Genetic basis of body weight regulation in the population: comparison with extreme phenotypes of severe obesity and persistent thinness

University of Cambridge

Lay summary

Obesity is defined as an excess of body fat that adversely affects health due to the increased risk of type 2 diabetes, cardiovascular disease and certain cancers. Body mass index (BMI; weight in kg/height in metres2) is a marker of fat mass. Using the World Health Organisation definition of obesity (BMI >30kg/m2), 15-20% of adults in European countries are obese. As a result, the rising prevalence of obesity represents a major threat to public health. Recent changes in our environment such as the wide availability of high calorie, highly palatable foods and more sedentary lifestyles have driven the rise in obesity prevalence. However, there is strong evidence from family, twin and adoption studies that within a population that shares the same environment, the variation in BMI is largely genetically determined, with heritability estimates ranging from 40-70%. Thus, genetic approaches can be applied to understand the mechanisms involved in weight regulation which will ultimately inform the development of more focussed preventative and therapeutic strategies.

The past decade has seen remarkable advances in the understanding of the fundamental biology of the control of body weight, with the identification of the hormone leptin which is made by fat cells. Candidate gene studies have shown that mutations that disrupt leptin, its receptor and downstream targets in the brain cause severe obesity that begins in childhood. Many of these genes work on the control of appetite but some work on how we burn calories. We have shown that discovery of the genetic defect can lead to effective treatment for patients in some cases.

In this project, our aim is to see if the genes we have found to be faulty in people with obesity and also with thinness can affect weight and BMI in the 0.5 million recruited to UK Biobank. By testing whether variants in the genes we are interested in are associated with weight and other closely related measurements such as blood pressure, risk of diabetes and cholesterol levels in such a large number of people, we will learn more about the role of these genes in the control of weight. If we can prove that new genes affect weight, we may be able to use this information to design new treatments to help people who struggle with their weight. The plan is for this project to last until December 2022 in keeping with our current research funding.