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

Abstract

SUMMARY 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, while 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.

Promoting brown and beige adipocyte biogenesis through the PRDM16 pathway

“…32 More recently, the Accili's group also proposed an additional mechanism in which Sirt1-dependent deacetylation of PPARγ enhances the interaction between PRDM16 and PPARγ. 33 These results imply a possibility that stabilization of PRDM16 protein may be a plausible strategy to induce WAT browning without directly agonizing the PPARγ transcriptional activity.…”

GLP-1 receptor agonist promotes brown remodelling in mouse white adipose tissue through SIRT1

“…While WAT glycerol content was also significantly decreased in exenatide-treated mice, it is reasonable to speculate that exenatide not only induces lipolysis in adipocytes but also promotes glycerol and lipid consumption. A growing number of studies have demonstrated the capacity of WAT to burn off excessive energy [30][31][32]; thus, the reduced adiposity is potentially connected with the increased oxidative metabolism in white adipocytes. In our study, a set of oxidative factors normally silent in white adipocytes, including UCP-1, PPARα and PGC-1α, were increased by exenatide both in vitro and in vivo.…”

Brown and beige fat: development, function and therapeutic potential

“…Additionally, thiazolidinediones (TZDs), which agonize Ppar-γ, induce thermogenic gene expression in fat cells through effects on Prdm16 (refs. 43,47). Interestingly, the muscle-enriched microRNA miR-133 directly targets and reduces the amounts of Prdm16 to block both brown and beige adipose development [46][47][48] .…”

“…43,47). Interestingly, the muscle-enriched microRNA miR-133 directly targets and reduces the amounts of Prdm16 to block both brown and beige adipose development [46][47][48] . Cold exposure suppresses miR-133 expression in fat cells, which leads to increased amounts of Prdm16 and increased expression of downstream thermogenic target genes 48 .…”

“…Regardless of whether BAT has a major physiological role in body weight regulation in mice and humans, there is no question that expanding the activity of brown fat, beige fat or both in mice through genetic manipulation, drugs or transplantation suppresses metabolic disease [15][16][17]47,[60][61][62][63] (Table 1). These results imply that counterregulatory mechanisms (for example, increased food intake), which might have been predicted to offset the effects of expanded BAT activity to preserve energy balance, are not fully effective in mice.…”