title: Caspase-12, but Not Caspase-11, Inhibits Obesity and Insulin Resistance.
abstract: Inflammation is well established to significantly impact metabolic diseases. The inflammatory protease caspase-1 has been implicated in metabolic dysfunction; however, a potential role for the related inflammatory caspases is currently unknown. In this study, we investigated a role for caspase-11 and caspase-12 in obesity and insulin resistance. Loss of caspase-12 in two independently generated mouse strains predisposed mice to develop obesity, metabolic inflammation, and insulin resistance, whereas loss of caspase-11 had no effect. The use of bone marrow chimeras determined that deletion of caspase-12 in the radio-resistant compartment was responsible for this metabolic phenotype. The Nlrp3 inflammasome pathway mediated the metabolic syndrome of caspase-12-deficient mice as ablation of Nlrp3 reversed Casp12(-/-) mice obesity phenotype. Although the majority of people lack a functional caspase-12 because of a T(125) single nucleotide polymorphism that introduces a premature stop codon, a fraction of African descendents express full-length caspase-12. Expression of caspase-12 was linked to decreased systemic and adipose tissue inflammation in a cohort of African American obese children. However, analysis of the Dallas Heart Study African American cohort indicated that the coding T(125)C single nucleotide polymorphism was not associated with metabolic parameters in humans, suggesting that host-specific differences mediate the expressivity of metabolic disease.
authors.affiliation: Department of Biochemistry, McGill University, Montreal, Quebec H3G 1Y6, Canada;
authors.forename: Alexander M
authors.initials: AM
authors.lastname: Skeldon
authors.affiliation: Department of Medicine, McGill University, Montreal, Quebec H3G 0B1, Canada;
authors.forename: Alexandre
authors.identifier: http://orcid.org/0000-0003-4787-7996
authors.initials: A
authors.lastname: Morizot
authors.affiliation: Department of Microbiology and Immunology McGill University, Montreal, Quebec H3A 2B4, Canada;
authors.forename: Todd
authors.initials: T
authors.lastname: Douglas
authors.affiliation: Department of Pediatrics, Yale University, New Haven, CT 06510;
authors.forename: Nicola
authors.identifier: http://orcid.org/0000-0001-6437-4173
authors.initials: N
authors.lastname: Santoro
authors.affiliation: Department of Pediatrics, Yale University, New Haven, CT 06510;
authors.forename: Romy
authors.initials: R
authors.lastname: Kursawe
authors.affiliation: McDermott Center for Human Growth and Development, University of Texas Southwestern Medical Center, Dallas, TX 75390; and.
authors.forename: Julia
authors.initials: J
authors.lastname: Kozlitina
authors.affiliation: Department of Pediatrics, Yale University, New Haven, CT 06510;
authors.forename: Sonia
authors.initials: S
authors.lastname: Caprio
authors.affiliation: Section of Digestive Diseases, Yale University, New Haven, CT 06520.
authors.forename: Wajahat Z
authors.initials: WZ
authors.lastname: Mehal
authors.affiliation: Department of Biochemistry, McGill University, Montreal, Quebec H3G 1Y6, Canada; Department of Medicine, McGill University, Montreal, Quebec H3G 0B1, Canada; Department of Microbiology and Immunology McGill University, Montreal, Quebec H3A 2B4, Canada; maya.saleh@mcgill.ca.
authors.forename: Maya
authors.initials: M
authors.lastname: Saleh
mesh_terms: D000818:Animals; D002352:Carrier Proteins / Q000235:genetics / Q000276:immunology; D053454:Caspase 12 / Q000235:genetics / Q000502:physiology*; D020169:Caspases / Q000235:genetics / Q000502:physiology*; D053471:Caspases, Initiator; D018149:Glucose Intolerance / Q000235:genetics; D006801:Humans; D007249:Inflammation / Q000235:genetics / Q000276:immunology; D007333:Insulin Resistance / Q000235:genetics*; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D000071199:NLR Family, Pyrin Domain-Containing 3 Protein; D009765:Obesity / Q000235:genetics*; D020641:Polymorphism, Single Nucleotide / Q000235:genetics; D053475:Receptor-Interacting Protein Serine-Threonine Kinase 2; D053422:Receptor-Interacting Protein Serine-Threonine Kinases / Q000235:genetics
chemical_list: D002352:Carrier Proteins; D000071199:NLR Family, Pyrin Domain-Containing 3 Protein; C492716:Nlrp3 protein, mouse; D053475:Receptor-Interacting Protein Serine-Threonine Kinase 2; D053422:Receptor-Interacting Protein Serine-Threonine Kinases; C506255:Ripk2 protein, mouse; C506444:CASP12 protein, human; C506440:Casp12 protein, mouse; C101136:Casp4 protein, mouse; D053454:Caspase 12; D020169:Caspases; D053471:Caspases, Initiator