Brown Remodeling of White Adipose Tissue by SirT1-Dependent Deacetylation of Pparγ

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)-gamma on Lys268 and Lys293. SirT1-dependent deacetylation of Lys268 and Lys293 is required to recruit the BAT program coactivator Prdm16 to Ppar gamma, leading to selective induction of BAT genes and repression of visceral WAT genes associated with insulin resistance. An acetylation-defective Pparg 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 Pparg deacetylation is a form of selective Ppar gamma modulation of potential therapeutic import.