A MUTATION IN THE HUMAN LEPTIN RECEPTOR GENE CAUSES OBESITY AND PITUITARY DYSFUNCTION

The adipocyte-specific hormone leptin, the product of the obese (ob) g ene, regulates adipose-tissue mass through hypothalamic effects on sat iety and energy expenditure(1-4), Leptin acts through the leptin recep tor, a single-transmembrane-domain receptor of the cytokine-receptor f amily(5-7). In rodents, homozygous mutations in genes encoding leptin( 1) or the leptin receptor(6) cause early-onset morbid obesity, hyperph agia and reduced energy expenditure, These rodents also show hypercort isolaemia, alterations in glucose homeostasis, dyslipidaemia, and infe rtility due to hypogonadotropic hypogonadism(8). In humans. leptin def iciency due to a mutation in the leptin gene is associated with early- onset obesity(9), Here we describe a homozygous mutation in the human leptin receptor gene that results in a truncated leptin receptor lacki ng both the transmembrane and the intracellular domains, In addition t o their early-onset morbid obesity, patients homozygous for this mutat ion have no pubertal development and their secretion of growth hormone and thyrotropin is reduced. These results indicate that leptin is an important physiological regulator of several endocrine functions in hu mans.