Investigation of the role of hypothalamic Y1 receptors in obesity

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The worldwide prevalence of obesity alarming, and is a major risk factor for diseases such as type 2 diabetes. Although the benefits of weight loss in overweight subjects are undisputed, there currently exists no effective long-term treatment for obesity. Therefore pharmacological interventions for obesity could dramatically reduce the burden of this disease. There is much interest in the development of treatments for obesity that prevent the action of proteins in the brain that are thought to lead to increased food intake and gain of body fat, such as neuropeptide Y and its receptor Y1, both of which are found in the hypothalamus in regions known to regulate body fat. However, the true role of Y1 receptors in regulating body weight in the hypothalamus is currently unclear, since there are no known pharmacological tools that can specifically block or activate this receptor in order to demonstrate its function. To circumvent this problem we have developed genetically modified mice that enable us to specifically delete the Y1 receptor from the hypothalamus of adult mice, and therefore determine its role in regulating body weight. This project will demonstrate whether hypothalamic Y1 receptor deletion can reduce food intake and body fat in mice in the long-term, and whether it can cause other changes in metabolism that might also contribute to reducing body fat. We will also show whether the obesity that results from either a high-fat diet, from an excess of the stress hormone corticosterone, or from genetic mutation in mice, can be prevented or reversed by deletion of hypothalamic Y1 receptors. The results will be instrumental in deciding whether developing medicines that specifically block Y1 receptors in the hypothalamus will be of significant benefit for the long-term treatment of human obesity, which is caused by multiple genetic and environmental factors.