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

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 5

2KR mice respond to TZD treatment.

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2KR mice respond to TZD treatment. (A) BW curve on Rosi treatment. Mice ...
(A) BW curve on Rosi treatment. Mice were rendered insulin resistant after 16 weeks of HFD feeding (started at 6 weeks old), then switched to a HFD containing Rosi. *P < 0.05 for female WT vs. female 2KR by 2-tailed t test. n = 8 male WT; n = 8 male 2KR; n = 7 female WT; n = 8 female 2KR. (B) Body composition of male mice on Rosi treatment for 10 weeks. Rosi treatment started at 8 weeks of HFD feeding. *P < 0.05; **P < 0.01 for WT vs. 2KR by 2-tailed t test. n = 8 WT; n = 8 2KR. (C) WAT fat pad sizes in male mice on 15-week Rosi treatment. Mice were sacrificed after overnight fasting followed by 4 hours of refeeding. *P < 0.05 for WT vs. 2KR by 2-tailed t test. n = 8 WT; n = 8 2KR. (D and E) ipGTT (D) and AUC (E) before and after 2 weeks of Rosi treatment in BW-matched DIO male mice. n = 7 WT; n = 6 2KR. (F) Fasting blood glucose levels in male mice after 16 weeks on Rosi treatment. n = 7 WT (vehicle [veh]); n = 7 2KR (vehicle); n = 8 WT (Rosi); n = 8 2KR (Rosi). (G and H) ITT (G) and AUC (H) in male mice at 18 weeks on Rosi treatment. n = 7 WT (vehicle); n = 7 2KR (vehicle); n = 8 WT (Rosi); n = 8 2KR (Rosi). (I) Plasma insulin levels in male mice after 18 weeks on Rosi treatment. n = 7 WT (vehicle); n = 7 2KR (vehicle); n = 8 WT (Rosi); n = 8 2KR (Rosi). (J and L) Liver size (J), histological analysis by H&E staining (K), and hepatic TG content (L) in male mice after 24 weeks of Rosi treatment. Mice were sacrificed after overnight fasting. Original magnification, ×100. n = 7 WT (vehicle); n = 7 2KR (vehicle); n = 8 WT (Rosi); n = 8 2KR (Rosi). In D–L, effects of 2KR (*P < 0.05; **P < 0.01, WT vs. 2KR) and Rosi (#P < 0.05; ##P < 0.01, vehicle vs. Rosi) by 2-way ANOVA. In F–L, n = 7 WT (vehicle); n = 7 2KR (vehicle); n = 8 WT (Rosi); n = 8 2KR (Rosi). Data represent mean ± SEM.