Human leptin in obesity and diabetes: Anthropometric, metabolic and genetic determinants.

摘要

Leptin is a mainly adipocyte-secreted hormone with an important role in energy balance and body weight regulation. Since its discovery it has been shown to interact with almost all neuropeptides known to be involved in food intake. Besides this central action, it affects metabolic and endocrine functions, such as sexual development and glucose homeostasis.; In this work we investigated possible determinants of circulating leptin levels in humans.; Since leptin is secreted mainly by adipose tissue, leptin levels are strongly determined by the total amount of body fat. Furthermore, subcutaneous adipocytes express more leptin than omental adipocytes, and subjects with a mainly subcutaneous fat accumulation have higher leptin levels compared with subjects of comparable adiposity but with a predominantly visceral fat accumulation. However, differences in leptin levels can not be explained completely by body composition. Therefore, we evaluated the relation of some metabolic, hormonal and genetic factors with leptin. Because of the marked and consistently observed gender difference in leptin levels, we hypothesized that sex hormones could play a role in this. As androgens had been shown to inhibit leptin secretion by adipose tissue, this could contribute to the lower leptin levels in men. In our studies we only found a relation with DHEA-s. Stronger evidence was found for interactions with glucose and insulin. Leptin levels are lower in diabetic patients compared with nondiabetics, and vary significantly among subjects with different glucose tolerance status. This can partly be explained by differences in body composition, but also insulin levels are an independent contributing factor. In addition, C-peptide levels, a measure of insulin secretion, were found to be associated with leptin mRNA expression by adipose tissue, confirming in vitro data for stimulation of leptin secretion by insulin. Moreover, leptin levels decreased after infusion of exogenous glucagon, which is known as a counterregulatory hormone for insulin, suggesting a direct inhibitory effect of glucagon on leptin secretion. We assessed possible genetic effects by evaluating associations of leptin levels with polymorphisms in some candidate genes for obesity: the uncoupling protein 2 gene, the β₂- and β₃-adrenergic receptors, the glucocorticoid receptor gene, the apolipoprotein E gene, and in the leptin receptor gene. None of these showed significant associations with circulating leptin levels.; Finally, we also assessed whether polymorphisms in the leptin receptor gene, through which leptin signalling is mediated, centrally as well as peripherally, were associated with some of the obesity phenotypes for which an action of leptin is proposed. Some associations were found between the Lys109Arg, Gin223Arg, Lys656Asn polymorphisms and the amount of subcutaneous fat, insulin levels, TSH levels and fat and carbohydrate oxidation rates.; Overall, we conclude that leptin levels in humans are largely determined by body composition, mainly by the amount of subcutaneous fat in the body, and further affected by circulating insulin levels, with possibly some minor effect of sex hormones. A possible genetic effect may exist, but this could not be shown for the polymorphisms analysed here. Furthermore, the effect of leptin on body fat distribution, insulin and energy metabolism could be altered slightly by genetic polymorphisms in its receptor.