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

Abstract

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) F2 Dilute Brown non-Agouti (DBA/2)×DU6i intercrosses, 142 Non Obese Diabetic (NOD/ShiLtJ×(NOD/ShiLtJ×129S1/SvImJ.H2g7) N2 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'; PDpLep and PDAFP). 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 PDpLep were detected, including possibly syntenic Chr 17 loci, but there was only a single position on Chr 6 for PDAFP. Coding SNP in genes linked to the consensus Chr 17 PDpLep 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 PDpLep. PDpLep had moderate heritability [Formula: see text] and PDAFP low heritability [Formula: 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.

Fig 1. Association mapping of phenotypic dispersion (absolute Studentized residuals from genetic model; ‘PD’) in plasma leptin (PD_pLep) on murine chromosomes 1–19 Jackson Laboratory in 402 (228M, 174F) F₂ Dilute Brown non-Agouti (DBA/2)×DU6i intercrosses (Brockman et al.), 144 Non Obese Diabetic (NOD/ShiLtJ×(NOD/ShiLtJ×129S1/SvImJ.H2^g7) N₂ backcross females (Leiter et al.), 204 male Nonobese Nondiabetic (NON)×New Zealand Obese (NZO/HlLtJ) reciprocal backcrosses (Reifsnyder et al.) house mice (Mus musculus).

Fig 2. Mean phenotypic dispersion in plasma leptin (PD_pLep) from Tobit limited model analysis in a cohort of 233 F₂ DBA/2× DU6i house mice (Mus musculus) (Brockmann et al.) by marker.

The significance of differences among mean PD_pLep by genotype (P < 0.05*, < 0.01**, < 0.001***) was determined using general linear contrast statements.

Fig 3. Strain-by-sex means for phenotypic dispersion in a) plasma leptin (PD_pLep) and arcin-transformed percent body fat (PD_APF) in all (solid circles), female (empty circles) and all (solid downwarn-facing triangles) from 43 mouse strains (n = 1,780; n_i = 4–26 per strain and sex) [31] using mixed models [25].