The role of hypothalamic astrocytes in homeostatic regulation of feeding behaviour

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Disturbed regulation of food intake contributes to obesity, which is a major, and growing, public health issue in the U.K. Obesity already affects greater than 25% of the adult population and is costing the NHS an estimated £4.2billion annually. To enable scientists and pharmaceutical companies to develop the most effective therapeutic interventions for diseases like obesity, where the body's mechanisms regulating food intake are not working correctly, it is critical that we develop a thorough and detailed understanding of how food intake is regulated normally.Mechanisms based within the central nervous system (CNS) contribute pivotally to control of food intake and body weight. Although many brain areas play a role in control of feeding behaviours, a region known as the hypothalamus is vital for orchestrating the regulation of food intake, something that occurs through both nervous and hormonal signalling processes. Basic research, like that proposed here, has already identified critical circuits of nerve cells within the hypothalamus that are vital for the regulation of food intake. These include specific neurons which increase the motivation to eat when they are active and different neurons which can produce the opposite outcome, namely suppressing food intake. Although neurons are the best known cell type within the brain, they are not the most abundant. This distinction falls to non-neuronal cells known as glia. The functional involvement of glia in the regulation of food intake remains poorly understood, although these cells can unquestionably influence other bodily functions. For example, we know an important class of glial cells known as astroglia can directly regulate the activity of hypothalamic nerve circuits that control reproduction and blood pressure, demonstrating precedence for a critical contribution of astroglia to the regulation of key body processes. Recently, we discovered that genetically altering astroglial signalling in mice, increased food intake when the animals were given a palatable high-fat diet, supporting for the first time, a role these cells in a process that acutely regulates feeding. The overall purpose of this project is to follow up on this important finding, and to identify the mechanisms by which astroglia regulate food intake in response to a high-fat diet i.e. nutrient excess, and also to establish if similar mechanisms are involved in the feeding response to the opposite extreme, nutritional insufficiency e.g. fasting.Our specific aims are:1. To identify states of nutritional imbalance that cause astroglial activation in the hypothalamus.2. To establish the role of astroglia in modulating the electrical activity of hypothalamic neurons that regulate feeding.3. To determine how altering signalling in hypothalamic astroglia impacts food intake in response to in vivo nutritional imbalance.4. To understand how manipulating astroglial signalling alters overall metabolism.An improved understanding of the mechanisms by which food intake is regulated will benefit other scientists and clinicians working towards developing new therapies for disorders of food intake including obesity and anorexia.