Suppression of NLRP3 inflammasome by γ-tocotrienol ameliorates type 2 diabetes

Authors

Yongeun Kim, University of Nebraska–LincolnFollow
Wei Wang, University of Nebraska–LincolnFollow
Meshail Okla, University of Nebraska–Lincoln
Inhae Kang, University of Nebraska–LincolnFollow
Regis Moreau, University of Nebraska–LincolnFollow
Soonkyu Chung, University of Nebraska-LincolnFollow

Document Type

Article

Date of this Version

1-2016

Citation

Published in Journal of Lipid Research 57 (2016), pp. 66–76. doi 10.1194/jlr.M062828

Comments

Copyright © 2016 by the American Society for Biochemistry and Molecular Biology, Inc. Used by permission.

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 γ-tocotrienol (γT3) attenuated adipose tissue inflammation and insulin resistance in diet-induced obesity, but the underlying mechanism remained elusive. Here, we investigated the effects of γT3 on NLRP3 inflammasome activation and attendant consequences on type 2 diabetes. γT3 repressed inflammasome activation, caspase-1 cleavage, and interleukin (IL) 1β secretion in murine macrophages, implicating the inhibition of NLRP3 inflammasome in the anti-inflammatory and antipyroptotic properties of γT3. Furthermore, supplementation of leptin-receptor KO mice with γT3 attenuated immune cell infiltration into adipose tissue, decreased circulating IL-18 levels, preserved pancreatic β-cells, and improved insulin sensitivity. Mechanistically, γT3 regulated the NLRP3 inflammasome via a two-pronged mechanism: 1) the induction of A20/TNF-α interacting protein 3 leading to the inhibition of the TNF receptor-associated factor 6/nuclear factor κB 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 γT3 inhibits the NLRP3 inflammasome thereby delaying the progression of type 2 diabetes. This study also provides an insight into the novel therapeutic values of γT3 for treating NLRP3 inflammasome-associated chronic diseases.