Tuesday February 24 2009
The action of the FTO gene differs in mice and humans
The Daily Telegraph has reported that a variation in a single gene means that “some people can eat and never put on weight while others struggle to shed an ounce”. The newspaper said that slight differences in the gene may be responsible for suppressing the metabolism, making its carriers permanently sluggish and unable to burn calories as effectively as thinner people.
The news is based on a study that has confirmed that the Fto gene plays a role in weight regulation in mice. The research shows that the gene may act by increasing the rate at which the mice burn energy, rather than by making them lose weight through being more physically active.
As the authors themselves point out, there appear to be some differences in how the FTO gene affects weight in humans, as humans who carry the high-risk variants of this gene seem to gain weight because of overeating rather than through having lower energy expenditure. This highlights the difficulties in applying findings in mice to humans. At the moment, these findings do not have direct implications for human health, but pave the way for further research. This research may eventually lead to the development of new treatments for obesity, but this is some way off.
Where did the story come from?
This research was conducted by Dr Julia Fischer from the Institute for Animal Developmental and Molecular Biology at the University of Düsseldorf and colleagues from elsewhere in Germany. The study was supported by Deutsche Forschungsgemeinschaft and NGFN-Plus organisations and published in Nature, the peer-reviewed scientific journal.
What kind of scientific study was this?
This was a genetic study conducted in mice. The researchers were aware that previous research has already shown a strong link between body mass index and common variations in the human FTO gene. People with a high-risk version of this FTO gene weigh on average three kilograms more than those with a low-risk version. The gene may affect weight either by influencing appetite and food intake or by controlling the rate of metabolism. These were the theories that the researchers investigated in this animal study.
The researchers genetically engineered mice to lack the mouse version of the FTO gene called Fto. They tested to make sure that this ‘knock out’ of the gene had worked, by looking to see whether the mice lacked the Fto protein. They also tested to make sure that no nearby genes had been affected by the removal of the Fto gene.
Over time, the scientists measured the length of and weighed the mice lacking the Fto gene, and compared them to normal mice. They also looked at how much body fat these mice had using MRI scanning. The researchers then took Fto-lacking and normal mice and fed them both on a high-fat diet for 12 weeks, and compared their weight gain. They measured levels of white and brown adipose tissue, two different kinds of body fat. White adipose tissue is used as an energy store, and brown adipose tissue is used to keep the body warm.
Researchers then looked at the food consumption of the mice and their activity levels to determine whether the Fto-lacking mice were less fat because they ate less or because they were more active.
The researchers also looked at the levels of different hormones and chemicals involved in appetite, energy expenditure and weight regulation. One such hormone is leptin, which is produced by fat tissue. They also looked at development in one part of the brain called the hypothalamus, which regulates energy intake (through the eating of food) and energy expenditure (through physical activity and maintenance of normal body function). They also looked at thyroid function, glucose metabolism and adrenaline levels.
What were the results of the study?
The researchers successfully managed to genetically engineer mice to lack the Fto gene. Mice lacking this gene displayed slowed growth after birth (though not before) and less fat tissue. By the age of six weeks, these mice weighed 30-40% less than their ‘normal’ counterparts. The Fto-lacking mice also had shorter bodies than normal mice.
Male Fto-lacking mice had 60% less body fat than normal mice, while female Fto-lacking mice had 23% less body fat. Lean mass among the Fto-lacking mice was also reduced, but to a lesser extent than body fat.
When fed a high-fat diet for 12 weeks, the Fto-lacking mice put on less weight than normal mice, and accumulated less white adipose tissue. The Fto-lacking mice also had lower levels of the hormone leptin in their blood. The researchers found that the Fto-lacking and normal mice ate similar total amounts of food, which meant that the Fto-lacking mice actually ate more than normal mice per unit of body weight.
Mice lacking the Fto gene had higher oxygen uptake and carbon dioxide production, and generated more body heat throughout the day and night than normal mice. This indicated that their energy expenditure was higher than that of normal mice. Despite this, the Fto-lacking mice were less physically active than normal mice.
There were no obvious differences between the mice in the structure of the hypothalamus in the brain. There were small changes in the levels of activity of certain genes involved in regulating energy balance in the Fto-lacking mice under certain conditions. There was also little change in how glucose was metabolised or in thyroid activity in the Fto-lacking mice.
However, the Fto-lacking mice did have higher levels of adrenaline than normal mice. This hormone affects what is called the ‘sympathetic’ nervous system, which controls the automatic functions of the body, such as the heart rate and function of other organs.
What interpretations did the researchers draw from these results?
The researchers conclude that their findings suggest that variation in the human FTO gene might affect the gene’s activity, and make people more susceptible to obesity. They point out that although humans with FTO variants appear to gain weight because of overeating, mice lacking the Fto gene do not put on weight because they are more active than normal mice.
They say that further studies will be needed to investigate exactly how the FTO gene works, and that these studies could lead to finding new targets for anti-obesity drugs.
What does the NHS Knowledge Service make of this study?
This animal study has confirmed that the Fto gene plays a role in weight regulation in mice, and given indications of how it has this effect. As the authors themselves point out, there appear to be some differences in how the Fto gene affects weight in humans and mice, through food intake or energy expenditure levels. This highlights the difficulties involved in applying findings in mice to humans.
At the minute, these findings do not have direct implications for human health, but pave the way for further research. This research may eventually lead to the development of new treatments for obesity, but this is a way off.