Dampening insulin signaling by an NLRP3 'meta-flammasome'

Abstract

The inflammasome has been linked to metabolic disorders such as obesity and type 2 diabetes. Data now suggest that the crosstalk between the inflammasome and autophagy critically mediates cytoplasmic receptor NLRP3–dependent activation of the inflammasome by the saturated fatty acids contained in a high-fat diet.

Figure 1

Involvement of the inflammasome in type 2 diabetes pathogenesis. (a) In macrophages, exogenous danger signals such as the saturated fatty acids contained in a high-fat diet and endogenous danger signals such as ceramide activate the NLRP3 inflammasome and trigger release of IL-1β. IL-1β deregulates insulin signaling, which potentially leads to insulin resistance in cells that are a target of insulin by both TNF-dependent and TNF-independent pathways. Enhanced expression of the NLRP3 inflammasome in adipose-tissue macrophages during an obese state is associated with activation of T cells, including production of interferon (IFN-γ) in adipose tissue, which promotes macrophage activation and systemic inflammation. NF-κB, transcription factor; IL-1R, IL-1 receptor; TNFR, TNF receptor; yellow ‘P’, phosphorylation. (b) Regulating the inflammasome via the machinery of autophagy could be a potent therapeutic target in type 2 diabetes. LKB1-mediated activation of AMPK promotes phosphorylation of ULK1, which initiates autophagy. The autophagy machinery controls mitochondrial homeostasis by removing old or damaged mitochondria (mitophagy). Fatty acids (such as palmitate) suppress the activation of AMPK, which leads to inhibition of autophagy and accumulation of dysfunctional mitochondria, along with enhanced generation of ROS. Enhancement of mitochondrial ROS promotes activation of the NLRP3 inflammasome and release of IL-1β. The pharmacological effects of anti-diabetes drugs are potentially linked to regulation of the autophagy and inflammsome pathways: metformin requires LKB1-dependent phosphorylation of AMPK to regulate glucose concentrations, and glibenclamide suppresses activation of the NLRP3 inflammasome in macrophages. Anakinra, an antagonist of the IL-1β receptor, may also be beneficial in type 2 diabetes.