PPARγ deacetylation dissociates thiazolidinedione's metabolic benefits from its adverse effects.

Thiazolidinediones (TZDs) are PPAR gamma agonists with potent insulin-sensitizing effects. However, their use has been curtailed by substantial adverse effects on weight, bone, heart, and hemodynamic balance, TZDs induce the deacetylation of PPAR gamma on K268 and K293 to cause the browning of white adipocytes. Here, we show that targeted PPAR gamma mutations resulting in constitutive deacetylation (K268R/K29SR, 2KR) increased energy expenditure and protected from viscera I adiposity and diet-induced obesity by augmenting brown remodeling of white adipose tissues. Strikingly, when 2KR mice were treated with rosiglitazone, they maintained the insulin-sensitizing, glucose-lowering response to TZDs, while displaying little, if any, adverse effects on fat deposition, bone density, fluid retention, and cardiac hypertrophy. Thus, deacetylation appears to fulfill the goal of dissociating the metabolic benefits of PPAR gamma activation from its adverse effects. Strategies to leverage PPAR gamma deacetylation may lead to the design of safer, more effective agonists of this nuclear receptor In the treatment of metabolic diseases.