title: Brown remodeling of white adipose tissue by SirT1-dependent deacetylation of Pparγ.
abstract: Brown adipose tissue (BAT) can disperse stored energy as heat. Promoting BAT-like features in white adipose (WAT) is an attractive, if elusive, therapeutic approach to staunch the current obesity epidemic. Here we report that gain of function of the NAD-dependent deacetylase SirT1 or loss of function of its endogenous inhibitor Deleted in breast cancer-1 (Dbc1) promote "browning" of WAT by deacetylating peroxisome proliferator-activated receptor (Ppar)-γ on Lys268 and Lys293. SirT1-dependent deacetylation of Lys268 and Lys293 is required to recruit the BAT program coactivator Prdm16 to Pparγ, leading to selective induction of BAT genes and repression of visceral WAT genes associated with insulin resistance. An acetylation-defective Pparγ mutant induces a brown phenotype in white adipocytes, whereas an acetylated mimetic fails to induce "brown" genes but retains the ability to activate "white" genes. We propose that SirT1-dependent Pparγ deacetylation is a form of selective Pparγ modulation of potential therapeutic import.
authors.affiliation: Naomi Berrie Diabetes Center, Department of Medicine, College of Physicians and Surgeons of Columbia University, New York, NY 10032, USA.
authors.forename: Li
authors.initials: L
authors.lastname: Qiang
authors.forename: Liheng
authors.initials: L
authors.lastname: Wang
authors.forename: Ning
authors.initials: N
authors.lastname: Kon
authors.forename: Wenhui
authors.initials: W
authors.lastname: Zhao
authors.forename: Sangkyu
authors.initials: S
authors.lastname: Lee
authors.forename: Yiying
authors.initials: Y
authors.lastname: Zhang
authors.forename: Michael
authors.initials: M
authors.lastname: Rosenbaum
authors.forename: Yingming
authors.initials: Y
authors.lastname: Zhao
authors.forename: Wei
authors.initials: W
authors.lastname: Gu
authors.forename: Stephen R
authors.initials: SR
authors.lastname: Farmer
authors.forename: Domenico
authors.initials: D
authors.lastname: Accili
mesh_terms: D016475:3T3 Cells; D000107:Acetylation; D002001:Adipose Tissue, Brown / Q000378:metabolism*; D052436:Adipose Tissue, White / Q000378:metabolism*; D000328:Adult; D000595:Amino Acid Sequence; D000818:Animals; D002478:Cells, Cultured; D004734:Energy Metabolism; D005260:Female; D006801:Humans; D007333:Insulin Resistance; D008024:Ligands; D008239:Lysine / Q000032:analysis / Q000378:metabolism; D051379:Mice; D057507:Mice, 129 Strain; D008810:Mice, Inbred C57BL; D008958:Models, Molecular; D008969:Molecular Sequence Data; D016297:Mutagenesis, Site-Directed; D009154:Mutation; D009765:Obesity / Q000150:complications / Q000378:metabolism; D047495:PPAR gamma / Q000737:chemistry / Q000378:metabolism*; D000077185:Resveratrol; D016415:Sequence Alignment; D056564:Sirtuin 1 / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D013267:Stilbenes / Q000494:pharmacology; D022722:Thermogenesis; D045162:Thiazolidinediones / Q000494:pharmacology
chemical_list: D008024:Ligands; D047495:PPAR gamma; D013267:Stilbenes; D045162:Thiazolidinediones; C470545:Sirt1 protein, mouse; D056564:Sirtuin 1; D008239:Lysine; D000077185:Resveratrol