30.05.2008 Doctoral dissertation: The role of ghrelin in obesity and insulin resistance

In her PhD work, Ursula Mager, MSc, investigated the possible associations between genetic variations in the ghrelin and ghrelin receptor genes and obesity, type 2 diabetes or related phenotypes in persons with impaired glucose tolerance. The public examination of her doctoral dissertation is on 30th May 2008 at the Faculty of Medicine, University of Kuopio.

Obesity has become a global public health problem and the prevalence and incidence is steadily rising worldwide. The metabolic syndrome is a combination of metabolic risk factors including central obesity, hypertension, dyslipidaemia, insulin resistance and type 2 diabetes. Obesity is a complex disease caused by an imbalance in energy input and energy expenditure. Environmental factors, dietary and physical activity habits, act in conjunction with predetermined genetic parameters. Ghrelin is an appetite-stimulating hormone, produced by the stomach, 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 genetic variations, so called 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 (DPS),

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.

The most studied Leu72Met SNP in GHRL was associated with type 2 diabetes in DPS. A common genotype combination of GHRL SNPs was associated with low blood pressure levels and lower risk of hypertension. One SNP in the promoter region of GHSR was associated with weight loss. This SNP disrupts a putative transcription factor binding site, which means that it could potentially influence the expression of the ghrelin receptor. An increased ghrelin receptor expression could theoretically lead to increased ghrelin signalling and ultimately to increased food intake in persons with the risk allele.

Ghrelin plasma concentrations are lower in obesity and metabolic syndrome compared to normal-weight persons, but weight loss achieved by dietary intervention did not increase reduced ghrelin levels in our study. Instead, persons with metabolic syndrome in the control group, who did not lose weight, 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 and did not change during lifestyle intervention. 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 pro-inflammatory 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.


Suomenkielinen väitöstiedote: http://www.uku.fi/vaitokset/2008/ISBN978-951-27-0948-9umager.htm

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