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

By Haitao Wen, Denis Gris, Y. Lei, Sushmita Jha, Lu Zhang, M. Huang, W. Brickey, J. Ting. Nature Immunology, 2011

1,681 citations recorded by the source corpus.

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.

Subfields: Epidemiology, Molecular Biology

View Paper: https://www.semanticscholar.org/paper/1914dd186cfd071bdecce9bf470e02de5487b30c

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In Epidemiology

1. N. Dupont
2. J. Tschopp
3. M. Lamkanfi
4. Manohar Pilli
5. Natascha Roehlen
6. V. Dixit
7. Wojciech Ornatowski
8. E. Crouchet

In Molecular Biology

1. J. Tschopp
2. M. Lamkanfi
3. V. Dixit
4. V. Deretic
5. Rongbin Zhou
6. E. Latz
7. F. Sutterwala
8. Eric I. Elliott

Citations in the corpus

• Redox Regulation of NLRP3 Inflammasomes: ROS as Trigger or Effector? (2015, background): “The mechanism of HFD-induced inflammasome activation may be due to the high production of the fatty acid metabolites ceramide and palmitate, since saturated fatty acids have been shown to induce inflammasome activation through a mechanism that involves defective autophagy and the accumulation of mit”
• Liver Fibrosis: Mechanistic Concepts and Therapeutic Perspectives (2020, background): “Even if NLRP3 inflammasome activation in different cell types has not been completely elucidated, several evidences demonstrated that accumulation of toxic lipids and DAMPs- and PAMPS-mediated TLR signaling activates NLRP3 inflammasome [45,163,165].”
• Autophagy‐based unconventional secretory pathway for extracellular delivery of IL‐1β (2011, background): “Connections between metabolic syndrome, high fat diet, and inflammasome activity are now beginning to be appreciated (Vandanmagsar et al, 2011; Wen et al, 2011), and we propose that autophagy-based unconventional secre- tion may be a key coupler between the metabolism and inflammation.”
• Omega-3 fatty acids prevent inflammation and metabolic disorder through inhibition of NLRP3 inflammasome activation. (2013, background): “…have shown that the NLRP3 inflammasome is implicated in the development of insulin resistance in T2D (Masters et al., 2010; Vandanmagsar et al., 2011; Wen et al., 2011; Zhou et al., 2010), we investigated whetheru-3 FAs can improve insulin sensitivity via inhibition of inflammasome activation.”