Genes implicated in the development of obesity and obesity-related disease

Abstract: Obesity is a major health problem because of its dramatic increase in prevalence and the association of obesity with type 2 diabetes, coronary heart disease, hypertension and stroke. Although mutations in certain genes have been shown to cause obesity, the molecular mechanisms underlying obesity and obesity-related disease are still largely unknown. It has long been known that the hypothalamus is important for the regulation of body weight homeostasis. The cloning of the leptin and leptin-receptor (leptin-R) genes showed that these two genes are part of a feedback system that forms a link between adipose tissue and the hypothalamus. The general aim of this thesis was to study the components of the leptin system in relation to the development of obesity and to search for adipose tissue-derived factors that may be involved in the development of obesity and obesity-related disease.Defects in the leptin system have been described in obese rodent models. We therefore studied the DNA sequence and the expression of the leptin gene in 94 obese adult human subjects. No defects were found, suggesting that mutations in the leptin gene are rare in human obesity.As leptin levels closely correlate to body fat mass in most obese subjects, leptin resistance has been proposed as a possible explanation for human obesity. It has long been known that food intake and body weight change during the oestrous cycle in rats. To explore the regulation of leptin sensitivity we assayed the leptin response during a hormonally induced oestrous cycle. The response to leptin in hypothalamic explants, as assayed by induction of tis11 expression, was higher at pro-oestrus than at oestrus. We next studied the regulation of rat leptin-R expression after treatments known to influence food intake and body weight, such as ovariectomy and oestradiol administration. Administration of oestradiol caused a relative increase in the ratio between the long and short leptin-R isoforms whereas ovariectomy led to a relative decrease. Analysis of the transcriptional start sites and the promoter of the rat leptin-R gene showed that at least four transcriptional start sites are used and that the promoter contains an imperfect oestrogen response element. This finding provides one possible explanation of oestrogen's impact on food intake. The background to obesity and obesity-related disease is often complex and probably includes allelic variation at many different loci. To search for genes not previously known to be important in the development of obesity and obesity-related disease, changes in global gene expression in adipose tissue was analysed by DNA microarray before and during diet-induced weight loss in obese male subjects. Weight loss resulted in changes in expression of several genes known to be involved in the adaptation to fasting as well as cholesterol homeostasis. Furthermore, we specifically analysed the possible expression of the renin-angiotensin system in adipose tissue. It was shown that there are prerequisites for local production of angiotensin II in human adipose tissue, which may contribute to the association between obesity and hypertension.These studies suggest that gonadal steroids influence the leptin system, and this may in part involve a direct action of oestrogen on leptin receptor expression. In addition to leptin, adipose tissue was shown to express several genes, which may provide possible clues to the association between obesity, hypertension and dyslipidaemia.