Caspase-12, but Not Caspase-11, Inhibits Obesity and Insulin Resistance

Area of Science:

• Immunology
• Metabolic disease research
• Molecular biology

Background:

• Inflammation significantly impacts metabolic diseases.
• The inflammatory protease caspase-1 is linked to metabolic dysfunction.
• The roles of related inflammatory caspases, such as caspase-11 and caspase-12, in metabolic health are largely unknown.

Purpose of the Study:

• To investigate the roles of caspase-11 and caspase-12 in the development of obesity and insulin resistance.
• To elucidate the specific cellular compartments and molecular pathways involved in caspase-12-mediated metabolic dysfunction.

Main Methods:

• Utilized two independently generated mouse strains lacking caspase-12.
• Employed bone marrow chimeras to identify the responsible cellular compartment.
• Investigated the involvement of the Nlrp3 inflammasome pathway by genetically ablating Nlrp3.
• Analyzed human cohorts, including African American obese children and the Dallas Heart Study cohort, to assess the relevance of caspase-12 in human metabolic disease.

Main Results:

• Loss of caspase-12, but not caspase-11, predisposed mice to obesity, metabolic inflammation, and insulin resistance.
• Bone marrow chimera experiments indicated that deletion of caspase-12 in the radio-resistant compartment drives the metabolic phenotype.
• Ablation of Nlrp3 reversed the obesity phenotype in caspase-12-deficient mice, implicating the Nlrp3 inflammasome pathway.
• While full-length caspase-12 expression correlated with reduced inflammation in some African American children, a common human polymorphism (T125C) was not associated with metabolic parameters in another cohort.

Conclusions:

• Caspase-12 plays a critical role in regulating metabolic homeostasis, with its absence promoting obesity and insulin resistance.
• The Nlrp3 inflammasome pathway is a key mediator of the metabolic syndrome observed in caspase-12-deficient states.
• The impact of caspase-12 on human metabolic disease may be complex, influenced by genetic variations and potentially other host-specific factors.