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Circulating Melanin-Concentrating Hormone, Agouti-Related Protein, and -Melanocyte-Stimulating Hormone Levels in Relation to Body Composition: Alterations in Response to Food Deprivation and Recombinant Human Leptin Administration

Division of Endocrinology and Metabolism, Department of Internal Medicine, Beth Israel Deaconess Medical Center (A.G., J.L.C., K.H., C.S.M.), Boston, Massachusetts 02215; Department of Biostatistics, Harvard School of Public Health (L.C.M.), Boston, Massachusetts 02115; and Department of Nutrition and Home Economics and Ecology, Harokopio University (N.Y.), Athens, Greece

Address all correspondence and requests for reprints to: Dr. Christos S. Mantzoros, Division of Endocrinology and Metabolism, Beth Israel Deaconess Medical Center, 330 Brookline Avenue, Stoneman 816-820, Boston, Massachusetts 02215. E-mail: cmantzor{at}caregroup.harvard.edu.

We evaluated whether circulating levels of melanin-concentrating hormone (MCH), agouti-related protein (AGRP), and -MSH could serve as useful markers of energy homeostasis in humans. We first assessed correlations of serum MCH, AGRP, and -MSH with anthropometric, dietary, and hormonal variables in a cross-sectional study of 108 healthy humans. We then performed interventional studies to evaluate the effects of fasting and/or leptin administration. In eight healthy, normal weight men, we measured serum MCH, AGRP, and -MSH levels at baseline, after 2 d of fasting alone (a low leptin state), and after 2 d of fasting with replacement dose recombinant methionyl human leptin (r-metHuLeptin) administration to normalize circulating leptin levels. In a separate group of five lean and five obese men, we measured MCH levels in response to increasing circulating leptin levels to the pharmacological range by administration of one r-metHuLeptin dose in the fed state. In the cross-sectional study, serum MCH levels were independently and positively associated with body mass index and fat mass and were higher in women than in men. Furthermore, in our interventional studies, fasting for 2 d significantly decreased leptin levels and increased serum MCH levels. Administration of replacement dose r-metHuLeptin during fasting prevented the fasting-induced increase in MCH levels, but administration of a pharmacological r-metHuLeptin dose in the fed state did not further alter MCH levels. Serum AGRP levels tended to change in directions similar to MCH, but this change was less pronounced and needs to be investigated in larger studies. In contrast, serum -MSH levels did not correlate with body composition parameters, were not associated with caloric or macronutrient intake, and were not significantly affected by fasting or r-metHuLeptin administration. These findings suggest that serum MCH and possibly AGRP levels could serve as useful peripheral markers of changes in energy homeostasis and thus merit additional investigation.

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