title: Berardinelli-Seip Congenital Lipodystrophy 2/Seipin Is Not Required for Brown Adipogenesis but Regulates Brown Adipose Tissue Development and Function.
abstract: Brown adipose tissue (BAT) plays a unique role in regulating whole-body energy homeostasis by dissipating energy through thermogenic uncoupling. Berardinelli-Seip congenital lipodystrophy (BSCL) type 2 (BSCL2; also known as seipin) is a lipodystrophy-associated endoplasmic reticulum membrane protein essential for white adipocyte differentiation. Whether BSCL2 directly participates in brown adipocyte differentiation, development, and function, however, is unknown. We show that BSCL2 expression is increased during brown adipocyte differentiation. Its deletion does not impair the classic brown adipogenic program but rather induces premature activation of differentiating brown adipocytes through cyclic AMP (cAMP)/protein kinase A (PKA)-mediated lipolysis and fatty acid and glucose oxidation, as well as uncoupling. cAMP/PKA signaling is physiologically activated during neonatal BAT development in wild-type mice and greatly potentiated in mice with genetic deletion of Bscl2 in brown progenitor cells, leading to reduced BAT mass and lipid content during neonatal brown fat formation. However, prolonged overactivation of cAMP/PKA signaling during BAT development ultimately causes apoptosis of brown adipocytes through inflammation, resulting in BAT atrophy and increased overall adiposity in adult mice. These findings reveal a key cell-autonomous role for BSCL2 in controlling BAT mass/activity and provide novel insights into therapeutic strategies targeting cAMP/PKA signaling to regulate brown adipocyte function, viability, and metabolic homeostasis.
authors.affiliation: Department of Physiology, Medical College of Georgia, Augusta University, Augusta, Georgia, USA.
authors.forename: Hongyi
authors.initials: H
authors.lastname: Zhou
authors.affiliation: Vascular Biology Center, Medical College of Georgia, Augusta University, Augusta, Georgia, USA.
authors.forename: Stephen M
authors.initials: SM
authors.lastname: Black
authors.affiliation: Vascular Biology Center, Medical College of Georgia, Augusta University, Augusta, Georgia, USA.
authors.forename: Tyler W
authors.initials: TW
authors.lastname: Benson
authors.affiliation: Vascular Biology Center, Medical College of Georgia, Augusta University, Augusta, Georgia, USA.
authors.forename: Neal L
authors.initials: NL
authors.lastname: Weintraub
authors.affiliation: Department of Physiology, Medical College of Georgia, Augusta University, Augusta, Georgia, USA wechen@augusta.edu.
authors.forename: Weiqin
authors.identifier: 0000-0002-3894-5953
authors.initials: W
authors.lastname: Chen
mesh_terms: D050156:Adipogenesis; D002001:Adipose Tissue, Brown / Q000254:growth & development* / Q000378:metabolism; D000818:Animals; D002454:Cell Differentiation; D002470:Cell Survival; D000242:Cyclic AMP / Q000378:metabolism; D017868:Cyclic AMP-Dependent Protein Kinases / Q000378:metabolism; D044388:GTP-Binding Protein gamma Subunits; D020962:Heterotrimeric GTP-Binding Proteins / Q000235:genetics* / Q000378:metabolism*; D006706:Homeostasis; D008066:Lipolysis; D051379:Mice
chemical_list: C115783:Bscl2 protein, mouse; D044388:GTP-Binding Protein gamma Subunits; D000242:Cyclic AMP; D017868:Cyclic AMP-Dependent Protein Kinases; D020962:Heterotrimeric GTP-Binding Proteins