Abstract

BackgroundGhrelin may influence the development of obesity through its role in the control of energy balance, food intake, and regulation of body weight. The effects of ghrelin are mediated via the growth hormone secretagogue receptor (GHSR).Methodology/Principal FindingsWe genotyped 7 single nucleotide polymorphisms (SNPs) in the GHSR gene and assessed the association between those SNPs and obesity and type 2 diabetes-related phenotypes from 507 middle-aged overweight persons with impaired glucose tolerance participating in the Finnish Diabetes Prevention Study (DPS). Additionally, we performed in silico screening of the 5′-regulatory region of GHSR and evaluated SNPs disrupting putative transcription factor (TF) binding sites in vitro with gelshift assays to determine differences in protein binding between different alleles of SNPs. Rs9819506 in the promoter region of GHSR was associated with body weight (p = 0.036); persons with rs9819506-AA genotype having the lowest body weight. Individuals with rs490683-CC genotype displayed highest weight loss in the whole study population (p = 0.032). The false discovery rate for these results was <10%. Rs490683 and rs509035 were associated with several measures of glucose and insulin metabolism during the follow-up. Rs490683 may be a functional SNP, since gelshift experiments showed differential protein binding between the alleles, with higher binding to the G-allele. Rs490683-C may disrupt a putative binding site for the TF nuclear factor 1 (NF-1), thus rs4906863-GG genotype where the NF-1 site is intact may lead to a higher GHSR gene expression.Conclusion/SignificancePolymorphisms in the GHSR promoter may modify changes in body weight during long-term lifestyle intervention and affect ghrelin receptor signalling through modulation of GHSR gene expression.

Highlights

  • Ghrelin is predominantly produced by the stomach and is the only known orexigenic hormone and endogenous ligand for the growth-hormone-secretagogue receptor (GHSR) [1,2]

  • A major target for ghrelin is the arcuate nucleus of the hypothalamus, where ghrelin acts on appetite-stimulating groups of neurons, which express the potent orexigenic neuropeptides neuropeptide Y (NPY) and agouti-related protein (AGRP) [7]

  • Rs490683, which was associated with weight loss and measures of glucose metabolism, is in strong linkage disequilibrium (LD) with rs509035 (Fig. 1B)

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Summary

Introduction

Ghrelin is predominantly produced by the stomach and is the only known orexigenic hormone and endogenous ligand for the growth-hormone-secretagogue receptor (GHSR) [1,2]. Ghrelin is composed of 28 amino acids and is uniquely modified by the addition of an octanoyl group to the serine residue at position three This acylation is necessary for ghrelin to bind to the GHSR and to cross the blood-brain barrier [3]. A major target for ghrelin is the arcuate nucleus of the hypothalamus, where ghrelin acts on appetite-stimulating groups of neurons, which express the potent orexigenic neuropeptides neuropeptide Y (NPY) and agouti-related protein (AGRP) [7]. These NPY/AGRP-containing neurons express ghrelin receptors [8]. The effects of ghrelin are mediated via the growth hormone secretagogue receptor (GHSR)

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