Abstract
Introduction and Aims: Obesity and its resulting metabolic disturbances are major health threats and are the main cause of nonalcoholic fatty liver disease (NAFLD). Comound C has been demonstrated to be not only an inhibitor of AMPK, but also has some actions independent of AMPK inhibition. In our previous studies, we unexpectedly found compound C is an anti-inflammatory and anti-NLRP3 inflammasome agent in vitro. The aim of this study was to investigate the effects of compound C on a mouse model of high-fat diet (HFD) (60 kcal% fat)-induced obesity and hepatosteatosis in vivo. Methods: C57BL/6 mice were fed with either a standard or a HFD for 14 weeks. These mice were divided in three groups [Normal chow, HFD + Vehicle, and HFD + compound C (6 mg/kg i.p., once a day)] and treated for an additional 4 weeks. All animals were weighed weekly and food intakes measured twice weekly. Liver histology as well as pro-inflammatory gene expression in liver and white adipose tissue (WAT) were examined. Results: There was a significant reduction in body-weight gain and daily food intake in compound C-treated group compared with HFD group (P < 0.05). Glucose tolerance test and insulin tolerance test showed that compound C increased glucose metabolism and alleviated insulin resistance compared with the HFD group. Histology analysis showed a significant reduction of hepatic steatosis and ballooning by compound C. To further characterize the activity of compound C, quantitative RT-PCR analysis of pro-inflammatory markers were performed, demonstrating that compound C significantly reduced IL-1β, IL-18, IL-6 and TNF-a gene expression in the liver as well as in the WAT (P < 0.01). Moreover, NLRP3 inflammasome which plays an important role in obesity and NAFLD was significantly decreased by compound C using western blot assay. Conclusions: Taken together, these results suggest that compound C offers the potential as a novel therapy for obesity and NAFLD, probably by impairing NLRP3 inflammasome activation and the related inflammasion. Disclosure F. Wang: None. W. Yang: None. R. Xiang: None. J. Yuan: None. Y. Liu: None. K. Chen: None. Z. Mo: None.
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