title: Suppression of adipogenesis by pathogenic seipin mutant is associated with inflammatory response.
abstract: BACKGROUND
  While pathogenic mutations in BSCL2/Seipin cause congenital generalized lipodystrophy, the underlying mechanism is largely unknown. In this study, we investigated whether and how the pathogenic missense A212P mutation of Seipin (Seipin-A212P) inhibits adipogenesis.
  
  
  RESULTS
  We analyzed gene expression and lipid accumulation in stable 3T3-L1 cell lines expressing wild type (3T3-WT), non-lipodystrophic mutants N88S (3T3-N88S) and S90L (3T3-S90L), or lipodystrophic mutant A212P Seipin (3T3-A212P). When treated with adipogenic cocktail, 3T3-WT, 3T3-N88S and 3T3-S90L cells exhibited proper differentiation into mature adipocytes, indistinguishable from control 3T3-L1 cells. In contrast, adipogenesis was significantly impaired in 3T3-A212P cells. The defective adipogenesis in 3T3-A212P cells could be partially rescued by either PPARγ agonist or PPARγ overexpression. Gene expression profiling by microarray revealed that inhibition of adipogenesis was associated with activation of inflammatory genes including IL-6 and iNOS. We further demonstrated that Seipin-A212P expression at pre-differentiation stages significantly activated inflammatory responses by using an inducible expression system. The inflammation-associated inhibition of adipogenesis could be rescued by treatment with anti-inflammatory agents.
  
  
  CONCLUSIONS
  These results suggest that pathogenic Seipin-A212P inhibits adipogenesis and the inhibition is associated with activation of inflammatory pathways at pre-differentiation stages. Use of anti-inflammatory drugs may be a potential strategy for the treatment of lipodystrophy.
authors.affiliation: Laboratory of Metabolic Medicine, Singapore Bioimaging Consortium, Agency for Science, Technology and Research, Singapore, Republic of Singapore.
authors.forename: Wenjie
authors.initials: W
authors.lastname: Qiu
authors.forename: Kenneth
authors.initials: K
authors.lastname: Wee
authors.forename: Kosuke
authors.initials: K
authors.lastname: Takeda
authors.forename: Xuemei
authors.initials: X
authors.lastname: Lim
authors.forename: Shigeki
authors.initials: S
authors.lastname: Sugii
authors.forename: George K
authors.initials: GK
authors.lastname: Radda
authors.forename: Weiping
authors.initials: W
authors.lastname: Han
mesh_terms: D041721:3T3-L1 Cells; D017667:Adipocytes / Q000201:enzymology* / Q000473:pathology; D050156:Adipogenesis; D019943:Amino Acid Substitution; D000818:Animals; D000893:Anti-Inflammatory Agents / Q000494:pharmacology / Q000627:therapeutic use; D002454:Cell Differentiation; D044388:GTP-Binding Protein gamma Subunits; D020869:Gene Expression Profiling; D015971:Gene Expression Regulation, Enzymologic / Q000187:drug effects / Q000235:genetics; D020962:Heterotrimeric GTP-Binding Proteins / Q000096:biosynthesis* / Q000235:genetics; D007249:Inflammation / Q000188:drug therapy / Q000201:enzymology / Q000473:pathology; D015850:Interleukin-6 / Q000096:biosynthesis / Q000235:genetics; D008060:Lipodystrophy / Q000188:drug therapy / Q000201:enzymology* / Q000235:genetics / Q000473:pathology; D051379:Mice; D020125:Mutation, Missense; D052247:Nitric Oxide Synthase Type II / Q000096:biosynthesis / Q000235:genetics; D020411:Oligonucleotide Array Sequence Analysis
chemical_list: D000893:Anti-Inflammatory Agents; C115783:Bscl2 protein, mouse; D044388:GTP-Binding Protein gamma Subunits; D015850:Interleukin-6; D052247:Nitric Oxide Synthase Type II; C496317:Nos2 protein, mouse; D020962:Heterotrimeric GTP-Binding Proteins