The melanocortin-4 receptor as target for obesity treatment: a systematic review of emerging pharmacological therapeutic options

Abstract

Obesity is one of the greatest public health challenges of the 21st century. Obesity is currently responsible for 0.7–2.8% of a country’s health costs worldwide. Treatment is often not effective because weight regulation is complex. Appetite and energy control are regulated in the brain. Melanocortin-4 receptor (MC4R) has a central role in this regulation. MC4R defects lead to a severe clinical phenotype with lack of satiety and early-onset severe obesity. Preclinical research has been carried out to understand the mechanism of MC4R regulation and possible effectors. The objective of this study is to systematically review the literature for emerging pharmacological obesity treatment options. A systematic literature search was performed in PubMed and Embase for articles published until June 2012. The search resulted in 664 papers matching the search terms, of which 15 papers remained after elimination, based on the specific inclusion and exclusion criteria. In these 15 papers, different MC4R agonists were studied in vivo in animal and human studies. Almost all studies are in the preclinical phase. There are currently no effective clinical treatments for MC4R-deficient obese patients, although MC4R agonists are being developed and are entering phase I and II trials.

Introduction

Controlling the global epidemic of obesity is one of today’s most important public health challenges. Obesity accounts for 0.7–2.8% of a country’s total healthcare expenditure.1 Its prevalence has doubled or tripled in many countries in the European Union, United States and even in some developing countries.2 Treatment is often not successful because weight regulation is very complex with many influencing factors such as genetic makeup, environmental and behavioural factors,3 as well as social and psychological dimensions.4 Important for weight regulation are appetite and energy control, which are predominantly regulated in the brain.

The brain control of appetite and energy balance is under the regulation of a complex interplay of several brain areas. The major centres involved are multiple hypothalamic nuclei, for example, the arcuate nucleus, paraventricular nucleus, lateral hypothalamic area, dorsomedial hypothalamus and the ventromedial hypothalamus. Interrelationships between these centres provide tight homoeostatic regulation of body weight.5

One of the key regulators of energy intake, expenditure, appetite and metabolism is the arcuate nucleus of the hypothalamus (Figure 1). There are neurons in the arcuate nucleus that stimulate appetite. These express orexigenic polypeptides, including neuropeptide Y and agouti-related peptide. Agouti-related peptide is a natural antagonist of the melanocortin-4 receptor (MC4R) activity. Other neurons in the arcuate nucleus decrease appetite by expressing anorexigenic polypeptides such as pro-opiomelanocortin and cocaine- and amphetamine-regulated transcript. Pro-opiomelanocortin is a prohormone that is processed to produce γ-melanocyte-stimulating hormone (MSH), adrenocorticotropic hormone (ACTH) and β-lipotropin. ACTH and β-lipotropin produce several substances including, respectively, α-MSH and β-MSH. MSH is the ligand that binds and activates the MC4R. The MC4R has a central role in weight regulation. MC4R activation decreases food intake while elevating energy utilization.6 The importance of this receptor in appetite and energy regulation is illustrated by naturally occurring mutations that lead to partial or complete dysfunction of MC4R in patients. This MC4R defect leads to a clinical phenotype with lack of satiety, extreme continuous hyperphagia, a decline in energy utilization, and consequently leads to severe early-onset obesity. In humans, homozygous or compound heterozygous MC4R gene defects are rare. However, the prevalence of carriage of heterozygous MC4R mutations is estimated to be as high as 0.5–6% in obese individuals in the Netherlands.7 The role of MC4R gene mutation carriage in the development of obesity is unclear, although it is conceivable that many of these mutations lead to a partial resistance of the receptor, which might be overcome by increased concentration of the MC4R ligand. The central role of MC4R in the regulation of appetite and energy expenditure makes MC4R agonist also an interesting target for studies on obesity drug development in general.7 To date, 80 distinct mutations8 of MC4R have been reported in humans.9 This systematic review focuses on MC4R agonists that have potential as future pharmacological obesity treatment.

Figure 1
figure1

Schematic representation of the regulation of food intake and energy expenditure by the MC4-receptor.

Materials and methods

The present systematic review aims at finding original articles published in the international medical literature, particularly those describing pharmacological compounds with MC4R agonist effects in (pre)clinical studies. The search was performed in the databases PubMed and Embase. Pubmed and Embase were searched on 25 June 2012. Articles in PubMed were sought using the search terms described in Table 1. All articles were then recruited into Endnote X3(1988–2009 Thomson Reuters, New York, NY, USA) in order to sort the articles using inclusion and exclusion criteria, as listed below. This was primarily performed by analysing the article titles. When the titles were not clear enough, abstracts were also scanned. When still in doubt, the whole article was read. The inclusion criteria were: (1) articles published in the english language in peer-reviewed medical journals and (2) original studies aimed at studying the effect of MC4R agonist therapeutics in obese animals or humans with MC4R mutations. The exclusion criteria were: (1) articles that merely described the molecular or biochemical bases of the therapeutics without investigating the effect of using it in vivo and (2) articles studying outcome parameters other than weight and energy expenditure.

Table 1 The search strategy used for (a) the Pubmed search (25 June 2012) and (b) the Embase search (25 June 2012)

Results

Systematic review results

The primary search resulted in 357 articles in Pubmed and 635 articles in Embase, with the elimination of redundant articles leading to 664 articles in total for analysis. After applying our inclusion and exclusion criteria to the search results, 15 articles remained.

The MC4R agonists from these articles comprise the following: melanotan II (MTII), tetrapeptides, MK-0489, MK-0493, urea-based piperazine, Ro27-3225, cyclophanes, ACTH-derivates, compound 1, pyrrolidine diastereoisomer, BIMs (BIM-22493 and BIM-22511) and β-MSH analogues. We will analyse the articles by showing the results of the studies by compounds. An overview of the studies and the main results is presented in Table 2. An overview of the agents’ effectivity and specificity is presented in Table 3.

Table 2 Review of literature from systematic review on MC4R agonist (pre)clinical studies in animals or humans
Table 3 Compounds’ half maximal effective concentration (EC50) to the MC4R in vitro and the relative potency to other MCRs

Melanotan II

In the study by Hansen et al.,10 the effect of the MC3/4R agonist MTII was investigated. Six-week-old male Sprague–Dawley rats were randomly divided into two groups. The first group was administered high-fat chow food supplemented with a cafeteria diet (30% fat) and the control group was chow fed (5% fat), both for 12 weeks. The rats were maintained under a 12-h light/dark cycle (lights on at 0600 hours). After intracerebroventricular (ICV) MTII administration, an inhibitory effect on food intake was found in both groups. The chronically overfed animals had a stronger inhibitory feeding response 15 and 24 h after MTII injection and lost more body weight (15±3 g) compared with control rats. In conclusion, MTII inhibited food intake and decreased body weight in overfed rats. One of the remaining issues of this compound is that it is non-specific for the MC4R, which might limit its use in humans owing to potential side effects. One of the described side effects is conditioned taste aversion, which may be due to off-target effects.

Tetrapeptides: compound 10 and BL3020

Several studies analysed the effects of tetrapeptides derived from α-MSH generated by creating analogues of the His-Phe-Arg-Trp sequence. This sequence is commonly shared by all the melanocortins and is critical for the activation of melanocortin receptors (MCRs) by α-MSH.11 Modification of this sequence has been shown to affect selectivity of the peptide for MC3R versus MC4R.

Ye et al.12 studied the pharmacological characteristics of several compounds based on the His-Phe-Arg-Trp analogue Tic-DPhe-Arg-Trp in vitro for their binding affinity, agonist activity and MC4R receptor selectivity. Tic and DPhe are synthetic amino acids designed to modulate the activity of the His-Phe-Arg-Trp sequence. These in vitro studies lead to development of the linear tetrapeptide compound 10, which was studied in rats. ICV administration of peptide 10 to Sprague–Dawley rats induced inhibition of food intake. Feeding duration reduced significantly over 18 h, whereas time between feeding events increased. The cumulative overnight food intake was reduced by 24% compared with control rats.

Hess et al.6 studied tetrapeptide analogues by changing the molecular structure of the tetrapeptide sequence by backbone peptidomimetic cyclization. In vitro analyses showed that one of the analogues tested from the BL3020 library, BL3020-1, had the best characteristics concerning high MC4R selectivity, intestinal metabolic stability, permeability and a relatively high bioavailability of 8.5%. In rats, BL3020-1 was detected in the brain following oral administration. In mice, a single oral dose led to reduced food consumption. Up to 48% less food consumption was found in the BL3020-1 group compared with the control group. This effect lasted for 5 h. When administered for 12 days in a once daily oral dose, these mice showed reduced weight gain compared with controls. BL3020 was among the first publications reporting on a MC4R compound that showed effect of reducing weight gain when administered orally and chronically. No further studies on BL3020 analogues were published.

Spiroindane-based acetyl amide compounds: MK-0489 and MK-0493

A study by He et al.13 investigated the function of the Merck compound MK-0489 (Rahway, NJ, USA), a spiroindane-based acetyl amide small molecule MC4R agonist, and several analogues. Initially, it was found that an N-methyl derivative of MK-0489 had good pharmacokinetic profiles in rats with a half-life of 15.1 h and good oral bioavailablity. This encouraged the authors to develop further amide analogues of this compound to improve MC4R specificity and bioavailability. In this study, MK-0489 itself was evaluated in rodent obesity models.

After oral dosage of MK-0489, reduction of food intake and body weight was observed in wild-type mice. Specificity was tested by treatment of MC4R/3R knockout (KO) mice in which this compound had no effect on food intake or body weight. The same compound was also tested in a 14-day diet-induced obese (DIO) rat model. In this study, following 13 days of twice daily oral dosing, the body weight of the rats was significantly decreased in the highest dosing group (20 mg kg−1), to an extent that was comparable to dexfenfluramine treatment at 3 mg kg−1 twice daily.

Following this, He et al.14 published another study that tested two other analogues of MK-0489 in vivo. Two models were used: a DIO mouse model and an MC4R/3R double KO mouse model. It turned out that two of the analogues tested, analogues 26 and 30, lowered food intake and body weight in the DIO mice. However, the same effect was present in the MC4/3R KO mouse models, suggesting non-MC4R-mediated effects. Analogue 32 was efficacious in the DIO mouse obesity model without an effect in the KO mice, suggesting that the efficacy was mediated through MC4R. When dosed orally in the DIO mouse study, analogue 32 reduced food intake up to 56% at the 4-h time point, followed by 28 and 15% at 18-h time point. It also lowered body weight significantly.

Krishna et al.15 described for the first time the effect of the MC4R agonist MK-0493 in obese humans (see Table 2). In earlier studies, oral administration of this drug to rodent models of diet-induced obesity caused a reduction in weight and energy intake. The effect of this drug in obese humans was compared with sibutramine, which is a serotonin and a norepinephrine reuptake inhibitor developed for the treatment of obesity. Phase I and II clinical trials were performed to qualify an ad libitum energy intake model and to determine the acute effects of two doses of MK-0493 as compared with placebo and sibutramine. In addition, the evaluation of the effects of chronically administered MK-0493 on weight loss was performed. It turned out that the administration of 30 mg of sibutramine caused a statistically significant greater reduction in energy intake when compared with a lower dose of 10 mg sibutramine and a placebo. However, neither dose of MK-0493 caused significant reductions in the energy intake or weight after 12 weeks of treatment when compared with placebo.

In conclusion, MK-0489 and MK-0493 demonstrated MC4R-mediated efficacy on food intake and weight reduction in rodent models of diet-induced obesity, but in obese humans MK-0493 showed no significant reduction on food intake or weight compared with placebo. MK-0493 was the first publication on a phase I/II trial in humans treated with an MC4R agonist. In contrast to the effect in rodents, the effect on weight loss in humans was insignificant.

Urea-based piperazine partial MC4R agonist

Hong et al.16 tested a urea-based piperazine, highly selective (>100-fold relative to other MCRs) MC4R partial agonist, compound 1. With its good oral bioavailability in rats, it also showed a positive pharmacokinetic profile, low clearance and high plasma drug exposure. In wild-type mouse models, 4 h after administration of compound 1, food intake was reduced by 37% compared with no effect in MC3R/MC4R KO mice. Importantly, at high doses compound 1 exhibited no penile erectile activity in mice. The efficacy of compound 1 was also investigated in a rat model of obesity. Compound 1 was administered orally for 14 days and compared with vehicle and MC4R-full agonist compound A23 as controls. Compound 1 reduced body weight more compared with the vehicle. It was comparable to MC4R-full agonist A23 in reducing the body weight. Piperazine compound 1 is a partial agonist with a relatively high half maximal effective concentration compared with the other compounds described in this review. However, its oral bioavailability is good and it is highly specific for the MC4R, which could be advantageous for its side effect profile.

Ro27-3225

Benoit et al.17 studied a compound, Ro27-3225, that is highly selective for MC1R and MC4R. When administered ICV to rats, it increased Fos-like immunoreactivity in many parts of the nervous system, such as the nucleus of the solitary tract, central nucleus of the amygdala, paraventricular nucleus and the area postrema. This increase is a pattern shown similarly by non-selective MC3/4R agonists. Ro27-3225 dose dependently reduced 4 h food intake when it was centrally given to rats or peripherally to db/db mice that lack functional leptin receptors. Although this compound is not specific for MC4R, no adverse effects were found in contrast to MTII (a non-selective MC3/4R agonist) that caused taste aversion.

A novel class of cyclophanes

Conde-Frieboes et al.18 studied a new class of cyclophanes as MC4R agonists that showed competition with the antagonist SHU9119 over the MC4R. Compound macrocycle 7, which showed threefold selectivity for MC4R compared with MC3R in in vitro-binding assays, was studied in scheduled fed male Sprague–Dawley rats, which had been trained to consume a 24-h food ration during 5 h. Macrocycle 7 was administered intraperitoneally to eight rats just before food was presented. Sibutramine was used as a positive control. Food intake was followed for 3 h and compared with a vehicle-treated group. Compared with controls, macrocycle 7 caused a 50% decrease in food intake within 3 h after administration. The authors suspect that this effect suggests high penetration rate of the blood–brain barrier, but studies on oral bioavailability, side effects and effect on body weight change after chronic administration have to be awaited.

ACTH and its derivates

Al-Barazanji et al.19 studied the central effect of ACTH and its derivates. The effect of the administration of ACTH 1–39 and peptides derived from the N-terminus (ACTH 1–10, ACTH 1–13 amide=α-MSH) and C-terminus (ACTH 18–29 and ACTH 22–39) of ACTH on food consumption was studied in fasted rats and ad libitum-fed rats. ACTH reduced food intake in fed and fasted rats, the effect being more pronounced in the fasted rats. The N-terminal-derived α-MSH peptide (ACTH 1–13), but not ACTH 1–10, reduced food consumption over 2 h after being injected ICV in rats that had been fasting for 16 h, but did not reduce food consumption in fed rats. The anorectic effects of the N-terminal fragments of ACTH are mediated through the MC4R, whereas the C-terminal fragments of ACTH stimulated feeding in fasted, but not fed, rats via an MC4R-independent mechanism. This study underlines previous findings that the natural ligand for MC4R leading to satiety is α-MSH (ACTH 1–13) and not the other splice variants of its prohormone pro-opiomelanocortin. One of the issues for the use of natural α-MSH in obesity treatment is that it is non-specific for the MC4R.

Compound 1

In a study by Cepoi et al.20 a small peptide mimetic MC4R-specific agonist was tested to determine its effects on inhibiting feeding in mice. The original pharmacological name was 1,2,3R,4-tetrahydroisoquinoline-3-carboxylic acid and is renamed for simplification by Cepoi et al.20 as compound 1. In vitro assays with HEK293 cells expressing human and mouse MCRs, using cyclic AMP levels and binding assays as end points, showed that compound 1 has high potency and selectivity for human MC4R.

When given ICV to mice, compound 1 decreased food consumption after an overnight fast, with the greatest effect in the first hour after administration. When administered at night, wild-type mice had significantly reduced food intake 4 h after the ICV injection of compound 1. This inhibition, under normal nocturnal feeding, persisted for over 6 h after administration, but was negligible after 18 h. Compound 1 did not reduce food intake in MC4R KO mice, indicating an MC4R-specific mechanism of action. Since their first publication in 2004, no further studies were published on this compound to our knowledge.

Pyrrolidine diastereoisomer

The study of Chen et al.21 investigated the activity of several pyrrolidine diastereoisomers. These compounds were tested in binding assays using membranes from HEK293 cells expressing MC4R and a radiolabeled ligand. The best compounds were then tested in a whole cell functional agonist assays using cAMP accumulation and competition-binding assays as end points. In the competitive-binding assays using MCR-expressing HEK293 cells, NDP-MSH was used as the radiolabeled ligand. Functional cAMP assays were used to further characterize compounds with highest affinity for MC4R. In competition-binding assays, both 13b-1 and 13b-2 were highly selective for hMC4R over other melanocortin receptor subtypes. The effect of pyrrolidine 13b-1 was subsequently examined in a model of deprivation-induced food intake in DIO rats. Both the 30-mg kg−1 dose and the positive control (fenfluramine) decreased food intake within 24 h after oral administration. Authors state that despite its high tissue distribution, which might be related to its disbasic structure, 13b-1 had delayed brain penetration. When administered daily, both the fenfluramine and 13b-1 significantly reduced food intake and weight for up to 1 week. After a week of administering 13b-1, fasting glucose and body composition were measured. Compound 13b-1 was proven to dose dependently increase fat loss compared with baseline measurements. Unlike fenfluramine, compound 13b-1 did not significantly affect lean mass. Compound 13b-1 also significantly decreased fasting glucose, whereas this was not the case with administration of fenfluramine. This compound, 13b-1, is one of the few compounds, together with the compound described in the next paragraph, that show an effect on glucose metabolism besides weight reduction.

BIM-22493 and BIM-22511

Kumar et al.22 investigated the MCR agonists BIM-22493 and BIM-22511 both in vitro and in vivo. Radioligand-binding assays showed relative non-selectivity of these compounds for MC3R and MC4R in CHO-K1 cells transfected with MCRs. However, functional cAMP assays indicated 10-fold selectivity of the compounds for MC4R compared with MC3R. Specificity of function was further determined using MC3R KO and MC4R KO female mice. When administered peripherally, the compounds had been shown to cross the blood–brain barrier and carry out their effects. Intraperitoneal injection of BIM-22493 led to acute reduction of food intake in wild-type and MC3R KO, but not MC4R KO mice. Fourteen days of BIM-22493 and BIM-22511 administration using subcutaneous mini-osmotic pumps led to weight loss in wild-type and MC3R KO, but not MC4R KO mice. However, only BIM-22493 suppressed food intake in wild-type mice. BIM-22493, but not BIM-22511, also ameliorated lipid profile in DIO wild-type mice. Interestingly, BIM-22551-treated MC4R KO mice showed a substantial reduction (50%) in fasting insulin levels.

Overall, these results suggest that the two MC4R agonists regulate body weight, liver metabolism and glucose homoeostasis through independent pathways. MC4R is necessary for melanocortin agonist-induced weight loss and improvements in the liver metabolism. However, MC4R is not required for the amelioration of hyperinsulinaemia by BIM-22511 in obese MC4R KO mice.

The BIM-22493 and BIM-22551 have the highest in vitro potency, while remaining highly specific for the MC4R, compared with the other compounds described in this review.

Beta-MSH analogue

This structure–activity relationship studied by Hsiung et al.23 used human β-MSH as a lead sequence to develop potent and selective agonists of MC4R and MC3R. A potent and selective agonist was discovered, namely, Ac-YRcyclo(CEHdFRWC)amide that reduced food intake and body weight in DIO rats and normal chow-fed rats. This was mediated through its MC4R activity, as shown by its lack of activity in MC4R-deficient mice.

Further study24 showed in vitro enzymatic cleavage of native human β-MSH(5–22) with two ubiquitous dipeptidyl peptidases (DPP), DPP-I and DPP-IV, which generated two potent MC3/4R peptide analogues: β-MSH(7–22) and β-MSH(9–22). On the test day, animals were injected ICV with compound or vehicle and indirect calorimetry was performed for 22–24 h after injection. The DPP-I/DPP-IV cleaved peptide, β-MSH(9–22), induced an acute negative energy balance in DIO rats, whereas its parent molecule, β-MSH(5–22), administered at the same dose, did not have any effect. For β-MSH, further studies on oral bioavailability, blood–brain barrier permeability and effect after chronic administration have to be awaited.

Discussion and Conclusion

In this study, we aimed to explore future therapeutic possibilities for obese patients. This systematic review shows that most compounds are in the preclinical phase. However, several promising pharmacological compounds influencing MC4R pathways have been found.

These animal studies show that a variety of pharmacologically modified MC4R agonists are able to reduce food intake, reduce body weight and some have been shown to increase energy expenditure. Most studies analysed acute effects (hours–24 h) and some analysed effects after chronic administration (days–2 weeks). An overall theme of these studies was the goal of generating compounds with improved specificity for MC4R in causing these metabolic effects. Crossing the blood–brain barrier is also necessary to reach the MC4R. Of the 15 reviewed studies, 5 studies administered the compounds ICV only, cross-passing the blood–brain barrier. The other 10 studies administered the compounds peripherally, either orally or subcutaneously. In 4/15 studies, blood–brain barrier penetration was mentioned in the article, of which 2 (compound 13b-1 and BIM-22493/ BIM-22511) studied it.

Many previously characterized MC4R agonists have side effects that are likely undesirable. For example, although both MTII10 and the urea-based piperazine compound16 cause reduced food intake and weight reduction in rodent animal models, MTII also causes penile erectile activity25 and conditioned taste aversion as an off-target effect,18 which limits its use as a therapeutic for metabolic dysfunction. Other important undesirable effects of acute treatment with MC4R agonists are increased blood pressure and heart rate.26

Oral administration is the most convenient mode of drug intake for patients, and is therefore preferred for chronic diseases that require long-term treatment. A major drawback of current MC4R agonists is that these have poor bioavailability, hence they cannot be taken orally. The study by Hess et al.6 and Linde et al.27 indicate that by utilizing backbone cyclization it is possible to make bioactive peptides that can cross the intestinal wall and are stable in the intestinal environment, thus providing an improvement in oral bioavailability. Similarly, the study by He et al.13 showed an enhanced oral bioavailability of 3 out of 16 different spiroindane amides. However, it should be noted that these are molecular studies that are still far away from being clinically integrated. The study of spiroindane was performed in both mice and rats and showed good efficacy of the MK-0489 compound.

The compounds described by Krishna et al.15 appear to be the closest in terms of development for clinical use. Their phase I and II clinical trial is the only study that has tested MC4R agonists in obese humans. Unfortunately, the observed effect of MK-0493 on energy intake and weight loss in humans was not as positive as expected from preclinical studies. This is probably due to differences in the potency of effect in rodent models of obesity and obese humans, and demonstrates the difficulty in translating preclinical studies to a clinical situation.

There are four studies that did not meet the inclusion criteria for this review but are worth mentioning because of their high potential for the future.

The first study did not meet the inclusion criteria because it is an in vitro study. The research approach described in this article is exceptional in its way of approaching a possible solution for defective MC4Rs. The study by René et al.8 tested the use of pharmacological chaperones28, 29 to restore cell surface expression and function of mutant MC4R. One of the five pharmacological chaperones tested restored function of some of the mutant receptors tested. This pharmacological chaperone first has to be tested in animal and human studies, but could be an interesting candidate for treatment of a specific subset of patients with MC4R-deficient obesity.

The second study of importance did not meet the inclusion criteria because it is an in vitro study. Interestingly, the authors used 11 naturally occurring MC4R mutations and describe the differences in pathogenesis between these mutations. In this study by Roubert et al.,30 the IRC-022493- and IRC-022511-ligands studied described good results for these agonists because of increasing potencies as compared with α-MSH in either wild-type or the mutated human MC4R. This was studied in transfected cells in test tubes containing the mutated MC4-receptors from 11 different mutated obese patients. This study also developed an excellent way of classifying MC4R mutations. Hereby, different links in the chain-reaction pathway resulting in different mutations on which different drugs can work were described. The classification was made based on the known functional alterations in cells that are the following: intracytoplasmatic retention, reduced basal activity, reduced α-MSH potency or association of both reduced basal activity and α-MSH potency. The IRC-022493- and IRC-022511 compounds have not been tested in vivo yet.

The third study did not meet the inclusion criteria owing to the fact that the study has only been presented as two posters.31, 32 The authors kindly provided the posters to us by mail. The study by Raun et al.31, 32 from the Novo Nordisk Research Unit (Måløv, Denmark) describes the effects of a long-acting MC4R agonist. They studied the in vivo effects in rats and minipigs after sub chronic treatment with a MC4R selective and long-acting α-MSH analogue (MC4-NN1) and compared with vehicle. DIO rats were injected daily for 3 weeks and minipigs were injected subcutaneously on every other day for 8 weeks. A dose-dependent reduction in food intake, body weight reduction and increase in energy expenditure was found in both rats and minipigs. For a more detailed data description, we will have to wait for the publication as original article.

The fourth study did not meet the inclusion criteria because it was published after we completed our systematic search. This study of Kievit et al.26 reports the longest treatment with promising results of the MC4R agonist BIM-22493, in non-human primates. This compound, BIM-22493, was previously mentioned in the study by Kumar et al.22 Treatment with BIM-22493 results in temporary decreases in food intake (35%), with persistent weight loss over 8 weeks of treatment (13.5%) in DIO rhesus macaques. These animals significantly decreased adiposity and improved glucose tolerance. The investigators did not observe any increase in the blood pressure or heart rate.

None of the MC4R agonists, described in literature, reached beyond phase I or II trials. Currently, only three drugs are approved by the Food and Drug Administration for the treatment of obesity, and two of them influence appetite through the brain.33 Phentermine plus extended-release topiramate is a fixed-dose combination of the sympathomimetic amine phentermine, which is an anorectic agent, and the antiepileptic drug topiramate. Phentermine works through the hypothalamus by stimulating the sympathetic system to produce catecholamines by the adrenal glands. In the brain it also releases serotonine and dopamine. Topiramate affects neurotransmitters in the brain. Both medications reduce appetite and, in some people, induce a negative energy balance. Lorcaserin is a selective 5-hydroxytryptamine-2 (serotonine)2C receptor agonist.34 The 5HT2CR pathway requires downstream activation of the MC4R. The mean percentage change in body weight reached by phentermine plus extended-release topiramate or lorcaserin was between 4.5 and 10.9% at 1 year of treatment compared with 1.2–2.5% in controls.33

In conclusion, there are currently no effective MC4R agonists for clinical treatment of obese humans. Despite there being no treatment, research for the defects in the pathways of MC4R are emerging, which provide insight into mechanisms that could be used as novel targets for future therapy. From this systematic review, we have come to the conclusion that there can be potential drugs for the treatment of MC4R-mutated and -obese patients in the future, while careful observation of clinical side effects in humans.

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Correspondence to E L T van den Akker.

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Fani, L., Bak, S., Delhanty, P. et al. The melanocortin-4 receptor as target for obesity treatment: a systematic review of emerging pharmacological therapeutic options. Int J Obes 38, 163–169 (2014). https://doi.org/10.1038/ijo.2013.80

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Keywords

  • MC4R
  • treatment
  • pharmacological
  • drug

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