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.
Just what we have been arguing for a few years. Work continues.
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