The Melanocortin 4 receptor (MC4R)

Unlocking the genetics of appetite, weight, and metabolism: what you need to know about MC4R SNPs. The Melanocortin 4 receptor (MC4R) is a hot topic in the world of genetics, obesity research, and personalised medicine. If you’ve ever wondered why some people seem to eat what they like and stay lean, while others struggle with weight despite their best efforts, MC4R could be part of the answer. In this blog, we’ll break down what MC4R is, why it matters, who should care, and how this knowledge can help you take charge of your health.

Five key takeaways:

• MC4R is a gene that plays a major role in appetite, metabolism, and body weight regulation.
• Variants in the MC4R gene can either increase the risk of obesity or offer protection against it.
• Some MC4R changes are rare but have a significant impact; others are common and affect the whole population.
• Knowing your MC4R status can help tailor nutrition, lifestyle, and weight management strategies.
• Personalised medicine is not science fiction – it’s here, and MC4R is a leading example.

What is the Melanocortin 4 receptor (MC4R)?

The Melanocortin 4 receptor (MC4R) is a protein encoded by the MC4R gene and found in the brain. It acts as a switchboard operator for hunger and energy use, helping to balance how much we eat and how much energy we burn. When MC4R works as it should, it helps keep our weight in check. But if there are changes (mutations or variants) in the gene, things can go off balance – leading to weight gain or, sometimes, protection against obesity [1], [2], [3].

Why does MC4R matter for health and weight?

MC4R is like a thermostat for your appetite and metabolism. When it’s set just right, you feel full at the right time and your body burns calories efficiently. But specific genetic variants can “turn down” the thermostat, making you feel hungrier or slowing your metabolism. This is why some people may have a genetic predisposition to obesity, while others might be naturally protected [4], [5].

A quick tour of MC4R genetics

What does the MC4R gene do?

MC4R encodes a G protein-coupled receptor in the brain that binds to the alpha-melanocyte-stimulating hormone (alpha-MSH). This interaction influences appetite, metabolism, sexual behaviour, and even male erectile function (in mice, at least!) [6], [7], [14], [15]. The gene acts as a central regulator—think of it as the conductor of the body’s hunger orchestra.

What are SNPs and alleles?

You might hear about “SNPs” (single-nucleotide polymorphisms) and “alleles” when talking about genetics. SNPs are tiny changes in DNA, and alleles are different versions of a gene. For MC4R, some SNPs can enhance the gene’s function, while others can reduce its function [8], [9], [3].

The famous rs2229616 (V103I) variant

One well-studied SNP in MC4R is rs2229616, also called V103I. People who carry the rarer “A” allele (which codes for isoleucine, or 103I) tend to have a lower risk of obesity, smaller waistlines, and better cholesterol profiles compared to those with the more common “G” allele [2]. In fact, carriers of the A allele are, on average, slightly leaner than those with the G/G genotype.

MC4R: The “Janus gene” of obesity

MC4R has a bit of a split personality. Some variants increase the risk of obesity (loss-of-function mutations), while others protect against it (gain-of-function mutations). That’s why scientists call it a “Janus gene”—named after the Roman god with two faces. Depending on your variant, MC4R can be your best friend or your most significant hurdle in the battle against weight gain [3].

How common are MC4R variants?

The MC4R gene helps the brain control hunger, energy use, and body weight. Changes (mutations) in this gene are the most common single-gene reason for severe obesity in children, causing around 1–6% of early-onset cases [16]. Fortunately, these  MC4R mutations are rare. More common variants, like V103I and I251L, are found in the general population and offer some protection against obesity [17].

What does the research say?

Rare and common MC4R variants

Medical sequencing studies have demonstrated that both rare and common variants in the MC4R gene can impact weight and metabolism. For example, people with rare “loss-of-function” mutations tend to be heavier, while those with “gain-of-function” variants are often leaner [2],  [5], [7], [10], [11], [14].

MC4R and metabolic syndrome

The V103I variant (rs2229616) has been associated with a lower risk of metabolic syndrome—a cluster of conditions that includes high blood pressure, high blood sugar, excess body fat around the waist, and abnormal cholesterol levels [1].

MC4R and population-level obesity risk

Large-scale genetic studies have found that common variants near MC4R are associated with higher fat mass, increased weight, and greater obesity risk across different populations—from Europe to Asia [13], [17].

Beyond body weight: MC4R and other health conditions

MC4R and type 2 diabetes

Some MC4R variants not only affect weight but also influence the risk of type 2 diabetes and insulin resistance, particularly in people with polycystic ovary syndrome (PCOS) [18], [19].

MC4R in mental health

Interestingly, MC4R variants have been linked to weight gain in patients with psychiatric disorders, especially those taking antipsychotic medications [11], [12].

MC4R and cancer cachexia

The Val103Ile polymorphism has even been studied in people with cancer cachexia—a severe form of weight loss seen in chronic illness [6].

How can knowing your MC4R status help you?

Personalised nutrition and lifestyle

If you know your MC4R variant, you can tailor your diet and exercise plan to suit your genetic profile. For example, someone with a “risk” variant may benefit from more structured meal planning and physical activity, while a “protective” variant might make it easier to maintain a healthy weight.

MC4R and weight management treatments

Some emerging treatments for obesity target the MC4R pathway. While these are mainly in the research phase, knowing your MC4R status could open doors to future therapies.

Genetic testing and MC4R

The Nutrigen genetic test, available at Courier Pharmacy, can check for MC4R variants. These tests are simple (usually a cheek swab), painless, and can provide valuable insights into your health risks and strengths.

MC4R: Who should care?

• Anyone struggling with weight that doesn’t seem to budge, despite diet and exercise.
• People with a strong family history of obesity.
• Those interested in personalised medicine and nutrition.
• Healthcare professionals seeking to understand patient variability in weight and metabolism.
• Anyone curious about how their genes influence their health.

How does MC4R testing work at Courier Pharmacy?

1. Order your test kit online – We’ll send you the Nutrigen genetic test kit, which contains a simple cheek swab kit.
2. Collect your sample – Swab the inside of your cheek (no needles!).
3. Send it back to our lab – We’ll analyse your DNA for MC4R variants and other relevant genes.
4. Get your results – We’ll send you a personalised report, along with FREE in-depth follow up consultation.

Frequently asked questions (FAQs)

What is the melanocortin 4 receptor (MC4R)?

MC4R is a gene that encodes a protein involved in regulating appetite and weight. It acts as a central switch for hunger and energy use.

How do MC4R variants affect weight?

Specific MC4R variants can make you more prone to weight gain, while others can protect against obesity.

Are MC4R mutations common?

Rare MC4R mutations are the most common single-gene cause of severe obesity, but they explain about 2% of cases. More common variants have smaller effects but are widespread.

Can MC4R testing help with weight loss?

Knowing your MC4R status can help tailor your weight loss strategy and may inform future treatment options.

Is MC4R testing available at Courier Pharmacy?

Yes! We offer genetic testing for MC4R and other important genes, which are available in the Nutrigen genetic test kit. It’s easy, painless, and can empower you to make better health decisions.

Does MC4R affect anything besides weight?

Yes, MC4R variants can also influence risk for metabolic syndrome, diabetes, and even weight changes related to some medications.

What if I have a “protective” MC4R variant?

Congratulations—your genes may make it easier to maintain a healthy weight! But lifestyle still matters, so keep up the good habits.

What if I have a “risk” MC4R variant?

Don’t panic. Knowledge is power. With the proper support and lifestyle changes, you can still reach your health goals.

Is MC4R testing right for children?

In some cases, yes—especially if there’s a strong family history of severe obesity. Always discuss with a healthcare professional.

Where can I learn more about MC4R?

Check out resources from the NHS, NICE, Medical Mojo, and our own blogs for more information.

Conclusion: Why MC4R matters for your health

The MC4R gene is a significant influencer of appetite, metabolism, and weight regulation. Whether you’re trying to lose weight, maintain it, or understand your body better, knowing your MC4R status can give you a real edge. At Courier Pharmacy, we’re here to help you harness the power of your genes—no hype, just science (and a dash of lighthearted support).

This information is for general guidance only. For personalised medical advice, please consult your doctor or healthcare provider.

References

• [1] Heid IM, Vollmert C, Kronenberg F, Huth C, Ankerst DP, Luchner A, Hinney A, Brönner G, Wichmann HE, Illig T, Döring A, Hebebrand J. Association of the MC4R V103I polymorphism with the metabolic syndrome: the KORA Study. Obesity (Silver Spring). 2008 Feb;16(2):369-76.
• [2] Geller F, Reichwald K, Dempfle A, Illig T, Vollmert C, Herpertz S, Siffert W, Platzer M, Hess C, Gudermann T, Biebermann H, Wichmann HE, Schäfer H, Hinney A, Hebebrand J. Melanocortin-4 receptor gene variant I103 is negatively associated with obesity. Am J Hum Genet. 2004 Mar;74(3):572-81.
• [3] Stutzmann F, Vatin V, Cauchi S, Morandi A, Jouret B, Landt O, Tounian P, Levy-Marchal C, Buzzetti R, Pinelli L, Balkau B, Horber F, Bougnères P, Froguel P, Meyre D. Non-synonymous polymorphisms in melanocortin-4 receptor protect against obesity: the two facets of a Janus obesity gene.
• [4] O’Rahilly, S. et al. (2007) ‘Medical sequencing at the extremes of human body mass’, Nature Genetics, 39(2), pp. 219-225. PMID: 17357083
• [5] Stutzmann, F., Vatin, V., Cauchi, S., Morandi, A., Jouret, B., Landt, O., Tounian, P., Levy-Marchal, C., Buzzetti, R., Pinelli, L., & Balkau, B. (2007). Non-synonymous polymorphisms in melanocortin-4 receptor protect against obesity: the two facets of a Janus obesity gene. Human molecular genetics, 16(15), pp.1837-1844.
• [6] Winkler, C. et al. (2008) ‘Val103Ile polymorphism of the melanocortin-4 receptor gene (MC4R) in cancer cachexia’, International Journal of Molecular Medicine, 21(3), pp. 361-365. PMID: 18377640
• [7] Loos, R.J.F. et al. (2008) ‘Common variants near MC4R are associated with fat mass, weight and risk of obesity’, Nature Genetics, 40(6), pp. 768-775. PMID: 18454148 Ta
• [8] Tan, S. et al. (2010) ‘Large effects on body mass index and insulin resistance of fat mass and obesity associated gene (FTO) variants in patients with polycystic ovary syndrome (PCOS)’, BMC Medical Genetics, 11, p. 12. PMID: 20092643
• [9] Walley, A.J. et al. (2010) ‘From monogenic to polygenic obesity: recent advances’, Genetics, 185(2), pp. 363-371. PMID: 20127379
• [10] Tunç, S., Demir, K., Tükün, F.A., Topal, C., Hazan, F., Sa?lam, B., Nalbanto?lu, Ö., Y?ld?z, M. and Özkan, B., 2017. Melanocortin-4 receptor gene mutations in a group of Turkish obese children and adolescents. Journal of Clinical Research in Pediatric Endocrinology, 9(3), p.216.
• [11] Kuo, P.H., Kao, C.F., Chen, P.Y., Chen, C.H., Tsai, Y.S., Lu, M.L. and Huang, M.C., 2011. Polymorphisms of INSIG2, MC4R, and LEP are associated with obesity-and metabolic-related traits in schizophrenic patients. Journal of Clinical Psychopharmacology, 31(6), pp.705-711.
• [12] Chowdhury, N.I., Tiwari, A.K., Souza, R.P., Zai, C.C., Shaikh, S.A., Chen, S., Liu, F., Lieberman, J.A., Meltzer, H.Y., Malhotra, A.K. and Kennedy, J.L., 2013. Genetic association study between antipsychotic-induced weight gain and the melanocortin-4 receptor gene. The pharmacogenomics journal, 13(3), pp.272-279.
• [13] Apalasamy, Y.D., Ming, M.F., Rampal, S., Bulgiba, A. and Mohamed, Z., 2013. Association of melanocortin-4 receptor gene polymorphisms with obesity-related parameters in Malaysian Malays. Annals of Human Biology, 40(1), pp.102-106.
• [14] Fan, W., Boston, B.A., Kesterson, R.A., Hruby, V.J., & Cone, R.D. (1997). Role of melanocortinergic neurons in feeding and the agouti obesity syndrome. Nature, 385(6612), pp.165-168.
• [15] Van der Ploeg, L.H., Martin, W.J., Howard, A.D., Nargund, R.P., Austin, C.P., Guan, X., Drisko, J., Cashen, D., Sebhat, I., Patchett, A.A. and Figueroa, D.J., 2002. A role for the melanocortin four receptor in sexual function. Proceedings of the National Academy of Sciences, 99(17), pp.11381-11386.
• [16] Doulla M, McIntyre AD, Hegele RA, Gallego PH. A novel MC4R mutation associated with childhood-onset obesity: A case report. Paediatr Child Health. 2014 Dec;19(10):515-8.
• [17] Wang, D., Ma, J., Zhang, S., Hinney, A., Hebebrand, J., Wang, Y. and Wang, H.J., 2010. Association of the MC4R V103I polymorphism with obesity: A Chinese case–control study and meta?analysis in 55,195 individuals. Obesity, 18(3), pp.573-579.
• [18] Batarfi AA, Filimban N, Bajouh OS, Dallol A, Chaudhary AG, Bakhashab S. MC4R variants rs12970134 and rs17782313 are associated with obese polycystic ovary syndrome patients in the Western region of Saudi Arabia. BMC Med Genet. 2019 Aug 20;20(1):144.
• [19] Wu, R., & Gragnoli, C. (2024). The melanocortin receptor genes are linked to and associated with the risk of polycystic ovary syndrome in Italian families—journal of Ovarian Research, 17(1), p.242.