FTO: The ‘fatso’ gene & weight loss options

Research shows that about 60% of obesity susceptibility is due to genetic differences, and the FTO gene is one of the key genes that has been consistently shown to impact weight. [ref] The FTO gene, or ‘fatso gene’, got its nickname because of its association with obesity. It was one of the first obesity genes discovered using genetic data from a large, multi-ethnic population, and the research has been replicated worldwide.

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 genetic 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.

The genetic variants in the FTO gene that are linked with obesity cause the gene to me more active or overly expressed.  The FTO gene is highly expressed in the hypothalamus, a region of the brain that controls appetite. Recent research shows that FTO is involved in regulating the amount of other proteins and signaling molecules that are involved in appetite and weight regulation. [ref]

Overview of research on 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 express more FTO, possibly altering ghrelin mRNA and causing higher ghrelin (‘hunger hormone’) levels. [ref]

A 2017 study points to FTO is 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]

FTO and Circadian rhythm:

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.

FTO and Lipids:

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.

Children who carry the FTO variant associated with obesity are more likely to have a greater energy consumption from fatty foods and also to have higher BMI. These children and adolescents also reported more ‘loss of control’ or binge eating episodes. [ref]

Trade offs:

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

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There are actually five FTO variants that are really well researched: rs9939609, rs1421085, rs1121980, rs1121980, and rs17817449.

The variants are all usually inherited together in a block of DNA in the gene, so I’ve only listed the first one below to check for on 23andMe or AncestryDNA data. (In other words, 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.[ref]  This doesn’t mean that everyone with the variant will be obese, just that when you at a group, on average, those with the FTO variants consistently 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][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

Members: Your genotype for rs9939609 is .

Other FTO variants:
These genetic variants haven’t been studied as extensively, but the may add to the impact of the above 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

Members: Your genotype for rs1558902 is .

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

Members: Your genotype for rs3751812 is .


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 likely 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.

What is the best diet for the FTO variants?

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]

 

Instead of having a clear picture of a single ‘best diet’ for the FTO variant, there are some specific foods and lifestyle factors that interact to impact weight gain.

Time restricted eating and circadian rhythm:

The fact that too much FTO decreases some of the circadian clock genes points to a strong circadian rhythm connection for the FTO gene.

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. (Read more about circadian rhythm and weight loss.)

Look into time-restricted eating, which is simply restricting the number of hours you eat during the day. As a society, we tend to eat all day long and into the night. I recommend reading the book The Circadian Code, by Dr. Satchin Panda. The author is a circadian researcher who does a great job of explaining all of the latest research on meal timing and time-restricted eating.

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 artificial sweeteners men with the FTO variants consumed, the greater the weight gain. [ref]

What about sugar? Ehh…

Sugar may not be a big factor interacting with the FTO variants.  A recent study (2019) found that sugar intake did not modify the risk of obesity with the FTO variants. (Of course, common sense dictates that if you know sweets are likely to trigger you to eat more, then you probably should cut them out if you are trying to lose weight.)

Instead of sugar, though, 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.

Get more active!

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 through out the day- take the stairs, park farther from your destination, go for a walk after dinner, move more….  Find an activity that you enjoy and do it regularly. Get an app or device that tracks physical activity and work towards increasing your overall daily movement scores.

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.

Ketogenic Diet and FTO:

A recent animal study looked at the effects of a ketogenic diet on the expression of FTO in the brain. (Recap – variants that increase FTO expression are linked with obesity).  The study was unique in that it use a true ketogenic diet instead of just a high fat diet.  The results were that the ketogenic diet increased FTO expression in the hypothalamus via the elevated beta-hydroxybuteyrate levels. The increase was transient and eventually the FTO levels decreased through a negative auto-feedback loop.[ref]  This makes sense when you think about when the body would naturally go into ketosis during times of fasting or famine. The increase in appetite then drives the body to seek food. But this up-regulation eventually returns to normal levels when the body adjusts to only burning fat (ketosis) and no longer thinks it is starving.


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 and an undergraduate degree in engineering. 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 the research hidden in scientific journals and everyone's ability to use that information. To contact Debbie, visit the contact page.