| First Author | Kraakman MJ | Year | 2018 |
| Journal | J Clin Invest | Volume | 128 |
| Issue | 6 | Pages | 2600-2612 |
| PubMed ID | 29589839 | Mgi Jnum | J:312317 |
| Mgi Id | MGI:6162200 | Doi | 10.1172/JCI98709 |
| Citation | Kraakman MJ, et al. (2018) PPARgamma deacetylation dissociates thiazolidinedione's metabolic benefits from its adverse effects. J Clin Invest 128(6):2600-2612 |
| abstractText | Thiazolidinediones (TZDs) are PPARgamma 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 PPARgamma on K268 and K293 to cause the browning of white adipocytes. Here, we show that targeted PPARgamma mutations resulting in constitutive deacetylation (K268R/K293R, 2KR) increased energy expenditure and protected from visceral 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 PPARgamma activation from its adverse effects. Strategies to leverage PPARgamma deacetylation may lead to the design of safer, more effective agonists of this nuclear receptor in the treatment of metabolic diseases. |
