Caspase-12, but not caspase-11, inhibits obesity and insulin resistance

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 T₁₂₅ 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 T₁₂₅C single nucleotide polymorphism was not associated with metabolic parameters in humans, suggesting that host-specific differences mediate the expressivity of metabolic disease.