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.
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]
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’.
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 birthweight 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 ACTH and other MSH’s. There are other melanocortin-receptors as well: MC1R is the receptor controlling hair color, which 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.
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 23andme results for rs17782313 (v.4 and v. 5):
23andMe results for rs17700633 (v.4 and v. 5):
Check your 23andMe results for rs12970134 (v.4 and v. 5):
Check your 23andMe results for rs571312 (v.4 and v. 5):
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 23andMe results for rs2229616 (v.4 and v. 5):
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. Here is one company that is currently in clinical trials for a prescription medication option.
Activity: 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.
Mold: 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.
BPA: The other side of the equation is 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.
Protein: 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 :-)
So you may have noticed that my “Lifehacks” are pretty slim for this gene. I’m hoping that some of this background information will help you to look into this more and come up with your own action steps, because, frankly, other than not feeding babies from BPA-containing plastic baby bottles and not living in a moldy house, I don’t really have a nutrition plan to work around the MC4R variants.
More to read: