Colchicine to decrease NLRP3-activated inflammation and improve obesity-related metabolic dysregulation

Abstract

Obesity is a major risk-factor for the development of insulin resistance, type 2 diabetes, and cardiovascular disease. Circulating molecules associated with obesity, such as saturated fatty acids and cholesterol crystals, stimulate the innate immune system to incite a chronic inflammatory state. Studies in mouse models suggest that suppressing the obesity-induced chronic inflammatory state may prevent or reverse obesity-associated metabolic dysregulation. Human studies, however, have been far less positive, possibly because targeted interventions were too far downstream of the inciting inflammatory events. Recently, it has been shown that, within adipose tissue macrophages, assembly of a multi-protein member of the innate immune system, the NOD-like receptor family pyrin domain containing 3 (NLRP3) inflammasome, is essential for the induction of this inflammatory state. Microtubules enable the necessary spatial arrangement of the components of the NLRP3 inflammasome in the cell, leading to its activation and propagation of the inflammatory cascade. Colchicine, a medication classically used for gout, mediates its anti-inflammatory effect by inhibiting tubulin polymerization, and has been shown to attenuate macrophage NLRP3 inflammasome arrangement and activation in vitro and in vivo. Given these findings, we hypothesize that, in at-risk individuals (those with obesity-induced inflammation and metabolic dysregulation), long-term colchicine use will lead to suppression of inflammation and thus cause improvements in insulin sensitivity and other obesity-related metabolic impairments.

Conflict of interest statement

Conflict of interest statement

The authors report no competing interests.

Published by Elsevier Ltd.

Figures

Fig. 1

(A) Insulin binding to its receptor stimulates tyrosine phosphorylation and activation of IRS-1 in adipocytes and myocytes. The resultant signaling cascade leads to GLUT4 sequestration vesicle trafficking to the plasma membrane, allowing for glucose entry into the cell. (B) Inflammation promotes insulin resistance by interfering with this pathway. Specifically, JNK and IKKβ inactivate IRS-1 via serine phosphorylation, while SOCS proteins prevent IRS-1 tyrosine phosphorylation and promote IRS-1 ubiquitination and subsequent degradation.

Fig. 2

(A) Components of the NLRP3 inflammasome in a quiescent macrophage. (B) Microtubules mediate NLRP3 inflammasome formation by bringing the mitochondrially-based ASC into apposition with NLRP3, located on the surface of the endoplasmic reticulum. Inflammasome formation cleaves procaspase-1 to caspase-1, which in turn activates IL-1β and IL-18 and initiates the inflammatory cascade. (C) Colchicine blocks NLRP3 inflammasome formation and activation by inhibiting microtubule polymerization.