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

Haitao Wen, Denis Gris, Yu Lei, Sushmita Jha, Lu Zhang, Max Tze Han Huang, Willie June Brickey, Jenny P.Y. Ting

Research output: Contribution to journalArticle

946 Scopus citations

Abstract

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 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-1β affects insulin sensitivity through tumor necrosis factor-independent and dependent pathways. These findings provide insights into the association of inflammation, diet and T2D.

Original languageEnglish (US)
Pages (from-to)408-415
Number of pages8
JournalNature Immunology
Volume12
Issue number5
DOIs
StatePublished - May 1 2011
Externally publishedYes

ASJC Scopus subject areas

  • Immunology and Allergy
  • Immunology

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    Wen, H., Gris, D., Lei, Y., Jha, S., Zhang, L., Huang, M. T. H., Brickey, W. J., & Ting, J. P. Y. (2011). Fatty acid-induced NLRP3-ASC inflammasome activation interferes with insulin signaling. Nature Immunology, 12(5), 408-415. https://doi.org/10.1038/ni.2022