Fatty acid–induced NLRP3-ASC inflammasome activation interferes with insulin signaling
Top Cited Papers
- 10 April 2011
- journal article
- research article
- Published by Springer Science and Business Media LLC in Nature Immunology
- Vol. 12 (5), 408-415
- https://doi.org/10.1038/ni.2022
Abstract
Obesity is characterized by chronic inflammation, but the triggers for this remain unclear. Ting and colleagues demonstrate that a high fat diet activates the inflammasome, resulting in IL-1β release and insulin resistance. 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.Keywords
This publication has 50 references indexed in Scilit:
- Critical Role for NALP3/CIAS1/Cryopyrin in Innate and Adaptive Immunity through Its Regulation of Caspase-1Immunity, 2006
- Differential activation of the inflammasome by caspase-1 adaptors ASC and IpafNature, 2004
- Inflammatory Cytokines and the Risk to Develop Type 2 DiabetesDiabetes, 2003
- Glucose-induced β cell production of IL-1β contributes to glucotoxicity in human pancreatic isletsJCI Insight, 2002
- Interaction between free fatty acids and glucose metabolismCurrent Opinion in Clinical Nutrition and Metabolic Care, 2002
- Characterization of the Role of AMP-Activated Protein Kinase in the Regulation of Glucose-Activated Gene Expression Using Constitutively Active and Dominant Negative Forms of the KinaseMolecular and Cellular Biology, 2000
- Protection from obesity-induced insulin resistance in mice lacking TNF-α functionNature, 1997
- Mice deficient in IL-1beta manifest impaired contact hypersensitivity to trinitrochlorobenzone.The Journal of Experimental Medicine, 1996
- IRS-1-Mediated Inhibition of Insulin Receptor Tyrosine Kinase Activity in TNF-α- and Obesity-Induced Insulin ResistanceScience, 1996
- Adipose Expression of Tumor Necrosis Factor-α: Direct Role in Obesity-Linked Insulin ResistanceScience, 1993