PPARγ: no SirT, no service

Abstract

A novel mechanism has been defined for controlling PPARγn activity in response to thiazolidinedione ligands, in which deacetylation of PPARγ by SirT1 remodels the transcriptional complex. This change favors expression of genes associated with increased energy utilization and insulin sensitization in white adipose tissue, and is required for a portion of the beneficial effects of thiazolidinediones. More broadly, PPARγ acetylation and other recently identified regulatory modifications are clarifying the mechanisms by which thiazolidinediones exert their antidiabetic effects in fat cells and other tissues.

Figure

Post-translational modified of PPARγ by acetylation impairs its transcriptional activity. In the current report, acetylation promotes energy storage through maintenance of the white adipocyte phenotype and gene expression program, and in response to high fat diets may promote insulin resistance. TZDs increase the association of PPARγ with SirT1 thus promoting deacetylation of PPARγ. Deacetylation of PPARγ by SirT1 or mutation of the acetylated lysines in PPARγ promotes disassociation of the co-repressor NCoR and association with PRDM16. This promotes browning of subcutaneous white adipocytes by stimulating them to adopt a brown adipose tissue gene expression profile, resulting in increased energy expenditure in WAT and insulin sensitivity. However, increased PPARγ activity promoted by TZDs also causes unwanted side effects. It remains unclear if endogenous ligands or new non-agonist PPARγ ligands can prevent PPARγ acetylation, or if deacetylation of PPARγ contributes to side effects caused by TZDs.