Phenotypic effects of leptin replacement on morbid obesity, diabetes mellitus, hypogonadism, and behavior in leptin-deficient adults.
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.
Licinio
Julio
J
Center for Pharmacogenomics, Neuropsychiatric Institute, Department of Psychiatry and Biobehavioral Sciences, David Geffen School of Medicine, University of California, Los Angeles, CA 90095-1761, USA. licinio@ucla.edu
Caglayan
Sinan
S
Ozata
Metin
M
Yildiz
Bulent O
BO
de Miranda
Patricia B
PB
O'Kirwan
Fiona
F
Whitby
Robert
R
Liang
Liyin
L
Cohen
Pinchas
P
Bhasin
Shalender
S
Krauss
Ronald M
RM
Veldhuis
Johannes D
JD
Wagner
Anthony J
AJ
DePaoli
Alex M
AM
McCann
Samuel M
SM
Wong
Ma-Li
ML
D000328:Adult; D001519:Behavior / Q000502:physiology*; D001823:Body Composition; D015992:Body Mass Index; D002940:Circadian Rhythm; D003924:Diabetes Mellitus, Type 2 / Q000235:genetics*; D005260:Female; D006801:Humans; D007006:Hypogonadism / Q000235:genetics*; D020738:Leptin / Q000172:deficiency* / Q000235:genetics / Q000627:therapeutic use*; D010641:Phenotype; D015431:Weight Loss
D020738:Leptin