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Overweight Humans Are Resistant to the Weight-Reducing Effects of Melanocortin_4–10

Departments of Neuroendocrinology (M.H., J.B.) and Internal Medicine I (R.S., H.L.F.), University of Lübeck, 23538 Lübeck, Germany; and Institute of Physiology (G.M.), Philipps-University of Marburg, 35037 Marburg, Germany

Address all correspondence and requests for reprints to: Jan Born, Department of Neuroendocrinology, Ratzeburger Allee 160, Haus 23, 23538 Lübeck, Germany. E-mail: born{at}kfg.mu-luebeck.de.

Context: By enhancing energy expenditure and suppressing appetite, melanocortin peptides derived from proopiomelanocortin play a primary role in the hypothalamic regulation of body weight. In a recent study in normal-weight adults, the 6-wk intranasal administration of the MSH/ACTH_4–10 core fragment of proopiomelanocortin resulted in a distinct reduction of body weight and body fat, accompanied by significant decreases in leptin and insulin plasma concentrations.

Objective: The present study aimed to generalize this finding to overweight patients.

Design, Subjects, and Intervention: MSH/ACTH_4–10 (0.5 mg) and placebo were intranasally administered once in the morning and once in the evening over a period of 12 wk in 23 overweight men (body mass index, mean ± SEM: 29.72 ± 0.43 kg/m²).

Results: MSH/ACTH_4–10 did not induce any significant reduction in body weight, body fat, and plasma levels of insulin and leptin as compared with the effects of placebo. Melanocortin treatment was accompanied by reduced cortisol concentrations.

Conclusions: We conclude that contrasting with normal-weight humans, overweight subjects are not susceptible to the effects of melanocortin administration on hypothalamic weight regulatory systems. In overweight subjects, a decreased sensitivity to ACTH/MSH peptides may derive from alterations at the level of the melanocortin receptor or at subsequent steps in the processing of the body fat signal.