Obesity-associated phenotypes and circulating levels of ghrelin, cholecystokinin, low-density lipoprotein and zinc: genetic and observational studies
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Obesity is a complex problem that is believed to result from both genetic and environmental factors. This condition greatly increases the risk of developing serious health consequences, such as metabolic syndrome and cardiovascular disease. The primary goal of this research was to study the genetic influence on plasma ghrelin, cholecystokinin (CCK), and low-density lipoprotein (LDL), and their relationship with obesity. A secondary goal was to investigate the effect of weight loss on plasma zinc and other risk factors for metabolic syndrome. Aims 1 and 2 were to estimate the additive heritabilities and to localize the responsible chromosomal quantitative trait loci associated with circulating levels of the appetite regulating hormones, ghrelin and CCK, in baboons. Plasma ghrelin and CCK were higher in baboons than humans, with males exhibiting greater levels. Ghrelin was inversely linked to body weight (r = 0.23, p < 0.001), insulin (r = - 0.19, p < 0.05), and leptin (r = - 0.14, p < 0.05). Significant heritabilities were observed for ghrelin and CCK. A strong signal was detected for plasma CCK on chromosome 17p12 (LOD = 3.1, p < 0.01). Aim 3 was to detect heritability and pleiotropy between the obesity-related anthropometric phenotypes and low- density lipoproteins (LDL) in humans. Effect of genes on LDL size was evident, with substantial heritability and strong genetic correlations between LDL and obesity-related traits; small LDL and weight (rhoG = 0.65, p < 0.001), waist (rhoG = 0.80, p < 0.001), and BMI (rhoG = 0.67, p < 0.001), respectively. Aim 4 was to study the impact of weight loss on plasma zinc and risk factors for metabolic syndrome in humans. Weight reduction significantly increased the low plasma zinc observed in obese women, and improved risk factors for metabolic syndrome (HDL, BMI, waist and body fat). A negative correlation was observed between changes in zinc and body fat (r = -0.28, p < 0.05). Collectively, these results demonstrate significant influence of genetic factors on plasma ghrelin, CCK, LDL and obesity phenotypes. In addition, weight loss produced beneficial effects of weight loss on plasma zinc and risk factors for metabolic syndrome.