Scientists explore role of fat gene

A recent study has brought us closer to understanding “why some people are more likely to become obese than others”, The Daily Telegraph and other newspapers reported today.

The Telegraph also said that this could “pave the way for developing new treatments for obesity within a few years”.

The study follows the discovery this year that a variation in the sequence of a particular gene (the FTO gene) is associated with increased weight. The Guardian said that “half of the UK population carry a variant of FTO and are, on average, 1.6kg heavier than those who do not have it; 16% of the population carry two copies of the gene and are, on average, 3kg heavier”.

The researchers of the latest study have concluded that the FTO gene may be involved in regulating genes that are involved in metabolism, or alternatively, it might be involved in DNA repair and when this function breaks down (as might be the case when there are variants in the gene) this may lead to excess weight gain.

The findings are exciting for the scientific community and provide a foundation on which more research can be done to determine how variations in the FTO gene affect weight.

However, as Prof Steve O’Rahilly, one of the researchers noted in the Telegraph, “… there is much work to do as we don't know yet whether turning up or turning down FTO would be the appropriate strategy … Even if an agent worked in model systems it would be several years before any potentially appropriate drug could be safely tested in humans."

Where did the story come from?

Scientists from the universities of Oxford, Cambridge and London conducted this research. The study was funded by the Biochemical and Biological Research Council, the Medical Research Council, Cancer Research UK, the European Community and the Wellcome Trust. One of the authors, Christopher J Schofield, is the co-founder of a company that “aims to exploit the hypoxic response for therapeutic benefit”. The study was published in the peer-reviewed scientific journal Science.

What kind of scientific study was this?

Proteins, the essential constituents of living cells, are comprised of amino acid sequences which are related to specific functions in the body. The make-up of proteins is determined by the genetic code.

In this laboratory and computer-based study, researchers explored the possible function of the FTO gene by comparing the sequence of its protein with other known protein sequences.

Once they had an idea of its possible function, they investigated further by inserting the mouse Fto gene into bacteria so that they could collect and purify the product of the gene (the Fto protein it codes for) for analysis. They analysed several of this protein’s characteristics to try and understand how it might function in the body.

They were also interested as to where in the cells the protein would be located. To examine this, they expressed the gene (inserted it into the cells so that it could be turned into a protein) along with a fluorescent protein (to see where the protein was concentrated) in cells grown in the laboratory.

They also examined where the Fto gene was expressed in mice bodies (particularly in their brains) and assessed whether the level of expression was affected by nutrition intake (by comparing the levels of expression in mice that were feeding normally, fasting for 48 hours, or fasting for 48 hours but receiving daily injections of leptin – a hormone that is normally released by the body after a meal to suppress appetite).

What were the results of the study?

Researchers found that the FTO protein contains a sequence of amino acids that is similar to that found in some well-known enzymes (biological catalysts) called the 2-oxoglutarate oxygenases. These are responsible for a variety of reactions in the body, including repairing DNA, metabolising fats, and modifying proteins.

The researchers found that the Fto protein acted as a catalyst for certain reactions which modify DNA (in these a specific chemical group, a methyl group, is removed). This type of reaction is important in regulating the activity of genes and also in DNA repair. They found that the protein concentrated in the cell nucleus – where the majority of DNA in cells is found - which is what would be expected if this protein has a role in modifying DNA.

In mice, the Fto gene was active in the brain, particularly in the hypothalamus, which is involved in regulation of food intake. The researchers found that the activity of the gene in the hypothalamus was dependent upon nutrient intake, being much lower in mice who were fasted than in those who were feeding normally.

What interpretations did the researchers draw from these results?

The researchers conclude that FTO may be involved in regulating genes that are involved in metabolism, or alternatively, it might be acting as an enzyme that repairs DNA, and when this function breaks down (as might be the case when there are variants in the gene) this may lead to excess weight gain.

They conclude in their findings that the way the Fto gene is expressed in the hypothalamus suggests that it may act similarly to other obesity-related genes, which exert their effects mainly via this region of the brain.

What does the NHS Knowledge Service make of this study?

This is a complex study conducted in the laboratory and using techniques that look at the sequence of proteins. The researchers have uncovered several roles in which the FTO protein could be involved in the body. These discoveries certainly give us more information about how the gene acts and will give scientists a foundation from which to explore what possible impact gene variants have on its functioning, and therefore how they may lead to obesity. Importantly:

• The researchers highlight the fact that we still don’t know whether alterations in FTO protein function is responsible for greater weight in people with variations of the FTO gene. It is also not known how changes to the protein’s function might lead to weight gain, whether it will affect food intake, energy expenditure, or both.
• We remind readers that obesity is a condition with many contributing factors. There is no one-to-one relationship between any one particular factor and being obese. Though this study is exciting for the scientific community and sheds light on the functioning of the FTO gene, we are still some way away from understanding why variations in that gene might affect weight. Only after that has happened, can this discovery be applied to developing interventions that may prevent or treat obesity.