Abstract
Based on studies in mice, leptin was expected to decrease body weight in obese individuals. However, the majority of the obese are hyperleptinemic and do not respond to leptin treatment, suggesting the presence of leptin tolerance and questioning the role of leptin as regulator of energy balance in humans. We thus performed detailed novel measurements and analyses of samples and data from our clinical trials biobank to investigate leptin effects on mechanisms of weight regulation in lean normo- and mildly hypo-leptinemic individuals without genetic disorders. We demonstrate that short-term leptin administration alters food intake during refeeding after fasting, whereas long-term leptin treatment reduces fat mass and body weight, and transiently alters circulating free fatty acids in lean mildly hypoleptinemic individuals. Leptin levels before treatment initiation and leptin dose do not predict the observed weight loss in lean individuals suggesting a saturable effect of leptin. In contrast to data from animal studies, leptin treatment does not affect energy expenditure, lipid utilization, SNS activity, heart rate, blood pressure or lean body mass.
Highlights
Based on studies in mice, leptin was expected to decrease body weight in obese individuals
Due to the poor efficacy of leptin treatments on weight regulation in obesity, it has been questioned whether leptin does act to reduce body weight in humans, emphasizing the need to investigate the physiology of leptin and its effects on metabolic outcomes in lean individuals who may be more likely to respond to leptin administration[24,25]
In study 1 and study 2, lean men had consistently lower levels of leptin before each intervention compared to lean women, whereas obese men had similar leptin levels to lean women (Fig. 2a, b, left and Supplementary Figs. 2 and 3). In both studies and across all interventions, the % body weight change was similar between lean men and women (Fig. 2a, b, middle) and lower in obese men (Fig. 2b, middle)
Summary
Based on studies in mice, leptin was expected to decrease body weight in obese individuals. We perform new measurements and analyze data from our previous studies[26–30] to (1) assess whether circulating concentrations of leptin before treatment initiation are associated with the weight loss observed in our study subjects, (2) investigate whether any effects of leptin either in the short term during fasting and/or in the fed state are dose-dependent, by employing physiological vs supraphysiological vs pharmacological doses of leptin, and explore whether such effects may differ between lean men, lean women, and obese men, (3) investigate the trajectories of weight and fat mass changes in relation to leptin levels during long-term leptin treatment and after its termination, and (4) determine the potential underlying mechanistic pathways through which leptin affects the physiology of energy homeostasis in lean subjects by testing energy intake
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