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

Alexander M. Skeldon, Alexandre Morizot, Todd Douglas, Nicola Santoro, Romy Kursawe, Julia Kozlitina, Sonia Caprio, Wajahat Z. Mehal, Maya Saleh

Research output: Contribution to journalArticlepeer-review

17 Scopus citations


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.

Original languageEnglish (US)
Pages (from-to)437-447
Number of pages11
JournalJournal of Immunology
Issue number1
StatePublished - Jan 1 2016

ASJC Scopus subject areas

  • Immunology and Allergy
  • Immunology


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