MC4R: Leptin, Melanin, Genes and Weight Gain

Key takeaways:
~ Leptin is a pivotal hormone in appetite regulation, and within the leptin pathway, a key regulator of our body weight is MC4R.
~ Decreased MC4R due to genetic variants is linked to increased appetite and a lifelong tendency toward a higher-than-average BMI.

Appetite, Weight Gain, MC4R gene:

MC4R, or melanocortin 4 receptor, is a receptor in the brain that is part of how appetite is regulated and energy is balanced. When activated by alpha-melanocyte-stimulating hormone (𝛼-MSH), MC4R promotes the satiety signal (feeling full) and increases your energy expenditure. Mutations in the MC4R that cause a deficiency in the receptor are linked to obesity due to hyperphagia.

MC4R is part of the leptin pathway. Activating MC4R causes a decrease in food intake along with an increase in energy expenditure, thus decreasing body weight.[ref]

Appetite regulation in the brain:

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

1. After you have eaten, your body releases the satiety hormone, leptin.
2. Later, when leptin levels drop, the hunger hormone ghrelin is released, signaling you to eat.
3. The MC4R receptor is part of the leptin signally pathway, transmitting the signal into the neuronal cells.

The, 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 satiety signal from leptin not to be heard.
• Ghrelin, the hunger hormone, can be overactive due to genetic variants.
• Within the hypothalamus, the melanocortin-4 receptors (MC4R) can be genetically impaired.

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]

Signaling pathways:

Hormones, such as leptin, signal the brain to produce α-MSH (alpha-melanocyte-stimulating hormone), which is a peptide hormone involved in appetite, skin pigmentation, and inflammation.

α-MSH hormone:

In the central nervous system, α-MSH is cleaved from proopiomelanocortin (POMC). It is then released into the hypothalamus and binds to MC4R receptor-expressing neurons, decreasing food intake and increasing energy expenditure.[ref] α-MSH is derived from the POMC hormone, which is a pituitary gland hormone that is the precursor to ACTH and other MSHs.

However, another molecule called the agouti-signaling peptide can also 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, starting at birth

MC4R deficiency is not only tied to increased appetite and higher BMI throughout life, but also to greater muscle mass. 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]

Obesity without heart problems:

While obesity is always included as a risk factor for heart disease, it turns out that people who are obese due to genetic mutations in MC4R have lower cholesterol and triglyceride levels and a lower risk of cardiovascular disease. Researchers found that after a high-fat meal, the rise in lipid levels is lower in people with MC4R mutations than normal.[ref]

Melanin:

The α-MSH hormone 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.

There are other melanocortin receptors as well: MC1R is the receptor controlling hair color, with genetic variants of MC1R producing red hair.

Lifehacks:

What can you do if you are overweight and carry the MC4R variants? This 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.
Let’s take a look at what studies show…

Get active:

In studies of MC4R genetic variants in childhood obesity, activity offsets the propensity toward 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 Exposure, MC4R and Weight:

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