Editors' ChoiceMetabolism

Fish Oil Cools the Inflammasome

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Science Translational Medicine  10 Jul 2013:
Vol. 5, Issue 193, pp. 193ec113
DOI: 10.1126/scitranslmed.3006920

Snake oil elixirs were falsely sold as cure-all medicines in the American Old West, but fish oil may be closer to the real deal. Omega-3 fatty acids derived from dietary fish and seafood have been associated with a wide array of potentially beneficial health effects. A striking example is the ability of omega-3 fatty acids to suppress inflammation and improve insulin sensitivity.

The inflammasome is a cytosolic protein complex that controls the production of the proinflammatory cytokines, interleukin-1β (IL-1β) and IL-18, in response to endogenous and exogenous danger signals. Abnormal activation of the NLRP3 inflammasome and IL-1β and IL-18 play a central role in the pathogenesis of obesity-induced tissue inflammation, insulin resistance, and type 2 diabetes.

Yan and colleagues wanted to know whether the decreased IL-1β levels reported with omega-3 fatty acid treatment were due to a direct effect on the NLRP3 inflammasome that could be used therapeutically. The authors started by showing that stimulated mouse and human macrophages secrete less IL-1β and IL-18 after omega-3 fatty acid treatment and confirmed that this effect was not observed with non–omega-3 fatty acids or biologically active intermediates. Next, they showed that the anti–IL-1β effect of omega-3 fatty acids was dependent on the cell-surface G-protein–coupled receptors, GPR120 and GPR40, which are known to bind omega-3 fatty acids, and noted that a small-molecule GPR120/GPR40 agonist also decreased IL-1β production. As further confirmation of this pathway, the authors showed that β-arrestin-2 (ARRB2), a downstream scaffold protein of GPR120, interacted with NLRP3 inflammasome proteins and that ARRB2 deficiency abrogates the effect of omega-3 fatty acids on IL-1β secretion. Last, the authors connected omega-3 fatty acid–mediated inflammasome inhibition with insulin and glucose metabolism in vivo using a high-fat diet (HFD) mouse model of hyperglycemia and insulin resistance. In these experiments, omega-3 fatty acid dietary supplementation reduced fasting blood glucose and insulin levels and improved glucose tolerance and insulin sensitivity in HFD mice, suggesting that omega-3 fatty acids might help patients with type 2 diabetes.

This study reveals an important new mechanism by which omega-3 fatty acids directly inhibit the NLRP3 inflammasome that could lead to new therapies for diseases in which abnormal inflammasome activation drives pathogenesis such as diabetes, arthritis, and atherosclerosis. Two crucial next steps are to determine whether omega-3 fatty acids inhibit the inflammasome in healthy and diseased people and whether omega-3 fatty acid–mediated inflammasome inhibition translates into meaningful differences in disease biomarkers and clinical outcomes.

Y. Yan et al., Omega-3 fatty acids prevent inflammation and metabolic disorder through inhibition of NLRP3 inflammasome activation. Immunity 38, 1154–1163 (2013). [Abstract]

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