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Fatty acid-induced NLRP3-ASC inflammasome activation interferes with insulin signaling.

ABSTRACT: High-fat diet (HFD) and inflammation are key contributors to insulin resistance and type 2 diabetes (T2D). Interleukin (IL)-1? plays a role in insulin resistance, yet how IL-1? is induced by the fatty acids in an HFD, and how this alters insulin signaling, is unclear. We show that the saturated fatty acid palmitate, but not unsaturated oleate, induces the activation of the NLRP3-ASC inflammasome, causing caspase-1, IL-1? and IL-18 production. This pathway involves mitochondrial reactive oxygen species and the AMP-activated protein kinase and unc-51-like kinase-1 (ULK1) autophagy signaling cascade. Inflammasome activation in hematopoietic cells impairs insulin signaling in several target tissues to reduce glucose tolerance and insulin sensitivity. Furthermore, IL-1? affects insulin sensitivity through tumor necrosis factor-independent and dependent pathways. These findings provide insights into the association of inflammation, diet and T2D.

SUBMITTER: Wen H

PROVIDER: S-EPMC4090391 | biostudies-literature | 2011 May

REPOSITORIES: biostudies-literature

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Fatty acid-induced NLRP3-ASC inflammasome activation interferes with insulin signaling.

Wen Haitao H Gris Denis D Lei Yu Y Jha Sushmita S Zhang Lu L Huang Max Tze-Han MT Brickey Willie June WJ Ting Jenny P-Y JP

Nature immunology 20110410 5

High-fat diet (HFD) and inflammation are key contributors to insulin resistance and type 2 diabetes (T2D). Interleukin (IL)-1β plays a role in insulin resistance, yet how IL-1β is induced by the fatty acids in an HFD, and how this alters insulin signaling, is unclear. We show that the saturated fatty acid palmitate, but not unsaturated oleate, induces the activation of the NLRP3-ASC inflammasome, causing caspase-1, IL-1β and IL-18 production. This pathway involves mitochondrial reactive oxygen s ...[more]

PMID: 21478880

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Project description:Alcohol-induced neuroinflammation is mediated by proinflammatory cytokines, including IL-1?. IL-1? production requires caspase-1 activation by inflammasomes-multiprotein complexes that are assembled in response to danger signals. We hypothesized that alcohol-induced inflammasome activation contributes to increased IL-1? in the brain. WT and TLR4-, NLRP3-, and ASC-deficient (KO) mice received an ethanol-containing or isocaloric control diet for 5 weeks, and some received the rIL-1ra, anakinra, or saline treatment. Inflammasome activation, proinflammatory cytokines, endotoxin, and HMGB1 were measured in the cerebellum. Expression of inflammasome components (NLRP1, NLRP3, ASC) and proinflammatory cytokines (TNF-?, MCP-1) was increased in brains of alcohol-fed compared with control mice. Increased caspase-1 activity and IL-1? protein in ethanol-fed mice indicated inflammasome activation. TLR4 deficiency protected from TNF-?, MCP-1, and attenuated alcohol-induced IL-1? increases. The TLR4 ligand, LPS, was not increased in the cerebellum. However, we found up-regulation of acetylated and phosphorylated HMGB1 and increased expression of the HMGB1 receptors (TLR2, TLR4, TLR9, RAGE) in alcohol-fed mice. NLRP3- or ASC-deficient mice were protected from caspase-1 activation and alcohol-induced IL-1? increase in the brain. Furthermore, in vivo treatment with rIL-1ra prevented alcohol-induced inflammasome activation and IL-1?, TNF-?, and acetylated HMGB1 increases in the cerebellum. Conversely, intracranial IL-1? administration induced TNF-? and MCP-1 in the cerebellum. In conclusion, alcohol up-regulates and activates the NLRP3/ASC inflammasome, leading to caspase-1 activation and IL-1? increase in the cerebellum. IL-1? amplifies neuroinflammation, and disruption of IL-1/IL-1R signaling prevents alcohol-induced inflammasome activation and neuroinflammation. Increased levels of acetylated and phosphorylated HMGB1 may contribute to alcoholic neuroinflammation.

Dataset Information

Fatty acid-induced NLRP3-ASC inflammasome activation interferes with insulin signaling.

Publications

Fatty acid-induced NLRP3-ASC inflammasome activation interferes with insulin signaling.

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