REVIEW The melanocortin-4 receptor as target for obesity treatment: a systematic review of emerging pharmacological therapeutic options L Fani 1,3 , S Bak 1,3 , P Delhanty 2 , EFC van Rossum 2 and ELT van den Akker 1 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 advance online publication, 18 June 2013; doi:10.1038/ijo.2013.80 Keywords: MC4R; treatment; pharmacological; drug INTRODUCTION Controlling the global epidemic of obesity is one of today’s most important public health challenges. Obesity accounts for B0.7–2.8% 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 hypotha- lamus. 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 hypotha- lamus (Figure 1). There are neurons in the arcuate nucleus that stimulate appetite. These express orexigenic polypeptides, includ- ing 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 g-melanocyte-stimulating hormone (MSH), adrenocorticotropic hormone (ACTH) and b-lipotropin. ACTH and b-lipotropin produce several substances including, respectively, a-MSH and b-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, B80 distinct mutations 8 of 1 Department of Pediatrics, Division of Endocrinology, Erasmus MC, Rotterdam, The Netherlands and 2 Department 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: e.l.t.vandenakker@erasmusmc.nl 3 These authors contributed equally to this work. Received 7 December 2012; revised 1 May 2013; accepted 12 May 2013 International Journal of Obesity (2013), 1–7 & 2013 Macmillan Publishers Limited All rights reserved 0307-0565/13 www.nature.com/ijo