News and EventsBrain genes associated with obesity
15th December 2008
Six new genetic variants that are associated with increased Body Mass Index (BMI, a common measure of obesity) have been identified in a genetic study of more than 90,000 people. Five of these genes are known to be active in the brain, suggesting that many genetic variants implicated in obesity might affect behaviour, rather than the chemical processes of energy or fat metabolism.
Obesity is an increasing problem. It results in individual risk to health as well as increasing burdens on health care services. By identifying genetic variants that affect obesity, researchers hope to improve their understanding of the mechanisms regulating energy balance. This will guide the development of new therapies and help to develop improved diagnosis.
"It might seem remarkable that it is the brain that is most commonly influenced by genetic variation in obesity, rather than fat tissue or digestive processes. Until 2007, no genetic associations had been found for 'common obesity', but today almost all those we have uncovered are likely to influence brain function."
Dr Inês Barroso, a senior author on the study from the Wellcome Trust Sanger Institute, Cambridge
Increase in weight occurs when the amount of calories consumed exceeds the amount of calories burned. However, behind that simple equation lie behavioural processes such as appetite and feeling full, as well as the biochemical mechanisms our bodies use to process foods and use stores of energy, such as fat tissue. A part of the brain called the hypothalamus controls many of our basic functions such as body temperature, hunger and fluid balance. It is the hypothalamus that is programmed to maintain the right balance.
"Very occasionally, mutations in genes active in the hypothalamus have dramatic consequences for weight gain such that people carrying these mutations are severely obese. Such mutations might be considered exceptional. However, we suggest that the picture for common obesity is very similar: many or most genes associated with increased BMI are active in the brain."
Dr Ruth Loos, a leading author from the Medical Research Council Epidemiology Unit, Cambridge
Studies in twins suggest that genetics can account for 40–70% of the variation in BMI. Yet only one of the genes that were previously discovered had been thought to be linked to increased BMI or obesity in humans. The six new candidate genes provide a rich pool of resources to understand some of the processes in the brain that drive increased BMI and common obesity. They also highlight the role of different types of mutation. For example, one of the variants seems to be the result of the loss of a region of DNA around 45,000 bases long. The authors suggest that this lack of genome sequence near a gene called NEGR1 might knock out genomic sequences that regulate the activity of this gene. Such a variant has not been previously detected in studies of common obesity.
"It may seem surprising that we know so little about the biology of such an important medical and social issue. We can use genetics to open the door on some of the processes that contribute to individual differences in the predisposition to obesity. We are finding that common diseases have complex causes, and it is only by understanding the biology that we can start to make rational attempts to treat and prevent conditions such as this. Studies such as this are uncovering more and more genetic changes that are involved in more and more diseases. This is a remarkable time for human genetics."
Mark McCarthy, a senior author on the paper and Robert Turner Professor of Diabetes at the University of Oxford.
The authors point out that perhaps dozens of similar variants remain to be discovered. The effects of the variants identified in the new study are modest: someone who carries all of the risk variants would typically be 1.5–2 kg heavier than an average person. The findings of this study will pave the way for future investigations to uncover more of the elusive variants.
The research also helps to set the stage to unravel the two influences of genetics and environment. Future research could harness the power of studies which track the health of many subjects through time, thereby providing the tools to map gene-environment interactions.
"As we uncover more variants, we will gain a better basic understanding of obesity, which in turn will open doors to previously unimagined areas of clinically relevant research. We hope that these advances will guide the development of more effective treatments and interventions."
Joel Hirschhorn, Associate Professor of Genetics at Children's Hospital/Harvard Medical School and at the Broad Institute
The findings described in this article are taken from the following publication:
Willer CJ, Speliotes EK, Loos RJF, Li S et al. (2008) Six new loci associated with body mass index highlight a neuronal influence on body weight regulation. Nature Genetics 2008. Published online in advance of print.
doi: http://www.nature.com/ng/journal/vaop/ncurrent/abs/ng.287.html
