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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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MSCA-IF - Marie Skłodowska-Curie Individual Fellowships (IF)

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Call for proposal

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(opens in new window) H2020-MSCA-IF-2020

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Coordinator

THE UNIVERSITY OF BIRMINGHAM
Net EU contribution

Net EU financial contribution. The sum of money that the participant receives, deducted by the EU contribution to its linked third party. It considers the distribution of the EU financial contribution between direct beneficiaries of the project and other types of participants, like third-party participants.

€ 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
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Total cost

The total costs incurred by this organisation to participate in the project, including direct and indirect costs. This amount is a subset of the overall project budget.

€ 224 933,76
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