Berardinelli-seip congenital lipodystrophy 2/seipin is a cell-autonomous regulator of lipolysis essential for adipocyte differentiation

Weiqin Chen, Benny Chang, Pradip Saha, Sean M. Hartig, Lan Li, Vasumathi Theegala Reddy, Yisheng Yang, Vijay Yechoor, Michael A. Mancini, Lawrence Chan

Research output: Contribution to journalArticle

97 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)1099-1111
Number of pages13
JournalMolecular and Cellular Biology
Volume32
Issue number6
DOIs
StatePublished - Mar 2012

ASJC Scopus subject areas

  • Molecular Biology
  • Cell Biology

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    Chen, W., Chang, B., Saha, P., Hartig, S. M., Li, L., Reddy, V. T., Yang, Y., Yechoor, V., Mancini, M. A., & Chan, L. (2012). Berardinelli-seip congenital lipodystrophy 2/seipin is a cell-autonomous regulator of lipolysis essential for adipocyte differentiation. Molecular and Cellular Biology, 32(6), 1099-1111. https://doi.org/10.1128/MCB.06465-11