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Study the functions of the hepatic sympathetic nerve and the receptor Adrb3 in liver-mediated adaptive thermogenesis.

Project description

Warming up to a new treatment target for liver disease

Thermogenesis literally means heat generation. Adaptive thermogenesis is another regulatory mechanism that occurs in response to changes in temperature and diet. It has gained increasing attention over the last decade for its potential role in obesity and prolonged dieting. It may also be important in liver disease, particularly non-alcoholic fatty liver disease (NAFLD) that is also associated with obesity and type 2 diabetes. The EU-funded Hepatic Thermogenesi project has targeted the liver as a potential site of adaptive thermogenesis. Scientists plan to tease out the molecular mechanisms and the role of sympathetic regulation. With NAFLD on the rise, results could provide new routes to treatment.

Objective

Core body temperature is among the best-guarded constants in homeothermic species. It results from the evolution of physiological mechanisms capable of regulating the production as well as the exchange of heat with the environment. The objective of my proposal is to define a new role for the liver in adaptive thermogenesis whereby the liver will be involved in heat production under the regulation of the hepatic sympathetic nerve. I will first ascertain that the liver can generate extra heat when adaptive thermogenesis is triggered (Aim 1). Hepatic adaptive thermogenesis will be demonstrated using a combination of interdisciplinary, cutting-edge technologies normally applied to the fields of physics and chemistry. I will then determine the molecular foundation of this hepatic heat production (Aim 2). For this purpose, OMICs data (transcriptomic, proteomic and metabolomics) will be generated from cold-exposed liver tissues in order to identify: (1) the hepatic molecular heating mechanism; (2) the expected metabolic rewiring necessary to sustain prolonged heat production from thermogenic hepatocytes. Finally, I will study how hepatic adaptive thermogenesis is regulated by the hepatic sympathetic nerve at the anatomical level and by the adrenergic receptor Adrb3 at the molecular level (Aim 3). For this purpose, I will use a combination of surgical (hepatic sympathectomy) and genetic (generation of liver-specific beta-adrenergic receptor 3 knockout mice) ablation techniques. Longstanding observations, together with my own preliminary results argue for this existence of hepatic adaptive thermogenesis and its molecular characterization would certainly represent a major breakthrough for both our fundamental understanding of homoeothermic physiology as well as for future clinical applications. Demonstrating that the liver is involved in adaptive thermogenesis would certainly open new avenues for the treatment of nonalcoholic fatty liver disease, a major disease in Europe.

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Coordinator

ECOLE POLYTECHNIQUE FEDERALE DE LAUSANNE
Net EU contribution
€ 203 149,44
Address
Batiment ce 3316 station 1
1015 Lausanne
Switzerland

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Region
Schweiz/Suisse/Svizzera Région lémanique Vaud
Activity type
Higher or Secondary Education Establishments
Links
Other funding
€ 0,00