Bursting out of our genes: FTO and obesity

 

donut-1194565_1920One-fifth of adults in the world will be clinically obese in ten years. So says a recent Lancet study, and this poses a huge problem both for global health care provision and our quality of life. Notably some of us can feast like kings and stay relatively thin; some might eat little and still struggle with their weight; others, despite being overweight, can never stick to a diet. ‘Lucky’, ‘unlucky’ and ‘weak-willed’ – or so it may seem. Yet we are gradually uncovering more genetic secrets linked to fat propensity. Do some of us have ‘fatness’ thrust upon us?

The greatest genetic culprit found so far is a gene shortened to ‘FTO’ – the aptly named fat-mass and obesity associated protein. We all have this gene. We either have one, or two copies (‘alleles’) of FTO. 

It’s a bit more complicated than that, however! The DNA that comprises the gene may have small variations: these are called Single Nucleotide Variants or SNVs, which equate to one-letter differences in the genetic code of the gene. Such variations within the sequence of ‘letters’ that make up this gene appear to affect our bodies in subtle ways. Variations in our DNA often appear together, making individual effects difficult for scientists to disentangle, but the ‘wrong’ types of variant are very strongly linked to a higher BMI, larger waist size and elevated risk of being overweight or obese.

Particular SNVs appear in several sites of the FTO gene. In general, certain variations almost always appear together with what is called ‘strong linkage disequilibrium’ – this essentially means that particular SNVs are grouped together with a far higher incidence than would be defined by chance. This makes disentangling the effects of each SNV rather difficult, as if you have one SNV, you probably have the others, though closer biochemical insights into each SNV’s function and genetic manipulation will provide more insights. I include some SNV names, however studies discussed include highly linked SNVs and are thus relevant to each other.

So how does one gene affect your weight, defined as it is by so many environmental and genetic factors? Investigation of FTO’s roles in various parts of the body is throwing up some interesting and wide-ranging answers.

One such discovery is related to our body’s development of fat: ‘brown’ fat tends to burn energy, while ‘white’ fat stores it – and so bulks up those rolls around the belly. The precursor cells to these two types of fat are the same, and a recent study has shown that FTO has an influence on which way your cells turn. It had been shown that individuals with two copies of a particular FTO allele (rs9939609) were on average 3kg heavier than those with two copies of a lower-risk allele. The people with two ‘risky’ alleles (rs9939609) were 1.7 times more likely to be obese than their counterparts.  Another common variant (rs9930506) in European populations lifts repression of a cellular weight gain program that slows down energy usage and enhances fat storage. 

By no means does this mean the writing is on the wall – many more factors are at play, and these cells won’t have excess fat to store if you’re trading burgers for salads. However, the long arm of FTO could even reach into your mind. A link has been found between the balance of key hunger hormones and an FTO variant. Ghrelin and leptin are the yin and yang of our appetites: when our stomach is empty, ghrelin is produced and we feel hungry. When the stomach is full, ghrelin production is inhibited and leptin signals take over, making us feel sated. Those carrying an obesity-associated FTO variant (rs17817449) tend to have lower levels of leptin and more ghrelin in the blood – making the person feel hungrier, markedly for those delicious (and highly calorific) foods.

It seems the cards are rather stacked against those with FTO risk variants, but there is a way to buck your destiny. Several studies separating subjects by activity levels suggest exercise reduces BMI correlation with FTO risk alleles. This paper shows weight-loss programs were equally effective in individuals with ‘high-risk’ and ‘lower-risk’ FTO profiles. So we can all benefit from exercise, no matter our genes. But what about our diets?

Interestingly, recent studies indicate we are probably eating no more than we have previously. This is even compared to WWII rationing (designed to give each person 3000 calories a day), when obesity was not a public health problem. So why is the average waistline inexorably expanding? It must be to do with intake vs expenditure: our lifestyles have become significantly more sedentary in that time, with Public Health England estimating physical activity has declined by 24% since the 1960s. Of course, the composition of our diets has changed, and time will tell whether the UK’s recently implemented ‘sugar tax’ has any bearing on the nation’s health.

There are many complex genetic factors that affect our weight and scientists are continuing to unravel these. It seems some of us may indeed be slightly more predisposed to finishing the pack of biscuits, burning less energy and putting on weight, but a cure is at hand. It’s free and has the potential to raise quality of life in the Western world significantly: more exercise!

– George Tetley.

george

George is a Biochemistry PhD student at Cambridge, focussing on disrupting a common cancer signalling pathway with a peptide drug. If not in the lab, George can otherwise found on the South coast of Cornwall sailing, whatever the weather.

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