International Journal of Obesity (2014) 38, 163–169 & 2014 Macmillan Publishers Limited All rights reserved 0307-0565/14 www.nature.com/ijo REVIEW The melanocortin-4 receptor as target for obesity treatment: a systematic review of emerging pharmacological therapeutic options L Fani1,3, S Bak1,3, P Delhanty2, EFC van Rossum2 and ELT van den Akker1 Obesity is one of the greatest public health challenges of the 21st century. Obesity is currently responsible for B0.7–2.8% 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. International Journal of Obesity (2014) 38, 163–169; doi:10.1038/ijo.2013.80; published online 18 June 2013 Keywords: MC4R; treatment; pharmacological; drug INTRODUCTION appetite by expressing anorexigenic polypeptides such as Controlling the global epidemic of obesity is one of today’s pro-opiomelanocortin and cocaine- and amphetamine-regulated most important public health challenges. Obesity accounts for transcript. Pro-opiomelanocortin is a prohormone that is B0.7–2.8% of a country’s total healthcare expenditure.1 Its processed to produce g-melanocyte-stimulating hormone (MSH), prevalence has doubled or tripled in many countries in the adrenocorticotropic hormone (ACTH) and b-lipotropin. ACTH and European Union, United States and even in some developing b-lipotropin produce several substances including, respectively, countries.2 Treatment is often not successful because weight a-MSH and b-MSH. MSH is the ligand that binds and activates the regulation is very complex with many influencing factors such as MC4R. The MC4R has a central role in weight regulation. genetic makeup, environmental and behavioural factors,3 as well MC4R activation decreases food intake while elevating energy as social and psychological dimensions.4 Important for weight utilization.6 The importance of this receptor in appetite and regulation are appetite and energy control, which are energy regulation is illustrated by naturally occurring mutations predominantly regulated in the brain. that lead to partial or complete dysfunction of MC4R in patients. The brain control of appetite and energy balance is under the This MC4R defect leads to a clinical phenotype with lack of satiety, regulation of a complex interplay of several brain areas. The major extreme continuous hyperphagia, a decline in energy utilization, centres involved are multiple hypothalamic nuclei, for example, and consequently leads to severe early-onset obesity. In humans, the arcuate nucleus, paraventricular nucleus, lateral hypothalamic homozygous or compound heterozygous MC4R gene defects are area, dorsomedial hypothalamus and the ventromedial hypotha- rare. However, the prevalence of carriage of heterozygous MC4R lamus. Interrelationships between these centres provide tight mutations is estimated to be as high as 0.5–6% in obese homoeostatic regulation of body weight.5 individuals in the Netherlands.7 The role of MC4R gene mutation One of the key regulators of energy intake, expenditure, carriage in the development of obesity is unclear, although it is appetite and metabolism is the arcuate nucleus of the hypotha- conceivable that many of these mutations lead to a partial lamus (Figure 1). There are neurons in the arcuate nucleus that resistance of the receptor, which might be overcome by increased stimulate appetite. These express orexigenic polypeptides, includ- concentration of the MC4R ligand. The central role of MC4R in the ing neuropeptide Y and agouti-related peptide. Agouti-related regulation of appetite and energy expenditure makes MC4R peptide is a natural antagonist of the melanocortin-4 receptor agonist also an interesting target for studies on obesity drug (MC4R) activity. Other neurons in the arcuate nucleus decrease development in general.7 To date, B80 distinct mutations8 of 1Department of Pediatrics, Division of Endocrinology, Erasmus MC, Rotterdam, The Netherlands and 2Department of Internal Medicine, Division of Endocrinology, Erasmus MC, Rotterdam, The Netherlands. Correspondence: Dr ELT van den Akker, Department of Pediatrics, Division of Endocrinology, Erasmus MC- Sophia, Office sp 1536, Dr Molewaterplein 60, 3015 GJ Rotterdam, The Netherlands. E-mail: [email protected] 3These authors contributed equally to this work. Received 7 December 2012; revised 1 May 2013; accepted 12 May 2013; published online 18 June 2013 MC4R as target for obesity treatment L Fani et al 164 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. 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 Figure 1. Schematic representation of the regulation of food intake b-MSH analogues. We will analyse the articles by showing the and energy expenditure by the MC4-receptor. 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 1. The search strategy used for (a) the Pubmed search (25 June 2012) and (b) the Embase search (25 June 2012) Melanotan II In the study by Hansen et al.,10 the effect of the MC3/4R agonist Search Query MTII was investigated. Six-week-old male Sprague–Dawley rats were randomly divided into two groups. The first group was (a) administered high-fat chow food supplemented with a cafeteria #1 melanocortin-4 receptor* OR MC4R OR MC4 Receptor* OR Receptor, Melanocortin, Type 4[mesh] OR diet (30% fat) and the control group was chow fed (5% fat), both (Melanocortin Receptor* AND ‘type 4’[tw]) for 12 weeks. The rats were maintained under a 12-h light/dark #2 Melanocortin Receptor* AND ‘type 4’[tw] cycle (lights on at 0600 hours). After intracerebroventricular (ICV) #3 #1 OR #2 MTII administration, an inhibitory effect on food intake was found #4 Drug therapy[mesh] OR Drug therapy[tw] OR drugs[tw] OR in both groups. The chronically overfed animals had a stronger drug[tw] OR pharmacotherap*[tw] OR pharmaceutic*[tw] inhibitory feeding response 15 and 24 h after MTII injection and #5 body weight[mesh] OR obesity[tw] OR obese[tw] OR lost more body weight (15±3 g) compared with control rats. In overweight[tw] OR weight[tw] OR BMI[tw] OR appetite[tw] conclusion, MTII inhibited food intake and decreased body weight OR food intake[tw] OR eating[tw] in overfed rats. One of the remaining issues of this compound is #6 #3 AND #4 AND #5 that it is non-specific for the MC4R, which might limit its use in (b) humans owing to potential side effects. One of the described side #1 ‘melanocortin-4’ NEXT/1 receptor*):de,ab,ti OR effects is conditioned taste aversion, which may be due to mc4r:de,ab,ti OR (mc4 NEXT/1 receptor*):de,ab,ti OR off-target effects. ((melanocortin NEAR/4 receptor*):de,ab,ti AND ‘type 4’:de,ab,ti #2 ‘drug therapy’/exp OR drugs:de,ab,ti OR drug:de,ab,ti OR Tetrapeptides: compound 10 and BL3020 pharmacotherap*:de,ab,ti OR pharmaceutic*:de,ab,ti Several studies analysed the effects of tetrapeptides derived from #3 obesity/exp OR obesity:de,ab,ti OR obese:de,ab,ti OR a-MSH generated by creating analogues of the His-Phe-Arg-Trp overweight:de,ab,ti OR weight:de,ab,ti OR BMI:de,ab,ti OR sequence. This sequence is commonly shared by all the appetite:de,ab,ti OR ‘food intake’:de,ab,ti OR eating:de,ab,ti melanocortins and is critical for the activation of melanocortin #4 #1 AND #2 AND #3 receptors (MCRs) by a-MSH.11 Modification of this sequence has been shown to affect selectivity of the peptide for MC3R versus MC4R have been reported in humans.9 This systematic review MC4R. focuses on MC4R agonists that have potential as future Ye et al.12 studied the pharmacological characteristics of several pharmacological obesity treatment. 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 MATERIALS AND METHODS acids designed to modulate the activity of the His-Phe-Arg-Trp The present systematic review aims at finding original articles published in sequence. These in vitro studies lead to development of the linear the international medical literature, particularly those describing pharma- tetrapeptide compound 10, which was studied in rats.