Human leptin regulation and promise in pharmacotherapy.
In rodents leptin inhibits food intake, stimulates energy expenditure, reverses obesity, ameliorates insulin resistance, and accelerates sexual maturation. These potent and diverse effects have stimulated interest in exploring a role for leptin in the treatment of human metabolic disorders. However, the significance of leptin in human (patho)physiology is still being investigated. The present review summarizes current knowledge of leptin regulation, provides a critical assessment of initial experience with leptin therapy, and discusses potential targets for recombinant leptin therapy in humans. The results of numerous studies indicate that leptin is indeed a regulated human hormone: The physiological factors that influence leptin secretion include gender, adiposity, physical exercise, feeding, and caloric restriction. Several hormones, including insulin, glucocorticoids, estradiol, growth hormone, testosterone, somatostatin, and insulin-like growth factor-I also modulate leptin secretion. The results of initial trials of leptin therapy in humans have become available. Treatment with recombinant human leptin (0.028 mg/kg) induced a progressive weight loss (without evidence of tachyphylaxis) in a morbidly obese patient with congenital leptin deficiency. The weight loss averaged 1-2 kg/month, was associated with preservation of lean muscle mass, and was almost exclusively accounted for by depletion of body fat. Administration ofrecombinant leptin (0.01-0.3 mg/kg) also resultedin a dose-dependentweight loss among lean and obese humans with presumably normal leptin genotype. Thus leptin may have a therapeutic role in humans, but its physiological functions and regulation first need to be fully unravelled.
Dagogo-Jack
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Department of Medicine, University of Mississippi Medical Center, Jackson 39216-4505, USA. sdagogojack@medicine.umsmed.edu
D000818:Animals; D001835:Body Weight / Q000187:drug effects; D005544:Forecasting; D005786:Gene Expression Regulation; D005951:Glucose Tolerance Test; D006728:Hormones / Q000502:physiology; D006801:Humans; D020738:Leptin / Q000235:genetics / Q000378:metabolism / Q000502:physiology / Q000627:therapeutic use; D012727:Sex Characteristics
D006728:Hormones; D020738:Leptin