The human lipodystrophy gene product Berardinelli-Seip congenital lipodystrophy 2/seipin plays a key role in adipocyte differentiation.
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-gamma 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-gamma, 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.
Chen
Weiqin
W
Division of Diabetes and Endocrinology, Department of Medicine, Baylor College of Medicine, Diabetes and Endocrinology Research Center, Houston, Texas 77030, USA.
Yechoor
Vijay K
VK
Chang
Benny Hung-Junn
BH
Li
Ming V
MV
March
Keith L
KL
Chan
Lawrence
L
D015056:1-Methyl-3-isobutylxanthine; D016475:3T3 Cells; D017667:Adipocytes / Q000166:cytology*; D050156:Adipogenesis; D000818:Animals; D002454:Cell Differentiation; D002460:Cell Line; D003907:Dexamethasone; D004721:Endoplasmic Reticulum / Q000378:metabolism; D044388:GTP-Binding Protein gamma Subunits / Q000235:genetics / Q000378:metabolism*; D055786:Gene Knockout Techniques; D020962:Heterotrimeric GTP-Binding Proteins / Q000235:genetics / Q000378:metabolism; D006801:Humans; D007328:Insulin; D052497:Lipodystrophy, Congenital Generalized / Q000378:metabolism; D059630:Mesenchymal Stem Cells / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D047495:PPAR gamma / Q000819:agonists / Q000378:metabolism*; D000077205:Pioglitazone; D045162:Thiazolidinediones; D015854:Up-Regulation
C432679:BSCL2 protein, human; C115783:Bscl2 protein, mouse; D044388:GTP-Binding Protein gamma Subunits; D007328:Insulin; D047495:PPAR gamma; D045162:Thiazolidinediones; D003907:Dexamethasone; D020962:Heterotrimeric GTP-Binding Proteins; D015056:1-Methyl-3-isobutylxanthine; D000077205:Pioglitazone