Phenotypic effects of leptin replacement on morbid obesity, diabetes mellitus, hypogonadism, and behavior in leptin-deficient adults

Julio Licinio, Sinan Caglayan, Metin Ozata, Bulent O. Yildiz, Patricia B. De Miranda, Fiona O'Kirwan, Robert Whitby, Liyin Liang, Pinchas Cohen, Shalender Bhasin, Ronald M. Krauss, Johannes D Veldhuis, Anthony J. Wagner, Alex M. DePaoli, Samuel M. McCann, Ma Li Wong

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Abstract

Genetic mutations in the leptin pathway can be a cause of human obesity. It is still unknown whether leptin can be effective in the treatment of fully established morbid obesity and its endocrine and metabolic consequences in adults. To test the hypothesis that leptin has a key role in metabolic and endocrine regulation in adults, we examined the effects of human leptin replacement in the only three adults identified to date who have genetically based leptin deficiency. We treated these three morbidly obese homozygous leptin-deficient adult patients with recombinant human leptin at low, physiological replacement doses in the range of 0.01-0.04 mg/kg for 18 months. Patients were hypogonadal, and one of them also had type 2 diabetes mellitus. We chose the doses of recombinant methionyl human leptin that would achieve normal leptin concentrations and administered them daily in the evening to model the normal circadian variation in endogenous leptin. The mean body mass index dropped from 51.2 ± 2.5 (mean ± SEM) at baseline to 26.9 ± 2.1 kg/m2 after 18 months of treatment, mainly because of loss of fat mass. We document here that leptin replacement therapy in leptin-deficient adults with established morbid obesity results in profound weight loss, increased physical activity, changes in endocrine function and metabolism, including resolution of type 2 diabetes mellitus and hypogonadism, and beneficial effects on ingestive and noningestive behavior. These results highlight the role of the leptin pathway in adults with key effects on the regulation of body weight, gonadal function, and behavior.

Original languageEnglish (US)
Pages (from-to)4531-4536
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume101
Issue number13
DOIs
StatePublished - Mar 30 2004

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Hypogonadism
Morbid Obesity
Leptin
Diabetes Mellitus
Type 2 Diabetes Mellitus
Weight Loss
Body Mass Index
Therapeutics
Obesity
Fats
Body Weight

ASJC Scopus subject areas

  • Genetics
  • General

Cite this

Phenotypic effects of leptin replacement on morbid obesity, diabetes mellitus, hypogonadism, and behavior in leptin-deficient adults. / Licinio, Julio; Caglayan, Sinan; Ozata, Metin; Yildiz, Bulent O.; De Miranda, Patricia B.; O'Kirwan, Fiona; Whitby, Robert; Liang, Liyin; Cohen, Pinchas; Bhasin, Shalender; Krauss, Ronald M.; Veldhuis, Johannes D; Wagner, Anthony J.; DePaoli, Alex M.; McCann, Samuel M.; Wong, Ma Li.

In: Proceedings of the National Academy of Sciences of the United States of America, Vol. 101, No. 13, 30.03.2004, p. 4531-4536.

Research output: Contribution to journalArticle

Licinio, J, Caglayan, S, Ozata, M, Yildiz, BO, De Miranda, PB, O'Kirwan, F, Whitby, R, Liang, L, Cohen, P, Bhasin, S, Krauss, RM, Veldhuis, JD, Wagner, AJ, DePaoli, AM, McCann, SM & Wong, ML 2004, 'Phenotypic effects of leptin replacement on morbid obesity, diabetes mellitus, hypogonadism, and behavior in leptin-deficient adults', Proceedings of the National Academy of Sciences of the United States of America, vol. 101, no. 13, pp. 4531-4536. https://doi.org/10.1073/pnas.0308767101
Licinio, Julio ; Caglayan, Sinan ; Ozata, Metin ; Yildiz, Bulent O. ; De Miranda, Patricia B. ; O'Kirwan, Fiona ; Whitby, Robert ; Liang, Liyin ; Cohen, Pinchas ; Bhasin, Shalender ; Krauss, Ronald M. ; Veldhuis, Johannes D ; Wagner, Anthony J. ; DePaoli, Alex M. ; McCann, Samuel M. ; Wong, Ma Li. / Phenotypic effects of leptin replacement on morbid obesity, diabetes mellitus, hypogonadism, and behavior in leptin-deficient adults. In: Proceedings of the National Academy of Sciences of the United States of America. 2004 ; Vol. 101, No. 13. pp. 4531-4536.
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AU - Krauss, Ronald M.

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