title: Berardinelli-seip congenital lipodystrophy 2/seipin is a cell-autonomous regulator of lipolysis essential for adipocyte differentiation.
abstract: Mutations in BSCL2 underlie human congenital generalized lipodystrophy. We inactivated Bscl2 in mice to examine the mechanisms whereby absence of Bscl2 leads to adipose tissue loss and metabolic disorders. Bscl2(-/-) mice develop severe lipodystrophy of white adipose tissue (WAT), dyslipidemia, insulin resistance, and hepatic steatosis. In vitro differentiation of both Bscl2(-/-) murine embryonic fibroblasts (MEFs) and stromal vascular cells (SVCs) reveals normal early-phase adipocyte differentiation but a striking failure in terminal differentiation due to unbridled cyclic AMP (cAMP)-dependent protein kinase A (PKA)-activated lipolysis, which leads to loss of lipid droplets and silencing of the expression of adipose tissue-specific transcription factors. Importantly, such defects in differentiation can be largely rescued by inhibitors of lipolysis but not by a gamma peroxisome proliferator-activated receptor (PPARγ) agonist. The residual epididymal WAT (EWAT) in Bscl2(-/-) mice displays enhanced lipolysis. It also assumes a "brown-like" phenotype with marked upregulation of UCP1 and other brown adipose tissue-specific markers. Together with decreased Pref1 but increased C/EBPβ levels, these changes highlight a possible increase in cAMP signaling that impairs terminal adipocyte differentiation in the EWAT of Bscl2(-/-) mice. Our study underscores the fundamental role of regulated cAMP/PKA-mediated lipolysis in adipose differentiation and identifies Bscl2 as a novel cell-autonomous determinant of activated lipolysis essential for terminal adipocyte differentiation.
authors.forename: Weiqin
authors.initials: W
authors.lastname: Chen
authors.forename: Benny
authors.initials: B
authors.lastname: Chang
authors.forename: Pradip
authors.initials: P
authors.lastname: Saha
authors.forename: Sean M
authors.initials: SM
authors.lastname: Hartig
authors.forename: Lan
authors.initials: L
authors.lastname: Li
authors.forename: Vasumathi Theegala
authors.initials: VT
authors.lastname: Reddy
authors.forename: Yisheng
authors.initials: Y
authors.lastname: Yang
authors.forename: Vijay
authors.initials: V
authors.lastname: Yechoor
authors.forename: Michael A
authors.initials: MA
authors.lastname: Mancini
authors.forename: Lawrence
authors.initials: L
authors.lastname: Chan
mesh_terms: D017667:Adipocytes / Q000166:cytology* / Q000378:metabolism; D050156:Adipogenesis / Q000187:drug effects; D052436:Adipose Tissue, White / Q000378:metabolism; D000818:Animals; D002478:Cells, Cultured; D000242:Cyclic AMP / Q000378:metabolism; D017868:Cyclic AMP-Dependent Protein Kinases / Q000378:metabolism; D005234:Fatty Liver / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D044388:GTP-Binding Protein gamma Subunits; D017353:Gene Deletion; D020962:Heterotrimeric GTP-Binding Proteins / Q000235:genetics / Q000378:metabolism*; D007333:Insulin Resistance / Q000235:genetics; D008049:Lipase / Q000037:antagonists & inhibitors; D008066:Lipolysis; D008099:Liver / Q000378:metabolism / Q000473:pathology; D008297:Male; D051379:Mice; D047495:PPAR gamma / Q000819:agonists
chemical_list: C115783:Bscl2 protein, mouse; D044388:GTP-Binding Protein gamma Subunits; D047495:PPAR gamma; D000242:Cyclic AMP; D017868:Cyclic AMP-Dependent Protein Kinases; D008049:Lipase; D020962:Heterotrimeric GTP-Binding Proteins