Studies on the regulation and in vitro metabolic effects of leptin in children and adults

University dissertation from Stockholm : Karolinska Institutet, Department of Clinical Sciences

Abstract: Leptin is a protein hormone secreted by adipocytes, which binds to receptors in the brain to affect food intake and energy expenditure. The leptin receptor is a member of the cytokine receptor family and is widely distributed in the body suggesting a broader role for leptin. In fact, there is evidence for a major role of leptin in the regulation of the neuro-endocrine response to fasting and in sexual maturation. Serum leptin levels, both in adults and children, are strongly correlated to total body fat. However, at any given body fat percentage, the levels vary significantly among individuals, suggesting that factors other than total body fat regulate leptin. Furthermore, leptin has a circadian rhythm with a nocturnal peak that can not be explained by food intake. The aim of this investigation was to study the regulation and metabolic effects of leptin in humans. In the first study, we measured leptin RNA and serum levels in children with Prader-Willi syndrome (PWs) or non-syndromal obesity. We found that obesity in children is associated with increased leptin RNA and serum levels. In addition, no difference between the two groups of obese children could be seen. The effect of growth hormone (GH) treatment on serum leptin levels in children with different GH levels was investigated in the second and third studies. We found that GH treatment of children with obesity, PWs and growth hormone deficiency, i.e. children with low GH secretion, downregulates plasma leptin levels independent of changes in BMI and fat mass. There was no effect in children with idiopathic short stature with normal GH levels. This suggests that GH directly affects leptin production, metabolism or clearance. In the fourth study, the relationship between endogenous cortisol and leptin and the effect of exogenous glucocorticoids on leptin were investigated. We found that variations in glucocorticoid tonus within the physiological range affect leptin levels in healthy men. This suggests that cortisol is an important regulator of circulating leptin levels under normal conditions. In the fifth study, total parenteral nutrition after surgery rapidly increased serum leptin levels. We hypothesised that the perioperative fasting and stress sensitised the leptin response to subsequent energy intake. This may have been mediated by the concomitant increases in serum insulin and cortisol. This was further investigated in the sixth study, where healthy volunteers were subjected to different durations of fasting with and without administration of dexamethasone. The results indicated that meal timing is an important factor determining leptin diurnal rhythm, but other factors must contribute since the leptin response to the evening meal was greater than to the morning meal. In addition, fasting sensitises the response of leptin to energy intake and abolishes the dexamethasoneinduced upregulation of leptin. In the seventh study, the in vitro metabolic effects of leptin on human adipocytes were investigated. Leptin had no direct lipolytic effect in adipocytes from either children or adults. Leptin reduced the insulin-induced lipogenesis but did not affect the insulin-induced inhibition of lipolysis. This suggests that leptin does not affect the proximal insulin signalling pathway but acts further downstream. In summary, we showed that, in man, leptin is regulated by body fat content, fasting, energy intake, meal timing, glucocorticoids and GH. In addition, we demonstrated that leptin has no lipolytic effect in human adipocytes, in contrast to findings in rodents.

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