Obesity is a major public health threat. While recent changes in the patterns of obesity in the population are certainly driven by environmental changes, the heritability of obesity is extremely strong. Thus, identical twins who are brought up in different families, will usually have very similar amounts, and distribution, of body fat in adult life, bearing little resemblance to the families into which they were adopted.

Researchers at the Institute of Metabolic Science have played a world-leading role in identifying genes that can influence human body weight. By focusing on a cohort of children with extreme obesity from an early age, they have discovered a number of gene mutations that lead directly to obesity. Thus far, all of the genes discovered have had their normal function in the hypothalamus, the area of the brain concerned with control of appetite and energy expenditure. These genes have been shown to influence the drive to eat, as well as feeding behaviour. In particular, one genetic defect, though rare, is dramatically curable with a daily injection of a recombinant protein called leptin. This condition is a graphic demonstration that obesity in humans can be purely biologically driven and amenable to mechanism-based therapy. Researchers in the Department of Pharmacology study hypothalamic anatomy and function in an effort to determine how defects in neurocircuitry lead to excess food consumption beyond metabolic need. In particular, hypothalamic neurons – both in isolation and inside their native neural networks – are assessed to explore how they generate their electrical signals, how these signals are communicated to other brain areas, and how they are altered by physiological and pharmacological stimuli.

Another obesity disorder, known as melanocortin 4 receptor deficiency, is one of the most common Mendelian disorders in humans. It is present in 5- 6% of severely obese children and 0.5- 1% of obese adults. Remarkably, the functional properties of the mutant receptor in vitro can predict spontaneous food intake behaviour at a test meal in individuals carrying these genetic defects. Further research at Cambridge has also clearly implicated the neurotrophin system in the regulation of human appetite and body weight. Collaborative research with the MRC Epidemiology Unit in Cambridge and the Sanger Institute at Hinxton is currently exploring the genetic basis of more common forms of obesity in the population, using large-scale population resources and high throughput genomics combined with expertise in functional biology.

A programme of research sponsored by the Woco Foundation has brought researchers from the Institute of Metabolic Science and the Department of Psychiatry together to explore the biology underlying higher cognitive processes involved in food seeking behaviour. Using a combination of psychometric and functional imaging studies applied to individuals with known genetic lesions in the appetitive pathways, Cambridge scientists are beginning to gain novel and exciting insights into the interactions between the homeostatic and hedonic control of food intake.