Abstract
BackgroundLeptin, 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.MethodologyData 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 findingsSeveral 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 and PDAFP low heritability ; dispersion in these traits was highly genetically correlated r = 0.8).ConclusionsGreater 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.
Highlights
Leptin, produced by white adipose cells, regulates appetite, basal metabolic rate, activity, growth and energetic homeostasis, providing negative feedback in the hypothalamus against hunger induced by ghrelin, neuropeptide Y and anandamide [1]
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
Summary
Leptin, produced by white adipose cells, regulates appetite, basal metabolic rate, activity, growth and energetic homeostasis, providing negative feedback in the hypothalamus against hunger induced by ghrelin, neuropeptide Y and anandamide [1]. Leptin was first identified as a hunger suppressant in spontaneous hyperphagic obese (ob) mutant mice (C57BL/KsJ) with glucose intolerance and diabetes [2]. Leptin treatment is corrective in animal models of diabetes [5] and leptin polymorphisms have been linked to obesity in humans [6]. Genetic loci have been linked to leptin production in mice (Chr 3 (143.2 MB), 10 (107.1 MB), 12 (100.6 MB) [7], 7 (~ 100 MB) [8] 14 (37–73 MB) [9], 2 (141.1 MB), 17 (40.2 MB) [10], 5 (93.3 MB), 12 (100.6 MB), 15 (55.3 MB) [11]) and such models may provide further useful information on the genetic structure of diabetes and its physiological construction.
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