Mechanisms in Disorders of Energy Balance

We aim to understand the biological processes controlling what we eat and how we store and use energy. These pathways are disturbed in obesity and related metabolic conditions such as Type 2 diabetes. This knowledge will, ultimately, lead to development of new treatments for these disorders.

We know that an individual’s genetic make-up has a significant role in determining susceptibility to developing obesity and its deleterious consequences. Recent advances have made it substantially easier to analyse human genetic code. We aim to exploit data from human genetic studies to gain fundamental insights into what causes human obesity, and propose to combine these genetic studies with laboratory studies based around cell lines and whole animal models to better understand the pathways involved.

This programme builds on our previous work centred around a large group of patients from around the world who developed severe obesity as children and formed the basis for subsequent detailed studies on food intake and energy use. While humans will always be our experimental subject of choice, there are important mechanistic questions that require alternative approaches. We will use rodent models to explore aspects of disease processes that cannot be readily addressed in humans. Further, rodents have the advantage of being readily susceptible to genetic manipulation allowing precise alteration of specific genes and, importantly, creation of animal models of relevant, specific, human diseases.

Obesity and its metabolic consequences are major threats to public health with an unmet need for improved therapy and prevention. Understanding the mechanisms involved in the control of human energy balance is essential to develop new treatments. By focusing upon a cohort of patients with severe early onset obesity, we have previously uncovered novel, highly penetrant alleles causing childhood obesity and gone on to establish the mechanisms of molecular dysfunction in many of these conditions.
Over this quinquennium our work on the biology of energy balance and its disorders will have three broad aims:
i) To continue to explore how human genetic variation that strongly predisposes to disorders of energy balance such as obesity exerts its effects at the molecular, cellular, organismal and human level and, where possible, to translate that knowledge into improved diagnosis or treatment
ii) To further understand how disruption of particular imprinted genes can lead to obesity phenotypes. This will include further exploration of the bi-stable, potentially stochastic pattern of obesity seen with loss of Nnat and the development of a murine model of PWS that exhibits hyperphagia and obesity
iii) To explore aspects of the basic biology underlying variation in leptin production and secretion, and to establish the extent to which a potentially clinically relevant phenotype of partial leptin deficiency might exist within the broader population of people with obesity