Sleeve Gastroplasty Combined with the NLRP3 Inflammasome Inhibitor CY-09 Reduces Body Weight, Improves Insulin Resistance and Alleviates Hepatic Steatosis in Mouse Model.

PURPOSE: Endoscopic sleeve gastroplasty (ESG) has been suggested to be effective for treating obesity and its related non-alcoholic fatty liver disease (NAFLD). A small molecule named CY-09 is the selective inhibitor of the NOD-like receptor pyrin domain-containing protein 3 (NLRP3) inflammasome. We aim to investigate whether a surgery imitating ESG combined with CY-09 is more effective for treatment of obesity and NAFLD in a mouse model. MATERIAL AND METHODS: Forty mice were randomly divided into a control group (n = 5) and an NAFLD group (n = 35) fed by high-fat diet (HFD). The NAFLD mice were randomly assigned to the following groups at the timepoint of 19 weeks: (1) sham surgery; (2) surgery; (3) the combination of surgery with CY-09 injection. NAFLD activity score (NAS) was used for histological evaluation of steatosis. We also detected fasting glucose and insulin to measure the homeostasis model assessment of insulin resistance (HOMA-IR). RESULTS: HFD resulted in significant obesity and metabolic disorders, indicating successful modelling of obesity and NAFLD. The combination therapy resulted in significantly lower body weight than surgery alone at the end of the 8-week follow-up (40.4 +/- 4.8 vs. 45.0 +/- 2.2 g, P = 0.025). Furthermore, more dramatic improvements in HOMA-IR (5.8 +/- 1.1 vs. 12.2 +/- 2.1 mmol mIU L(-2), P = 0.036) and NAS (4.5 +/- 1.3 vs. 8.0 +/- 1.8, P = 0.006) were also observed in the combination group. CONCLUSIONS: Surgery imitating ESG combined with CY-09 reduces body weight, improves insulin resistance and alleviates hepatic steatosis. The combination therapy may be a promising method for treating obesity and NAFLD.