Genetic mutations in the
leptin pathway can be a cause of human
obesity. It is still unknown whether
leptin can be effective in the treatment of fully established
morbid obesity and its endocrine and metabolic consequences in adults. To test the hypothesis that
leptin has a key role in metabolic and endocrine regulation in adults, we examined the effects of human
leptin replacement in the only three adults identified to date who have genetically based
leptin deficiency. We treated these three morbidly obese homozygous
leptin-deficient adult patients with recombinant human
leptin at low, physiological replacement doses in the range of 0.01-0.04 mg/kg for 18 months. Patients were hypogonadal, and one of them also had
type 2 diabetes mellitus. We chose the doses of
recombinant methionyl human leptin that would achieve normal
leptin concentrations and administered them daily in the evening to model the normal circadian variation in endogenous
leptin. The mean body mass index dropped from 51.2 +/- 2.5 (mean +/- SEM) at baseline to 26.9 +/- 2.1 kg/m2 after 18 months of treatment, mainly because of loss of fat mass. We document here that
leptin replacement
therapy in
leptin-deficient adults with established
morbid obesity results in profound
weight loss, increased physical activity, changes in endocrine function and metabolism, including resolution of
type 2 diabetes mellitus and
hypogonadism, and beneficial effects on ingestive and noningestive behavior. These results highlight the role of the
leptin pathway in adults with key effects on the regulation of
body weight, gonadal function, and behavior.