Descrizione del progetto
Il riscaldamento come nuovo bersaglio terapeutico per le malattie del fegato
Termogenesi significa letteralmente generazione di calore. La termogenesi adattativa è un altro meccanismo regolatore che si verifica in risposta ai cambiamenti di temperatura e dieta. Negli ultimi dieci anni ha guadagnato una crescente attenzione per il suo potenziale ruolo nell’obesità e nella dieta prolungata. Potrebbe anche essere importante nelle malattie del fegato, in particolare nella steatosi epatica non alcolica (NAFLD), che si associa inoltre all’obesità e al diabete di tipo 2. Il progetto Hepatic Thermogenesi, finanziato dall’UE, ha puntato al fegato come potenziale sito di termogenesi adattativa. Gli scienziati hanno in programma di elaborare i meccanismi molecolari e il ruolo della regolazione simpatica. Con la NAFLD in aumento, i risultati potrebbero fornire nuovi percorsi di trattamento.
Obiettivo
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.
Campo scientifico
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Meccanismo di finanziamento
MSCA-IF-EF-RI - RI – Reintegration panelCoordinatore
1015 Lausanne
Svizzera