A child’s genetic code can lock them into severe obesity from infancy, overriding any amount of diet or exercise. This programme tackles a fundamental gap in knowledge: why some people’s bodies relentlessly store fat and drive hunger, even when they want to stop. The researchers already study a global group of children who became severely obese very early in life—patients whose biology reveals that obesity is not simply a failure of willpower. By combining human genetic data with experiments in cell lines and genetically modified rodents, the team aims to map the exact biological pathways that control appetite and energy use. This is fundamental science. It will not produce a new drug or diet tomorrow. But understanding the core mechanisms that go wrong in obesity and Type 2 diabetes is the necessary first step. Similar fundamental work on appetite-regulating hormones like leptin eventually led to treatments for rare obesity syndromes. A clearer map of these pathways could, in time, guide the development of therapies that target the underlying biology rather than blaming the patient.
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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.
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