Journal of Clinical Endocrinology & Metabolism, doi:10.1210/jc.2005-0906
The Journal of Clinical Endocrinology & Metabolism Vol. 91, No. 2 522-525
Copyright © 2006 by The Endocrine Society
Overweight Humans Are Resistant to the Weight-Reducing Effects of Melanocortin4–10
Manfred Hallschmid,
Rüdiger Smolnik,
Gerard McGregor,
Jan Born and
Horst L. Fehm
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.
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Abstract
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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/ACTH4–10 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/ACTH4–10 (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/ACTH4–10 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.
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Introduction
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THE PROOPIOMELANOCORTIN (POMC)-derived melanocortin system of the hypothalamus is critically involved in the long-term homeostasis of body weight. The melanocortin system mediates increased energy expenditure, which, in combination with reduced food intake, leads to weight loss (1, 2, 3). Prolonged systemic administration of melanocortin-related peptides in POMC-deficient obese mice was found to reduce body weight (4). In healthy, normal-weight humans, intranasal administration of the melanocortin core fragment MSH/ACTH4–10 over a period of 6 wk resulted in a reduction of body weight and body fat that was accompanied by decreases in leptin and insulin plasma concentrations (5). We investigated whether similar effects can be demonstrated in overweight humans, with a view to evaluating the therapeutic potential of the compound.
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Subjects and Methods
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Subjects
Experiments were conducted in 26 healthy, overweight men [body mass index (BMI), mean ± SEM: 29.85 ± 0.35 kg/m2] aged between 23 and 46 yr. They were nonsmokers and had to abstain from alcohol, caffeine, and food intake for at least 12 h before the test sessions. Informed consent was obtained from all participants. The study was approved by the local ethics committee.
Design and procedure
Experiments were conducted in a double-blind fashion. Subjects were randomly assigned to two groups, MSH/ACTH4–10 and placebo (each 13 men), that were closely comparable regarding mean age and BMI. Subjects received placebo during the 2-wk baseline phase, followed by a 12-wk phase of treatment with placebo or MSH/ACTH4–10 (0.50 mg/d) intranasally administered before and after nocturnal bed time. To assure compliance, subjects reported on their intake routine and were reminded by telephone calls to take the spray. There was no evidence that the overweight subjects of this study more frequently forgot to take the spray than lean subjects of comparable previous studies (5). Overall, less than 5% of the subjects reported once to have forgotten to take the spray in time. Because of two drop-outs and one technical failure during measurements, the data of three subjects (of the placebo group) were excluded. MSH/ACTH4–10 was provided by Bachem Biochemica (Heidelberg, Germany; for further details regarding substance preparation and administration, see Ref.5). After a baseline session, test sessions took place between 1330 h and 1530 h: 1) at the end of the 2-wk baseline phase, 2) after 6 wk of treatment, and 3) at the end of the 12-wk treatment phase.
Subjects were kept unaware of the study aims by embedding experimental examinations into psychological memory tests. In each session, body composition was measured by standard bioelectrical impedance analysis (BIA 2000-M, Data Input GmbH, Frankfurt, Germany; for details, see Ref.5). Blood was sampled at the end of each session for the determination of leptin, insulin, ACTH, and cortisol and routine laboratory measures. Also, concentrations of epinephrine in 24-h urine, heart rate, and blood pressure were assessed (for details regarding measurements and assays, see Ref.5). Weekly, subjects were weighed and interviewed regarding possible complaints and any subjective awareness of treatment effects.
Statistical analyses
Comparisons between the effects of placebo and MSH/ACTH4–10 were based upon analyses of covariance with the group factor treatment. Baseline values were included as covariates. A P value of less than 0.05 (two-tailed) was considered significant.
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Results
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Neither after 6 nor after 12 wk of treatment were there any significant changes in body weight and body fat mass compared with the effects of placebo (P > 0.23 for all differences, Tables 1
and 2). Moreover, there were no changes in body composition and in plasma levels of leptin and insulin. This outcome is of striking difference to our observations in normal-weight subjects where only 6 wk of MSH/ACTH4–10 treatment reduced body weight, body fat, and insulin and leptin levels (Table 1; data from Ref.5). An overall analysis comparing treatment effects in normal-weight and overweight subjects yielded significant interactions between the factors treatment (MSH/ACTH4–10 vs. placebo) and body weight status (normal weight vs. overweight) for the main parameters body weight [F(1,42) = 5.69, P < 0.01], body fat [F(1,42) = 2.86, P < 0.05], and plasma insulin [F(1,42) = 8.74, P < 0.01], indicating that intranasal MSH/ACTH4–10 is effective in normal weight but not in overweight humans. This held also (at a P < 0.05 level of significance) when comparing the (exclusively male) overweight subjects with the men of the normal-weight study only. Furthermore, in the latter study no significant interactions between the factors treatment and sex were observed, excluding any sex specificity of the observed positive results in normal-weight subjects.
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TABLE 1. Mean ± SEM body weight, body mass index, measures of body composition, and plasma hormone levels after 6 wk of treatment with placebo and MSH/ACTH4–10 in normal-weight and overweight humans
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TABLE 2. Mean ± SEM body weight, body mass index, measures of body composition, and plasma hormone levels during baseline and after 12 wk of treatment with placebo and MSH/ACTH4–10 in overweight humans
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MSH/ACTH4–10 decreased plasma cortisol levels in overweight subjects on average by 29% after 12 wk of treatment as compared with placebo [F(1,19) = 7.13, P < 0.05], an effect that had not been observed after 6 wk of treatment neither in our normal-weight nor in our overweight subjects (Table 1
). Changes in ACTH levels were nonsignificant. Urine concentrations of epinephrine and routine laboratory measures as well as cardiovascular parameters were also not affected. None of the subjects reported side effects of drug or placebo administration.
Intranasal administration of MSH/ACTH4–10 allows direct access to the cerebrospinal fluid (CSF) compartment within 30 min (6). To ascertain that intranasally administered MSH/ACTH4–10 reaches the brain compartment also in overweight humans, in supplementary experiments concentrations of MSH/ACTH4–10 in the CSF of six overweight subjects (age, 35.25 ± 5.20 yr; BMI, 30.30 ± 1.37 kg/m2) 30 min after intranasal administration of 10 mg of the peptide were compared with basal concentrations (see Ref.6). After intranasal administration of the peptide, MSH/ACTH4–10 was detected in the CSF of the overweight subjects at levels of more than 10 ng/ml and well above the detection limit of the assay, whereas after placebo administration, no peptide was detectable.
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Discussion
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Our data indicate that in overweight subjects, the administration of MSH/ACTH4–10 over a period of 12 wk does not reduce body weight and body fat. Correspondingly, insulin and leptin levels remained unchanged. These results contrast with the significant reduction of body weight, body fat, and insulin and leptin after 6 wk of MSH/ACTH4–10 treatment in normal-weight subjects (Ref.5 ; Table 1). In those subjects, body weight gradually decreased during MSH/ACTH4–10 treatment, so that one might expect additional weight loss from longer treatment. The absence of catabolic effects in overweight humans, even when prolonging the treatment duration to 12 wk (Table 2), indicates that MSH/ACTH4–10 administration does not exert substantial effects on body weight regulation in overweight humans. Our data do not exclude that with much higher doses or by prolonging the treatment duration, positive effects may be achieved in overweight subjects as well. Nevertheless, it seems unlikely that overweight men, being completely insensitive to doses of MSH/ACTH4–10 proven to be effective in normal-weight humans, would show a considerably improved response to higher doses in the physiologic range, although further substantiation of this view seems desirable. After 12 wk of MSH/ACTH4–10, there was a significant reduction of plasma cortisol concentrations. However, single plasma cortisol levels assessed once a week may be too crude for measuring cortisol secretion, and because there were no concurrent changes in ACTH levels, this unexpected finding remains to be corroborated.
It could be argued that after nasal administration, the peptide did not develop its normal central nervous activity in the overweight subjects. Our supplementary experiments, however, indicate that intranasal administration of MSH/ACTH4–10 yields sufficient accumulation of the peptide in the CSF of overweight subjects. Those data do not provide any evidence that the failure of MSH/ACTH4–10 to decrease body weight in the overweight subjects was due to a specific failure of intranasal MSH/ACTH4–10 to enter the CSF compartment.
Although the findings are negative in nature, they may allow some tentative conclusions on the mechanisms underlying the impaired regulation of body weight in human obesity. Compared with the normal-weight subjects (5), the overweight subjects exhibited markedly higher baseline plasma levels of leptin (7.35 ± 0.74 vs. 6.67 ± 0.77 ng/ml). Obesity is generally associated with elevated leptin levels, suggesting that obese humans become resistant to leptin (7). An intracellular signaling defect in leptin-responsive hypothalamic neurons (including POMC neurons) has been identified as one cause for leptin resistance (8) that, in turn, may lead to a down-regulation of the POMC system (9). However, 
-MSH plasma concentrations are significantly higher in obese than in nonobese humans (10) so that even increased -MSH levels do not seem to reduce body weight. This agrees with the present data showing that MSH/ACTH4–10 does not affect body weight in obese subjects although intranasal administration provides direct access to the brain (6, 11) (for review, see Ref.12). Further evidence for decreased sensitivity to MSH/ACTH-related peptides in obesity stems from experiments where the sympathetic and cardiovascular effects of intracerebroventricularly administered -MSH/ACTH1–13 were impaired in obese animals (13).
Mutations in the gene encoding the melanocortin-4 receptor are the most commonly known monogenetic causes of human obesity (14, 15). However, given a prevalence of 4% in a large population of morbidly obese patients (14), there is only a low probability that our sample of subjects included more than one or two cases. Also, mutations in the melanocortin-4 receptor appear to be less frequent in subjects with moderate overweight as examined here. Studies in children with complete loss-of-function mutations of the human POMC gene indicate that genetically obese humans may be equally resistant to the catabolic effects of intranasal MSH/ACTH4–10 (16), casting further doubt on the possibility of inducing substantial weight loss in obese humans by administering MSH/ACTH4–10. It is also important to point out that our results in overweight humans do not agree with reports in rodent models of genetic, and also of diet-induced, obesity, in which the administration of melanocortin agonists resulted in weight normalization (4, 17). Whether this discrepancy is due to differences in the applied compounds or reflects a basic difference in the mechanisms of experimental obesity in rodents and overweight humans is unclear. However, the present findings, together with observations of increased -MSH plasma concentrations in obese subjects (10), are pertinent to the view that obesity is associated with increased melanocortin release and that a deficit in the melanocortin receptor or downstream signaling cascades of body weight regulation contributes to the disease.
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Acknowledgments
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We thank Aero Pump GmbH (Hochheim/Main, Germany) for providing precision nasal spray pumps. We are grateful to Y. Berner, N. Kropp, A. Otterbein, and C. Otten for skilled technical assistance.
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Footnotes
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This work was supported by the Deutsche Forschungsgemeinschaft.
First Published Online November 29, 2005
Abbreviations: BMI, Body mass index; CSF, cerebrospinal fluid; POMC, proopiomelanocortin.
Received April 26, 2005.
Accepted November 22, 2005.
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Abstract
Introduction
