Obesity: genetics and beyond – supported by LIMNA

Abstract

The rising prevalence of obesity is driven by environmental factors such as changes in diet and levels of physical activity. However, within a given environment, some people develop severe obesity which is strongly influenced by inherited factors.

To try to identify the genes and therefore the mechanisms involved in regulating weight, we have studied a cohort of individuals with severe, early onset severe obesity (n=6000) called the Genetics of Obesity Study (GOOS). Candidate gene studies in this cohort have led to 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. Several genetic disorders that cause severe obesity are now treatable.

Whole exome sequencing is proving to be an increasingly important tool in understanding the genetic heterogeneity associated with obesity leading to the discovery of multiple new genes. The discovery of how genetic variation at an individual and at a population level contributes to weight gain can drive further understanding of the molecular and physiological pathways involved in weight regulation and suggest targets for drug discovery and for therapeutic intervention.