title: Targeting the NLRP3 Inflammasome to Reduce Diet-Induced Metabolic Abnormalities in Mice.
abstract: Although the molecular links underlying the causative relationship between chronic low-grade inflammation and insulin resistance are not completely understood, compelling evidence suggests a pivotal role of the nucleotide-binding oligomerization domain (NOD)-like receptor pyrin domain containing 3 (NLRP3) inflammasome. Here we tested the hypothesis that either a selective pharmacological inhibition or a genetic downregulation of the NLRP3 inflammasome results in reduction of the diet-induced metabolic alterations. Male C57/BL6 wild-type mice and NLRP3-/-littermates were fed control diet or high-fat, high-fructose diet (HD). A subgroup of HD-fed wild-type mice was treated with the NLRP3 inflammasome inhibitor BAY 11-7082 (3 mg/kg intraperitoneally [IP]). HD feeding increased plasma and hepatic lipids and impaired glucose homeostasis and renal function. Renal and hepatic injury was associated with robust increases in profibrogenic markers, while only minimal fibrosis was recorded. None of these metabolic abnormalities were detected in HD-fed NLRP3-/-mice, and they were dramatically reduced in HD-mice treated with the NLRP3 inflammasome inhibitor. BAY 11-7082 also attenuated the diet-induced increase in NLRP3 inflammasome expression, resulting in inhibition of caspase-1 activation and interleukin (IL)-1β and IL-18 production (in liver and kidney). Interestingly, BAY 11-7082, but not gene silencing, inhibited nuclear factor (NF)-κB nuclear translocation. Overall, these results demonstrate that the selective pharmacological modulation of the NLRP3 inflammasome attenuates the metabolic abnormalities and the related organ injury/dysfunction caused by chronic exposure to HD, with effects similar to those obtained by NLRP3 gene silencing.
authors.affiliation: Dipartimento di Scienza e Tecnologia del Farmaco, Università di Torino, Turin, Italy.
authors.forename: Fausto
authors.initials: F
authors.lastname: Chiazza
authors.affiliation: CNRS, UMR7355 INEM, Immunologie et Neurogénétique Expérimentales et Moléculaires, University of Orléans, Orléans, France.
authors.forename: Aurélie
authors.initials: A
authors.lastname: Couturier-Maillard
authors.affiliation: Dipartimento di Scienza e Tecnologia del Farmaco, Università di Torino, Turin, Italy.
authors.forename: Elisa
authors.initials: E
authors.lastname: Benetti
authors.affiliation: Dipartimento di Scienze Cliniche e Biologiche, Università di Torino, Turin, Italy.
authors.forename: Raffaella
authors.initials: R
authors.lastname: Mastrocola
authors.affiliation: Dipartimento di Scienze Cliniche e Biologiche, Università di Torino, Turin, Italy.
authors.forename: Debora
authors.initials: D
authors.lastname: Nigro
authors.affiliation: Dipartimento di Biotecnologie Molecolari e Scienze per la Salute, Università di Torino, Turin, Italy.|ININCA-CONICET, Buenos Aires, Argentina.
authors.forename: Juan C
authors.initials: JC
authors.lastname: Cutrin
authors.affiliation: Dipartimento di Scienza e Tecnologia del Farmaco, Universià di Torino, Turin, Italy.
authors.forename: Loredana
authors.initials: L
authors.lastname: Serpe
authors.affiliation: Dipartimento di Scienze Cliniche e Biologiche, Università di Torino, Turin, Italy.
authors.forename: Manuela
authors.initials: M
authors.lastname: Aragno
authors.affiliation: Dipartimento di Scienza e Tecnologia del Farmaco, Università di Torino, Turin, Italy.
authors.forename: Roberto
authors.initials: R
authors.lastname: Fantozzi
authors.affiliation: CNRS, UMR7355 INEM, Immunologie et Neurogénétique Expérimentales et Moléculaires, University of Orléans, Orléans, France.
authors.forename: Bernard
authors.initials: B
authors.lastname: Ryffel
authors.affiliation: Queen Mary University of London, Centre for Translational Medicine and Therapeutics, William Harvey Research Institute, Barts, and the London School of Medicine and Dentistry, London, United Kingdom.
authors.forename: Christoph
authors.initials: C
authors.lastname: Thiemermann
authors.affiliation: Dipartimento di Scienza e Tecnologia del Farmaco, Università di Torino, Turin, Italy.
authors.forename: Massimo
authors.initials: M
authors.lastname: Collino