‘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 [Image: see text] and PD(AFP) low heritability [Image: see text] ; 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.