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Ghrelin Levels Are Not Regulated by Recombinant Leptin Administration and/or Three Days of Fasting in Healthy Subjects

Division of Endocrinology, Diabetes, and Metabolism, Department of Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School (J.L.C., J.B., J.H.L., C.S.M.), Boston, Massachusetts 02215; and Department of Home Economics and Ecology, Harokopio University (N.Y.), Athens, Greece

Address all correspondence and requests for reprints to: Christos S. Mantzoros, M.D., Division of Endocrinology, Diabetes, and Metabolism, Beth Israel Deaconess Medical Center, Harvard Medical School, 330 Brookline Avenue, ST816, Boston, Massachusetts 02215. E-mail: cmantzor{at}bidmc.harvard.edu.

Ghrelin, a stomach-derived orexigenic peptide, and leptin, a fat-derived anorexigenic hormone, act primarily in the hypothalamus to regulate energy homeostasis and have been reported to be regulated in opposite directions by acute and chronic changes in nutritional state. Nutritional, anthropometric, and hormonal predictors of circulating ghrelin have not yet been fully elucidated, and whether ghrelin is regulated by leptin in humans remains unknown. To address these questions, we performed cross-sectional and interventional studies. In 120 healthy men and women, ghrelin was negatively associated with leptin as well as overall and central adiposity, but not with total energy or specific macronutrient intake. The sexual dimorphism in ghrelin levels (higher levels in women than in men) and the negative correlation between ghrelin and insulin are largely mediated by central adiposity. In six lean men, complete fasting for 3 d resulted in a low leptin state without a major change in fat mass and abolished the meal-related secretory pattern of ghrelin without increasing 24-h ghrelin levels. In addition, recombinant human leptin administration in physiological and pharmacological doses did not regulate ghrelin over several hours to a few days. These data do not support a role for regulation of circulating ghrelin by leptin levels independently of changes in adiposity and suggest that the leptin and ghrelin systems for energy homeostasis function independently of each other in healthy humans.

This work was supported by NIDDK Grant DK-58785 and NIH Grant MO1-RR-01032 (to C.S.M. and the BIDMC General Clinical Research Center), NIH Grant K30-HL-04095, and a grant from Amgen, Inc. (to C.S.M.).

Abbreviations: AUC, Area under the curve; BIA, bioelectrical impedance analysis; BMI, body mass index; CV, coefficient of variation; DEXA, dual energy x-ray absorptiometry; %FM, percent fat mass; r-metHuLeptin, recombinant methionyl human leptin; WC, waist circumference; WHR, waist to hip ratio.

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