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 here – researchers really call it that!) There is a really clear link between the FTO variants and increased BMI.

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.

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]  Some studies found that FTO deficient mice suffer from the opposite problem – reduced lean mass and fat mass,[ref] but not all studies come to agree.[ref]

More recently, 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]  Mouse models of increased FTO also show that it decreases the amplitude of the core circadian rhythm genes.[ref]

Quick recap:
FTO genetic variants increase its levels, possibly leading to more ghrelin, aka the hunger hormone.

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 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.  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 23andMe results for 23andMe results for rs9939609 (v4, v5)

  • AA: higher risk of obesity, increased BMI
  • AT: increased risk of obesity, BMI
  • TT: normal

Studies on this genetic variant show:

  • a low-fat, low-calorie diet worked better for those carrying the risk variant [ref]
  • in children, the risk variant affected childhood weight gain more for those with low vitamin D levels.  [ref] [ref]
  • The variant prevents the binding of repressor protein ARID5B, therefore leading to increased FTO activity.  ARID5B represses IRX3 and IRX5, which leads to more white fat tissue instead of heat-producing brown fat.[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]

Other FTO variants:

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

  • AA: higher BMI, but not obesity related problems[ref]
  • AT: slightly increased risk of higher BMI
  • TT: 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 23andMe data for rs3751812 (T is the minor allele )

  • TT: higher BMI, no increase in diabetes risk [ref]
  • GT: slight risk of higher BMI
  • GG: normal
  • Associated with higher BMI, lower HDL, higher LDL [ref]

 


Lifehacks:

High protein, low-fat diet: There seems to be a small link between higher protein / lower fat diets working better for weight loss with FTO genetic variants.

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]

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.

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.

More to read:

Growing up ‘big boned’: MC4R gene and obesity

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

 

Categories: Weight Loss

5 Comments

Maria · July 20, 2018 at 1:05 am

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

    Debbie Moon · July 21, 2018 at 8:07 pm

    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: http://www.geneticlifehacks.com/circadian-rhythm-connections-part-2-weight-loss-and-meal-timing/
    Thanks for reading and commenting!
    Debbie

dresha · October 10, 2018 at 8:57 am

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

    Debbie Moon · October 11, 2018 at 6:19 pm

    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

Weight Loss Genetics – Circadian Rhythm genes | Genetic Lifehacks · October 10, 2016 at 10:53 pm

[…] FTO is another gene associated with obesity.  A 2015 study found that FTO deficient mice had robust circadian locomotor activity rhythms, while “Overexpression of FTO represses the transcriptional activation by CLOCK and BMAL1.”[ref]  Other studies have shown that over-expression of FTO leads to increased body fat.  [ref] […]

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