Growing up ‘big boned’: MC4R gene and obesity

There are several key players in our body’s regulation of hunger, satiety, and energy expenditure. Leptin and ghrelin are two pivotal hormones involved in our desire to eat. 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.

Appetite, Weight Gain, MC4R gene:

Within our brains is a region of the hypothalamus called the arcuate nucleus. This cluster of nerve cells has several important functions including controlling appetite.

Leptin is a hormone that is released when you have eaten; it is the satiety hormone.

After a while, when leptin levels fall, ghrelin is released to signal that you need to eat; it is the hunger hormone.

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 how much MC4R is produced. [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 it is 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]

Note that I said above 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 hair and skin. The agouti-related peptide also plays a role in pigmentation and is named for the agouti coloring of animal coats. α-MSH is derived from the POMC hormone, which is a pituitary gland hormone that is the precursor to A/C/TH and other MSH’s.  There are other melanocortin-receptors as well: MC1R is the receptor controlling hair color, with genetic variants of MC1R producing red hair.

MC4R genetic variations:

Below are some of the better studied MC4R variants along with a few of the studies about them.  There are quite a few additional studies, so please do more research if you are interested in this topic. This is a well-studied gene with solid links to increased BMI.

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: normal

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: normal

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: normal

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: normal

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: normal


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.

In studies of MC4R genetic variants in childhood obesity, it was found that activity offset the propensity towards higher BMI. In other words, more active children with the variant were less likely to be obese than sedentary children with the variant.[ref] While I can see some of you mentally saying ‘duh’, the point is that while some kids can be sedentary and thin, not everyone is made that way. So this is one more reason for encouraging (not nagging or bullying!) kids to be more active.

α-MSH binds to and activates the MC4R receptor. It makes sense that you would want plentiful α-MSH to bind to the MC4R receptors. Reduced α-MSH production is found in mold illness, and mold illness is often linked to weight gain.  The Surviving Mold website has an explanation of the proposed mechanism.  Make sure your home is not water damaged with mold growth.

The other side of the equation is the Agouti signaling protein, the “off” switch for MC4R, which isn’t good when it comes to obesity. Studies in mice show that BPA exposure increases agouti-signaling protein, changing coat color and increasing weight.[ref]  If you haven’t read about Agouti mice studies before, the article Obesity, Epigenetics, and Gene Regulation is a great introduction and explains how epigenetics altered mice offspring causing a change in hair color and obesity. The article points to BPA in plastic bottles as being a trigger to produce obese yellow mice.

One study found that those with an MC4R deficient variant had better weight loss results on a low protein instead of a high protein diet (with no difference found for carbs and fat variation). This contradicts most weight loss studies that show higher protein levels leading to satiety, but I included it here in case it works for you.

Blame your mom:
Several studies point to the influence of maternal diet in the regulation of MC4R and obesity. Maternal BPA consumption and fat consumption both downregulate MC4R. [ref]  (Blaming your mom does no good…  so if my kids are reading this, stop blaming me :-)

Keep your circadian rhythm on track:
A mouse study found that the MC4R gene is involved in the circadian system. The study concludes “Our data provide evidence that the melanocortin system, classically associated to the control of nutrient availability, is also involved in regulating the circadian control of glucose homeostasis. Specifically, these data suggest that Mc4r signaling, including that within the PVN, plays a protective role in minimizing glucose fluctuations due to circadian rhythms and environmental light cues. Likewise, we propose that circadian fluctuations contribute to the glucose intolerance of Mc4r-deficient mice “. [ref]

So how do you keep your circadian rhythm on track? Block blue light at night, stick to a routine sleep/wake pattern, and eat at the same time each day.

Time restricted eating (TRE) may be a ‘diet’ pattern that would work well here. The basis of TRE is that you eat only during certain hours of the day. So eat dinner earlier (say 6 pm) and cut out the night time snacks. Move breakfast to 7:30 am– thus, you have an 11-hour eating window. It isn’t a quick weight loss plan, but it is a consistent weight plan that is completely sustainable for the long term.

More to read:


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8 Comments on “Growing up ‘big boned’: MC4R gene and obesity

  1. Fascinating. We have an 11 year old with MC4R mutation and struggle to balance life hacks with giving her a complex. Thanks for posting!

  2. I have mutations of MC4R- I got a RNY about a year ago- and for 3 full months I knew what it was like to be a normal person- I ate- got full didn’t need to keep eating…then over a period of about two weeks it came roaring back- I got down to the weight I wanted- I take Vyvanse to try to control my eating…but dam it’s hard as hell to stay at a normal weight- I hate living with this- no one understands unless they have it – no doctor can fix it- no science can fix it yet and I’ll probably be too old when they finally develop it….Sometimes I just am so so sad that I’ve got this and everyone gets to judge you for ‘eating too much’ – just very depressing, I’ve done everything – drugs, exercise, ‘starving’ myself causing so much anxiety- no one ‘gets’ this condition-

    • I completely understand your frustration! And I’m glad you were able to find a solution, albeit a difficult one, to control your eating.
      I actually have a note for myself to update this blog post with a new study that came out on MC4R. Basically, it shows the involvement of MC4R in the circadian rhythm and clearance of glucose at night.
      One thing that is slowly working for me for weight loss and weight maintenance is ‘time restricted eating’. I only eat during the daytime – for example, eating breakfast after 7am and finishing dinner by 6pm. This change alone has let me drop 20 lbs over a year — which, I’m sure you can understand, is pretty much a miracle :-) To be fair, I carry other genetic variants linked to weight gain and the circadian system as well, so I can’t say for sure that it is due to normalizing the MC4R variant impact a bit.

  3. I amm wondering how this might relate to red hair genes or neanderthal genes. Ive been doing a lot of reading into nutrition and genetics and found that those with MC1 related to red hair had higher issues with food intolerance. and that red hair is considered a Neanderthal gene and that they were pure carnivores. many of my food intolerant patients with red genes lose body fat better on a higher protein higher fat lower carb diet, including myself.

    • Hi Georgia,
      Thanks for reading and commenting.

      You are correct that the MC1R (melanocortin 1 receptor) gene variants are what give us red hair ( I wasn’t familiar with the idea that Neanderthal genes were responsible for the MC1R red hair variant so I did a bit of quick reading on it this morning. It looks like that might have been a theory from a few years back, but more recent genome sequencing doesn’t back that idea up. Here is a cool study on it:

      So the link between food intolerances and MC1R variants is something that I can’t find any research or mechanism/pathway to support. The MC1R receptor is located in melanocytes – skin cells and hair cells. It is highly linked to increased risk of skin cancer, and it is also linked in a few studies to heart disease due to changes in the epithelial tissue of blood vessels. Perhaps the connection you’re seeing in clients has more to do with other genetic variants that are common in the same population? For example, red hair is common in people with British and Irish backgrounds — along with a high percentage carrying the genetic variants related to celiac disease.

      In regards to weight, the difference here between MC4R and MC1R is that the melanocortin 4 receptors are located in the regions of the brain that control appetite. The receptors do overlap in the pathways of the molecules that bind to them, but they do different things in the body.

  4. I tried to post a comment yesterday from my phone, but am not sure it went through, so I will try again from my PC. I am confused about one specific genetic variation – rs571312. You information above lists three different possible genotypes: T/T, G/T, or G/G. However, when I check my genotype on 23 and Me I see a result of A/C. What am I missing here? Thanks.

    • Hi Brian,
      Thanks for reading and commenting. You ask a good question :-) I forgot to switch the orientation on that one to match with 23andMe. DNA is a double-stranded molecule, and researchers can look at either strand. 23andMe always lists your genotype based on the plus strand, but for this variant, research studies always list the information for the minus strand. So to ‘translate’ between the strands: A=T and C=G.
      I usually catch that and switch the orientation on my articles, but I missed it on that variant. Thanks for letting me know. I’ll fix the article today.

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