**Emanuela Micioni Di Bonaventura 1,**†**, Luca Botticelli 1,**†**, Daniele Tomassoni 2, Seyed Khosrow Tayebati 1, Maria Vittoria Micioni Di Bonaventura 1,\*,**‡ **and Carlo Cifani 1,**‡


Received: 30 September 2020; Accepted: 11 November 2020; Published: 14 November 2020

**Abstract:** The dysfunction of melanocortin signaling has been associated with obesity, given the important role in the regulation of energy homeostasis, food intake, satiety and body weight. In the hypothalamus, the melanocortin-3 receptor (MC3R) and melanocortin-4 receptor (MC4R) contribute to the stability of these processes, but MC3R and MC4R are also localized in the mesolimbic dopamine system, the region that responds to the reinforcing properties of highly palatable food (HPF) and where these two receptors seem to affect food reward and motivation. Loss of function of the MC4R, resulting from genetic mutations, leads to overeating in humans, but to date, a clear understanding of the underlying mechanisms and behaviors that promote overconsumption of caloric foods remains unknown. Moreover, the MC4R demonstrated to be a crucial modulator of the stress response, factor that is known to be strictly related to binge eating behavior. In this review, we will explore the preclinical and clinical studies, and the controversies regarding the involvement of melanocortin system in altered eating patterns, especially binge eating behavior, food reward and motivation.

**Keywords:** melanocortin system; MC3R; MC4R; eating disorders; binge eating disorder; food reward; obesity; *MC4R* mutation; rs17782313; stress
