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

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.

Pubmed ID: 22269949

Authors

  • Chen W
  • Chang B
  • Saha P
  • Hartig SM
  • Li L
  • Reddy VT
  • Yang Y
  • Yechoor V
  • Mancini MA
  • Chan L

Journal

Molecular and cellular biology

Publication Data

March 23, 2012

Associated Grants

  • Agency: NIDDK NIH HHS, Id: F32 DK085970
  • Agency: NCI NIH HHS, Id: P30 CA-125123
  • Agency: NIDDK NIH HHS, Id: P30 DK-56338
  • Agency: NIDDK NIH HHS, Id: P30 DK056338
  • Agency: NHLBI NIH HHS, Id: R01 HL051586
  • Agency: NICHD NIH HHS, Id: U54 HD-007495

Mesh Terms

  • Adipocytes
  • Adipogenesis
  • Adipose Tissue, White
  • Animals
  • Cells, Cultured
  • Cyclic AMP
  • Cyclic AMP-Dependent Protein Kinases
  • Fatty Liver
  • Gene Deletion
  • Heterotrimeric GTP-Binding Proteins
  • Insulin Resistance
  • Lipase
  • Lipolysis
  • Liver
  • Male
  • Mice
  • PPAR gamma