title: Inflammasome is a central player in the induction of obesity and insulin resistance.
abstract: Inflammation plays a key role in the pathogenesis of obesity. Chronic overfeeding leads to macrophage infiltration in the adipose tissue, resulting in proinflammatory cytokine production. Both microbial and endogenous danger signals trigger assembly of the intracellular innate immune sensor Nlrp3, resulting in caspase-1 activation and production of proinflammatory cytokines IL-1β and IL-18. Here, we showed that mice deficient in Nlrp3, apoptosis-associated speck-like protein, and caspase-1 were resistant to the development of high-fat diet-induced obesity, which correlated with protection from obesity-induced insulin resistance. Furthermore, hepatic triglyceride content, adipocyte size, and macrophage infiltration in adipose tissue were all reduced in mice deficient in inflammasome components. Monocyte chemoattractant protein (MCP)-1 is a key molecule that mediates macrophage infiltration. Indeed, defective inflammasome activation was associated with reduced MCP-1 production in adipose tissue. Furthermore, plasma leptin and resistin that affect energy use and insulin sensitivity were also changed by inflammasome-deficiency. Detailed metabolic and molecular phenotyping demonstrated that the inflammasome controls energy expenditure and adipogenic gene expression during chronic overfeeding. These findings reveal a critical function of the inflammasome in obesity and insulin resistance, and suggest inhibition of the inflammasome as a potential therapeutic strategy.
authors.affiliation: Department of Medicine, Radboud University Nijmegen Medical Centre, and Nijmegen Institute for Infection, Inflammation and Immunity, 6525 GA Nijmegen, The Netherlands.
authors.forename: Rinke
authors.initials: R
authors.lastname: Stienstra
authors.forename: Janna A
authors.initials: JA
authors.lastname: van Diepen
authors.forename: Cees J
authors.initials: CJ
authors.lastname: Tack
authors.forename: Md Hasan
authors.initials: MH
authors.lastname: Zaki
authors.forename: Frank L
authors.initials: FL
authors.lastname: van de Veerdonk
authors.forename: Deshani
authors.initials: D
authors.lastname: Perera
authors.forename: Geoffrey A
authors.initials: GA
authors.lastname: Neale
authors.forename: Guido J
authors.initials: GJ
authors.lastname: Hooiveld
authors.forename: Anneke
authors.initials: A
authors.lastname: Hijmans
authors.forename: Irene
authors.initials: I
authors.lastname: Vroegrijk
authors.forename: Sjoerd
authors.initials: S
authors.lastname: van den Berg
authors.forename: Johannes
authors.initials: J
authors.lastname: Romijn
authors.forename: Patrick C N
authors.initials: PC
authors.lastname: Rensen
authors.forename: Leo A B
authors.initials: LA
authors.lastname: Joosten
authors.forename: Mihai G
authors.initials: MG
authors.lastname: Netea
authors.forename: Thirumala-Devi
authors.initials: TD
authors.lastname: Kanneganti
mesh_terms: D017667:Adipocytes / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D000273:Adipose Tissue / Q000473:pathology; D000818:Animals; D051017:Apoptosis Regulatory Proteins; D053468:CARD Signaling Adaptor Proteins; D002352:Carrier Proteins / Q000378:metabolism; D020170:Caspase 1 / Q000378:metabolism; D002465:Cell Movement / Q000187:drug effects; D002784:Cholesterol / Q000097:blood; D003598:Cytoskeletal Proteins / Q000172:deficiency / Q000378:metabolism; D004041:Dietary Fats / Q000008:administration & dosage / Q000494:pharmacology; D004734:Energy Metabolism / Q000187:drug effects; D005234:Fatty Liver / Q000150:complications / Q000473:pathology / Q000517:prevention & control; D015309:Glucose Clamp Technique; D006801:Humans; D006946:Hyperinsulinism / Q000150:complications / Q000473:pathology; D006984:Hypertrophy; D058847:Inflammasomes / Q000378:metabolism*; D007333:Insulin Resistance; D008264:Macrophages / Q000187:drug effects / Q000473:pathology; D008297:Male; D051379:Mice; D000071199:NLR Family, Pyrin Domain-Containing 3 Protein; D009765:Obesity / Q000097:blood / Q000150:complications / Q000378:metabolism*; D014280:Triglycerides / Q000097:blood
chemical_list: D051017:Apoptosis Regulatory Proteins; D053468:CARD Signaling Adaptor Proteins; D002352:Carrier Proteins; D003598:Cytoskeletal Proteins; D004041:Dietary Fats; D058847:Inflammasomes; D000071199:NLR Family, Pyrin Domain-Containing 3 Protein; C492716:Nlrp3 protein, mouse; C498534:Pycard protein, mouse; D014280:Triglycerides; D002784:Cholesterol; D020170:Caspase 1