title: Suppression of NLRP3 inflammasome by γ-tocotrienol ameliorates type 2 diabetes.
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.
authors.affiliation: Department of Nutrition and Health Sciences, University of Nebraska-Lincoln, Lincoln, NE 68583.
authors.forename: Yongeun
authors.initials: Y
authors.lastname: Kim
authors.affiliation: Department of Nutrition and Health Sciences, University of Nebraska-Lincoln, Lincoln, NE 68583.
authors.forename: Wei
authors.initials: W
authors.lastname: Wang
authors.affiliation: Department of Nutrition and Health Sciences, University of Nebraska-Lincoln, Lincoln, NE 68583.
authors.forename: Meshail
authors.initials: M
authors.lastname: Okla
authors.affiliation: Department of Nutrition and Health Sciences, University of Nebraska-Lincoln, Lincoln, NE 68583.
authors.forename: Inhae
authors.initials: I
authors.lastname: Kang
authors.affiliation: Department of Nutrition and Health Sciences, University of Nebraska-Lincoln, Lincoln, NE 68583.
authors.forename: Regis
authors.initials: R
authors.lastname: Moreau
authors.affiliation: Department of Nutrition and Health Sciences, University of Nebraska-Lincoln, Lincoln, NE 68583 schung4@unl.edu.
authors.forename: Soonkyu
authors.initials: S
authors.lastname: Chung
mesh_terms: D055372:AMP-Activated Protein Kinases / Q000276:immunology; D000273:Adipose Tissue / Q000187:drug effects / Q000276:immunology; D000818:Animals; D002352:Carrier Proteins / Q000037:antagonists & inhibitors* / Q000276:immunology; D020170:Caspase 1 / Q000378:metabolism; D002839:Chromans / Q000276:immunology / Q000494:pharmacology*; D003924:Diabetes Mellitus, Type 2 / Q000188:drug therapy* / Q000276:immunology; D058847:Inflammasomes / Q000037:antagonists & inhibitors* / Q000276:immunology; D007249:Inflammation / Q000188:drug therapy / Q000276:immunology; D007333:Insulin Resistance; D053583:Interleukin-1beta / Q000276:immunology; D008070:Lipopolysaccharides / Q000494:pharmacology; D017737:Macrophages, Peritoneal / Q000187:drug effects / Q000276:immunology; D008297:Male; D051379:Mice; D016688:Mice, Inbred NOD; D018345:Mice, Knockout; D016328:NF-kappa B / Q000378:metabolism; D000071199:NLR Family, Pyrin Domain-Containing 3 Protein; D009765:Obesity / Q000276:immunology; D015398:Signal Transduction / Q000187:drug effects / Q000276:immunology; D014409:Tumor Necrosis Factor-alpha / Q000276:immunology; D014810:Vitamin E / Q000031:analogs & derivatives* / Q000276:immunology / Q000494:pharmacology
chemical_list: D002352:Carrier Proteins; D002839:Chromans; D058847:Inflammasomes; D053583:Interleukin-1beta; D008070:Lipopolysaccharides; D016328:NF-kappa B; D000071199:NLR Family, Pyrin Domain-Containing 3 Protein; C492716:Nlrp3 protein, mouse; D014409:Tumor Necrosis Factor-alpha; D014810:Vitamin E; C013649:plastochromanol 8; D055372:AMP-Activated Protein Kinases; D020170:Caspase 1
keywords: A20; NOD-like receptor protein 3; caspase 1; diet and dietary lipids; inflammation; insulin signaling; obesity; vitamin E