FTO: The ‘fatso’ gene.

The FTO gene is nick-named the ‘fatso gene’ because of its association with obesity. (Please don’t think that I’m fat-shaming a gene – researchers really call it that!)

This article digs into the current research on the FTO gene and then will give you some science-based options for controlling your weight if you carry the FTO genetic variant.

What is the FTO Gene?

There is a really clear link between the FTO variants and increased BMI. In fact, it is one of the best researched genetic links to increased weight — and one that researchers still don’t have all the answers for.

The FTO gene was identified about ten years ago in a genome-wide association study which looked at over 35,000 people to determine genes involved in obesity.  But just identifying the gene didn’t explain why it was so widely linked to higher BMI as well as ADHD, depression, and dementia.

Overview of what the studies show about the FTO gene:

Early studies concluded that those with increased BMI and FTO variants also tended to have an increased energy intake with an association with elevated fat consumption.[ref]

In 2013, a study found that those with variants in the FTO gene are expressing more FTO, which was thought to alter ghrelin mRNA causing higher ghrelin (‘hunger hormone’) levels.[ref]

A 2017 study points to FTO being important to the creation of muscle fiber and the creation of new mitochondria. Decreased FTO resulted in decreased muscle mass and decreased energy production by mitochondria. [ref]

Mouse models of increased FTO also show that it decreases the amplitude of the core circadian rhythm genes.[ref] Disruptions to the core circadian genes are tied to obesity in a lot of studies.

A 2015 study published in the New England Journal of Medicine points to FTO polymorphisms disrupting ARID5B which leads to increase IRX3 and IRX5.  These two genes are involved in turning fat cells into white fat that stores lipids instead of brown fat which is involved in thermogenesis. Other research points towards FTO interacting with mTOR, AMPK, and UCP2 which acts as central metabolic energy sensors.[ref]

A mouse study showed that FTO interacts with leptin – and increases leptin resistance. The mouse study used a high-fat diet model to show the leptin resistance.[ref] This is not necessarily the same effect as a human low -arb/high-fat diet, but instead may be similar to a diet of fried foods and donuts.

Another recent study points to what happens without the FTO gene. In a mouse model, researchers have shown that deleting the FTO gene decreases weight — but it also activates the HPA axis and induces anxiety in the mice. [ref]

Quick recap:
FTO genetic variants increase its levels, possibly leading to more ghrelin, aka the hunger hormone. It also disrupts core circadian gene expression.

FTO Genetic Variants

There are actually five FTO variants that are well researched and referenced in many studies: rs9939609, rs1421085, rs1121980, rs1121980, and rs17817449.  These are all in a block of DNA that is usually inherited together, so I’ve only listed the first one below to check for on 23andMe or AncestryDNA data. (If you have a variant allele for one, you almost always inherit the variant for all of them).

The research on these FTO variants shows that those carrying the variant form are more likely to have a higher BMI and be at a risk for obesity. These variants cause an average increase in BMI of around 1.8 kg/m2. [ref]This doesn’t mean that everyone with the variant will be obese, just that when you look at large groups of people, averaging together those with the variant shows that they have higher BMI’s than those without the variant.

Check your genetic data for rs9939609 (23andMe v4, v5; AncestryDNA)

  • A/A: higher risk of obesity, increased BMI, increased FTO expression
  • A/T: increased risk of obesity, increased BMI, increased FTO expression
  • T/T: normal

Studies on this genetic variant are quite clear that it is linked to higher BMI, but they show a lot of variation when it comes to the best diet:

  • a low-fat, low-calorie diet worked better for those carrying the risk variant [ref]
  • Carriers of the risk variant had 2.5x greater risk of obesity with high carb intake compared to those with the normal FTO version[ref]
  • in one study, the risk variant is linked to higher BMI only with high saturated fat intake. [ref]
  • kids with the risk variant were more likely to have a higher BMI if they also had low vitamin D levels.  [ref] [ref]

Other FTO variants:

Check your genetic data for rs1558902 (23andMe v4, v5; AncestryDNA):

  • A/A: higher BMI, but not associated with obesity-related problems[ref]
  • A/T: slightly increased risk of higher BMI
  • T/T: normal

Carriers of the risk allele had a greater reduction in weight, body composition, and fat distribution in response to a high-protein diet, whereas an opposite genetic effect was observed on changes in fat distribution in response to a low-protein diet. [ref]

Check your genetic data for rs3751812 (23andMe v4, v5; AncestryDNA):

  • T/T: higher BMI, no increase in diabetes risk [ref] lower HDL, higher LDL [ref]
  • G/T: slight risk of higher BMI
  • G/G: normal

 


Lifehacks:

These Lifehacks are all based around losing weight with the FTO variants.  Keep in mind, though, that the FTO variants are also associated with lean muscle mass, which you probably don’t want to lose. So while the studies on rapamycin and BCAA’s interacting with FTO are interesting, they may not be your best bet if you are worried about maintaining lean muscle.

Eliminate artificial sweeteners:

For men with the obesity causing FTO variant, artificial sweetener consumption increased the weight gain. The study didn’t define which artificial sweeteners, just that the more they were consumed, the greater the weight gain.[ref]

Circadian Synchronization:

The fact that too much FTO decreases some of the circadian clock genes points to a circadian rhythm connection for FTO.  Get your circadian rhythm in sync by blocking blue light at night and getting sunlight during the day.

High protein, low-fat diet:

There seems to be a link between higher protein / lower fat diets working better for weight loss with FTO genetic variants.  Although one study did show that lower carb (along with higher protein?) may work better.

Physical Activity:

People with the highest levels of physical activity don’t seem to have an impact from the FTO gene on their BMI. [ref]  Find an activity that you enjoy and do it regularly.

Vitamin D Levels in kids:

Can increasing your vitamin D levels help with weight loss?  A higher BMI leads to a lower vitamin D status, but not vice-versa, according to one study.[ref]  But the studies on childhood obesity and FTO seem to tell a different story.  Vitamin D levels in childhood may make a difference in weight gain, and children with higher vitamin D levels along with FTO variants were less likely to have increased weight than those with lower vitamin D levels. [ref]  So if you are worried about your kids’ weight with the FTO variants, send them outside to run around and play more often.

Supplements:

Angelica Sinensis, also known as Dong Quai,  has been shown in mouse studies to ameliorate obesity in a mouse model of FTO variants. This is a traditional Chinese herbal supplement available in stores and online.

Rapamycin?

There are several studies linking FTO with mTOR (mechanistic target of rapamycin). Rapamycin decreases FTO in animal studies.[ref] So it might follow that rapamycin might help prevent weight gain for people with the FTO variant…  just a guess, though, and I don’t know of any human studies on this.

Milk Consumption:

One study points to milk, or rather the BCAA’s in milk, as a possible epigenetic modifyer that increases FTO expression.  The takeaway from this study, if it is right, is that milk consumption may be increasing FTO and driving obesity, diabetes, etc. Read the study and see what you think.  [ref]  My questioning of this comes from the studies that show that dairy consumption is tied to lower weight in some populations.

 

More to read:

Growing up ‘big boned’: MC4R gene and obesity

5 ways you can optimize your diet today, based on your genes

 



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5 Comments on “FTO: The ‘fatso’ gene.

  1. Pingback: Weight Loss Genetics – Circadian Rhythm genes | Genetic Lifehacks

  2. Hello and thank you for sharing this very informative post!

    I risk to appear stupid by asking this but, here i go..

    If disabling the genes IRX3 and IRX5 in mice switched their fat cells to burn the stored energy, is it possible to apply this on a human body? I mean, how far do you think we are from such treatment for potential clients who struggle with these genes? Would it be a prescribed medication under the form of a pill or injection?

    Apparently I am not a doctor or have studied the human body in such depth. I just got very curious reading your post and wanted to ask this.

    Thank you in advance!

    -Maria

    • Hi Maria,
      Good question. I think all the news about CRISPR and gene editing makes us think that it is right around the corner. But I don’t think that we will be able to switch off a gene like IRX3/5 any time soon. The gene editing that may be possible fairly soon seems to be in the field of blood cancers like leukemia because blood cells have a high turnover rate.
      There does seem to be research going on as far as being able to manipulate IRX3 for weight loss, but no breakthroughs so far that I know of. There would be lots of money there if the could find a way to turn IRX3 down safely.
      I need to update the FTO article… I was just reading a study the other day linking FTO genetic variants to changes in circadian rhythm gene functions. You may want to check out my article on circadian rhythm, meal timing, and weight loss: https://www.geneticlifehacks.com/circadian-rhythm-connections-part-2-weight-loss-and-meal-timing/
      Thanks for reading and commenting!
      Debbie

  3. Hello. Is there a difference between FTO AT variation and FTO TA variation? And what does minor allele mean?

    • Hi – There is no difference between AT and TA. If you are using 23andMe, they usually report it in alphabetical order (AT), but other genetic test companies may report it as “TA”.
      The minor allele is the allele that is least common in the population. For rs9939609, A is the minor allele because it has a frequency of 35%.
      Thanks for posting your questions! I’ll go back and edit the article to make it more clear.
      Debbie

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