Grant: Project Grant

Obesity is a major health threat due to its strong association with diabetes, cardiovascular diseases and cancer. As obesity has reached pandemic proportions interventional strategies are urgently needed. Obesity is based on an excessive increase in the body's fat mass. Key to fat mass regulation is the hormone leptin, which is produced by the fat cells and in order to keep a constant body weight, circulating leptin acts on brain areas that control feeding to trigger a reduction in food intake. While the weight lowering effect of leptin has been known since its discovery some 20 years ago, we still do not know where and how leptin enters the brain to exert its weight lowering effect. However, understanding of this process is important as obesity is usually associated with leptin resistance, i.e., while circulating leptin levels increase in proportion with fat mass, leptin seemingly looses its ability to reduce appetite in obese individuals. We have recently discovered a novel structure within the nerve cells that respond to leptin. We found that this structure, a specific bulbous enlargement in the nerve cell's filaments, to be typically located close to blood vessels and it could thus serve a sensing function for circulating leptin. We wish to study this structure in much greater detail, to establish if and how it senses leptin. We want to determine if the leptin resistance associated with mouse models of obesity is due to a selective functional impairment or degeneration of the bulbous structure we discovered. Elucidating its functional role in the context of body weight control, may critically help to develop targeted therapeutic interventions aimed at 're-sensitizing' the brain to leptin, which would lead to reduced food intake and thus weight loss.