Why are we so fat?

One of the most important public health issues of today is obesity. Why do people gain weight? Is it simply about eating too much food and taking too little exercise? Why do some people gain a lot of weight while others stay thin yet share the same environment? Dr Sadaf Farooqi, working with Professor Stephen O’Rahilly in the University Department of Clinical Biochemistry, is helping to answer some of these questions.

Obesity is defined as an excess of body fat that’s large enough to result in adverse consequences for health – the most common being high blood pressure, type 2 diabetes, coronary heart disease and certain cancers. Although calculating exactly how much body fat a person has requires sophisticated techniques, we usually use body mass index or BMI (weight in kilograms/height in metres squared) as a measure of heaviness as it correlates reasonably well with body fat content. Obesity is defined as a BMI greater than 30 kg/m2.

In the UK, current estimates of obesity indicate that 23% of men and 24% of women are obese. The World Health Organization has warned that obesity has reached epidemic proportions globally, with more than 1 billion adults overweight and is now ‘a major contributor to the global burden of chronic disease and disability.’

Why is obesity on the increase? We live in an age of increased availability of palatable, energy-dense foods and yet we have a reduced requirement for physical exertion during our working and domestic life. All this contributes to a state of positive energy balance, which over a period of time is enough to shift the mean BMI of a population. Obesity can run in families, which might point to the sharing of a common lifestyle but might also point to a genetic link. In fact, the heritability of body weight and fat mass is very high, at 40–70%, based on studies in twins and adopted children. How can we find the genes that control body weight?

Finding the ‘fat’ genes

Dr Sadaf Farooqi and her colleagues have made progress in uncovering the molecular basis of obesity by focusing on patients who have severe forms of the condition. Many of the patients they study are extremely obese from a young age, with excessive food consumption beyond what is needed for their basic energy requirements – a type of behaviour known as hyperphagia.

The story began a decade ago, with the finding of two severely obese Pakistani cousins with uncontrollable appetites. Dr Farooqi’s studies revealed that the children had undetectable levels of a protein called leptin in their serum and further analysis showed that they carried homozygous mutations in the leptin gene. The story unfolded as other families were identified with mutations either in this gene or in the receptor that binds leptin. When the patients were given daily injections of synthetic leptin in a clinical trial, dramatic beneficial effects were seen: within two weeks, the uncontrollable food-seeking behaviour had normalised, and their body weight and fat mass slowly reduced to normal levels.

To date, the team have identified seven genes that, when defective, result in severe obesity in children. All are part of the leptin–melanocortin system and all are involved in the control of appetite. One of these, the gene encoding the melanocortin receptor MC4R, is turning out to be the commonest single gene disorder causing obesity, with mutations found in 0.1% of the general population, a prevalence higher than for cystic fibrosis. Dr Farooqi and colleagues have studied 2000 severely obese individuals as part of the Genetics of Obesity Study (GOOS), discovering that as many as 5–6% of participants have pathogenic mutations in this gene.

Unfortunately no therapy yet exists for patients with MC4R deficiency, although much has been learnt about how mutations change the structure and function of the receptor and also about the range of associated clinical problems. By studying over 150 patients with MC4R deficiency, Dr Farooqi and colleagues have shown that when MC4R doesn’t work at all, this leads to a more severe form of the disease. This is even reflected in the amount of food eaten. People with a defective MC4R eat much more when given free access to food at a test meal, compared with people in whom the MC4R gene is working at 50%. This shows that MC4R acts as a brake on food intake and suggests that targeting MC4R may be useful as a treatment for obesity.

It’s all in the mind

Eating behaviour results from the innate drive to eat. Although this is genetically determined, it’s also influenced by the hedonic or rewarding properties of food – which can override the biological cues that govern hunger and fullness and result in hyperphagia. Eating behaviour is unique in that some of the key molecular determinants of the drive to eat are being identified. The genetic disorders involving the leptin–melanocortin pathway studied by Dr Farooqi affect a signalling pathway that starts with leptin released from fat calls and leads back to the hypothalamus in the brain. Studies in patients with defects in the proteins involved in this pathway should provide the opportunity to find out how the biological pathways link with the reward pathways to influence eating behaviour.

The drive to eat: what’s next?

Progress towards defining the molecular basis of obesity in some patients has helped not only to suggest treatment strategies but also to highlight that, for many people, theirs is a medical condition. The seven disorders found so far are likely to be joined by the identification of many other gene defects that lead to severe obesity. These findings provide insights into the pathways that regulate body weight, which in turn is a starting point for developing treatments that may well be applicable to more common forms of obesity.

Although several groups in the UK have recently identified the first gene, FTO, that increases the risk of common obesity in the population, uncovering the basis of common forms of obesity or more subtle genetic defects will undoubtedly prove harder, and new approaches to assessing obesity are an attractive option. One new avenue of research has been to look directly at what is happening in the brain in response to food. Considerable experience exists in Cambridge in the use of imaging techniques to study brain function and to assess human behaviour in conjunction with biological correlates. Recent advances in these technologies are helping scientists to understand the brain pathways involved in eating behaviour. Dr Farooqi is working with Dr Paul Fletcher in the Department of Psychiatry and Drs Andrew Lawrence and Andy Calder at the Medical Research Council (MRC) Cognition and Brain Sciences Unit on one such technique. They are using functional magnetic resonance imaging (fMRI) to measure patterns of brain activity when people see images of food compared with everyday items such as toys, trees and trains. It is hoped that these studies will shed light on the areas of the brain involved in food reward and explain why some people have uncontrollable urges to eat.

For more information, please contact the author Dr Sadaf Farooqi (isf20@cam.ac.uk) at the Department of Clinical Biochemistry. This research is supported by the Wellcome Trust and the MRC, and the functional imaging studies are supported by an endowment from the WOCO Foundation.