Targeting therapy to molecular mechanism of disease in obesity and related metabolic disorders

Obesity and its complications such as diabetes are major and growing public health problems. We have been investigating genetic factors involved in human obesity and a condition called insulin resistance which leads to diabetes, by focusing on patients with severe forms of these diseases from an early age. We have found defects in several genes that cause these diseases. In one disease, called congenital leptin deficiency, we have been able to show the dramatically beneficial effects of leptin therapy. We now want to study the effects of different diets and drug treatments including leptin in additional patient groups. Defining treatment responses in patients with a known genetic condition that effects a key system in the body will help us to understand and treat these patients but also guide our approach to the more common forms of these important diseases.

Despite the fact that obesity and type 2 diabetes are among the most common chronic diseases, the range of therapeutic options available for the treatment of these disorders is very limited and the therapeutic responses to such interventions are highly variable. This is likely to reflect, at least in part, the underlying heterogeneity of these disorders with multiple pathophysiological routes leading to the end points of increased adipose mass or hyperglycaemia respectively. Over the past decade or more we have been attempting to unravel the aetiological complexity of these disorders. By focusing on subjects with extreme phenotypes of obesity or insulin resistance we have discovered several previously unknown monogenic/digenic disorders leading to these conditions. These include disorders of the leptin-melanocortin signalling pathways leading to obesity and defects in insulin signalling molecules and PPARgamma leading to extreme insulin resistance.

We now propose to undertake interventional studies in patients with genetically defined syndromes of severe obesity and insulin resistance. These will allow the efficacy of commonly used interventions to be tested in patients with a specific defect in a particular physiological pathway. We will perform a range of detailed metabolic measurements in well-defined subgroups of patients and controls before and in response to dietary and pharmacological manipulations. These mechanistic studies in humans will provide novel information about the requirement for the intactness of specific pathways in the mediation of a therapeutic effect. These interventions will provide novel information about the mechanism of drug action in humans and may pave the way for better targeting of therapy in commoner forms of diabetes and obesity.