The Melanocortin Melanocyte-Stimulating Hormone/Adrenocorticotropin4–10 Decreases Body Fat in Humans

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/ACTH4–10 (MSH/ACTH4–10) 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/ACTH4–10. The third group received placebo. Treatments were given intranasally twice daily for 6 weeks, at equimolar doses (MSH/ACTH4–10, 0.5 mg; desacetyl-MSH, 0.84 mg). Body weight, body composition, and plasma hormone concentrations were measured before and after treatment. MSH/ACTH4–10 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/ACTH4–10. Changes after desacetyl-MSH remained nonsignificant. The finding of reduced body adiposity after MSH/ACTH4–10 confirms and extends to the human the findings of animal models indicating an essential role of the hypothalamic melanocortin system in body weight control.

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. 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. 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). 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. 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. Thus, genetic deficiency of the MC4-R in mice is accompanied by hyperphagia, hyperinsulinemia, hyperglycemia, and obesity. In humans, various mutations of the MC4-R have been identified, mostly in extremely obese individuals with body mass indexes above the 99th percentile. In one such patient, the mutant MC4-R was shown to be severely impaired in ligand binding and signaling. Obesity is also a key symptom of human patients and mutant mice with deficient synthesis of melanocortins. Moreover, in the latter animal model daily treatment with an MSH/ACTH agonist was found to induce distinct weight loss.

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. 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/ACTH4–10 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. Desacetyl-MSH may represent one of the natural ligands of the MC4-R, and in vitro has been found to exhibit a distinctly greater potency in activating MC4-R-coupled adenylyl cyclase than MSH/ACTH4–10.

Compared with the effects of placebo, the 6-week treatment with MSH/ACTH4–10 decreased body fat, on the average, by 1.68 kg [F = 4.55; P < 0.05] and body weight, on the average, by 0.79 kg [F = 14.63; P < 0.001]. Also, the weekly measurements of body weight indicated a trend toward reduced weight after MSH/ACTH4–10 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/ACTH4–10 [F = 14.93; P < 0.001]. Lean body mass and body cell mass, both of which index extra adipose tissue, remained unchanged. Total body water slightly increased during MSH/ACTH4–10, 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 = 3.56; P < 0.10]. There were no changes in any of the other parameters of body composition after desacetyl-MSH.

A reduction in body fat after subchronic administration of MSH/ACTH4–10 was associated with a 24% decrease in plasma leptin [F= 6.39; P < 0.02] and a 20% decrease in plasma insulin [F = 4.41; P < 0.05]. Desacetyl-MSH did not affect these hormone concentrations. Compared with the effects of placebo, there was a slight trend toward diminished plasma concentrations of ACTH after treatment with both MSH/ACTH4–10 and desacetyl-MSH (P < 0.1). However, cortisol concentrations as well as concentrations of TSH and thyroid hormones remained completely unchanged by the melanocortins. Also, peptide treatments did not affect cardiovascular parameters (systolic and diastolic blood pressure and heart rate) or routine laboratory measures (serum concentrations of sodium, potassium, calcium, chloride, creatinine, protein, C-reactive protein, aspartate aminotransferase, alanine aminotransferase, and -glutamyltransferase). There was no awareness of active treatment in the subjects receiving MSH/ACTH4–10, whereas after subchronic treatment with desacetyl-MSH, more subjects than after placebo believed that they had received an active agent (2 = 6.21; P < 0.05).

The present data indicate a reducing effect of the melanocortin sequence MSH/ACTH4–10 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, bio-electrical 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/ACTH4–10, so that one might expect additional weight loss from longer treatment. A mediation of this effect by peripheral mechanisms is unlikely, as MSH/ACTH4–10 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, which was also confirmed in supplementary experiments (see Materials and Methods). In principle, MSH/ACTH4–10 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. 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. 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/ACTH4–10, 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/ACTH4–10. Moreover, cardiovascular measurements in the present study failed to reveal any signs of increased sympathetic tone during treatment with MSH/ACTH4–10. 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. 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/ACTH4–10. Surprisingly, here the overall effect of desacetyl-MSH on body composition was less distinct than that of MSH/ACTH4–10, and failed to reach significance compared with that during the placebo control condition. It should be noted that MSH/ACTH4–10 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. Currently, a direct comparison of the kinetics and conversion of desacetyl-MSH and MSH/ACTH4–10 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/ACTH4–10. 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/ACTH4–10 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.