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

Yongeun Kim, Wei Wang, Meshail Okla, Inhae Kang, Regis Moreau, Soonkyu Chung

Research output: Contribution to journalArticle

31 Scopus citations

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 infl ammation 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 infi ltration 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 fi rst 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.

Original languageEnglish (US)
Pages (from-to)66-76
Number of pages11
JournalJournal of Lipid Research
Volume57
Issue number1
DOIs
StatePublished - Jan 1 2016

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Keywords

  • A20
  • Caspase 1
  • Diet and dietary lipids
  • Inflammation
  • Insulin signaling
  • NOD-like receptor protein 3
  • Obesity
  • Vitamin E

ASJC Scopus subject areas

  • Biochemistry
  • Endocrinology
  • Cell Biology

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