IPA: Anorectic signaling by the central GDF15/GFRAL system

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.

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, we are aiming to prevent undesirable weight loss whilst protecting normal, healthy appetite.
Diseased and damaged tissues release a number of cytokines into the bloodstream, some of which act on the brain to cause sickness behaviour. One of these is GDF15, which normally circulates at very low levels, but which is greatly increased during disease states, including cancer and inflammatory disease. Last year, the receptor for GDF15, GFRAL was identified and found to be expressed exclusively in the caudal brainstem. We have identified the neuronal type expressing GFRAL and can block GDF15-induced anorexia by blocking the relevant neurotransmitter. Importantly, GFRAL-expressing neurones do not respond to other anorectic or satiety signals.
In this project we will use different cre-expressing mice to determine the downstream pathways mediating GDF15-induced anorexia. We will investigate acute anorectic signals as well as a number of different disease states. We hope to be able to block anorexia produced in these states without affecting normal, physiological regulation of appetite.

Unintentional weight loss is encountered in 27% of people over 65-years old and is associated with poorer quality of life, increased risk of illness and mortality. By 2039, people aged 65 or over are going to represent 23% of the UK population. Although weight loss is common in the aged, it is a critical problem for people with long-term illness, and it is often the first sign of disease. Approximately 40% of people report unexplained weight loss when they are first diagnosed with cancer. Up to 80% of people with advanced cancer experience loss of appetite which can exacerbate cachexia and fatigue. Another common cause of weight loss is not the disease, but the treatment. Radiation and chemotherapy often cause a decrease in appetite, nausea and vomiting. Treatments to increase appetite are ineffective and, therefore, patients may require costly nutritional interventions. This project will provide knowledge to both academics and clinicians at international conferences and by publication in high-impact journals. Following publication, the new mouse model generated will be made freely available.
Appetite loss and wasting related to ageing and increased disease burden create major financial costs. The chances to improve quality of life, decrease complications and make savings for the NHS are enormous. However, there are also specific opportunities for commercialisation. In 2016, the global cancer cachexia market alone (pharmaceuticals, nutrition, etc.) was US$1.63 billion, and is set to grow to US$2.51 billion by 2025. By comparison, a conservative commercial estimate of the annual market opportunity for anti-obesity drugs is over US$100 bn. The PI has been involved previously in successful collaborative projects with a number of industrial partners, providing evidence for several novel targets for drug development that has underpinned commercial programs.
During the lifetime of the grant, the basic research will be discussed at meetings organised by the Child Health Research Network, the Diabetes and Obesity Research Network and the Association for the Study of Obesity. These annual meetings are forums for basic researchers, psychologists, clinicians, community nurses and other health professionals, patient group representatives and policy makers. Outreach work will be encouraged at all levels within the laboratory. Over the three years, the applicants will lecture at two local schools and at a local Café Scientifique-type meeting. The PDRA will be strongly encouraged to follow the example set by previous lab members, to tutor for the Manchester Access and STEM programmes (aimed at helping under-privileged children into further education), and to complete both a Wellcome Trust Researchers in Residence Scheme and a UK GRADschool.
This project will provide strong training in both in vivo skills and specialist techniques in transgenics, chemogenetics and optogenetics, metabolic and behavioural research. The applicants has supervised fifteen PDRAs, fifteen PhD students and twenty six masters students, the majority of whom have remained in science (some have their own independent research groups and others have moved into the commercial sector). The PI directs a cross-University IMB initiative to promote and expand research and training in in vivo biology. This problematic area is crucial to the UK economy and to the ambitions of Manchester to be a world-leading university. The applicant has acted as external examiners on a number of courses at other Universities.