The Genetic Link Between Appetite and Obesity (MC4R)

The MC4R gene encodes the melanocortin 4 (MC4) receptor, which binds alpha-melanocyte-stimulating hormone or a-MSH. The primary location of this receptor is the brain, more precisely the hypothalamus, where it controls food intake, metabolism, reproductive behavior, and more [R].

MC4R in Weight Control

Source: Huvenne et al. (2016), Rare Genetic Forms of Obesity: Clinical Approach and Current Treatments in 2016

The MC4 receptor is a part of the leptin-melanocortin pathway in the hypothalamus. Leptin is a crucial hormone for appetite and weight control, released by fat tissue. When fat stores are adequate, leptin suppresses appetite by stimulating the production of a-MSH (see the image). On the other hand, low leptin reduces MC4R activity and thus promotes energy intake [R].

Even though leptin suppresses appetite and stimulates energy expenditure, excess levels are typical in obese people. Over-secretion leads to leptin resistance, a condition in which leptin loses the ability to reduce food intake via melanocortins [R].

MC4R is the most studied gene when it comes to obesity. Reduced activity of the MC4 receptor is the most common genetic cause of obesity, mediated by increased food intake [R, R].

Did you know? MC4R deficiency might have played a crucial role in our evolution. People with mutations that impaired MC4R function were prone to overeating, which likely brought them an evolutionary advantage during food shortages. However, now that food is abundant for the majority, these mutations are showing their other face and contributing to obesity [R].

Besides food intake, MC4R can also impact weight control via glucose and fat metabolism and growth stimulation [R].

The MC4R gene encodes the melanocortin 4 receptor, which regulates food intake, metabolism, and more. In conjunction with leptin, it plays a key role in appetite and weight control.

Rs17782313

Obesity

Rs17782313 is the most studied SNP near the MC4R gene when it comes to obesity. In a huge meta-analysis of 61 studies and over 300,000 subjects, the “C” allele was associated with 18% higher obesity rates. The results were consistent across different ages and ethnic groups (European/Asian) [R].

In a meta-analysis of 77,200 European adults, each “C” allele was associated with a 0.22 increase in BMI, 8% higher chances of being overweight (BMI ≥ 25), and 12% of being obese (BMI ≥ 30). The same analysis found 30% higher obesity rates among 10,500 children, suggesting they might be more sensitive to MC4R variants than adults [R].

A study of 8,400 subjects confirmed a link between this SNP and obesity in European children but not in African American children [R].

Eating Habits

Among 18,600 participants from different European countries, rs17782313-C was associated with increased hunger, snacking, and eating large amounts of food [R].

In a study of 5,724 women, this variant correlated with higher intakes of calories and dietary fat [R].

A review of clinical trials confirmed the link between rs17782313 and the above eating habits but found no influence on emotional eating [R].

The “C” allele at rs17782313 is associated with obesity, likely due to unhealthy snacking and increased intake of total calories and dietary fat.

Rs6567160

In a meta-analysis of over 100,000 people from different ethnic groups, the “C” allele at rs6567160 correlated with [R]:

• A higher percentage of body fat
• Lower HDL cholesterol
• Increased diabetes rates
• Leptin resistance 

The same variant showed a link with body mass index (BMI) in another study of 28,600 participants [R].

Rs12970134

In a meta-analysis of 34,400 people, predominantly from European countries, the “A” allele at rs12970134 was associated with higher BMI. Among 14,600 Europeans and Indian Asians, this variant showed a link with waist circumference and insulin resistance. People with the “AA” genotype had approximately 2 cm higher waist circumference [R, R].

The same SNP correlated with 21% higher odds of being overweight or obese in a trial of 2,179 Chinese children and adolescents. However, the impact was significant only in children who had <1 hour of physical activity and >2 hours of sitting daily [R].

Among 151 Chinese children and their parents, those with rs12970134-A were more easily attracted by food, and they consumed more beverages [R].

Rs2229616

One meta-analysis summarized 37 studies involving over 55,000 subjects from different ethnic groups. According to the results, the “T” allele at rs2229616 correlates with significantly lower obesity rates [R].

Rs6567160-C and rs12970134-A correlate with higher and rs2229616-T with lower obesity rates.

How It Works

As mentioned, MC4R is essential for appetite control. The above studies have confirmed increased energy intake, especially from high-calorie food and unhealthy snacks, as the primary cause of weight gain [R].

Mice without MC4R are prone to obesity and overeating. Obesity-associated MC4R mutations reduce gene expression and hinder the binding of alpha-MSH. Hence, the discussed SNPs likely reduce MC4R expression or activity, although functional tests haven’t confirmed this yet [R, R, R].

The activation of MC4 receptors triggered by high leptin levels is the primary “satiety signal” (a signal to stop eating). In mice without these receptors, leptin is unable to reduce appetite [R].

In lab animals, chronic activation of the MC4 receptors reduced abdominal fat and improved glucose metabolism, suggesting another crucial metabolic role of MC4R [R].

The discussed MC4R variants likely reduce gene expression or receptor activity, thus increasing food intake and hindering glucose and fat metabolism.

Limitations

Different SNPs near the MC4R gene have shown a robust link with obesity in diverse populations, but the evidence is less consistent in African Americans. Additionally, this genetic effect seems to peak in childhood and decline with age [R, R].

Even though MC4R has one of the strongest genetic effects on body weight measures, the discussed SNPs contribute to only ~0.14% of variations in BMI and ~0.26% of variations in fat mass [R].

SNP Summary

Primary SNP:

MC4R rs17782313

• ‘C’ = associated with obesity, snacking, and overeating
• ‘T’ = not associated with obesity or food intake

Other Important SNPs:

MC4R rs6567160

• ‘C’ = associated with obesity and higher body fat percentage 
• ‘T’ = not associated with obesity or body fat

MC4R rs12970134

• ‘A’ = associated with obesity and increased waist circumference 
• ‘G’ = not associated with obesity

MC4R rs2229616

• ‘T’ = associated with lower obesity rates
• ‘C’ = not associated with obesity

Population Frequency

The first three variants are usually inherited together in European populations, which means they act as a single genetic factor. Around 36-39% of European descendants carry one copy, and 6-7% carry both copies of the problematic alleles (C, C, and A, respectively).

When it comes to rs2229616, only around 3% of the general population carries the protective “T” allele. It’s even less common among Europeans (1.5%).