3.2.3. The Polymorphism rs17782313 Nearby *MC4R* Gene and Eating Behavior

Recently, a genomewide association study (GWAS) identified several single nucleotide polymorphisms (SNPs) of the *MC4R* gene, associated with high BMI and the risk of the development of obesity [139]. Among them, the SNP rs17782313, mapping to a locus 188kb downstream from the coding sequence of *MC4R* gene region, has become increasingly relevant in relation to obesity and aberrant eating behaviors [140]. Additionally, this SNP rs17782313 seems to affect expression and function of the MC4R and it has been proposed, in several studies, as a factor leading to altered eating behavior patterns, increased vulnerability to higher BMI and changes in human brain regions, especially in women and children [141–144].

In the study of Qi et al., high preference and intake of nutrients rich in fat, saturated fat and partly protein, without any appetite deregulation regarding carbohydrate, were found in women carriers of this SNP compared to the non-carrier participants [142], leading to an elevated risk of severe obesity. Moreover, the following works have tried to clarify the possible implication of this *MC4R* SNP in feeding behavior: Stutzmann et al. revealed an excessive appetite in a large cohort of European populations, especially eating a large amount of food during meals with a higher frequency of snacking in children and teenagers carriers of this SNP, and a greater hunger in adults carriers of the same polymorphism [143]. Snacking is a particular dietary pattern, principally during childhood, in which energy-dense and nutrient-poor food is consumed between meals exhibiting a recurrent "snack episode", which can be translated into a bad feeding style and a risk factor for altered eating behavior and elevated BMI [145,146].

Furthermore, another study evidenced less postprandial satiation symptoms after a fully caloric satiating meal in obese individuals, carriers of rs17782313 polymorphism, promoting to eat more frequently and to increase the caloric intake in the subsequent meal, leading to higher BMI [147]. In addition, the presence of this genotypic variant demonstrated low satiety responsiveness scores, and high scores for enjoyment of food in Chilean obese children compared to the non-carrier participants [148], assessed through the Child Eating Behavior Questionnaire (CEBQ) [149] and 19-item Three-Factor Eating Questionnaire Parent (TFEQP-19) Chilean version of the TFEQ-R18 [150]. A following study, always conducted in a Chilean population, focused on obese children carriers of SNP rs17782313 revealing, in addition to lower satiety responsiveness and elevated enjoyment of food, even an overconsumption of snacks after a standard meal, using the Eating in the Absence of Hunger (EAH) Test and the CEBQ [17]. Moreover, in a three-generation Chilean family of obese women, the presence of a genetic variant of *MC4R*, generating an amino acid substitution Thr150Ile, characterized by a decreased activity of the MC4R, led to an elevated BMI and remarkable scores of cognitive restraint (CR), uncontrolled eating (UE) and emotional eating (EE), measured by TFEQ-R18 [19]. These three parameters indicate respectively: conscious lower consumption of HPF but higher intake of vegetables and proteins in order to control BMI; the tendency to eat unhealthy food more than usual in response to external stimuli with loss of control and hunger for extreme unstoppable appetite; and, finally, the inability to resist stress events, negative emotions and mood states, which often cause binge eating episodes [150–152]. These paradigms were also evaluated in Chilean adults, carriers of SNP rs17782313, presenting higher EE scores compared with non-carriers, while only women showed UE, evidencing a difference between women and men with this SNP [20].

Recent studies in obese, overweight and normal weight Chilean children extended the evidence about the SNP rs17782313, investigating how this genetic variant affects the ingestive behaviors related to reward properties of food [153]. Eating behavior scores were calculated from the EAH Test, CEBQ, TFEQ and Food Reinforcement Value Questionnaire (RVFQ), reporting differences between gender in eating patterns, but not in elevated BMI: in obese boys, carriers of the SNP, a significantly lower reinforcing value of food was observed compared to the non-carriers; meanwhile, obese girls, carriers of this polymorphism, showed lower satiety responsiveness, and UE with respect to obese girls without the SNP. These results are in accordance with the study of Vega et al., in which Chilean obese adults showed UE, suggesting the involvement of MC4R in dopamine pathways relating to food reward [153]. The hypothesis of a possible link between dopamine and melanocortin pathways has also been proposed by Yilmaz et al., underlying that this interaction could be responsible for the results of the study, in which, through the use of several questionnaires, significant EE, food craving, elevated BMI and depressive mood in European adult carriers of SNP rs17782313 were found [144]. Furthermore, the results of the case control comparisons with a group of female participants who had Anorexia or Bulimia Nervosa did not find any evidence that linked the genetic variant with these eating disorders [154].

The evidence concerning this specific polymorphism that might contribute to overweight and altered feeding patterns is not limited to the populations mentioned above, but it has been also investigated and found in subjects of different nationalities and ethnic origins [147,155–162], where the majority of these studies addressed the vulnerability of women and children to moderate and severe obesity and aberrant eating behaviors [141,157,161,163].

Horstmann et al. suggested that the genetic variation rs17782313 could affect reward mechanisms, showing that only women, homozygous carriers of the risk SNP, demonstrated EE and Disinhibition of Eating (loss of control over feeding, possibly due to external stimuli) measured by TFEQ-R18 and TFEQ-51. Moreover, through Magnetic Resonance Imaging (MRI), a sex-specific association was found between rs17782313 and an increased gray matter volume in the right amygdala, the anterior hippocampus, the medial orbitofrontal cortex and the left and the right PFC [141], crucial regions known to be involved in eating behavior [164,165].

All the studies discussed in this section (summarized in Table 2) highlighted that the partial or total loss of MC4R function, due to *MC4R* mutations, as well as the SNP rs17782313, are positively correlated with altered appetite and dysfunctional eating patterns, promoting obesity and elevated BMI.



BMI: Body Mass Index; MC4R: Melanocortin-4 receptor.
