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.
This gene is way more than a ‘fatso gene’. Recently, researchers have figured out what the FTO protein does, opening up a wide field of research covering everything from metabolic health to cancer.
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?
The FTO gene was identified in 2007 in a genome-wide association study that looked at over 35,000 people to determine genes involved in obesity.[ref]
But… identifying the gene didn’t explain why it was so widely linked to higher BMI, as well as an increased risk of ADHD, depression, cancer, and dementia.
Recently, researchers discovered that FTO acts as an RNA demethylase. This means that the protein encoded by the FTO gene acts to regulate gene expression of other genes.
Quick background science:
I often explain that genes code for proteins, but that is an oversimplification that leaves out a few key pieces that you likely remember from high school biology.
Genes are segments of DNA that are transcribed into mRNA (messenger RNA). The mRNA leaves the nucleus of the cell and is then translated by ribosomes into the amino acids that make up the protein.
Not all genes in the nuclear genome get translated into proteins, and the process of managing which proteins are made is called the regulation of gene expression.
There are several ways that gene expression can be regulated in a cell:
- epigenetics is the turning on and off of genes so that they aren’t transcribed into mRNA
- post-translational regulation can prevent the transcribed mRNA from being translated into the protein.
The FTO protein acts on specific mRNAs to control whether they are converted into their proteins. Specifically, FTO works like an eraser and takes away the markers, called m6A, on mRNA that stops it from being translated. By erasing the methylation mark, the mRNA can be translated into the protein.
Keep in mind: The genetic variants in the FTO gene that are linked with obesity cause the gene to be more active or overly expressed.[ref] Thus, it is causing more of certain proteins to be created.
Let’s take a look at the research on the FTO gene – where it started and where it is today:
Overview of research on the FTO gene:
Prior to understanding the role of FTO as an RNA demethylase, a lot of research pointed towards the various pathways this gene touches upon.
- 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]
Related article: Ghrelin Genes
- A 2017 study points to FTO as 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]
- Animal 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 showed that FTO polymorphisms disrupt ARID5B, which leads to increased 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 are 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 leptin resistance.[ref]
- Children who carry the FTO variant associated with obesity are more likely to have 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]
All of these initial studies make sense when you look at how the FTO protein regulates the formation of other proteins.
More recent studies elucidate the role of FTO and show that it is not only important in weight, but it also plays a regulatory role in many types of cancer. In cancer, FTO “regulates cancer stem cell function, and promotes the growth, self-renewal and metastasis of cancer cells.”[ref] (Perhaps this is one reason why obesity is a risk factor for cancer?)
FTO impacts a lot of genes:
To recap: FTO is a modifier and regulator of proteins, many of which have to do with growth — from embryonic development to the growth of fat cells or the growth of cancer cells.
Looking at the specific proteins that are impacted by FTO shows not only why it is associated with obesity, but perhaps explains why obesity is correlated with other diseases such as cancer, NAFLD, high blood pressure, heart disease, and more.[ref]
When it comes to metabolic regulation, FTO erases marks on the mRNA of FOXO1, G6PC, and DGAT2, increasing the expression of those proteins, which are all involved in glucose metabolism.[ref]
FTO also regulates ATG5 and ATG7, proteins that are important in autophagy and adipogenesis (formation of fat cells).[ref]
The FTO protein also regulates the expression of several important genes for heart health.[ref]
Trade-offs: FTO is necessary!
Please don’t get the idea that FTO is ‘bad’. The FTO protein is essential and shouldn’t be eliminated. 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] Instead, there are pros and cons of higher or lower levels of the FTO protein, with lifestyle factors coming into play.
FTO Geotype Report
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There are actually five FTO variants that are well-researched: rs9939609, rs1421085, rs1121980, rs1121980, and rs17817449. The variants are all usually inherited together in a block of DNA in the FTO gene. In other words, if you have a variant allele for one, you almost always inherit the variant for all of them. Thus, I’ve only listed the first one below.
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][ref][ref]; even greater impact in women with PCOS (average increase of >20 lbs)[ref]; increased risk of colon cancer[ref]; plus side: lower risk of sarcopenia in the elderly[ref]
- A/T: increased risk of obesity, increased BMI, increased FTO expression
- T/T: typical
Members: Your genotype for rs9939609 is —.
How common are these FTO variants that increase weight?
Other FTO variants:
The following FTO genetic variants haven’t been studied as extensively, but they 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 —.
What is the best diet for the FTO variants?
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Debbie Moon is the founder of Genetic Lifehacks. Fascinated by the connections between genes, diet, and health, her goal is to help you understand how to apply genetics to your diet and lifestyle decisions. Debbie has a BS in engineering and also an MSc in biological sciences from Clemson University. Debbie combines an engineering mindset with a biological systems approach to help you understand how genetic differences impact your optimal health.