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

English version

Autoři: Guy M. L. Perry ^aff001
Působiště autorů: Department of Biology, University of Prince Edward Island, Charlottetown, PEI, Canada ^aff001
Vyšlo v časopise: PLoS ONE 14(10)
Kategorie: Research Article
prolekare.web.journal.doi_sk: https://doi.org/10.1371/journal.pone.0222654

Souhrn

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.H2^g7) 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’; 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 (hs2=0.29) and PD_AFP low heritability (hs2=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.

Klíčová slova:

leptin – Genetic loci – Phenotypes – Molecular genetics – Fats – Mouse models – Obesity

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