An experimental therapeutic approach to genetically-based obesity leptin replacement therapy resolves morbid obesity, hypogonadism and diabetes mellitus in leptin-deficient adults

Abstract

Background Genetic mutations in the leptin pathway can be a cause of human obesity. We examined the effects of human leptin replacement in the only three adults identified to date who have genetically-based leptin deficiency. Their phenotype consisted of morbid obesity, with hypogonadism, but without hypertension or hyperlipidemia. Methods Human leptin was administered at physiological replacement doses in the range of 0.01–0.04 mg/kg for 18 months by daily evening leptin injection to mimic the endogenous nocturnal rise in leptin concentrations. Patients were hypogonadal and one of them also had type 2 diabetes mellitus. Food intake, body composition, physical activity, endocrine and lipid profiles were assessed during the course of leptin replacement. Results The mean BMI dropped from 51.2±2.5 (mean±sem) at baseline to 26.9±2.1 kg/m2 after 18 months of treatment, mainly due to loss of fat mass. The mean daily caloric intake changed from a baseline of 2330±322 to 1180±52 kcal/day two weeks after treatment initiation, and to 2742±364 kcal/day after 18 months of treatment. As body weight decreased, physical activity increased. Leptin had beneficial effects on endocrine function in all patients, causing reproductive maturity and complex changes in 24-h hormone dynamics. Treatment resulted in normalization of glucose homeostasis in the diabetic patient. Conclusions We document here that leptin replacement therapy in leptin-deficient adults with established morbid obesity results in profound weight loss, increased physical activity, beneficial effects on endocrine function and metabolism, including resolution of type 2 diabetes mellitus and hypogonadism. Clinical Pharmacology & Therapeutics (2004) 75, P11–P11; doi: 10.1016/j.clpt.2003.11.041