Descripción del proyecto
Preparación para una nueva diana terapéutica para enfermedades hepáticas
La termogénesis significa literalmente generación de calor. La termogénesis adaptativa es otro mecanismo regulador que se produce como respuesta a cambios de temperatura y en la dieta. Ha captado una atención cada vez mayor a lo largo de la última década por su posible función en la obesidad y las dietas prolongadas. Además, podría ser importante en enfermedades hepáticas, especialmente en la esteatohepatitis no alcohólica (EHNA), que también se relaciona con la obesidad y la diabetes de tipo 2. El proyecto Hepatic Thermogenesi, financiado con fondos europeos, se centró en el hígado como posible escenario de termogénesis adaptativa. Los científicos prevén desentrañar los mecanismos moleculares y la función de la regulación simpática. Ante el aumento de la EHNA, los resultados podrían aportar nuevas vías terapéuticas.
Objetivo
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.
Ámbito científico
Programa(s)
Régimen de financiación
MSCA-IF-EF-RI - RI – Reintegration panelCoordinador
1015 Lausanne
Suiza