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Dissecting and leveraging glucagon-like peptide-1 brain pathways in obesity

Project description

Insight into the neuroendocrine control of appetite

Currently, there are no effective therapies against obesity, which represents a major medical challenge of modern societies. To design novel treatments, it is necessary to understand how the nervous system controls appetite. The EU-funded Ob_GLP1 project will investigate the brain glucagon-like peptide-1 (GLP1) system which plays a role in insulin secretion. Agonists that bind to GLP1 receptors in the brain promote insulin release and can be used to treat type 2 diabetes. By studying the distribution and function of GLP1 receptors in the brain, researchers hope to provide fundamental knowledge on the brain's control over obesity and help design novel anti-obesity treatments.

Objective

Obesity is a major health challenge in the EU and globally, and yet the best drug therapies achieve only modest reductions in weight loss and require life-long treatment. To prevent and treat obesity it is crucial we understand the neural pathways controlling appetite and how they can be ‘hijacked’ therapeutically. The brain glucagon-like peptide-1 (GLP1) system is a promising target. GLP1 receptor agonists (GLP1RAs) decrease food intake and bodyweight in obese patients, effects which are mediated by two brain regions: the arcuate nucleus of the hypothalamus (Arc) and the nucleus of the solitary tract (NTS). This project, Ob_GLP1, combines the neuroscience background of Dr Holt with the next-generation technology and imaging expertise of Dr Hodson to test the hypothesis that obesity disrupts the function of GLP1RA-responsive Arc and NTS circuits and that obesity can be rescued by selectively targeting intracellular signalling in GLP1RA-activated neurons. This hypothesis will be tested through the completion of four independent, yet complementary work packages. Work package 1-3 will determine the effect of obesity on 1) GLP1RA access to the Arc and NTS measured using fluorescently labelled GLP1R antagonist and whole-brain light-sheet microscopy; 2) the molecular distribution and oligomerisation state of GLP1Rs in the Arc and NTS; and 3) the innervation pattern and synaptic density of Arc and NTS GLP1R neurons. Work package 4 will assess the potential of a novel GLP1-conjugated antisense nucleotide as an effective anti-obesity treatment. Ob_GLP1 will advance our knowledge of the brain’s control over obesity, while allowing Dr Holt to reintegrate into the European research environment and will facilitate substantial two-way transfer of knowledge between the host lab and Dr Holt, ultimately benefitting both parties, as well as society as a whole.

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Coordinator

THE UNIVERSITY OF BIRMINGHAM
Net EU contribution
€ 224 933,76
Address
Edgbaston
B15 2TT Birmingham
United Kingdom

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Region
West Midlands (England) West Midlands Birmingham
Activity type
Higher or Secondary Education Establishments
Links
Other funding
€ 0,00