Is there a gene for obesity?

It's not uncommon for people to search for external reasons as to why they have gained fat, or why they struggle to lose fat. Some of the reasons given for this include "I just have a weak spot for chocolate", or "I'm big boned". When I'm delivering the DNAFit education programme to personal trainers and nutritionists, I ask if people believe there is a gene, or genes, which cause obesity. A fair percentage of people on these courses say that there is. But is this true?

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We do know that our genes can affect how we respond to foods. Some genes make us more sensitive to certain macronutrients, and others can increase our requirements for certain micronutrients. Some genes, like the LCT gene, have an effect on how well we can produce lactase, and therefore determine how well we can handle dairy products. A group of HLA genes, which are part of the bodies auto-immune system, can impact our risk of coeliac disease, which in turn is a factor in determining whether to follow a gluten free diet.

With regards to gaining fat through foods, one of the most well studied genes is the FTO gene. By itself, this gene has been shown to have an effect on how well we tolerate fat in our diet, especially saturated fat. Two studies by Emily Sonestedt illustrate this really nicely. The first, from 2009  looked at the effects of the FTO gene in 4839 men and women born in Malmo, Sweden, from 1923 to 1950. The researchers asked the subjects questions about their dietary intake and leisure time physical activity. Finally, the subjects were weighed and had their height measured, and from there their BMI was calculated (lets not get side-tracked by arguing about BMI; suffice to say that as cheap, easy measure it is fine for the general populationfine to use in studies but probably not alright for individuals with high muscle mass. What the researchers found was interesting; FTO appeared to interact with macronutrient composition of the diet to have an effect on BMI. Those people with the AA genotype of FTO had an odd ratio (OR) of 2.47 of being obese on a high fat diet compared to the TT genotype. On a low fat diet, this OR had reduced to 1.29 compared to the TT genotype. To put this into terms of BMI, on a high fat diet, the AA genotypes mean BMI was 26.3, and the TT genotypes mean was 25.3. This was statistically significant, and translates into roughly 3.25kg for someone who is 1.8m tall.

The second study from this research group was published in 2011, and again found that fat intake interacted with FTO genotype to have an impact on body fat percentage. When shown as a graph, the results looked like so:

In this graph, we can see the trends quite nicely; again those with the TT genotype don’t see an increase in body fat with a concurrent increase in fat intake; those with the AA genotype do. In the highest quintile of fat intake, those with the AA genotype had a body fat almost one percentage point higher than those with the TT genotype. Similar results were found by another research group, headed by Corella, in 2011, but this time looking especially at saturated fat.

So, we know that the FTO gene can impact how well we tolerate fat, especially saturated fat. The FTO gene is also associated with obesity; a 2007 study led by Tim Frayling found that AA allele carriers weighed an average of 3kg more than TT genotypes, and were 1.67 times more likely to be obese. Similar results were reported in a group of Chinese teenagers.

On the surface then, it appears that there is an association between the FTO A allele and an increased risk of obesity. What we need to know is whether this is deterministic or not – i.e. if I have the FTO AA genotype, or even just the A allele, will I be obese? To answer this question, we need to understand a little bit about genetics. We all have our genes, which remain static over time, from the moment we are conceived until when we die (and, in fact, even after we die). These genes represent our potential, or what we can be. Lets hypothetically say that Usain Bolt has an identical twin – when they are born they both have exactly the same genes, which means they both have exactly the same chance of becoming the fastest man ever. However, Usain Bolt’s twin brother is tragically and rather dramatically separated from his family at birth, and adopted by another family living in rural China. Usain and his brother now have very different environments. Growing up, Usain has access to an athletics track and a coach, and is able to do meaningful training. He has some success, and is signs a big sponsorship deal aged 15, giving him the chance to afford the best support required. His brother, in contrast, is working 14 hour days in rice fields. His nearest track is 1200 miles away, and so he never gets chance to train. Even though he has the genetic capabilities to be successful, his environment is not allowing him to capitalise on these genes. Both these twin brothers’ genes are interacting with their environment to create their phenotype, or outcome. For Usain Bolt, this gene and environment interaction creates the fastest person ever to walk this planet; for his brother it doesn’t.

All this goes to show that the environment plays a massive role in determining how likely we are to be obese, and so we might start to think that the FTO gene does not cause us to be obese. Is this the case?

Well, lets take a group of elite athletes and find out. Elite athletes generally aren’t overweight, and they almost certainly aren’t obese (in terms of body fat, not BMI). If the FTO AA gene was deterministic in causing obesity, then we would expect it to be much less common in our group of elite athletes. According to a 2013 study, this isn’t the case at all. Comparing 551 athletes (57% of which had competed internationally) to 1416 controls, Eynon and his colleagues found that there was no real difference in FTO genotype frequencies between the groups; roughly 16% of control subjects had the AA risk genotype, and about 15.5% of athletes did. Elite athletes are generally very active, and so it appears that these high activity levels are potentially mitigating any risk that may be associated with the FTO AA genotype.

Examining the effects of physical activity further, Andreasen et al. (2008) looked at the FTO genotype of 17,508 Danes. They found, once again, that those with the AA genotype of FTO were more likely to be obese than those with the TT genotype, replicating earlier studies. However, they also measured the effect of physical activity on this risk. When looking at sedentary individuals, the BMI of AA genotypes compared to TT genotypes was on average 1.95kg/m2 higher – the equivalent of 6.3kg for someone 1.8m tall. However, once these individuals started to be active, this difference dropped; in moderately active individuals, AA genotypes only had a BMI of 0.69kg/m2 higher, and in highly active individuals this dropped further to 0.47 kg/m2 (equivalent to 1.5kg in a 1.8m tall person). Yes, the risk is still there, but physical activity greatly reduces that risk.

There are other environmental factors that can mitigate or increase any risk associated with the FTO gene, such as level of education. In this study the researchers found that, as expected, the A allele was associated with an increase in BMI. What they then did is find out the education level of the subjects, and split them into two groups; those that were university educated, and those that weren’t. Doing this showed that the FTO A allele carried no risk of obesity in university educated subjects; i.e. in those that went to university, there was no difference in BMI between AA genotypes and TT genotypes. This was not the case in non-university educated individuals, with AA genotypes having an average BMI 2 kg/m2 higher than TT individuals. So what does this mean in real terms? Should everyone go to university in order to reduce obesity? Well, no, not really. This is a good example of a confounding variable. Research generally indicates that those who are educated to a higher level usually have healthier lifestyles. This might be down to something they have learned during the education process. It might be that they are generally from a higher socio-economic background, which means they can afford gym memberships and higher quality food. It could be down to a whole number of different reasons. But it does show the importance of environment in creating the phenotype, or outcome, for individuals.

Another example of how environment can impact the effects of the FTO gene is this one, which examined the impact of year of birth on the FTO/BMI interaction. What they found is that in individuals born before 1942, the association of the FTO gene and BMI were greatly reduced. For example, in a group of individuals aged 45-50, for those born before 1942 the difference in BMI between AA and TT genotypes was about 0.5 kg/m2. However, in those born after 1942, the difference was almost 2kg/m2. Again, this doesn’t mean that we should travel back in time when we want to have kids; the FTO gene is still the same and humans haven’t evolved - but it does point to the possibility that after 1942 we have been living in a more obesity-promoting environment. We likely consume more calories and are less active in the post-World War II years than we were pre-War, and this in turn affects our obesity risk.

So what does all this mean then? It means that if you have a risk allele of the FTO gene (A), you are not destined to be obese. Similarly, if you have the TT genotype, and therefore carry no risk alleles, it doesn’t mean that you won’t be obese. Your environment is what causes you to become obese. You can, however, reduce your risks. As we saw earlier in this article, research indicates that carriers of the A allele of FTO are more likely to be obese with high intakes of saturated fat, and that this risk decreases with lower intakes of saturated fat. It seems very logical, therefore, for A allele carrier to potentially limit their saturated fat intake to a greater extent than TT genotypes. It may well also be a powerful tool for behavioural change. Everyone knows that they should be more active, but they don’t always think the rules apply to them. Perhaps, by showing someone that they have an increased risk of obesity due to the FTO gene, they might take more ownership over their activity or dietary habits.

We are facing an obesity crisis within the developed world, and understanding an individuals genotype, not just for the FTO gene but a whole host of other genes, might play a role in combating that. We know that diet motivation is fragile, with early failures potentially causing drop out, and so increasing early success is really important. Research seems to show that genetically matched diets improve outcomes, in terms of weight loss and adherence - showing that a one-size fits all approach to our nutrition is potentially flawed. Research is also starting to look at the effect these obesity-related genes might have on exercise. A research paper from the end of last year found that in a group of overweight women, those with a high genetic risk score for obesity didn’t respond as well to a resistance training intervention as those with a low genetic risk score. Hopefully, further research will be able to example whether aerobic exercise offsets this (the paper only looked at resistance training). The researchers also did not control for calories, so it could be that those with a higher genetic risk score were eating more food – but it’s a start towards getting some answers.

To sum up, our genes can increase or reduce our risk of developing obesity, but they don’t directly cause it. Instead, our environment plays a crucial role, particularly in the form of macronutrient composition of the diet and activity levels. With specific regards to the FTO gene, the AA genotype is associated with an increased risk of obesity, but this risk can be reduced, and possibly eliminated, through exercise and dietary choices - such as reducing fat intake.

Craig Pickering


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