title: 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.
authors.affiliation: Section on Growth and Obesity, Division of Translational Medicine, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, DHHS, United States. Electronic address: andrew.demidowich@nih.gov.
authors.forename: Andrew P
authors.initials: AP
authors.lastname: Demidowich
authors.affiliation: Section on Growth and Obesity, Division of Translational Medicine, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, DHHS, United States.
authors.forename: Angela I
authors.initials: AI
authors.lastname: Davis
authors.affiliation: Section on Growth and Obesity, Division of Translational Medicine, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, DHHS, United States.
authors.forename: Nicket
authors.initials: N
authors.lastname: Dedhia
authors.affiliation: Section on Growth and Obesity, Division of Translational Medicine, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, DHHS, United States.
authors.forename: Jack A
authors.initials: JA
authors.lastname: Yanovski
mesh_terms: D000273:Adipose Tissue / Q000378:metabolism; D000818:Animals; D003078:Colchicine / Q000494:pharmacology*; D003924:Diabetes Mellitus, Type 2 / Q000150:complications; D006074:Gout Suppressants / Q000494:pharmacology; D006801:Humans; D007113:Immunity, Innate; D058847:Inflammasomes / Q000378:metabolism; D007249:Inflammation; D007333:Insulin Resistance; D008264:Macrophages / Q000378:metabolism; D008659:Metabolic Diseases / Q000150:complications / Q000378:metabolism*; D051379:Mice; D000071199:NLR Family, Pyrin Domain-Containing 3 Protein / Q000378:metabolism*; D009765:Obesity / Q000150:complications / Q000188:drug therapy*; D012307:Risk Factors
chemical_list: D006074:Gout Suppressants; D058847:Inflammasomes; D000071199:NLR Family, Pyrin Domain-Containing 3 Protein; C453881:NLRP3 protein, human; D003078:Colchicine