PPARγ deacetylation dissociates thiazolidinedione’s metabolic benefits from its adverse effects
Michael J. Kraakman, … , Remi J. Creusot, Li Qiang
Michael J. Kraakman, … , Remi J. Creusot, Li Qiang
Published March 27, 2018
Citation Information: J Clin Invest. 2018;128(6):2600-2612. https://doi.org/10.1172/JCI98709.
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Research Article Metabolism Therapeutics

PPARγ deacetylation dissociates thiazolidinedione’s metabolic benefits from its adverse effects

Abstract

Thiazolidinediones (TZDs) are PPARγ 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 PPARγ on K268 and K293 to cause the browning of white adipocytes. Here, we show that targeted PPARγ 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 PPARγ activation from its adverse effects. Strategies to leverage PPARγ deacetylation may lead to the design of safer, more effective agonists of this nuclear receptor in the treatment of metabolic diseases.

Authors

Michael J. Kraakman, Qiongming Liu, Jorge Postigo-Fernandez, Ruiping Ji, Ning Kon, Delfina Larrea, Maria Namwanje, Lihong Fan, Michelle Chan, Estela Area-Gomez, Wenxian Fu, Remi J. Creusot, Li Qiang

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Figure 2

PPARγ deacetylation promotes thermogenic responses.

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PPARγ deacetylation promotes thermogenic responses. (A–D) Calorimetric a...
(A–D) Calorimetric analyses of 4-month-old male mice fed a chow diet during acute cold exposure (day 1) and after chronic cold exposure (day 5). (A) Food intake. (B) RER. (C) Oxygen consumption and (D) heat production. *P < 0.05 at multiple detection points. n = 9 WT; n = 11 2KR (2 WT and 1 mutant mice were hypothermic at the cold exposure and terminated). (E and F) qPCR analyses of gene expression in iWAT (E) and BAT (F) of 5- to 6-month-old chow-fed male mice after 5-day cold exposure. *P < 0.05; **P < 0.01 for WT vs. 2KR. n = 6 WT; n = 6 2KR. (G) qPCR analyses of gene expression in iWAT primary adipocytes after 4-hour forskolin (5 μM) treatment. *P < 0.05; **P < 0.01 for WT vs. 2KR. n = 5 WT; n = 5 2KR. Data represent mean ± SEM. Student’s t test was used for statistical analyses.