Project description
The neuronal basis of weight management
Regaining the lost weight after a diet is a common phenomenon and is known as the yo-yo effect. Understanding the mechanisms responsible for maintaining weight loss is thus important especially for the treatment of obesity. The EU-funded Yoyo-LepReSens project will focus on the epigenetic mechanisms that drive weight regain through overeating. Scientists will study the epigenetics of a specific subset of neurons in the hypothalamus and decipher how they are involved in weight management. Moreover, the project will investigate the emergence of resistance to the hormone leptin, known for its role in satiety regulation. Results will form the basis for the design of novel interventions to tackle obesity.
Objective
Obesity and its comorbid sequelae are major health burdens across European nations. Many citizens would greatly benefit from permanent weight loss, but only a few succeed. They rather suffer from weight regain after dieting, often referred to as Yoyo effect. Delineating the largely unexplored, CNS-driven molecular events that impede sustainable weight loss and drive the Yoyo effect is a prerequisite for future therapies, and a major goal of my proposal.
Recently, my lab demonstrated unprecedented weight loss in diet-induced obese mice treated with the plant-derived leptin sensitizer celastrol. Our data suggested breakthrough potential for therapeutic anti-obesity strategies built upon leptin re-sensitization, and pointed towards a key role for orexigenic circuitry and AgRP neurons residing in the hypothalamic arcuate nucleus. As 1st objective, we will 1) establish if leptin resistance originates in AgRP neurons, 2) delineate the molecular underpinnings of leptin resistance and leptin resensitization in AgRP neurons, 3) verify novel drug-able leptin signalling components in murine and human iPSC-derived cells and 4) identify leptin sensitizing weight loss drugs.
AgRP neurons will also be in the focus of my 2nd objective that targets epigenetic mechanisms of Yoyo dieting. Building upon our own data on epigenetic mechanisms that drive weight re-gain through hyperphagia, we will 1) establish if an epigenetic memory for obesity in AgRP neurons exists, 2) explore by Crispr-Cas9-based trans-epigenetic modulation of AgRP neurons in mice whether resetting the epigenetic memory for obesity can prevent weight regain and 3) demonstrate the human relevance of our new weight regulatory genes in post-mortem human hypothalami of lean, obese or type 2 diabetic donors.
Overall, my proposal will establish hypothalamic AgRP neurons as crucial drivers for leptin resistance and Yoyo dieting. My translational aims are further providing the groundwork for future anti-obesity therapeutics.
Fields of science (EuroSciVoc)
CORDIS classifies projects with EuroSciVoc, a multilingual taxonomy of fields of science, through a semi-automatic process based on NLP techniques. See: The European Science Vocabulary.
CORDIS classifies projects with EuroSciVoc, a multilingual taxonomy of fields of science, through a semi-automatic process based on NLP techniques. See: The European Science Vocabulary.
- medical and health sciences clinical medicine endocrinology diabetes
- medical and health sciences health sciences nutrition obesity
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Keywords
Project’s keywords as indicated by the project coordinator. Not to be confused with the EuroSciVoc taxonomy (Fields of science)
Project’s keywords as indicated by the project coordinator. Not to be confused with the EuroSciVoc taxonomy (Fields of science)
Programme(s)
Multi-annual funding programmes that define the EU’s priorities for research and innovation.
Multi-annual funding programmes that define the EU’s priorities for research and innovation.
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H2020-EU.1.1. - EXCELLENT SCIENCE - European Research Council (ERC)
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Topic(s)
Calls for proposals are divided into topics. A topic defines a specific subject or area for which applicants can submit proposals. The description of a topic comprises its specific scope and the expected impact of the funded project.
Calls for proposals are divided into topics. A topic defines a specific subject or area for which applicants can submit proposals. The description of a topic comprises its specific scope and the expected impact of the funded project.
Funding Scheme
Funding scheme (or “Type of Action”) inside a programme with common features. It specifies: the scope of what is funded; the reimbursement rate; specific evaluation criteria to qualify for funding; and the use of simplified forms of costs like lump sums.
Funding scheme (or “Type of Action”) inside a programme with common features. It specifies: the scope of what is funded; the reimbursement rate; specific evaluation criteria to qualify for funding; and the use of simplified forms of costs like lump sums.
ERC-COG - Consolidator Grant
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Call for proposal
Procedure for inviting applicants to submit project proposals, with the aim of receiving EU funding.
Procedure for inviting applicants to submit project proposals, with the aim of receiving EU funding.
(opens in new window) ERC-2020-COG
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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.
85764 Neuherberg
Germany
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.