Genetic Regulation of Energy Homeostasis and Obesity

Prevalence of obesity is rapidly increasing all over the world. Even though the explosion of obesity epidemic is a result of environment that favours unhealthy diet and sedentary lifestyle the genes contribute to individual's susceptibility to obesity. High energy intake and low energy expenditure can lead to obesity. The melanocortin system, located in the hypothalamus, is an important central regulator of energy intake, and potentially also energy expenditure. Rare mutations in the MC4R gene leading to impaired melanocortin signalling can cause severe obesity. On the other hand, activation of energy expenditure by increased mitochondrial biogenesis in mice can prevent insulin resistance and diet-induced obesity, suggesting that impaired mitochondrial energy expenditure may cause obesity. In this thesis we examined mechanisms affecting energy expenditure and/or energy intake in a group of healthy offspring of subjects with type 2 diabetes and in a group of healthy subjects together with family members of patients with familial combined hyperlipidemia. Insulin sensitivity was measured with the hyperinsulinemic euglycemic clamp and energy expenditure with indirect calorymetry. First, we demonstrated that insulin-stimulated increase in energy expenditure was strongly associated with insulin sensitivity in humans. Furthermore, we showed that adipose tissue silent information regulator 1 (SIRT1) mRNA and the expression of several other genes regulating mitochondrial function correlated with energy expenditure (EE) and insulin sensitivity during hyperinsulinemia. These findings support the possibility that molecules activating SIRT1, enhancing mitochondrial biogenesis and energy expenditure can potentially be used to treat metabolic disease. Our results that the Val103Ile polymorphism of the melanocortin receptor-4 (MC4R) associates with energy expenditure support the view that the central melanocortin system and in particular MC4R regulate not only energy intake but also energy expenditure. In addition, we observed that common inactivating polymorphisms of melanocortin receptor-3 gene (MC3R) were associated with substrate oxidation and first-phase insulin release. These results are in line with animal studies suggesting that defects in the MC3R signalling lead to impaired lipid oxidation. Polymorphisms of melanin concentrating hormone-1 gene (MCHR1) were also investigated but they did not have any significant associations with obesity or metabolic parameters. In this work we present the close association between energy expenditure, genes regulating mitochondrial function and insulin sensitivity, and an association between gene polymorphisms in the melanocortin system and energy expenditure. However, the exact mechanisms how these genes can predispose to obesity remains to be determined. National Library of Medicine Classification: QU 125, QU 475, QU 500, WD 210, WK 810, WK 880 Medical Subject Headings: Case-Control Studies; Diabetes Mellitus, Type 2; Energy Intake; Energy Metabolism; Finland; Gene Expression Regulation; Genes; Glucose Clamp Technique; Humans; Hyperinsulinism; Hyperlipidemia, Familial Combined; Insulin Resistance; Lipid Metabolism; Melanocyte-Stimulating Hormones; Obesity; Oxidation-Reduction; Receptors, Melanocortin, Type 3; Receptor, Melanocortin, Type 4; Polymorphism, Genetic; Receptors, Pituitary Hormones “Use the Force, Luke” Obi-Wan Kenobi – Yedi Master