IPA: Anorectic signaling by the central GDF15/GFRAL system

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Loss of appetite and the associated reduction in body weight are a major problem for old and sick people. Together they lead to a reduction in quality of life and can even cause premature death. Furthermore, treating the elderly and sick is putting an ever increasing burden on the NHS. Thus, it would be extremely useful to be able to prevent undesirable weight loss whilst protecting normal, healthy appetite.Diseased and damaged tissues release a number of chemical messengers into the bloodstream, some of which are thought to cause the feeling of sickness. One of these is a chemical called GDF15, which normally circulates at very low levels, but which is greatly increased during illnesses, including cancers and inflammatory diseases. Very recently, the site at which GDF15 works was identified - just in a very small region of the brain which has previously been associated with mediating nausea and the wish to vomit. We have identified the type of brain cell which recognises GDF15 and which mediates its effects. Thus, if we block these brain cells from sending messages in laboratory mice, we can stop GDF15 from causing eating to be reduced. Importantly, this specific brain cell type responds to GDF15, but not to other important signals which control normal appetite.In this project, we will use different types of laboratory mouse to determine where in the brain the GDF15 signal is transmitted. This will then allow us to block the signal at different sites so that, hopefully, we can reverse the appetite loss associated with a number of different illnesses, but without disrupting healthy eating. All of our experiments will be carried out in laboratory mice, but they will guide the development of drugs for use in humans. In this way, we hope to help improve outcomes for those suffering from different illnesses and, in particular, improve the quality of life for the elderly.