‘Fat’s chances’: Loci for phenotypic dispersion in plasma leptin in mouse models of diabetes mellitus

Background Leptin, a critical mediator of feeding, metabolism and diabetes, is expressed on an incidental basis according to satiety. The genetic regulation of leptin should similarly be episodic. Methodology Data from three mouse cohorts hosted by the Jackson Laboratory– 402 (174F, 228M) F 2 Dilute Brown non-Agouti (DBA/2)×DU6i intercrosses, 142 Non Obese Diabetic (NOD/ShiLtJ×(NOD/ShiLtJ×129S1/SvImJ. H2 g7 ) N 2 backcross females, and 204 male Nonobese Nondiabetic (NON)×New Zealand Obese (NZO/HlLtJ) reciprocal backcrosses–were used to test for loci associated with absolute residuals in plasma leptin and arcsin-transformed percent fat (‘phenotypic dispersion’; PD pLep and PD AFP ). Individual data from 1,780 mice from 43 inbred strains was also used to estimate genetic variances and covariances for dispersion in each trait. Principal findings Several loci for PD pLep were detected, including possibly syntenic Chr 17 loci, but there was only a single position on Chr 6 for PD AFP . Coding SNP in genes linked to the consensus Chr 17 PD pLep locus occurred in immunological and cancer genes, genes linked to diabetes and energy regulation, post-transcriptional processors and vomeronasal variants. There was evidence of intersexual differences in the genetic architecture of PD pLep . PD pLep had moderate heritability( h s 2 = 0.29 )and PD AFP low heritability( h s 2 = 0.12 ) ; dispersion in these traits was highly genetically correlated r = 0.8). Conclusions Greater genetic variance for dispersion in plasma leptin, a physiological trait, may reflect its more ephemeral nature compared to body fat, an accrued progressive character. Genetic effects on incidental phenotypes such as leptin might be effectively characterized with randomization-detection methodologies in addition to classical approaches, helping identify incipient or borderline cases or providing new therapeutic targets.