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Genetic variants influence obesity at the population level. Fat distribution is an additional determinant of individual risk: waste/hip ratio is correlated with age-related diabetes, cardiovascular disorders and some cancers. Understanding the underlying biological pathways might help us establish better therapies and better preventive actions.

Q: How much of obesity can we blame on our genes?

CL: Obesity is generally measured by looking at somebody's body weight by height in metres squared; it's a measure of general adiposity. Obesity occurs when someone is eating too much and exercising too little. There are epidemiological studies that suggest that about 70% of the variability of BMI is due to genetics. However with recent research we have found about 30 genes and gene regions that are associated to BMI but we can only explain about 10% of that variability. If you look at the individual, a person that has all risk alleles that we identified, and you compare that person to another individual of the same height who has no risk alleles, the person with the risk alleles will weigh between 8-9 kilograms more than the other one. It's still a substantial effect even if it translates to a little proportion of the heritability.

Q: Is there a difference between men and women?

CL: Yes, women are generally slightly more obese than men but if you look at men and women you will see that our body shapes and our body fat patterning are quite different. It's quite interesting: if you look at women they tend to have a more pear shaped body shape where they aggregate fat more around the buttocks and the thighs; men usually are more apple shaped where they aggregate fat more in and around the stomach. We usually measure fat distribution by looking at waist circumference (measured by a simple tape measurement) and hip circumference (measured by another simple tape measurement) and taking the ratio between the two. Epidemiological studies have shown that about half of the variants in waist to hip ratio are genetically determined and there are indications that this is higher again in women than in men. We have recently seen in our genetic studies of waist to hip ratio where we have identified 14 gene regions associated to waist/hip ratio, that half of these loci have a much stronger effect on woman than in men and that's really interesting. We don't know exactly why but it's sort of pointing towards new biology.

Q: How does the distribution of fat influence vulnerability to diabetes?

CL: Waist/hip ratio or fat distribution is correlated on a population level with adverse metabolic outcomes as we call it, and with that I mean age-related diabetes or type 2 diabetes, cardiovascular disorders and even some cancers. The underlying biological mechanisms by how this is happening is not yet totally clear. It is however interesting that the 14 gene regions that I mentioned before contain genes that have been linked with cholesterol, insulin levels, insulin resistance, all of which are correlated with type 2 diabetes and cardiovascular outcomes. There seems to be some correlation also on a genetic level but we don't know how that works yet.

Q: What are the most important lines of research that have developed over the past 5 or 10 years?

CL: From my own personal point of view during the last 5 years I think that the biggest step forward was that funding agencies allowed us to go larger and do more global scale studies, or global scale genetic studies I should say. We started to screen the entire genome by looking at about 3 million genetic variants in thousands of individuals, something we couldn't dream about doing 10 years ago, and that has been really successful. It started out here in Oxford actually where we identified the first gene that was linked to obesity: the FTO gene - our team did that. That success was rapidly followed by the identification of the second obesity gene MC4R which is also a gene affecting monogenic forms, extreme forms of early onset obesity; now to date we have more than 30 gene regions that affect overall obesity. The second thing would be that it's getting more and more recognized now that overall obesity does not give you the full picture, it's not explaining everything. Fat distribution has a distinct and independent effect on metabolic consequences of obesity. With the 14 gene regions that we've identified there, one of the most exciting things is that it builds on already existing evidence that fat distribution and fat patterning are affecting pathways that have to do with fat cell growth and also which fat depots on the body where you are accumulating fat when you gain weight and, as I talked about before, that's closely linked to cardiovascular disease and type 2 diabetes. That's really exciting and that's something that's just emerging from the last few years.

Q: Could this lead to better therapies?

CL: I think the best and maybe easiest therapy for obesity is to eat less and to exercise more. However as we can see from the general population today that's not really working so we need to come up with better management strategies to help people. I think that our data is the first stepping stone towards understanding why some people are more prone than others to gaining weight, to gain weight in unfavorable positions in the body. When we understand that hopefully that can lend itself to better therapeutics and better preventive actions.

Q: Why does your line of research matter? Why should we put money into it?

CL: Today obesity is surging in the population. I think I read numbers last week in the UK that the average BMI is 25.4 in adults, which means that the average British person is now overweight. On top of that a quarter of adults are clinically obese. With that said it means that half the population has an increased risk for all of these disorders including cardiovascular disease and cancer and so forth, so that's a big socioeconomic impact that obesity confers. Interestingly again, if you look at adult individuals, BMI is not a direct measure of our deposits it's a surrogate measure. If you add on the component of the fat distribution which is getting more and more recommended in various guidelines, and NHS are talking about that too, you will see that about 20% of adults are now in the high risk category of getting these metabolic disorders. That's something that is costing society billions of pounds and there's also a social and personal stigma attached to being obese and having an unfavorable body shape I think.

Q: How does your research fit into translational medicine within the department?

CL: My hope is that the gene regions and the different genes that we find will lend itself to the first stepping stone towards treatment, and when we can identify the underlying mechanisms and pathways that different groups within the department that work with translational aspects of medicine, and also pharmaceutical companies, can utilize that information and bring better therapies and also better prevention.

Cecilia Lindgren

Obesity

Obesity and its consequences are major and growing challenges for health care worldwide. Over 30 genes associated with body mass index have now been identified. Professor Cecilia Lindgren uses genetic and genomic approaches to better understand the underlying mechanisms and pathways involved in the regulation of overall energy balance.

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