Abstract
BackgroundWhile 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.Methodology/ResultsWe 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.ConclusionsThese 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.
Highlights
Congenital generalized lipodystrophy (CGL), known as Berardinelli-Seip congenital lipodystrophy (BSCL), is a rare autosomal recessive disease characterized by the near total absence of adipose tissue from birth or early infancy [1]
These results suggest that pathogenic Seipin-A212P inhibits adipogenesis and the inhibition is associated with activation of inflammatory pathways at pre-differentiation stages
As the A212P mutation leads to Seipin misfolding, we examined whether the adipogenic defects were due to protein misfoldingassociated ER stress by testing two other Seipin misfolding mutants Seipin-N88S and Seipin-S90L, and an unrelated protein a-synuclein
Summary
Congenital generalized lipodystrophy (CGL), known as Berardinelli-Seip congenital lipodystrophy (BSCL), is a rare autosomal recessive disease characterized by the near total absence of adipose tissue from birth or early infancy [1]. The BSCL2 gene encodes for the protein Seipin, a molecule hypothesized to be involved in the regulation of adipogenesis and the formation of lipid droplet (LD) [5,6,7]. A more recently established CGL3 related protein caveolin-1 (Cav-1) was identified as an essential component of caveolae [8], and a fatty-acid binding protein with a potential role in lipid transport, lipolysis and LD formation [9]. Another protein essential for caveolae biogenesis, PTRF-Cavin, was found responsible for a novel lipodystrophic subtype, CGL4 [10,11]. We investigated whether and how the pathogenic missense A212P mutation of Seipin (Seipin-A212P) inhibits adipogenesis
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