Whilst the rise in the prevalence of obesity has been driven by environmental factors, there is considerable evidence that body weight and fat mass are highly heritable traits. Differences in susceptibility to obesity between individuals have strong genetic determinants.
Our strategy has been based on studies of patients with severe obesity where we hypothesised that major highly penetrant genetic variants were likely to be playing an important role.
The identification of patients with mutations in the gene encoding the hormone leptin, and their successful treatment with recombinant human leptin, have provided insights into the role of leptin responsive pathways in the regulation of eating behaviour, the onset of puberty and T-cell mediated immunity. Leptin acts by regulating a complex network of brain responses that can be studied using functional imaging, to co-ordinate changes in nutritional state with changes in food intake and the liking of food. A downstream target of leptin action, the melanocortin 4 receptor (MC4R), plays a key role in modulating sympathetic nervous system mediated changes in blood pressure.
Recently, genome wide approaches are proving to be an increasingly important tool in understanding the genetic heterogeneity associated with obesity. The discovery of how genetic variation at an individual and at a population level contributes to weight gain will drive further understanding of the molecular and physiological pathways involved in weight regulation.