Journal
NATURE IMMUNOLOGY
Volume 12, Issue 5, Pages 408-U61Publisher
NATURE PUBLISHING GROUP
DOI: 10.1038/ni.2022
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Funding
- US National Institutes of Health [R37-AI029564-17, CA-156330-01]
- American Heart Association Mid-Atlantic Affiliate
- Cancer Research Institute
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High-fat diet (HFD) and inflammation are key contributors to insulin resistance and type 2 diabetes (T2D). Interleukin (IL)-1 beta plays a role in insulin resistance, yet how IL-1 beta 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 beta 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 beta affects insulin sensitivity through tumor necrosis factor-independent and dependent pathways. These findings provide insights into the association of inflammation, diet and T2D.
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