The role of ghrelin in obesity and insulin resistance (Greliinin merkitys lihavuudessa ja insuliiniresistenssissä)
Year: 2008
Type: dissertation
Abstract: Obesity has become a global public health problem and is a major risk factor for type 2 diabetes.Ghrelin is an appetite-stimulating hormone which acts through its receptor on the hypothalamus to regulate energy balance and thus plays a major role in the aetiology of metabolic diseases.The aims of the studies conducted were 1) to investigate possible associations between single nucleotide polymorphisms (SNPs) in the ghrelin (GHRL) and ghrelin receptor (GHSR) genes and obesity, type 2 diabetes or related phenotypes in persons with impaired glucose tolerance participating in the Finnish Diabetes Prevention Study, 2) to study the role of circulating ghrelin concentrations in the context of metabolic disturbances and 3) to evaluate the possibility of ghrelin gene expression in peripheral blood mononuclear cells (PBMCs) for use as a surrogate marker for ghrelin metabolism.SNPs were genotyped using either a restriction fragment length polymorphism technique or TaqMan allelic discrimination assays.The Leu72Met SNP in GHRL was associated with type 2 diabetes.A common genotype combination of GHRL SNPs was associated with low blood pressure levels and lower risk of hypertension.The rs490683 SNP in the 5' -region of GHSR was associated with weight loss and disrupts a putative binding site for the transcription factor nuclear factor-1.Further gelshift experiments conducted with nuclear extract from rat hypothalamus showed higher protein binding to the minor G allele of the rs490683 SNP in vitro, which could lead to increased GHSR expression and thus increased food intake in persons with the risk allele.Ghrelin plasma concentrations were not restored by weight loss in persons with the metabolic syndrome; instead, those in the control group showed a further decrease in ghrelin levels.GHRL and GHSR were expressed in PBMCs but were not altered upon metabolic changes or associated with certain phenotypes.Thus, ghrelin expression in PBMCs seems unsuitable as a surrogate marker for ghrelin metabolism during lifestyle changes.Nevertheless, ghrelin expression correlated with the expression of proinflammatory cytokines, suggesting that ghrelin may play a role as an autocrine factor in the immune system.In conclusion, SNPs in the GHRL gene may indicate a risk of hypertension, one of the features of metabolic syndrome; however, variations in GHRL seem not to be strong risk factors for type 2 diabetes or obesity.Genetic factors leading to increased GHSR expression and thus potentially to increased ghrelin signalling might ultimately lead to an increase in appetite and weight gain.
Author: Ursula Mager
Language: Finnish
Subfield: Endocrine and Autonomic Systems
Field: Neuroscience
Domain: Life Sciences
Open Access status: green
OpenAlex ID: W3097905354