Growing up ‘big boned’: MC4R gene and obesity

There are several key players in our body’s regulation of hunger, satiety, and energy expenditure. Two pivotal hormones involved in appetite are leptin and ghrelin. Within that leptin pathway, another key regulator of our body weight is MC4R.

This explanation is going to get a bit complicated, so for all of you impatient people: Jump ahead to check your genes for MC4R variants. Be sure to check out the solutions in the Lifehacks section, including the link to mold.

Appetite, Weight Gain, MC4R gene:

The arcuate nucleus is a region within the hypothalamus in our brain. This cluster of nerve cells has several important functions, including controlling appetite.

After you have eaten, your body releases the satiety hormone, leptin.

Later, when leptin levels drop, the hunger hormone ghrelin is released, signaling you to eat.

Along that leptin signaling pathway is the MC4R receptor, which is part of transmitting the signal into the neuronal cells.

So the normal way things work is that you eat, you’re full for a while, and then your body signals that you should eat again.

Why, then, would anyone eat more than their body needs? Along the way, that natural cascade of reactions can go awry in several ways: leptin receptor gene variants cause the signal from leptin not to be heard; ghrelin, the hunger hormone, can be increased; or within the hypothalamus, the melanocortin-4 receptors (MC4R) can be genetically impaired. (Yes, there are many other players here as well. One interesting example is a mother’s diet can play an epigenetic role in obesity in their offspring: Agouti mouse study.)

There are hundreds of research studies on the genetic variants of MC4R, and most of the variants studied show a decrease in MC4R, resulting in increased BMI. If there aren’t enough of the receptors generated by the cell, then the ‘stop eating’ signal can be impaired. Thyroid hormone levels also play a role in the production of MC4R.[ref]

α-MSH hormone

Digging a little deeper, the melanocortin-4 receptor (MC4R gene) is a receptor that binds to a hormone called α-MSH, which is a melanocyte-stimulating hormone. α-MSH binding to the MC4R receptor gets the ‘full signal’ through. Another molecule called the agouti-signaling peptide also can bind to the MC4R receptor, blocking it from binding with α-MSH. The agouti-signaling peptide can be thought of as an ‘off switch’, with α-MSH being the ‘on switch’.

Increased appetite, increased muscle mass

MC4R deficiency is not only tied to increased appetite and higher BMI throughout life but also tied to greater muscle mass as well. In my mind, the term ‘big-boned’ leaps to mind, which is backed up by studies showing the relation to bone mass, fat mass, and the MC4R variants.[ref][ref]

Previously, I mentioned that some MC4R variants are tied to higher BMI throughout life. A study looked at infants carrying the MC4R variant and found no differences in birth weight based on the variant, but by 2 weeks of age, they could detect a difference in BMI and appetite.[ref]

An interesting aside: α-MSH does more than just bind to the MC4R receptor and moderate feeding, it also stimulates the production of pigment (melanin) in the hair and skin. Named for the agouti coloring of animal coats, the agouti-related peptide also plays a role in pigmentation. The α-MSH is derived from the POMC hormone, which is a pituitary gland hormone that is the precursor to ACTH and other MSHs. There are other melanocortin receptors as well: MC1R is the receptor controlling hair color, with genetic variants of MC1R producing red hair.

MC4R Genotype Report

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MC4R variants linked to increased weight:

Keep in mind that, as with most genetic variants, the variants listed below do not necessarily mean that a person will become obese. Everyone has lots of different genetic variants that interact differently with diet and environment. Epigenetics, the turning off and on of genes, also plays a role here.

Check your genetic data for rs17782313 (23andme v4, v5):

  • C/C: risk of increased BMI in both children and adults[ref][ref][ref]
  • C/T: risk of increased BMI in both children and adults
  • T/T: typical

Members: Your genotype for rs17782313 is .

Check your genetic data for rs17700633 (23andme v4, v5; AncestryDNA):

  • A/A: risk of increased BMI, obesity[ref][ref][ref]
  • A/G: risk of increased BMI, obesity
  • G/G: typical

Members: Your genotype for rs17700633 is .

Check your genetic data for rs12970134 (23andMe v4, v5; AncestryDNA):

  • A/A: risk of increased BMI, increased waist circumference[ref][ref][ref]
  • A/G: risk of increased BMI, increased waist circumference
  • G/G: typical

Members: Your genotype for rs12970134 is .

Check your genetic data for rs571312 (23andMe v4, v5; AncestryDNA):

  • A/A: risk of increased BMI[ref][ref][ref]
  • A/C: risk of increased BMI
  • C/C: typical

Members: Your genotype for rs571312 is .

MC4R variants that keep you lean:

Just as genetic variants can cause a deficiency in MC4R, other variants can cause a more active version of the gene that protects against obesity.

Check your genetic data for rs2229616 (23andMe v4, v5; AncestryDNA):

  • T/T: protective against obesity[ref][ref]
  • C/T: protective against obesity
  • C/C: typical

Members: Your genotype for rs2229616 is .


What do you do if you are overweight and carry the MC4R variants?
That seems to be the million-dollar question – quite literally, for the pharmaceutical company that figures out the answer. There is, of course, great interest in finding a way to increase the activation of the receptor.

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About the Author:
Debbie Moon is the founder of Genetic Lifehacks. Fascinated by the connections between genes, diet, and health, her goal is to help you understand how to apply genetics to your diet and lifestyle decisions. Debbie has a BS in engineering and also an MSc in biological sciences from Clemson University. Debbie combines an engineering mindset with a biological systems approach to help you understand how genetic differences impact your optimal health.

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