Weight Loss Genetics – MC4R Revisited

I was catching up on podcasts this weekend and listened to a fascinating one by Dr. Rhonda Patrick.  She does the Found My Fitness podcast and had recently interviewed Dr. Panda.  The interview was on circadian rhythms and time restricted feeding.  In a nutshell, time restricted feeding is simply limiting your daily period of eating to a certain time window of twelve hours or less.  Listen to the interview to find out all of the science and research studies behind it.  You can watch it on YouTube or search for Found My Fitness in the Apple podcast app.

One brief part of the podcast discussed melatonin, its production in the gut, and the link between melatonin receptors and obesity.  The podcast brought to my mind the blog post that I wrote last year on the MC4R receptor and its link to obesity.  Check out that post for a list of SNPs involved.

To give an update on the MC4R variants research, I’m going to cover some of the recent studies that look at MC4R and the body’s circadian rhythm.  The main question for me is whether (or how)  variants in the MC4R gene would affect circadian rhythm and time restricted feeding.

Circadian Rhythms

Circadian rhythms control many functions in our bodies from sleep patterns and hormone production to brain waves and body temperature.  Zeitgebers is a term meaning external cues that synchronizes your circadian rhythm to the environment such as daylight which changes through the seasons.

One of the studies by Dr. Panda that was discussed in the podcast can be found in Cell Metabolism from June 2012. The study looked at the effect of time restricted feeding on mice that were fed a high-fat diet.  The study summarizes: “To test whether obesity and metabolic diseases result from HFD or disruption of metabolic cycles, we subjected mice to either ad lib or time-restricted feeding (tRF) of a HFD for 8 hr per day. Mice under tRF consume equivalent calories from HFD as those with ad lib access yet are protected against obesity, hyperinsulinemia, hepatic steatosis, and inflammation and have improved motor coordination.”   The whole study is available to read, and the introduction includes some interesting information about feeding and circadian rhythms.

Quick Overview of MC4R

The melanocortin-4 recptor (MC4R) is found mainly in the brain.  Mouse studies have shown that activating MC4R causes a decrease in food intake along with an increase in energy expenditure thus decreasing body weight.[ref]  But it is not fully understood how the MC4R variants are related to the risk for obesity in humans. Studies have looked at types of food eaten[ref], amount of food eaten, physical activity[ref], and emotional eating[ref].  It seems that there is a small link between all of these and MC4R variants.  In general, MC4R variants seem to cause a small increase in food intake and a small decrease in energy expenditure. For example, the study on physical activity found that those with a MC4R variant had a 3% decrease in physical activity compared to those without the variant.

It has also recently been discovered the MC4R cells are found in the enteroendocrine L cells in the gut[ref] as well as in cholinergic neurons [ref].  These areas outside of the brain may hold the key to the decreased energy expenditure, while the brain may hold the key to the increase in eating.


Cortisol and MC4R

Cortisol levels in the body have a natural rhythm over the day.  Levels normally peak in the morning between 6 and 9 am, and then decline throughout the day, unless activated by stress.  Here is a quick overview: The Role of Cortisol.

While most of the MC4R variants cause an increase in the risk for higher BMI, one variant, rs2229616 (minor allele is T (A) and found in less than 3% of people), leads to a lower average BMI, reduced risk of metabolic syndrome, and decreased HbA1c.   This is the opposite effect from other, more common MC4R variants.  So it is interesting to find that for this specific variant, individuals had significantly higher morning cortisol (21.4 vs 14.6 nmol/l), and higher concentrations before and after lunch compared to those without the variant.

A 2014 study using rats investigated the effect of a loss-of-function mutation for Mc4r. It found that while loss-of-function for Mc4r caused an increase in body weight, both ACTH and cortisol had a typical rhythm over the course of a day with no difference from wild-type rats.    When they stressed out the rats, those with a loss-of-function mutation for Mc4r had a blunted ACTH and corticosterone response.  I’m not sure if this is caused by the Mc4r mutation or due to the greater body weight of the mutated rats.  Studies in humans have also found that those who are overweight have a blunted cortisol stress response in emotional eating. [ref] Blunted cortisol response is also tied to type 2 diabetes, depression, and various other issues.

Glucose and MC4R

A 2015 study in the journal Endocrinology looked at the effect of Mc4r deficiency on mice circadian rhythms and light exposure.  Again, this is a mouse study, so I’m not sure all of the results would be the same for humans since our circadian rhythms are different from mice.  The study did find that there was a relationship between circadian disruptions due to varying light/dark times and the melanocortin 4 receptor.  They bred mice to be deficient in Mc4r and found that those mice had higher fluctuations of blood glucose levels over a day at baseline, but that disrupting the circadian rhythm with constant light brought those glucose peaks to being the same as wild-type mice.  But if you look at the graphs of the data that are included, it looks to me like the wild-type mice changed to be more like the Mc4r deficient mice when exposed to constant light.  I may be totally wrong on this, so please read the study for yourself.  My takeaway is that MC4R and light exposure impacts daily blood glucose level fluctuations — somehow.

A study from the journal Obesity in 2009 found that for individuals with heterozygous and homozygous MC4R variants (specifically rs17782313), weight and BMI were increased but insulin and glucose levels were not affected.  I don’t know if it is a matter of timing as to when the insulin and glucose levels were measured or not.

Food Intake:

So the MC4R receptor is turned on by alpha-MSH when leptin is high leading to feeling full or satiated.  It is turned off/blocked by Agouti protein when leptin is low leading to feeling hungry.

A 2000 study in the Journal of Neuroscience looked at the effects of MC4R agonists and antagonist on feeding in rats.  The agonist or antagonist was administered at the beginning of the dark cycle (when rats usually feed) and had the desired effect (less food eaten or more food eaten) over a four hour period. The results of the study showed that giving an agonist of MC4R suppressed food intake and it was not due to the rats feeling sick.

Many other studies show that a lack of MC4R causes “hyperphagia” or increased hunger.  One study notes that “Humans with MC4 mutations show a more or less similar phenotype as has been described for mice with mutations in the MC4 receptor gene. Those people show clear hyperphagia, hyperinsulinemia, increased fat mass, lean body mass, bone mineral density and linear growth rate, with no changes in cortisol levels, gonadotropin, thyroid and sex-steroid level “.  The study goes on to say “The exhibited hyperphagia observed upon a test meal is less severe than that observed in people with a leptin deficiency (Farooqi and O’Rahilly, 2005). The severity of MC4 receptor dysfunction seen in assays in vitro can predict the amount of food ingested at a test meal by the subject harboring that particular mutation and correlates with the onset and severity of the obese phenotype (Farooqi et al., 2003; Lubrano-Berthelier et al., 2006). At least 90 different MC4 receptor mutations have been associated with obesity.” [ref]

Another mouse study found that Mc4r null mice had higher body weight even when fed exactly the same amount as wild-type mice, so it isn’t just overeating that is contributing to weight gain with MC4R variants.  In that same study, Mc4r null mice that were allowed free feeding gained even more weight and ended up one and a half times heavier than wild-type mice.  The study did find that male Mc4r null mice traveled less distance during the dark period (active time for mice). Another interesting find was that Mc4r-null mice consumed 20% less oxygen and were resistant to leptin.

Fat content in the diet also seems to play a role.  Another mouse study found that “In response to moderately increased dietary fat content, melanocortin-4 receptor-null mutant (MC4R-/-) mice exhibit hyperphagia and accelerated weight gain compared to wild-type mice.”  The study goes on to discuss that wild-type mice on the same increased fat content also have increased thermogenesis and physical activity, which was not seen in the mice deficient in MC4R.  [ref]

Suggestions for Weight Loss:

GB HealthWatch has some information on this gene and suggests that portion control and calorie restriction are the way to go.  (To me, that was kind of a ‘duh’ and not very helpful!)  The article is well written, though, and will give you more background on the variants that are covered.

Everything with circadian rhythm seems to keep coming back to the time of light.  And it is undeniable that TVs and computer screens have changed the amount of light, specifically blue light, that most of us get both during the day and in the evening.  There are several easy ways to decrease the amount of blue light hitting your eyes in the evening.  Free apps to help control the amount of blue light on computers, tablets, and phones are available.  Flux is one that I use on my laptop.  www.justgetflux.com  It is free, easy to install, and just works.  The iPhone settings also now include a “night shift mode” so you don’t even need to install anything if you are up to date on your OS.

Time-restricted feeding is another fairly easy thing to implement.  I would love to see a study on time-restricted feeding broken out by genetic variants.

One more idea for weight loss with this variant would be to decrease fat in the diet.



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