title: Empagliflozin Protects against Diet-Induced NLRP-3 Inflammasome Activation and Lipid Accumulation.
abstract: The aim of this study was to evaluate the effects of chronic treatment with empagliflozin, a potent and selective sodium glucose cotransporter-2 inhibitor, in a murine model of diet-induced obesity and insulin resistance, focusing on drug effects on body weight reduction and nucleotide-binding domain, leucine-rich repeat containing protein (NLRP)-3 inflammasome activation, which have never been investigated to date. Male C57BL/6 mice were fed control or a high fat-high sugar (HFHS) diet for 4 months. Over the last 2 months, subsets of animals were treated with empagliflozin (1-10 mg/kg) added to the diet. Empagliflozin evoked body weight reduction (P < 0.001 for the highest dose) and positive effects on fasting glycemia and homeostasis model assessment of insulin resistance. In addition, the drug was able to reduce renal tubular damage and liver triglycerides level in a dose-dependent manner. Interestingly, empagliflozin also decreased cardiac lipid accumulation. Moreover, diet-induced activation of NLRP-3 in kidney and liver (not observed in the heart) was dose-dependently attenuated by empagliflozin. Our results clearly demonstrate the ability of empagliflozin to counteract the deleterious effects evoked by chronic exposure to HFHS diet. Most notably, empagliflozin treatment was associated with NLRP-3 inflammasome signaling modulation, suggesting that this inhibition may contribute to the drug therapeutic effects.
authors.affiliation: Departments of Drug Science and Technology (E.B., G.V., F.C., M.C., R.F.), Clinical and Biological Sciences (R.M., D.N.), and Biotechnology and Sciences for the Health (J.C.C.), University of Turin, Turin, Italy; and Boehringer Ingelheim Pharma, Biberach an der Riss, Germany (E.M.) elisa.benetti@unito.it.
authors.forename: Elisa
authors.identifier: 0000-0002-4481-0756
authors.initials: E
authors.lastname: Benetti
authors.affiliation: Departments of Drug Science and Technology (E.B., G.V., F.C., M.C., R.F.), Clinical and Biological Sciences (R.M., D.N.), and Biotechnology and Sciences for the Health (J.C.C.), University of Turin, Turin, Italy; and Boehringer Ingelheim Pharma, Biberach an der Riss, Germany (E.M.).
authors.forename: Raffaella
authors.initials: R
authors.lastname: Mastrocola
authors.affiliation: Departments of Drug Science and Technology (E.B., G.V., F.C., M.C., R.F.), Clinical and Biological Sciences (R.M., D.N.), and Biotechnology and Sciences for the Health (J.C.C.), University of Turin, Turin, Italy; and Boehringer Ingelheim Pharma, Biberach an der Riss, Germany (E.M.).
authors.forename: Giovanna
authors.initials: G
authors.lastname: Vitarelli
authors.affiliation: Departments of Drug Science and Technology (E.B., G.V., F.C., M.C., R.F.), Clinical and Biological Sciences (R.M., D.N.), and Biotechnology and Sciences for the Health (J.C.C.), University of Turin, Turin, Italy; and Boehringer Ingelheim Pharma, Biberach an der Riss, Germany (E.M.).
authors.forename: Juan Carlos
authors.initials: JC
authors.lastname: Cutrin
authors.affiliation: Departments of Drug Science and Technology (E.B., G.V., F.C., M.C., R.F.), Clinical and Biological Sciences (R.M., D.N.), and Biotechnology and Sciences for the Health (J.C.C.), University of Turin, Turin, Italy; and Boehringer Ingelheim Pharma, Biberach an der Riss, Germany (E.M.).
authors.forename: Debora
authors.initials: D
authors.lastname: Nigro
authors.affiliation: Departments of Drug Science and Technology (E.B., G.V., F.C., M.C., R.F.), Clinical and Biological Sciences (R.M., D.N.), and Biotechnology and Sciences for the Health (J.C.C.), University of Turin, Turin, Italy; and Boehringer Ingelheim Pharma, Biberach an der Riss, Germany (E.M.).
authors.forename: Fausto
authors.initials: F
authors.lastname: Chiazza
authors.affiliation: Departments of Drug Science and Technology (E.B., G.V., F.C., M.C., R.F.), Clinical and Biological Sciences (R.M., D.N.), and Biotechnology and Sciences for the Health (J.C.C.), University of Turin, Turin, Italy; and Boehringer Ingelheim Pharma, Biberach an der Riss, Germany (E.M.).
authors.forename: Eric
authors.initials: E
authors.lastname: Mayoux
authors.affiliation: Departments of Drug Science and Technology (E.B., G.V., F.C., M.C., R.F.), Clinical and Biological Sciences (R.M., D.N.), and Biotechnology and Sciences for the Health (J.C.C.), University of Turin, Turin, Italy; and Boehringer Ingelheim Pharma, Biberach an der Riss, Germany (E.M.).
authors.forename: Massimo
authors.initials: M
authors.lastname: Collino
authors.affiliation: Departments of Drug Science and Technology (E.B., G.V., F.C., M.C., R.F.), Clinical and Biological Sciences (R.M., D.N.), and Biotechnology and Sciences for the Health (J.C.C.), University of Turin, Turin, Italy; and Boehringer Ingelheim Pharma, Biberach an der Riss, Germany (E.M.).
authors.forename: Roberto
authors.initials: R
authors.lastname: Fantozzi
mesh_terms: D000818:Animals; D001559:Benzhydryl Compounds / Q000494:pharmacology* / Q000627:therapeutic use; D001786:Blood Glucose / Q000378:metabolism; D001835:Body Weight / Q000187:drug effects; D004032:Diet / Q000009:adverse effects*; D005215:Fasting / Q000097:blood; D005951:Glucose Tolerance Test; D005960:Glucosides / Q000494:pharmacology* / Q000627:therapeutic use; D058847:Inflammasomes / Q000378:metabolism*; D007668:Kidney / Q000187:drug effects / Q000378:metabolism; D050356:Lipid Metabolism / Q000187:drug effects*; D008099:Liver / Q000187:drug effects / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009206:Myocardium / Q000378:metabolism; D009765:Obesity / Q000139:chemically induced / Q000188:drug therapy / Q000378:metabolism
chemical_list: D001559:Benzhydryl Compounds; D001786:Blood Glucose; D005960:Glucosides; D058847:Inflammasomes; C570240:empagliflozin