OR01-5 Leptin Acts through Altering Energy Intake and Lipolysis to Reduce Body Weight but Has No Effect on Energy Expenditure, Physical Activity, and Sympathetic Nervous System in Humans

It remains unknown whether leptin regulates body weight in humans and whether this occurs through actions centrally and/or peripherally i.e. by altering hormone and sympathetic nervous system (SNS) activity in humans as it has been suggested by experiments in rodents. We explored body weight and body composition changes in response to short and long term leptin administration to lean humans and explored potential underlying mechanisms by studying changes in energy intake, energy expenditure, lipolysis and hormonal and SNS changes in response to leptin administered in physiological and supraphysiological doses in lean subjects. We utilized the following study designs: a) open-label long-term leptin replacement study aiming at keeping circulating leptin levels within the physiological range and b) randomized, placebo-controlled, long-term leptin replacement study aiming at keeping total body weight stable by adjusting leptin doses in females with acquired hypoleptinemia. To further explore underlying mechanisms we also performed a) short-term placebo vs. leptin physiological replacement study during a three day long fasting-induced hypoleptinemia in lean subjects; and b) short-term leptin dose escalation study to supraphysiological levels in the fed i.e. normoleptinemic vs. in fasting-induced hypoleptinemic state for three days in both lean and overweight individuals. Long-term leptin replacement decreased body weight (p-value<0.001) through decreasing fat mass (p-value<0.001) and without affecting lean mass. Underlying mechanisms included decreased energy intake with leptin (caloric intake - leptin association r=-0.644, p-value<0.001), but not energy expenditure. Leptin also increased lipolysis demonstrated by elevated free fatty acids which were increased in response to leptin at time points that corresponded to fat mass loss (p-value=0.01). Long- but not short-term leptin replacement downregulated the renin-angiotensin-aldosterone axis at time points corresponding to maximum lipolytic effects (p-value=0.024 renin; p-value=0.001 aldosterone). Importantly, no changes in heart rate, blood pressure and body temperature were demonstrated with leptin. Thus, leptin administration decreases body weight in lean subjects, without changes to lean mass, by acting through decreasing body fat primarily through lipolysis and decreased caloric intake.