New Link Between Genetics And Obesity Discovered, UK

Main Category: Obesity / Weight Loss / Fitness
Also Included In: Genetics
Article Date: 09 Nov 2007 - 4:00 PDT

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A group of scientists that includes Professor Chris Ponting of the MRC Functional Genetics Unit in Oxford and Prof Stephen O'Rahilly, University of Cambridge, has made a second breakthrough in twelve months in understanding how the 'obesity gene' triggers weight gain in some individuals. The team, led by Prof Chris Schofield of the University of Oxford and comprising experts from Oxford, Cambridge and Cancer Research UK in London, has been studying FTO, a gene that was linked to obesity earlier this year. Their findings, reported online t in Science Express, could have implications for the future treatment of obesity as well as adult onset diabetes.

Earlier this year, researchers discovered that variations in the FTO gene influence people's risk of becoming obese. While genetic defects causing human obesity had been previously described, the FTO discovery was of considerable interest because the genetic variant in FTO that predisposes to obesity is very common.

About half the UK population carry a copy of the variant and they are on average 1.6 kilograms heaver than those who don't have the variant, while 16 per cent of the population carry two copies of the variant and are on average three kilograms heavier. Carriers of the variant also had an increased risk of diabetes. However the function of FTO was completely unknown.

Now, scientists have found that the FTO gene codes for an enzyme that can act directly on DNA to modify it - suggesting that it might have a role in controlling the turning on and off of other genes.

They also found that FTO is highly expressed in a region of the brain called the hypothalamus, which has important roles in the control of hunger and satiety and that, in certain parts of the hypothalamus, the levels of FTO are influenced by feeding and fasting.

This work benefited from an unusual and exciting collaboration. Initially, the Oxford and Cambridge/London teams were working independently on this problem but recently pooled their complementary expertise to ensure that the findings were reliably repeatable using different approaches in different laboratories.

Prof. Ponting said: "This is an astonishing finding. We never expected this first obesity gene to have such a direct effect on DNA".

Prof. O'Rahilly, Director of the MRC Centre for Obesity and Related Metabolic Disease (MRC CORD) added: "A lot of work is still needed to figure out how its actions influence body weight. The finding that FTO may have some involvement in the control of the function of the hypothalamus suggest that, like other obesity genes previously discovered, it may play some role in influencing how well the brain senses hunger and fullness. As the activity of FTO can be altered by small molecules like metabolites, it is possible, in the future, that FTO could be manipulated therapeutically to help treat obesity."

This breakthrough will provide new leads for scientists' investigations into how chemical changes to our DNA cause an increase in fat mass and will ultimately help new drugs for obesity to be developed.

Notes:

1. Schofield et al. (2007). The Obesity-Associated FTO Gene Encodes a 2-Oxoglutarate-Dependent Nucleic Acid Demethylase, Science Express, 8 November 2007. The paper will appear in the journal Science.

2. In the UK it is estimated that 20% of men and 25% of women are obese, and that as many as 30,000 people die prematurely from obesity-related conditions every year. At the current rate of increase, three-quarters of the UK population could be overweight by 2025. Obesity-related conditions are expensive to treat and cost the NHS at least £500m a year.

3. MRC Functional Genetics Unit: The availability of genome sequence from many organisms is providing new opportunities to understand gene function and hence understand disease. The MRC Functional Genetics Unit (FGU) was set up in 1999 to exploit this genome information. Four groups of scientists work to study genes involved in neurological and neuromuscular disorders. The research ranges from the functional analysis of single genes to the development of novel therapies in the clinic for a variety of human diseases, such as muscular dystrophy, motor neuron disease, ataxia (inability to control motor coordination) and Alzheimer's disease. For more information on the FGU, go to http://www.mrcfgu.ox.ac.uk. For more information on the MRC go to http://www.mrc.ac.uk

4. The MRC Centre for Obesity and Related Metabolic Diseases (MRC CORD) aims to increase our understanding of the fundamental causes of obesity and how it is related to insulin resistance, diabetes and cardiovascular disease. It will complement other MRC research into obesity, helping to speed the translation of findings into better treatment and prevention of these diseases. The centre exploits existing links between clinical and basic research at the University of Cambridge, relevant MRC units within the Cambridge area, the Wellcome Trust Sanger Institute and Oxford University. It is located alongside the MRC Epidemiology Unit in the new Institute of Metabolic Science in Cambridge.

http://www.mrc.ac.uk