Abstract
The Nod-like receptor 3 (NLRP3) inflammasome is an intracellular sensor that sets off the innate immune system in response to microbial-derived and endogenous metabolic danger signals. We previously reported that gamma-tocotrienol (gamma T3) attenuated adipose tissue inflammation and insulin resistance in diet-induced obesity, but the underlying mechanism remained elusive. Here, we investigated the effects of gamma T3 on NLRP3 inflammasome activation and attendant consequences on type 2 diabetes. gamma T3 repressed inflammasome activation, caspase-1 cleavage, and interleukin (IL) 1 beta secretion in murine macrophages, implicating the inhibition of NLRP3 inflammasome in the anti-inflammatory and antipyroptotic properties of gamma T3. Furthermore, supplementation of leptin-receptor KO mice with gamma T3 attenuated immune cell infiltration into adipose tissue, decreased circulating IL-18 levels, preserved pancreatic beta-cells, and improved insulin sensitivity. Mechanistically, gamma T3 regulated the NLRP3 inflammasome via a two-pronged mechanism: 1) the induction of A20/TNF-alpha interacting protein 3 leading to the inhibition of the TNF receptor-associated factor 6/nuclear factor kappa B pathway and 2) the activation of AMP-activated protein kinase/autophagy axis leading to the attenuation of caspase-1 cleavage. Collectively, we demonstrated, for the first time, that gamma T3 inhibits the NLRP3 inflammasome thereby delaying the progression of type 2 diabetes. 11311 This study also provides an insight into the novel therapeutic values of gamma T3 for treating NLRP3 inflammasome-associated chronic diseases.