GW9662, a peroxisome proliferator-activated receptor gamma antagonist, attenuates the development of non-alcoholic fatty liver disease

Metabolism. 2022 Aug;133:155233. doi: 10.1016/j.metabol.2022.155233. Epub 2022 May 30.


Background and aims: Insulin resistance is among the key risk factors for the development of non-alcoholic fatty liver disease (NAFLD). Recently, it has been reported that GW9662, shown to be a potent peroxisome proliferator-activated receptor gamma (PPARγ) antagonist, may improve insulin sensitivity in settings of type 2 diabetes. Here, we determined the effects of GW9662 on the development of NAFLD and molecular mechanisms involved.

Methods: Female C57BL/6J mice were pair-fed either a liquid control diet (C) or a fat-, fructose- and cholesterol-rich diet (FFC) for 8 weeks while either being treated with GW9662 (1 mg/kg body weight; C+GW9662 and FFC+GW9662) or vehicle (C and FFC) i.p. three times weekly. Indices of liver damage and inflammation, parameters of glucose metabolism and portal endotoxin levels were determined. Lipopolysaccharide (LPS)-challenged J774A.1 cells were treated with 10 μM GW9662.

Results: Despite similar caloric intake the development of NAFLD and insulin resistance were significantly attenuated in FFC+GW9662-treated mice when compared to FFC-fed animals. Bacterial endotoxin levels in portal plasma were almost similarly increased in both FFC-fed groups while expressions of toll-like receptor 4 (Tlr4), myeloid differentiation primary response 88 (Myd88) and interleukin 1 beta (Il1b) as well as nitrite (NO2-) concentration in liver were significantly higher in FFC-fed mice than in FFC+GW9662-treated animals. In J774A.1 cells, treatment with GW9662 significantly attenuated LPS-induced expression of Il1b, interleukin 6 (Il6) and inducible nitric oxide synthase (iNos) as well as NO2- formation.

Conclusion: In summary, our data suggest that the PPARγ antagonist GW9662 attenuates the development of a diet-induced NAFLD and that this is associated with a protection against the activation of the TLR4 signaling cascade.

Keywords: Endotoxin; Glucose tolerance; Inflammation; Non-alcoholic steatohepatitis; Peroxisome proliferator-activated receptor gamma.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Anilides
  • Animals
  • Diabetes Mellitus, Type 2* / metabolism
  • Endotoxins / metabolism
  • Female
  • Insulin Resistance*
  • Lipopolysaccharides / pharmacology
  • Liver / metabolism
  • Mice
  • Mice, Inbred C57BL
  • Nitrogen Dioxide / metabolism
  • Nitrogen Dioxide / pharmacology
  • Non-alcoholic Fatty Liver Disease* / metabolism
  • PPAR gamma / metabolism
  • Toll-Like Receptor 4 / metabolism


  • 2-chloro-5-nitrobenzanilide
  • Anilides
  • Endotoxins
  • Lipopolysaccharides
  • PPAR gamma
  • Toll-Like Receptor 4
  • Nitrogen Dioxide