Berberine Ameliorates Insulin Resistance Via Preventing Fatty Acid-induced NLRP3 Inflammasome Activation

NLRP3 inflammasome has been reported to contribute to obesity-induced inflammation and insulin resistance. However, there are few drugs targeting NLRP3 inflammasome for the treatment of insulin resistance.In Chapter one, we showed that berberine (BBR) significantly suppressed saturated fatty acid palmitate (PA)-induced NLRP3 inflammasome activation and IL-1β release in macrophages, which was one of the most important mediators in the insulin sensitivity of adipose tissue.In Chapter two, BBR treatment dramatically upregulated autophagic proteins Beclinl (ATG6) and LC3B-II expression and increased the numbers of autophagosome formation in macrophages. More importantly, autophagy inhibition almost reversed the inhibitory effects of BBR on NLRP3 inflammasome activation.Furthermore, we demonstrated that AMPK was phosphorylated by BBR treatment and AMPK inhibitor Adenine 9-β-D-arabinofuranoside (Ara-A) blocked most effects of BBR, suggesting that AMPK signals may be involved in BBR-induced macrophage autophagy.In Chapter three, we firstly established a mouse model of insulin resistance. Mice were fed with HFD or normal chow diet (NCD) for 14 weeks. Concurrently with a HFD, BBR (75,150 mg/kg) were given orally for the last 3 weeks. We found BBR also prevented NLRP3 inflammasome-dependent inflammation and metabolic disorder in a high-fat-diet-induced insulin resistance model, as IL-1β and cleaved Caspase-1 in adipose tissue were decreased. The BBR administration significantly improved insulin sensitivity. In ITT assay, mice exhibited a state of insulin resistance after 14 weeks of HFD treatment. Similarly, GTT assay also showed that BBR increased glucose tolerance as compared with control mice. Moreover, BBR reversed the elevations in fasting serum insulin concentrations caused by HFD. Gross inspection of BBR-treated mice indicated a reduction in adipose tissue mass. Histological analysis showed that BBR administration reduced adipocyte size and proinflammatory CD11c+ ATMs infiltration. Adoptive transfer of BBR-treated BMDMs, which was induced by LPS plus PA-BSA, significantly ameliorated insulin resistance of ob/ob mice as compared with control mice. However, the co-treatment of the BMDMs with autophagy inhibitor 3-MA reversed the effect of BBR almost completely.Taken together, BBR exerted its anti-inflammatory effects through activation of AMPK-dependent autophagy in adipose tissue macrophages (ATMs). This study provides a new approach to the treatment of insulin resistance.