Genetic variance in the murine defensin locus modulates glucose homeostasis

Insulin resistance is heritable; however, the underlying genetic drivers remain elusive. In seeking these, we performed genetic mapping of insulin sensitivity in 670 chow-fed Diversity Outbred in Australia (DOz) mice and identified a genome-wide significant quantitative trait loci (QTL) within the chromosome 8 defensin gene cluster. Defensins are antimicrobial peptides secreted from Paneth cells into the intestinal lumen that can alter the abundance of beneficial and detrimental microbes. Proteomic analysis of the small intestine from Diversity Outbred founder strains revealed that alpha-defensin 26 positively correlated with whole-body insulin sensitivity, and founder strain genetic contributions to the insulin sensitivity QTL. To validate these findings, we synthesised the secreted form of alpha-defensin 26 and performed diet supplementation experiments in two mouse strains with distinct endogenous alpha-defensin 26 expression levels. In validation of our DOz data, the strain with lower endogenous expression (C57BL/6J) exhibited improved insulin sensitivity and reduced gut permeability following defensin supplementation. In contrast, the higher expressing strain (A/J) exhibited hypoinsulinemia, glucose intolerance and muscle wasting. Gut microbiome profiling in these mice revealed both global and strain-specific changes including some observed in DOz mice positive for the putative insulin sensitivity allele. Inspired by previous work linking glucose homeostasis to gut microbiome mediated changes in plasma bile acids, we investigated these as a potential mechanism. As with metabolic changes, A/J but not C57BL/6J mice exhibited differential plasma bile acid concentrations following defensin supplementation. These data highlight the importance of considering individual differences when designing metabolic therapeutics and paves the way for further studies investigating links between the host genetics and the microbiome.