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A mutation in the human leptin receptor gene causes obesity and pituitary dysfunction


The adipocyte-specific hormone leptin, the product of the obese (ob) gene,regulates adipose-tissue mass through hypothalamic effects on satiety and energy expenditure1,2,3,4. Leptin acts through the leptin receptor, a single-transmembrane-domain receptor of the cytokine-receptor family5,6,7. In rodents, homozygous mutations ingenes encoding leptin1 or the leptin receptor6 cause early-onsetmorbid obesity, hyperphagia and reduced energy expenditure. These rodents also show hypercortisolaemia, alterations in glucose homeostasis, dyslipidaemia, and infertility due to hypogonadotropic hypogonadism8. In humans, leptin deficiency due to a mutation in the leptin gene is associated with early-onset obesity9. Here we describe a homozygous mutation in the human leptin receptor gene that results in a truncated leptin receptor lacking both the transmembrane and the intracellular domains. In addition to their early-onset morbid obesity, patients homozygous for this mutation 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 humans.

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Figure 1: Pedigree and clinical characteristics of the HD family, and analysis of exon 16 of the leptin receptor in this family.
Figure 2: SSCP scanning and DNA-sequence analysis of exon 16 of the human leptin receptor.
Figure 3: Height and weight curves for the three affected sisters from birth to adult age.


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This work was supported by the French Ministère de l'Education, de la Recherche etde la Technologie, the Direction de la Recherche Clinique/Assistance Publique-Hopitaux de Paris, Programme Hospitalier de Recherche Clinique and the Institut de Recherche Endocrinienne et Métabolique. We thank E. R. Serra, D. Pepin, S. Carrera, P. Boutin., L. Perrin, J. Le Fourn and Y. Le Bihan for technical help; J. Di Santo for critical reviewing of the manuscript; and the patients and their families for their cooperation. Informed personal and parental consents were obtained and ethical permission was granted by the local ethics committee (CCPPRB, Hôtel-Dieu, Paris).

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Correspondence to Philippe Froguel.

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Clément, K., Vaisse, C., Lahlou, N. et al. A mutation in the human leptin receptor gene causes obesity and pituitary dysfunction. Nature 392, 398–401 (1998).

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