FTO: The ‘fatso’ gene.

The FTO gene, or ‘fatso gene’, got its nickname because of its association with obesity. It is one of the first ‘obesity genes’ discovered using large multi-ethnic population group genetic data.

This article digs into the current research on the FTO gene and then gives 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, the gene seems to be one of the best-researched genes linked to increased weight.  — and one that researchers still don’t have all the answers for.

The FTO gene was identified in 2007 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 an increased risk of ADHD, depression, and dementia.

Overview of what researchers have discovered about 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 express more FTO, possibly altering ghrelin mRNA and 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 help to turn fat cells into white fat that stores lipids instead of the brown fat 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 -carb/high-fat diet, but instead may be similar to a diet of fried foods and donuts.

Equally important, 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]


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 risk for obesity. These variants cause an average increase in BMI of around 1.8 kg/m2. [refThis 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[ref][ref] even greater impact in women with PCOS (average increase of >20 lbs) [ref]
  • A/T: increased risk of obesity, increased BMI, increased FTO expression
  • T/T: typical

Studies on this genetic variant are quite clear linking it to a higher BMI, but research shows a lot of contradictions when it comes to the best diet:

  • In one study, a low-fat, low-calorie diet worked better for those carrying the risk variant. [ref]
  • In another study, 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] high-protein diet worked best for weight loss [ref]
  • A/T: slightly increased risk of higher BMI
  • T/T: typical

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: typical

Lifehacks:

These Lifehacks are all based around losing weight with the FTO variants. Keep in mind, there is an association between the FTO variants and lean muscle mass, something you 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.

Circadian Synchronization – Meal Timing:

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. Sleep on a regular schedule (don’t stay up later every weekend), and eat on a regular schedule.

Look into time-restricted eating – and read The Circadian Code, by Dr. Satchin Panda.

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]

What about sugar?

A recent study (2019) found that sugar intake did not modify the risk of obesity with the FTO variants. Instead, the study found that trans-fat intake seemed particularly bad for weight gain with the FTO variants. [ref]

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]

Even being ‘lightly active’ is better than being sedentary for people with the FTO risk alleles. [ref] Make an effort to incorporate more activity – take the stairs, park farther from your destination, go for a walk after dinner, move more throughout the day…  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 your kids’ weight with the FTO variants worries you, 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 modifier 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]  However, other studies have shown some populations have lower weight with dairy consumption.


Related Genes and Topics:

MC4R- Growing Up Big Boned
There are several key players in our body’s regulation of hunger, satiety, and energy expenditure. Two pivotal hormones involved in our desire to eat are leptin and ghrelin. Within that leptin pathway, another key regulator of our body weight is MC4R.

Leptin Receptors
Do you wonder why other people don’t seem to struggle with wanting to eat more? Ever wished your body could just naturally know that it has had enough food — and turn off the desire to eat? You could be carrying a genetic variant in the leptin receptor gene which is linked to not feeling as full or satisfied by your meal. 



Author Information:   Debbie Moon
Debbie Moon is the founder of Genetic Lifehacks. She holds a Master of Science in Biological Sciences from Clemson University. Debbie is a science communicator who is passionate about explaining evidence-based health information. Her goal with Genetic Lifehacks is to bridge the gap between scientific research and the lay person's ability to utilize that information. To contact Debbie, visit the contact page.

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