**1. Introduction**

Nowadays, the increased consumption of food highly rich in fat, sugar and palatable components has fueled the so called Western diet, leading to excessive and non-homeostatic feeding behavior that impacts the quality of life [1,2]. The melanocortin system, known to be a key pathway in the regulation of food intake, body weight and energy balance [3–6], has been proposed as a possible underlying factor not only in obesity, in which there is evidence of a consistent relationship [7–14], but also in several dysfunctional eating patterns [15–20] that can lead to obesity, modulating the motivation for hedonic properties of food [21–23]. Among the altered feeding patterns, binge eating behavior is one of the most studied, due to the overlaps that exist with obesity [24–26], and melanocortin signaling can influence reward-related behaviors, given the presence of melanocortin receptors (MCRs) not only in the hypothalamus, but also in reward-related brain areas such as in the mesolimbic dopamine pathway [27,28].

Binge eating is a typical feature in eating disorders, in particular Bulimia Nervosa, binge/purging subtype of Anorexia Nervosa and Binge Eating Disorder (BED). A binge eating episode is characterized by an unusual consumption of a large amount of food that most people would not eat in the same discrete period of time, connected with the inability to stop overeating, accompanied by feelings of guilt, shame and regret [29]. Differently from Bulimia Nervosa and Anorexia Nervosa, BED is characterized by recurrent episodes of binge eating not followed by inappropriate compensatory behaviors, such as vomiting, prolonged fasting, or excessive exercise for controlling weight gain [29]. BED is the most prevalent eating disorder in adolescents and young women [24,25,30], and it is associated in some instances with overweight or obesity [31,32]. The subgroup of obese individuals that suffers also from BED seems to increase food-related impulsivity and reward sensitivity in comparison to obese people without BED [33,34]. Additionally, food craving is significantly higher under negative emotional states (including disappointment, anger, guilt, depressive symptoms) [35,36] and stress exposure [37–39] in obese binge eaters rather than obese. Thus, binge eating is a risk factor for obesity and, at the same time, overweight and obesity might enhance the possibility to engage binge eating behavior [40]. In light of these interconnected aberrant feeding patterns and the involvement of the MCRs in overeating and stress, the aim of this review is to revise the current literature on PubMed, regarding the role of the melanocortin system as a mutual underlying factor that may increase the susceptibility to develop aberrant eating behaviors. After a brief summary of the localization and the physiological functions of the melanocortin system, we will describe the role of melanocortin-3 receptor (MC3R) and melanocortin-4 receptor (MC4R) on food intake, focusing on their interaction with the brain reward system. Subsequently, we will highlight the impact of genetic mutations of MC4R on food consumption in humans. Finally, the melanocortin system, principally via MC4R, will be explored in stress response, considering stress as a key factor triggering altered feeding patterns.

## **2. An Overview of the Melanocortin Receptors in the Control of Food Intake**

Pro-opiomelanocortin (POMC) is the precursor molecule of α-melanocyte-stimulating hormone (α-MSH), one of its proteolytic cleavage products, which has a regulatory role in feeding related behavior and satiety; the other active peptides are β-MSH, γ-MSH, adrenocorticotropic hormone (ACTH) and β-endorphin [3,4,9]. Localization of POMC neurons in the central nervous system (CNS) is in the arcuate nucleus of the hypothalamus (ARC) and in the nucleus of the tractus solitarius (NTS) of the brainstem, areas implicated in body weight loss, energy homeostasis and signaling of satiety, showing anorexigenic effects [4]. Adjacent to POMC cells, in the hypothalamic ARC, are localized agouti-related protein (AgRP) neurons and the neuropeptide Y (NPY) neurons producing, respectively, the endogenous antagonist of MCRs AgRP and the orexigenic neuropeptide NPY, both able to increase food intake [3,41,42]. In the 1990s, the first MCRs were initially cloned, and, subsequently, all five MCRs, members of the superfamily of G protein-coupled receptors, have been identified [43–46]. MC3R and MC4R are widely expressed in CNS, and, binding the endogenous MCRs agonist, α-MSH, are able to activate adenylate cyclase to elevate intracellular cAMP levels, generating an anorexigenic signal [41,47], regulating the homeostasis of energy intake and feeding behavior and suppressing food consumption [4,6,16]. Conversely, MC1R, MC2R and MC5R are primarily found in the periphery: the MC1R especially in the melanocytes, the MC2R in the adrenal cortex and MC5R in the exocrine glands [4,48].

The MC3R is predominantly expressed in the brain within the hypothalamus, mainly in the ARC and less in the dorsomedial portion of the ventromedial nucleus, anteroventral preoptic area, posterior hypothalamic area, the medial preoptic area and paraventricular nucleus (PVN) of the hypothalamus, but there is evidence of MC3R moderately localized also in the limbic system, in ventral tegmental area (VTA), central linear nucleus of raphe, in the lateral nucleus of the septum and in the medial habenula nucleus of the thalamus [43,46,48,49].

In contrast with MC3R, the MC4R has a more widespread expression in the CNS; indeed, the MC4R shows high prevalence in hypothalamic sites including PVN, the medial preoptic area, anterior hypothalamic nucleus, ventromedial nucleus of the hypothalamus, dorsomedial nucleus of the hypothalamus, tuberomammillary nucleus and other several hypothalamic areas, but it is also strongly expressed in the brainstem and moderately in the cortex, hippocampus, corpus striatum, amygdala, thalamus, spinal cord and also detected in the peripheral nervous system [27,43,48,50,51].

In the brain, the distinct localization, more widely for MC4R than for MC3R, also reflects a different binding with the peptides deriving from POMC cleavage: α-MSH and γ-MSH have high affinity for MC3R; meanwhile, MC4R is preferentially bound by α-MSH and less by γ-MSH [44,46,50,51]. Moreover, AgRP, endogenous antagonist of MCRs, has high affinity for both these receptors [41,42], reflecting a differential regulation of the metabolic response and food consumption [7,42,52]. Furthermore, in the hypothalamus, the melanocortin pathway interacts with other crucial hormones, such as leptin and insulin, which promote the processing of POMC to the anorexigenic α-MSH, signaling a decreased energy intake and contributing to the fed state (for details see ref. [12,53–55]). In addition, another functional interaction of the melanocortin system in the ARC nucleus is with the orexigenic neuropeptide Nociceptin/Orphanin FQ [56,57], which exerts an inhibitory influence on α-MSH cells [58], and is strictly involved in stress mechanisms [59,60] and binge eating behavior [56,61–64].

Preliminary information about the functions and physiological role related to feeding of MC3R and MC4R was provided by studies with the deletion of these MCRs in mice, which developed obesity, increased adipose mass, hyperphagia and lack of appetite control, in particular more pronounced in MC4R knockout (KO) mice rather than MC3R KO mice, even though mice lacking both receptors become significantly heavier than MC4R KO [11,16,65–68]. Additionally, all the previous effects, characteristic of severe obesity, are predominantly linked to *MC4R* mutations and defects in MC4R signaling in humans, compared to the alterations of MC3R, which frequently cause only moderate obesity or limited hyperphagia; to date, the role of MC3R remains an element that needs to be clarified [11,13,14,69–72]. Taking into account all these findings, it is interesting to explore the studies conducted so far regarding the association of MCRs with compulsive eating, food reward and motivation, and to support the possibility of their implication in binge eating behavior.
