The Human Lipodystrophy Gene Product Berardinelli-Seip Congenital Lipodystrophy 2/Seipin Plays a Key Role in Adipocyte Differentiation

• Published in: Endocrinology (Philadelphia) 2009-10, Vol.150 (10), p.4552-4561
• Main Authors: Chen, Weiqin, Yechoor, Vijay K, Chang, Benny Hung-Junn, Li, Ming V, March, Keith L, Chan, Lawrence
• Format: Article
• Language: English
• Subjects: 1-Methyl-3-isobutylxanthine; 3T3 Cells; Adipocytes; Adipocytes - cytology; Adipogenesis; Animals; Bone morphogenetic protein 4; Cell Differentiation; Cell Line; Dexamethasone; Differentiation (biology); Endoplasmic Reticulum - metabolism; Gene expression; Gene Knockout Techniques; GTP-Binding Protein gamma Subunits - genetics; GTP-Binding Protein gamma Subunits - metabolism; Heterotrimeric GTP-Binding Proteins - genetics; Heterotrimeric GTP-Binding Proteins - metabolism; Humans; Insulin; Lipodystrophy; Lipodystrophy, Congenital Generalized - metabolism; Mesenchymal stem cells; Mesenchymal Stromal Cells - metabolism; Mice; Mice, Inbred C57BL; Peroxisome proliferator-activated receptors; Pioglitazone; PPAR gamma - agonists; PPAR gamma - metabolism; Proteins; Receptors; Ribonucleic acid; RNA; Stem cells; Thiazolidinediones; Up-Regulation
• ISSN: 0013-7227; 1945-7170
• DOI: 10.1210/en.2009-0236

Mutations in the Berardinelli-Seip congenital lipodystrophy 2 gene (BSCL2) are the underlying defect in patients with congenital generalized lipodystrophy type 2. BSCL2 encodes a protein called seipin, whose function is largely unknown. In this study, we investigated the role of Bscl2 in the regulation of adipocyte differentiation. Bscl2 mRNA is highly up-regulated during standard hormone-induced adipogenesis in 3T3-L1 cells in vitro. However, this up-regulation does not occur during mesenchymal stem cell (C3H10T1/2 cells) commitment to the preadipocyte lineage. Knockdown of Bscl2 by short hairpin RNA in C3H10T1/2 cells has no effect on bone morphogenetic protein-4-induced preadipocyte commitment. However, knockdown in 3T3-L1 cells prevents adipogenesis induced by a standard hormone cocktail, but adipogenesis can be rescued by the addition of peroxisome proliferator-activated receptor-γ agonist pioglitazone at an early stage of differentiation. Interestingly, pioglitazone-induced differentiation in the absence of standard hormone is not associated with up-regulated Bscl2 expression. On the other hand, short hairpin RNA-knockdown of Bscl2 largely blocks pioglitazone-induced adipose differentiation. These experiments suggest that Bscl2 may be essential for normal adipogenesis; it works upstream or at the level of peroxisome proliferator-activated receptor-γ, enabling the latter to exert its full activity during adipogenesis. Loss of Bscl2 function thus interferes with the normal transcriptional cascade of adipogenesis during fat cell differentiation, resulting in near total loss of fat or lipodystrophy. Mutations in Seipin underlie Berardinelli-Seip congenital generalized lipodystrophy-2; Seipin is required for adipocyte differentiation, working upstream or at the level of PPARγ during adipogenesis.