PPARγ: no SirT, no service.

A novel mechanism has been defined for controlling per-oxisome proliferator-activated receptors γ (PPARγ) activity in response to thiazolidinedione (TZD) ligands, in which deacetylation of PPARγ by SirT1 remodels the transcriptional complex. This change favors expression of genes associated with increased energy use and insulin sensitization in white adipose tissue (WAT), and is required for a portion of the beneficial effects of TZDs. More broadly, PPARγ acetylation and other recently identified regulatory modifications are clarifying the mechanisms by which TZDs exert their antidiabetic effects in fat cells and other tissues. PPARγ is a ligand-activated transcription factor first studied for its importance in adipogenesis. From then, it has become recognized that PPARγ also mediates diverse effects in non-adipose tissues including liver, skeletal muscle, brain, bone, and blood vessels. PPARγ is thought to be a fatty acid and lipid sensor, which when activated can stimulate expression of genes that promote insulin action, fatty acid storage, and glucose metabolism. Other beneficial effects of PPARγ activity may be garnered by inhibition of proinflammatory and prooxi-dant gene expression. The therapeutic importance of PPARγ in providing glycemic control is underscored by the actions of the TZD class of drugs, which can markedly improve insulin sensitivity in patients with type 2 diabetes mellitus. The beneficial actions of TZDs are believed to be centered on their ability to act as high-affinity ligands for PPARγ, where they act in place of endogenous PPARγ ligands to functionally convert PPARγ from a transcriptional repressor to a transcrip-tional activator. This transition occurs by the disassociation of a corepressor, NCoR, from the PPARγ complex and its replacement by an activator complex. Since the discovery that TZD drugs have potent antidiabetic activity, the mechanism through which they exert their beneficial effects has gained significant clinical importance. In addition to the classic model of ligand-mediated activation , recently, PPARγ has been shown to be regulated by a series of posttranslational modifications, many of which can be effected by TZDs. One such modification is sumoylation, which has been reported to stabilize the association of PPARγ with the corepressor complex and inhibit PPARγ transcrip-tional activity. 1 TZDs promote PPARγ transcriptional activity in WAT, in part, by promoting expression of fibroblast growth factor 21, a PPARγ target gene, which acts in a feed-forward mechanism to inhibit PPARγ sumoylation. 2 Rather than promoting general activating or repressing activities of PPARγ, other modifications have been identified which regulate subsets of PPARγ …