Fat Mass and Obesity-Associated Gene (FTO)

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By Sally Robertson, BSc

Obesity arises when a person has a calorie intake that is consistently more than is required for their metabolic rate and level of physical activity.

The prevalence of obesity has rapidly increased over recent decades. This has been attributed to what is referred to as an “obesogenic environment” ─ the availability of calorie-rich foods and drinks but limited opportunity to engage in physical activity.

However, even within such an environment, obesity is not always the outcome for everybody. In fact, studies have shown a genetic element to much of the weight variation that is seen between individuals.

The gene that has been the most strongly and frequently associated with susceptibility to obesity is the fat mass and obesity-associated (FTO) gene, which has most influence on body mass index (BMI) of all known genes. Initially, scientists found an association between obesity and a specific FTO variant, but the mechanism by which the gene regulates fat and weight and predisposes to obesity remained unclear.

The FTO gene comes in two forms - a high obesity-risk variant and a low-obesity risk variant. Each person inherits two copies of this gene, one from each parent. Among people who inherit two high-risk copies, the risk of obesity is thought to be increased by around 70%.

In 2013, Rachel Batterham (University College London) and colleagues conducted a study that included 359 healthy, normal-weight males who were divided into those who had two high-risk FTO genes and those who were at low risk.

The study, which was published in the Journal of Clinical Investigation, showed that people with the high obesity-risk FTO variant had increased circulating levels of the “hunger hormone” ghrelin after they had eaten. After eating, the ghrelin level did not fall as low in these high risk individuals as it did among the low-risk men. It also began to climb more quickly following meals, suggesting that the high-risk men did not suppress ghrelin as appropriately after eating.

In further tests, the researchers performed real-time magnetic resonance imaging of the brain in a different group of high-risk and low-risk men, after they had eaten. The high-risk men rated pictures of calorie-rich foods as more appealing after they had eaten more often than the low-risk men did.

The brain scans also showed differences between the groups in how the men’s brains responded to images of food. The most significant differences seen were between the brain’s reward regions and the hypothalamus, a brain region known to regulate appetite.

Batterham says the high-risk men are “biologically programmed” to eat more. “Not only do these people have higher ghrelin levels and therefore feel hungrier, their brains respond differently to ghrelin and to pictures of food.”

Understanding how FTO affects the risk of becoming overweight could help patients, says Batterham. For example, activities such as cycling are known to lower ghrelin levels and anything that suppresses the hormone is likely to be of benefit to high-risk individuals.

In another study by researchers at Oxford University, the FTO gene seemed to have a significant influence on the amount of fat cells produced in response to over-eating.

The study, which is published in Nature Communications, examined the role of FTO in adipogenesis – the production of fat cells from stem cells ─ in mice that had been genetically engineered to lack FTO or to overexpress it. The team found that cells with overexpressed FTO were more likely to become fat cells than cells without FTO. In addition, the mice with overexpressed FTO made more new fat cells than the mice without FTO.

Senior author of the paper, Dyan Sellayah, says individuals with high levels of the FTO gene may be more likely to become obese due to increased production of fat cells, which would expand storage capacity and favor the deposition of energy over energy burning.

Reviewed by Afsaneh Khetrapal BSc (Hons)