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The Melanocortin Melanocyte-Stimulating Hormone/Adrenocorticotropin_4–10 Decreases Body Fat in Humans¹

Internal Medicine (H.L.F., R.S., W.K.), Department of Physiology (G.P.M., U.B.), University of Marburg, Marburg, Germany; and Clinical Neuroendocrinology, University of Lubeck (J.B.), 23538 Lubeck, Germany

Address all correspondence and requests for reprints to: Dr. J. Born, Clinical Neuroendocrinology, Ratzeburger Allee 160, Haus 23, 23538 Lubeck, Germany. E-mail: born{at}kfg.mu-luebeck.de

	Abstract

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The control of body fat is a prominent factor in human health. Animal studies have indicated a homeostatic central nervous system regulation of body fat with particular involvement of the melanocortin receptor pathway. This study provides evidence for a similar role for melanocortins in the long-term control of fat stores in humans. Thirty-six normal weight humans were assigned to one of three experimental groups. After a 4-week baseline, one group was treated with MSH/ACTH_4–10 (MSH/ACTH_4–10) representing the core sequence of all melanocortins. Another group received desacetyl-MSH, a selective agonist of the brain melanocortin-4 receptor, which shares the 4–10 sequence with MSH/ACTH_4–10. The third group received placebo. Treatments were given intranasally twice daily for 6 weeks, at equimolar doses (MSH/ACTH_4–10, 0.5 mg; desacetyl-MSH, 0.84 mg). Body weight, body composition, and plasma hormone concentrations were measured before and after treatment. MSH/ACTH_4–10 reduced body fat, on the average, by 1.68 kg (P < 0.05) and body weight by 0.79 kg (P < 0.001). Concurrently, plasma leptin levels were decreased by 24% (P < 0.02), and insulin levels were decreased by 20% (P < 0.05) after MSH/ACTH_4–10. Changes after desacetyl-MSH remained nonsignificant. The finding of reduced body adiposity after MSH/ACTH_4–10 confirms and extends to the human the findings of animal models indicating an essential role of the hypothalamic melanocortin system in body weight control.

	Introduction

Top Abstract Introduction Subjects and Methods Results Discussion References

 
THE LONG-TERM homeostasis of body weight is accomplished by hypothalamic centers that integrate hormonal signals from the periphery such as leptin and insulin, the levels of which reflect the proportion of body fat (1, 2, 3, 4, 5, 6). The output from this control system results in a balanced regulation of anabolic and catabolic pathways. The latter pathways mediate increased energy expenditure, which in combination with reduced food intake leads to weight loss (7, 8, 9, 10). Among the neurotransmitter systems that stimulate catabolic effects, the melanocortin system of the arcuate nucleus of the hypothalamus is of major importance. Striking evidence of this has emerged from studies of the agouti protein, which exerts its effects through a competitive antagonism of the natural ligand MSH at the melanocortin receptor (MC-R) (11, 12, 13). A mutation at the agouti gene locus (Ay) causing ectopic expression of the agouti peptide leads to a lethal syndrome characterized by pronounced obesity and the development of diabetes and neoplasms (12). Among the five subtypes of the MC-R (MC1-R to MC5-R), the MC4-R appears to be most closely linked to the regulation of body weight (7, 8, 9, 14, 15). Thus, genetic deficiency of the MC4-R in mice is accompanied by hyperphagia, hyperinsulinemia, hyperglycemia, and obesity (13, 14). In humans, various mutations of the MC4-R have been identified, mostly in extremely obese individuals with body mass indexes above the 99th percentile (16, 17). In one such patient, the mutant MC4-R was shown to be severely impaired in ligand binding and signaling (17). Obesity is also a key symptom of human patients and mutant mice with deficient synthesis of melanocortins (18, 19). Moreover, in the latter animal model daily treatment with an MSH/ACTH agonist was found to induce distinct weight loss (19).

Dysregulation of body weight, as seen in obese patients, is associated with altered life style and culture in industrial societies. Specific components of this life style are an unlimited access to food and insufficient physical activity, which act in concert with a variety of other socio-environmental factors (20, 21, 22). As the factors that lead to human overweight are mostly specific for the human species, working models of body fat regulation derived from in vitro trials and studies of mice are in strong need of validation in humans. Here, we examined in normal weight humans the effects of a 6-week (daily) treatment with two different MC4-R agonists, MSH/ACTH_4–10 and desacetyl-MSH, on body weight, body fat, as well as plasma concentrations of leptin and insulin. These agonists share all seven amino residues representing the core sequence of melanocortins (23, 24, 25). Desacetyl-MSH may represent one of the natural ligands of the MC4-R (26, 27), and in vitro has been found to exhibit a distinctly greater potency in activating MC4-R-coupled adenylyl cyclase than MSH/ACTH_4–10 (28).

	Subjects and Methods

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Subjects

Experiments were conducted in 36 healthy, normal weight students [body mass index (mean ± SEM), 21.98 ± 0.34 kg/m²], aged 19–35 yr, who were nonsmokers and had abstained from alcohol, caffeine, and food intake for at least 12 h before testing. Informed consent was obtained after the nature of the study was explained. The study was approved by the local ethics committee. Experiments were conducted in a double blind fashion.

Design and procedure

Subjects were randomly assigned to three experimental groups (each including six men and six women), who received, after a 4-week baseline phase, placebo, MSH/ACTH_4–10, or desacetyl-MSH. Groups were comparable with regard to the subjects’ mean age and body mass index. All subjects received placebo during the 4-week baseline phase, followed by a 6-week phase of treatment with the assigned substance. Substances were administered intranasally once in the morning and once in the evening (i.e. before and after nocturnal bedtime) at equimolar doses of MSH/ACTH_4–10 (0.50 mg) and desacetyl-MSH (0.84 mg).

Substances were provided by Bachem Biochemica (Heidelberg, Germany). The amino acid sequences were: for MSH/ACTH_4–10, H-Met-Glu-His-Phe-Arg-Trp-Gly-OH; and for desacetyl-MSH; H-Ser-Tyr-Ser-Met-Glu-His-Phe-Arg-Trp-Gly-Lys-Pro-Val-NH₂. For intranasal administration, MSH/ACTH_4–10 and desacetyl-MSH were dissolved in sterile water. Each puff administered to the nostril with a nasal spray atomizer contained, respectively, 0.25 mg MSH/ACTH_4–10 and 0.42 mg desacetyl-MSH, dissolved in a defined volume of 0.08 mL. Sprays were continuously stored at 2–7 C and were replaced by new substance every 7 days. High performance liquid chromatography confirmed that at the end of a 7-day interval the contents of MSH/ACTH_4–10 and desacetyl-MSH were still above 90% of the original concentrations. Subjects had to record in a diary every time they used the nasal spray, to assure compliance.

An intranasal route of substance administration was adopted because previous studies in humans, monkeys, and rodents indicated that peptides, and even larger molecules such as horseradish peroxidase, after intranasal administration can directly enter the cerebrospinal fluid (CSF) compartment within about 60 min (29, 30, 31, 32). To assure the accumulation of substances in the brain, in a complementary study CSF samples were collected (via an intraspinal catheter) from five subjects between 15 min before and 75 min after intranasal administration of 10 mg MSH/ACTH_4–10. MSH/ACTH_4–10 was determined by RIA as described previously (33, 34). Compared with baseline concentrations (0.67 ± 0.28 ng/mL), CSF concentrations of MSH/ACTH_4–10 increased to 10.24 ± 3.80 ng/mL 10–30 min after peptide administration. Changes in serum samples remained nonsignificant, suggesting that MSH/ACTH_4–10 directly entered the brain compartment.

The experiment started with a preparatory session to adapt the subject to the laboratory setting. Thereafter, two test sessions were scheduled taking place 1) at the end of the 4-week baseline phase and 2) at the end of the 6-week treatment phase. The first test session served as the baseline reference for a comparison of effects among the substances after 6 weeks of treatment.

Sessions were scheduled between 1330 and 1530 h. Care was taken for subjects not to become aware of the study aims and thus not to pay more attention than usual to habits of food intake and body weight. For this reason, experimental examinations were embedded into an assessment of psychological memory function, and the monitoring of subjective measures of appetite, food intake, and exercise patterns was avoided. Aside from presenting memory tasks, in each session body weight and body composition were measured by standard bioelectrical impedance analysis (BIA 2000-M, Data Input GmbH, Frankfurt, Germany), performed according to the guidelines of the NIH Technology Assessment Statement, U.S. DHHS, 1994 (35). Frequencies of 1, 5, 50, and 100 kHz were employed. Eurobody software (Data Input GmbH) was used to calculate total body water, lean body mass, body fat, body cell mass, and basal metabolism. For a single resistance measurement, the test-retest correlation coefficient over 5 days was greater than 0.98 (36). Bioelectric impedance analysis predicts fat and fat-free mass with a precision similar to that of conventional anthropometry, using published equations to estimate body composition from skinfold measurements (37). These data indicate a considerable validity of measures of body composition, in particular of body fat, as determined by bioelectric impedance analysis, although some degree of error variability must be taken into account.

Blood was sampled at the end of each session for determination of leptin and insulin concentrations. A number of further parameters were monitored to control for possible side-effects, including plasma concentrations of ACTH and cortisol, TSH, free T₃, free T₄, blood pressure, and routine laboratory measures (serum electrolytes, creatinine, C-reactive protein, and liver enzymes). On a weekly base, subjects were weighed and interviewed regarding possible complaints and any subjective awareness of treatment effects.

Assays

Blood samples were centrifuged immediately, and plasma was stored at -20 C. Concentrations of leptin, insulin, and ACTH were assessed using standard RIAs (Human Leptin RIA Kit, catalogue no. HL-81K, Linco Research, Inc., St. Charles, MO; Pharmacia Insulin RIA 100, Pharmacia & Upjohn, Inc., Uppsala, Sweden; Lumitest ACTH, Brahms Diagnostica GmbH, Berlin, Germany). For determination of cortisol, TSH, free T₃, and free T₄, enzyme immunometric and immunoluminometric assays were used, respectively (Enzymun-Test Cortisol ES 300 and Elecsys, Roche Molecular Biochemicals, Mannheim, Germany). All samples were measured in duplicate in the same assay.

Statistical analyses

Comparisons between the effects of placebo and MSH/ACTH_4–10 or desacetyl-MSH were based upon analyses of covariance, with a group factor representing the treatment conditions. Values of the baseline session were included as a covariate. An additional covariate was introduced representing progesterone levels at the test sessions, to control for fluctuations in body water in women across the menstrual cycle. P < 0.05 (two-tailed) was considered significant.

	Results

Top Abstract Introduction Subjects and Methods Results Discussion References

 
Compared with the effects of placebo, the 6-week treatment with MSH/ACTH_4–10 decreased body fat, on the average, by 1.68 kg [F(1, 21) = 4.55; P < 0.05] and body weight, on the average, by 0.79 kg [F(1, 21) = 14.63; P < 0.001; Fig. 1]. Also, the weekly measurements of body weight indicated a trend toward reduced weight after MSH/ACTH_4–10 by 0.55 kg at week 3 (P < 0.1, compared with the placebo condition), with the average weight loss steadily increasing thereafter until the end of the treatment phase. Decreases in body fat and weight resulted in a diminished body mass index after subchronic MSH/ACTH_4–10 [F(1, 21) = 14.93; P < 0.001; Table 1]. Lean body mass and body cell mass, both of which index extra adipose tissue, remained unchanged. Total body water slightly increased during MSH/ACTH_4–10, yet this change remained nonsignificant. Although body fat was also slightly reduced after subchronic administration of desacetyl-MSH, this effect did not reach significance [F(1, 21) = 3.56; P < 0.10]. There were no changes in any of the other parameters of body composition after desacetyl-MSH.

View larger version (29K): [in this window] [in a new window]   Figure 1. Body fat (A), body weight (B), plasma leptin (C), and plasma insulin (D) in healthy normal weight humans after a 6-week period of daily treatment with placebo (), MSH/ACTH4–10 (), and desacetyl-MSH (). MSH/ACTH4–10 induced a reduction in all measures. **, P 0.001; *, P < 0.05 (pairwise comparison with the effects of placebo). Means and SEMs are indicated. A baseline adjustment of the values was achieved by analysis of covariance.

View this table: [in this window] [in a new window]   Table 1. Mean (±SEM) body weight, body mass index, measures of body composition, and plasma hormone levels after a 6-week treatment with placebo, MSH/ACTH4–10, and desacetyl-MSH in normal weight humans

	Discussion

Top Abstract Introduction Subjects and Methods Results Discussion References

 
The present data indicate a reducing effect of the melanocortin sequence MSH/ACTH_4–10 on human body adiposity within a short treatment period of only 6 weeks. Notably, the effect was confirmed by converging results from measures of body weight, bioelectrical impedance analysis of body fat, and hormonal measures of leptin and insulin. No side-effects occurred, and the weekly measurements of body weight indicated a gradual increase in the effect of MSH/ACTH_4–10, so that one might expect additional weight loss from longer treatment. A mediation of this effect by peripheral mechanisms is unlikely, as MSH/ACTH_4–10 does not show any binding to the peripheral MC-R (MC1-R and MC2-R). Accordingly, here the peptide did not exert any adrenocorticotropic action. Also, intranasal administration of the peptides used here is assumed to facilitate direct access to the brain (27, 28, 29, 30, 38, 39), which was also confirmed in supplementary experiments (see Materials and Methods). In principle, MSH/ACTH_4–10 at the central nervous system level may act via inhibiting anabolic pathways, such as the neuropeptide Y system of the arcuate nucleus of the hypothalamus (7, 8, 9, 10). Alternatively, the neuropeptide Y and melanocortin systems may be parallel anabolic and catabolic pathways that both act on systems downstream of the arcuate nucleus, such as the melanocyte-concentrating hormone neurons in the lateral hypothalamus (40, 41). Also, a catabolic effect is possible through reducing food intake and increasing energy expenditure. However, in a related study, compared with placebo subjects after the subchronic administration of MSH/ACTH_4–10, the subjects’ performance on an attention task did not depend on whether the targets to be attended were food-related stimuli or stimuli not related to food (42). Those results do not support the idea that attraction and sensitivity to food signals are changed in humans after treatment with MSH/ACTH_4–10. Moreover, cardiovascular measurements in the present study failed to reveal any signs of increased sympathetic tone during treatment with MSH/ACTH_4–10. Yet, these measures as well as measures of thyroid hormone activity are probably not sensitive enough to unravel slight, but persistent, increases in basal metabolism.

Animal and in vitro studies have indicated a particular relevance of the MC4-R subtype in mediating weight loss (7, 8, 9, 14). Desacetyl-MSH is the major melanocortin of the rat and human hypothalamus, and its potency in activating the MC4-R subtype in vitro was 300-fold higher than that for MSH/ACTH_4–10 (28). Surprisingly, here the overall effect of desacetyl-MSH on body composition was less distinct than that of MSH/ACTH_4–10, and failed to reach significance compared with that during the placebo control condition. It should be noted that MSH/ACTH_4–10 is considerably smaller than desacetyl-MSH and might therefore be more readily transported to the CSF compartment via the intranasal route. Although unlikely, the in vivo degradation of the substances might also differ (33, 43). Currently, a direct comparison of the kinetics and conversion of desacetyl-MSH and MSH/ACTH_4–10 by brain peptidases is lacking. Alternatively, the lack of significant changes in body adiposity after desacetyl-MSH could point to an involvement of receptor mechanisms other than the MC4-R in the effects of MSH/ACTH_4–10. However, this view is presently speculative, and further investigation is needed to identify the receptor system involved in the effects. The findings of reduced body fat in conjunction with reduced plasma concentrations of leptin and insulin after treatment with the melanocortin MSH/ACTH_4–10 strengthens the model of hypothalamic weight regulation based to date essentially on data derived from animal experiments. To our knowledge, the present study represents the first successful attempt to regulate body weight in humans by means of neuropeptides targeted at a central neuropeptide system involved in the regulation of energy balance. These findings could pave the way for the therapeutic use of melanocortin peptides in the control of body adiposity in humans.

	Acknowledgments

 
We are grateful to C. Bluhm, T. Jarosch, A. Otterbein, and C. Zinke for their skilled technical assistance. We thank David DeWied, Denis G. Baskin, and Jeffrey S. Flier for critical reading and valuable comments on an earlier draft of this manuscript.

	Footnotes

 
¹ This work was supported by the Deutsche Forschungsgemeinschaft.

² These authors contributed equally to this work.

Received May 22, 2000.

Revised October 19, 2000.

Accepted November 9, 2000.

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