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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.


  1. 1

    Zhang, Y. et al. Positional cloning of the mouse obese gene and its human homologue. Nature 372, 425–432 (1994).

    ADS  CAS  Article  Google Scholar 

  2. 2

    Halaas, J. L. et al. Weight reducing effects of the plasma protein encoded by the obese gene (ob). Science 269, 543–546 (1995).

    ADS  CAS  Article  Google Scholar 

  3. 3

    Pelleymounter, M. A. et al. Effects of the obese gene product on body weight regulation in ob/ob mice. Science 269, 540–543 (1995).

    ADS  CAS  Article  Google Scholar 

  4. 4

    Campfield, L. A., Smith, F. J., Guisez, Y., Devos, R. & Burn, P. Recombinant mouse OB protein: evidence for a peripheral signal linking adiposity and central neural networks. Science 269, 546–549 (1995).

    ADS  CAS  Article  Google Scholar 

  5. 5

    Tartaglia, L. A. et al. Identification and expression cloning of a leptin receptor, OB-R. Cell 83, 1263–1271 (1995).

    CAS  Article  Google Scholar 

  6. 6

    Lee, G. H. et al. Abnormal splicing of the leptin receptor in diabetic mice. Nature 379, 632–635 (1996).

    ADS  CAS  Article  Google Scholar 

  7. 7

    Vaisse, C. et al. Leptin activation of Stat3 in the hypothalamus of wild-type and ob/ob mice but not db/db mice. Nature Genet. 14, 95–97 (1996).

    CAS  Article  Google Scholar 

  8. 8

    Coleman, D. L. Obese and Diabetes: two mutant genes causing diabetes-obesity syndromes in mice. Diabetologia 14, 141–148 (1978).

    CAS  Article  Google Scholar 

  9. 9

    Montague, C. T. et al. Congenital leptin deficiency is associated with severe early-onset obesity in humans. Nature 387, 903–907 (1997).

    ADS  CAS  Article  Google Scholar 

  10. 10

    Clément, K. et al. Association of poorly controlled diabetes with low serum leptin in morbid obesity. Int. J. Obes. 21, 556–561 (1997).

    Article  Google Scholar 

  11. 11

    Liu, C. et al. Expresison and characterization of a putative high affinity human soluble leptin receptor. Endocrinology 138, 3548–3554 (1997).

    CAS  Article  Google Scholar 

  12. 12

    Houseknecht, K. L. et al. Evidence for leptin binding to proteins in serum of rodents and humans: modulation with obesity. Diabetes 45, 1638–1643 (1996).

    CAS  Article  Google Scholar 

  13. 13

    Diamond, F. B. et al. Demonstration of a leptin binding factor in human serum. Biochem. Biophys. Res. Commun. 233, 818–822 (1997).

    CAS  Article  Google Scholar 

  14. 14

    Chehab, F. F., Lim, M. E. & Lu, R. Correction of the sterility defect in homozygous obese female mice by treatment with the human recombinant leptin. Nature Genet. 12, 318–320 (1996).

    CAS  Article  Google Scholar 

  15. 15

    Chehab, F. F., Mounzih, K., Lu, R. H. & Lim, M. E. Early onset of reproductive function in normal female mice treated with leptin. Science 275, 88–90 (1997).

    CAS  Article  Google Scholar 

  16. 16

    Ahima, R. S., Dushay, J., Flier, S. N., Prabakaran, D. & Flier, J. S. Leptin accelerates the onset of puberty in normal female mice. J. Clin. Invest. 99, 391–395 (1997).

    CAS  Article  Google Scholar 

  17. 17

    Mantzoros, C. S., Flier, J. S. & Rogol, A. D. Alongitudinal assessment of hormonal and physical alterations during normal puberty in boys. Rising leptin levels may signal the onset of puberty. J. Clin. Endocrinol. Metab. 82, 1066–1070 (1997).

    CAS  PubMed  Google Scholar 

  18. 18

    Clayton, P. E. et al. Serum leptin through childhood and adolescence. Clin. Endocrinol. 46, 727–733 (1997).

    CAS  Article  Google Scholar 

  19. 19

    Bernini, G. P. et al. Impaired growth hormone response to insulin-induced hypoglycemia in obese patients: restoration blocked by ritanserin after fenfluramine adminsitration. Clin. Endocrinol. 32, 453–459 (1990).

    CAS  Article  Google Scholar 

  20. 20

    Thissen, J. P., Ketelslegers, J.-M. & Underwood, L. Nutritional regulation of the insulin-growth factors. Endocr. Rev. 15, 80–101 (1994).

    CAS  Google Scholar 

  21. 21

    Vignolo, M., Naselli, A., Di Battista, E., Mostert, M. & Aicardi, G. Growth and development in simple obesity. Eur. J. Pediatr. 147, 242–244 (1988).

    CAS  Article  Google Scholar 

  22. 22

    Bray, G. A. & York, D. A. Hypothalamic and genetic obesity in experimental animals: an autonomic and endocrine hypothesis. Physiol. Rev. 59, 719–790 (1979).

    CAS  Article  Google Scholar 

  23. 23

    Tannenbaum, G. S., Lapointe, M., Gurd, W. & Finkelstein, F. A. Mechanism of impaired growth hormone secretion in genetically obese Zucker rats: roles of growth hormone factor and somatostatine. Endocrinology 127, 3080–3095 (1990).

    Article  Google Scholar 

  24. 24

    Carro, E., Senaris, R., Considine, R. V., Casanueva, F. F. & Dieguez, C. Regulation of in vivo growth hormone secretion by leptin. Endocrinology 138, 2203–2206 (1997).

    CAS  Article  Google Scholar 

  25. 25

    Ahima, R. S. et al. Role of leptin in the neuroendocrine response to fasting. Nature 382, 250–252 (1996).

    ADS  CAS  Article  Google Scholar 

  26. 26

    Björntorp, P. Body fat distribution, insulin resistance, and metabolic diseases. Nutrition 13, 795–803 (1997).

    Article  Google Scholar 

  27. 27

    Hummel, K. P., Coleman, D. L. & Lane, P. W. The influence of genetic background on expression of mutations at the diabetes locus in the mouse C57BL/KsJ and C57BL/6J strains. Biochem. Genet. 7, 1–13 (1972).

    CAS  Article  Google Scholar 

  28. 28

    Coleman, D. L. & Hummel, K. P. The influence of the genetic background on the expression of the obese (ob) gene in the mouse. Diabetologia 9, 287–293 (1973).

    CAS  Article  Google Scholar 

  29. 29

    Echwald, S. M. et al. Amino acid variants in the human leptin receptor — lack of association to juvenile onset obesity. Biochem. Biophys. Res. Commun. 233, 248–252 (1997).

    CAS  Article  Google Scholar 

  30. 30

    Hardouin, S. et al. Molecular forms of serum insulin-like growth factor (IGF) binding proteins in man: relationships with growth hormone and IGF1s and physiological significance. J. Clin. Endocrinol. Metab. 69, 1291–1301 (1989).

    CAS  Article  Google Scholar 

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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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