors.initials: N
authors.lastname: Grimsey
authors.forename: Antoinette
authors.initials: A
authors.lastname: Tuthill
authors.forename: Sam
authors.initials: S
authors.lastname: Virtue
authors.forename: Sarah L
authors.initials: SL
authors.lastname: Gray
authors.forename: Edoardo
authors.initials: E
authors.lastname: Dalla Nora
authors.forename: Robert K
authors.initials: RK
authors.lastname: Semple
authors.forename: Stephen
authors.initials: S
authors.lastname: O'Rahilly
authors.forename: Justin J
authors.initials: JJ
authors.lastname: Rochford
mesh_terms: D017667:Adipocytes / Q000166:cytology / Q000378:metabolism*; D050156:Adipogenesis / Q000235:genetics; D000818:Animals; D015153:Blotting, Western; D002454:Cell Differentiation / Q000235:genetics*; D002460:Cell Line; D002478:Cells, Cultured; D005455:Fluorescent Antibody Technique; D044388:GTP-Binding Protein gamma Subunits / Q000235:genetics* / Q000378:metabolism; D006801:Humans; D008060:Lipodystrophy / Q000235:genetics*; D008297:Male; D059630:Mesenchymal Stem Cells / Q000166:cytology / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D034741:RNA, Small Interfering / Q000235:genetics; D012190:Retroviridae / Q000235:genetics; D020133:Reverse Transcriptase Polymerase Chain Reaction
chemical_list: C432679:BSCL2 protein, human; D044388:GTP-Binding Protein gamma Subunits; D012333:RNA, Messenger; D034741:RNA, Small Interfering