Does This Fat-Burning Gene Play a Role in Obesity? (MC3R)

The MC3R gene encodes the melanocortin 3 receptor, activated by alpha-MSH and other melanocortins. MC3R is primarily expressed in the brain and fat tissue; it controls feeding behavior, fat burning, energy balance, and more [R, R].

Unlike MC4R, which suppresses appetite, the activation of MC3R in the brain stimulates short-term feeding after energy restriction [R, R]. 

As you’re about to see, the overall effect of MC3R on food intake and weight control is much more complex and includes local metabolic effects.

MC3R in Weight Control

Clinical and animal studies have extensively researched the impact of MC3R on energy balance and obesity [R, R].

In the post about MC4R and obesity, we talked about the leptin-melanocortin pathway and its importance for appetite and weight control. MC3 receptors are also a part of that pathway and share some features with MC4R, but they also have unique metabolic effects [R].

Mice lacking MC3R are moderately obese and have much higher fat mass. Interestingly, they eat less but also move less and have impaired fat metabolism. In simple terms, the lack of MC3R stimulates fat buildup, independent of food intake [R, R, R].

These effects become even more pronounced in the presence of a high-fat diet [R].

Likewise, mutations and variants in the MC3R gene may correlate with obesity, fat mass, and different metabolic conditions in humans [R, R].

MC3R stimulates appetite, physical activity, and fat burning. Mice lacking this receptor are prone to fat buildup, especially on a high-fat diet. 

Scientists have identified two major SNPs in the MC3R gene with a potential impact on body-weight measures: rs3746619 (Thr6Lys) and rs3827103 (Val81Ile). They are almost always inherited together, and the studies often refer to them in a pair.

Children & Adolescents

One study followed 1,090 Asian children for 4 years after birth—the minor “A” alleles at this SNP pair correlated with higher weight and fat mass. The children had 58% higher odds of obesity per copy of the minor allele [R].

Two studies of 771 children (Caucasian and African American) found a link between the “AA” genotypes and higher BMI and fat mass [R, R].

The “AA” genotype at rs3827103 was associated with a higher body fat percentage among 1,151 Malaysian adolescents [R].

On the other hand, a trial including 257 Polish children and adolescents observed no significant effects of MC3R variants [R].

The minor “A” alleles at rs3746619 and rs3827103 correlate with higher weight and fat mass in children, mostly of African and Asian descent.

Adults

Among 237 African American adults, those with the pair of “AA” genotypes had higher average BMI (37.6 vs. 35.2) and fat mass (45 vs. 39.7 kg) [R].

However, other studies have mostly failed to establish a connection between these SNPs and obesity in adults [R, R, R, R].

The obesity-associated “AA” genotypes are scarce among European descendants, so the majority of trials had insufficient sample sizes to investigate these variants.

Additionally, these genotypes are associated with a higher fat mass and lower lean mass, which may balance out and result in negligible BMI changes [R].

The above variants may correlate with obesity in African Americans, but they don’t seem to impact adults from other populations.

How It Works

The “AA” genotypes at rs3746619 and rs3827103 change two amino acids in the MC3R structure. In test tubes, scientists found that this combination reduces receptor expression and activity [R, R].

Mice with these SNPs quickly accumulate fat and have reduced lean mass. They have higher leptin levels, likely due to local production by fat deposits. Research suggests impaired fat burning as the primary mechanism behind weight gain, rather than changes in appetite [R, R].

Clinical studies have confirmed the link between the “A” alleles, excess leptin, and suppressed fat oxidation [R, R, R, R].

Did you know? The reduction in MC3R activity has likely brought an evolutionary advantage to people during periods of starvation. They were able to build fat stores more efficiently, which increased their chances of survival. This phenomenon is called the thrifty gene hypothesis and may be responsible for a much higher frequency of the “A” allele in African populations [R].

MC3R variants reduce receptor expression and activity, contributing to fat buildup and excess leptin levels.

SNP Summary

Primary SNPs:

MC3R rs3827103

• ‘G’ = not associated with obesity
• ‘A’ = associated with obesity and higher fat mass, mostly in children 

MC3R rs3746619

• ‘C’ = not associated with obesity
• ‘A’ = associated with obesity and higher fat mass, mostly in children 

Population Frequency: These two SNPs are almost always inherited together, which means they act as a single genetic factor. The obesity-associated “AA” genotypes are nearly non-existent among European descendants (0.6%). They are more common in East Asian (5.6%) and much more common in African (23-26%) populations.