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Abstract

The extreme obesity of the obese (ob/ob) mouse is attributable to mutations in the gene encoding leptin1, an adipocyte-specific secreted protein which has profound effects on appetite and energy expenditure. We know of no equivalent evidence regarding leptin's role in the control of fat mass in humans. We have examined two severely obese children who are members of the same highly consanguineous pedigree. Their serum leptin levels were very low despite their markedly elevated fat mass and, in both, a homozygous frame-shift mutation involving the deletion of a single guanine nucleotide in codon 133 of the gene for leptin was found. The severe obesity found in these congenitally leptin-deficient subjects provides the first genetic evidence that leptin is an important regulator of energy balance in humans.

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Acknowledgements

We thank S. Jebb for help with analysis of body composition; C. N. Hales, S. Kumar, A. Kelly and P. Raggett for access to control samples; A. Roberts for help with clinical studies; M.McCaleb, F. Martin, N. Hernday, C. N. Hales, A. Krook, S. Jebb, A. Prentice and N. Finer for discussions; T. M. Cox, V. K. K. Chatterjee and P. Luzio for reading the manuscript; and M. Flint for secretarial assistance. This research was supported by grants from the Wellcome Trust, the British Diabetic Association and a Medical Research Council (UK) studentship to C.T.M. H.R. is supported by the TMR programme of the EC.

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Author notes

    • Carl T. Montague
    •  & I. Sadaf Farooqi

    These authors contributed equally to this study.

Affiliations

  1. *Departments of Medicine, University of Cambridge, Addenbrooke's Hospital,, Hills Road, Cambridge CB2 2QR, UK

    • Carl T. Montague
    • , I. Sadaf Farooqi
    • , Jonathan P. Whitehead
    • , Maria A. Soos
    • , Harald Rau
    • , Ciaran P. Sewter
    • , Janet E. Digby
    • , Johannes B. Prins
    •  & Stephen O'Rahilly
  2. ‡Departments of Clinical Biochemistry, University of Cambridge, Addenbrooke's Hospital Hills Road, Cambridge CB2 2QR, UK

    • I. Sadaf Farooqi
    • , Jonathan P. Whitehead
    • , Maria A. Soos
    • , Harald Rau
    • , Ciaran P. Sewter
    • , Janet E. Digby
    •  & Johannes B. Prins
  3. §Departments of Community Medicine, University of Cambridge, Addenbrooke's Hospital Hills Road, Cambridge CB2 2QR, UK

    • Nicholas J. Wareham
  4. South Thames Regional Genetics Centre (East), Guy's Hospital, LondonSE1 9RT, UK

    • Shehla N. Mohammed
  5. ¶Oxford Regional Genetics Service, Churchill Hospital, Oxford OX3 7LJ, UK

    • Jane A. Hurst
  6. #Wycombe General Hospital, Queen Alexandra Road, High Wycombe, Buckinghamshire HP11 2TT, UK

    • Christopher H. Cheetham#
    •  & Alison R. Earley#
  7. Department of Medicine, University of Birmingham and Birmingham Heartlands Hospital, Birmingham B9 5SS, UK

    • Anthony H. Barnett

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Correspondence to Stephen O'Rahilly.

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https://doi.org/10.1038/43185

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