Editors' ChoiceDiabetes

Fat Fans the Flames

See allHide authors and affiliations

Science Translational Medicine  04 May 2011:
Vol. 3, Issue 81, pp. 81ec63
DOI: 10.1126/scitranslmed.3002569

The last decade has seen a dramatic growth in our understanding of the impact of cellular stresses and innate immunity on metabolic disorders. Insulin resistance, obesity, and type 2 diabetes have been linked to chronic inflammation and increased oxidative stress; yet, a molecular basis that integrates these associations is lacking. Now, Wen et al. suggest that the inflammasome may be a central piece in the puzzle.

Inflammasomes are multiprotein complexes that are activated by the innate immune system in response to pathogens and endogenous “danger signals” through the actions of caspase-1; this activation culminates in the production of the proinflammatory cytokines IL-1β and IL-18. Because a high-fat diet and increased free fatty acids have been linked to type 2 diabetes, Wen and colleagues asked whether free fatty acids could activate the inflammasome and mediate metabolic changes. The authors demonstrated that palmitate, as part of a high-fat diet, triggered inflammasome activation in macrophages through the generation of reactive oxygen species (ROS), resulting in increased secretion of IL-1β and IL-18. In vivo, high-fat diet led to inflammasome activation and impaired insulin signaling with increased insulin resistance in wild-type mice, whereas similarly fed mice deficient for inflammasome genes Nlrp3 or Pycard were protected from these effects. Most surprisingly, palmitate treatment in macrophages reduced 5′ adenosine monophosphate-activated protein kinase (AMPK) activity and autophagy, the cellular process that facilitates the turnover of damaged proteins and organelles, with a concomitant increase in mitochondrial ROS. Pharmacological activation of AMPK in palmitate-treated macrophages rescued these defects, indicating a previously unknown role for fatty acid in the upstream regulation of autophagy and mitochondrial ROS through AMPK signaling.

Wen and colleagues provide a molecular basis for how fatty acids can invoke several mediators associated with insulin resistance through activation of the inflammasome to impair insulin signaling. These studies offer an insight into the success of a recent clinical trial of anakinra (an IL-1 receptor antagonist) in type 2 diabetes; the authors show in hepatocyte cells that inhibition of insulin signaling by inflammasome-generated IL-1β was ameliorated by addition of anakinra. Considering that AMPK is inhibited with inflammasome activation, combination therapies with anakinra and metformin (an AMPK activator) will be of great interest. Future therapies targeting the inflammasome may be the key for many metabolic diseases. Let the flame wars begin.

H. Wen et al., Fatty acid-induced NLRP3-ASC inflammasome activation interferes with insulin signaling. Nat. Immunol. 12, 408–415 (2011). [PubMed]

Navigate This Article