Journal
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
Volume 101, Issue 13, Pages 4531-4536Publisher
NATL ACAD SCIENCES
DOI: 10.1073/pnas.0308767101
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Funding
- NCI NIH HHS [P50 CA092131, CA92131, CA100938, R01 CA100938] Funding Source: Medline
- NCRR NIH HHS [K24 RR016996-03, M01 RR000865-320706, K12 RR017611, K24 RR016996-02, K24 RR016996-04, RR017365, M01 RR000865-320723, RR00585, RR000865, M01 RR000865-338725, M01 RR000865-338780, M01 RR000865, K24 RR017365, M01 RR000865-328485, K24 RR016996, M01 RR000865-338779, K24 RR016996-01, M01 RR000865-310723, RR16996, K24 RR016996-05, RR017611, K24 RR016996-06, M01 RR000865-310706, M01 RR000865-338718, M01 RR000585] Funding Source: Medline
- NHGRI NIH HHS [R03 HG002500, HG002500] Funding Source: Medline
- NHLBI NIH HHS [HL069757, U19 HL069757, U01 HL069757, K30HL04526, K30 HL004526] Funding Source: Medline
- NIA NIH HHS [AG23133, AG20954, R01 AG020954, R01 AG023133] Funding Source: Medline
- NIDDK NIH HHS [R01 DK058851-01, R01 DK063240-01, DK60717, R01 DK063240, R01 DK058851-06, DK063491, R01 DK058851-02, DK58851, R01 DK058851-05, R01 DK058851, P30 DK063491, R01 DK058851-03, DK063240, R01 DK060717, R01 DK063240-02, R01 DK058851-04] Funding Source: Medline
- NIGMS NIH HHS [GM61394, U01 GM061394] Funding Source: Medline
- NIMH NIH HHS [MH062777] Funding Source: Medline
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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/m(2) 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.
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