Obesity genes: MC4R

One common polymorphic gene that is linked to obesity is the melanocortin 4 recptor – MC4R.  So far, mouse models have show that this gene is involved in “feeding behavior, the regulation of metabolism, sexual behavior, and male erectile function”. [ref]  α-MSH (alpha-melanocyte-stimulating hormone) binds to the MC4R receptor to regulate appetite and metabolism.  Agouti-related peptide is an antagonist of the MC4R receptor.

A Science Daily article from 2015 summarizes a Vanderbilt University study which gives an easy to understand explanation of how MC4R is involved in obesity:

For years, MC4R has been characterized as a classic “on-off” switch typical of GPCRs. Alpha-melanocyte stimulating hormone (alpha-MSH) and agouti-related peptide (AgRP) compete for the same binding site on the receptor. Activation of the receptor by alpha-MSH turns appetite off, whereas inhibition by AgRP stimulates appetite.

The article, which is worth reading,  goes on to say:

The current study found that AgRP not only competes with alpha-MSH for binding to the receptor, but also is a “biased agonist” that induces the MC4R to open Kir7.1. Opening the potassium channel “hyperpolarizes” and inhibits neurons involved in blocking appetite, and thus increases the sensation of hunger.

Keep in mind that, as with most genetic variants, the ones listed here do not necessarily mean that a person having the SNP will become obese.  These large population studies give trends that may or may not hold true for an individual.  Everyone has lots of different genetic variants that interact differently with diet and environment.

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.

rs17782313 (C is the minor allele) (v.4 and v. 5)

  • The minor allele, C, is found in about 30% of most populations and has been linked in many studies to higher BMI.
  • A large 2008 study of over 60,000 adults and almost 6,000 children found that the C allele is linked to fat mass, weight, and obesity risk.  [ref]
  • Another 2008 study of women only found this SNP to be associated with a higher intake of total energy, total fat, and protein.  It also found a slightly increased risk of type-2 diabetes.  [ref]
  • A small study in 2011 linked the C allele to cerebral insulin resistance. [ref]

rs10871777 (G is the minor allele)  (v.4 and v. 5)

  • Increased risk of childhood obesity in European-Americans but not African-Americans [ref]
  • Increased BMI and waist circumference in a study of over 2,000 people.  [ref]

rs17700633 ( A is the minor allele)  (v.4 and v. 5)

  • This is a very common polymorphism in Caucasian and African populations, but much less frequently found in Asian populations.
  • A study of almost 1,900 youth (average age 16.7 years) found this polymorphism to be associated with waist circumference, weight and BMI, especially in females.  [ref]
  • A Danish study found the A allele to be associated with being overweight or obese. [ref]

rs2229616 (T is the minor allele, 23andme orientation)  (v.4 and v. 5)

  • The minor allele (T) is protective against obesity
  • A 2008 study of almost 8,000 participants found this SNP  to be associated with decreased waist circumference, decreased HbA1c, and increased HDL cholesterol.[ref]

rs12970134 (A is the minor allele)  (v.4 and v. 5)

  • A 2008 study of over 14,000 people of mixed European or Indian Asian ancestry found that this SNP is associated with waist circumference and insulin resistance. [ref]
  • A 2014 study of a Chinese population found the A allele to give a slightly higher risk of diabetes before adjusting for BMI. [ref]

rs571312 (T is the minor allele, which corresponds to A for 23andme (plus) orientation)  (v.4 and v. 5)

  • A huge (almost 250,000 person) study includes this SNP near MC4R as significant for increased BMI.  [ref]
  • This SNP is significantly associated with BMI in female European smokers, but not non-smokers.  [ref]

Diet and lifestyle solutions:
So you may be wondering what to do if you are overweight and have MC4R variants.  Well, 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 by α-MSH.

So what is α-MSH?  It not only plays a role in metabolism through activation of the MC4R receptor, but it also activates MC1R  in the skin to activate the production of melanin which gives skin a tan.  α-MSH is a hormone that comes from a precursor polypeptide called proopiomelanocortin (POMC).  Another hormone made from POMC is ACTH – the adrenocorticotropic hormone.

It is interesting to note that MSH production is found to be reduced in mold illness.  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 Agouti signaling protein.  Not only is it the “off” switch for MC4R, but it also works to regulate MC1R in tanning ability and hair color. (Variants of the  MC1R gene are associated with red hair.) Agouti signaling protein is coded for by the ASIP gene.  It produces the hair coloring associated with sable and tan points in dogs, bay colored horses, and fat yellow mice.  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.

In wondering if/how researchers in the Agouti mice studies could turn obese yellow mice back to brown lean mice, I came across a study on MC4R expression and cholesterol which states in the introduction: “Moreover, trafficking of intracellular MC4R back to the cell surface rather than to lysosomes underlies the ability of mutations of attraction and Mahogunin Ring Finger-1 (Mgrn1) to rectify the obesity in mice overexpressing agouti-signaling protein, an antagonist of MC4R”.   In the discussion, it goes on to describe the role of cholesterol including: “Membrane cholesterol depletion inhibits constitutive internalization of MC4R, while leaving recycling of the receptor unchanged. This causes accumulation of MC4R at the plasma membrane and loss of MC4R localized in the endosomal compartment”  [ref]

Finally, leptin, another metabolism hormone,  also plays a role in the balance between MSH (produced by POMC)  and Agouti-signaling protein.  A study from 2014 states “Leptin promotes its effects on body weight partly by activating POMC neurons and inhibiting AgRP neurons” [ref]  There is much written about leptin and weight regulation.  A quick Google search will bring you to lots of web gurus explaining all of their methods of regulating leptin.

So you may have noticed that my “action steps” don’t include many actions.  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.

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