Obesity-induced hepatic steatosis in mice is reverted by AAV9-mediated enhanced fatty-acid oxidation

Título: Obesity-induced hepatic steatosis in mice is reverted by AAV9-mediated enhanced fatty-acid oxidation Autor: Serra, Dolors; Weber, Minéia; Casas, Josefina; Sebastian, D.; Recalde, Sergio; Mir, Joan Francesc; Fucho, Raquel; Calderon-Dominguez, María; Mera, P.; Zagmutt, Sebastián; Soler-Vazquez, M. C.; Ibeas, K.; Escolà-Gil, Joan Carles; Llorente-Cortés, Vicenta; Casals, Núria; Zorzano, A.; Fabriàs, Gemma; Herrero, L. Resumen: [Background] Obesity‐induced insulin resistance is associated, among others, with both ectopic lipid deposition and chronic, low‐grade adipose tissue inflammation. Despite the excess of fat, obese individuals show lower fatty‐acid oxidation rates. Thus, burning off the excess of fat could improve the obese metabolic phenotype. The aim of the present study was to evaluate the therapeutic potential of adenoassociated viruses (AAV) 9‐mediated liver expression of a human malonyl‐CoA‐insensitive carnitine palmitoyltransferase 1A (hCPT1AM), the key enzyme in fatty‐acid β‐oxidation (FAO), in a diet‐induced obese mouse model.; [Materials and methods] We analyzed the metabolic and physiological effects of the long‐term liver hCPT1AM expression and the enhanced FAO on the diet‐induced obese mice.; [Results] The enhanced hepatic FAO resulted in the reversion of the obese phenotype reducing body weight, hyperglycemia, hyperinsulinemia and hepatic steatosis. The mechanism involved are the hepatic activation of autophagy, lipolysis, cholesterol mobilization and energy dissipation by increasing liver temperature and the production of CO2, ATP and ketone bodies. Notably, the increase in hepatic FAO produced deep changes in the hepatic and serum lipidomic profile pointing out some ceramide and phosphatidylcholine species as potential markers for obesity reversion and hepatic steatosis improvement.; [Conclusion] An increase in liver FAO improves the obese metabolic phenotype, which indicates that AAV9‐mediated hCPT1AM expression could be a potential molecular therapy for obesity and diabetes. Descripción: Trabajo presentado en la 52nd Annual Scientifi Meeting of the European Society for Clinical Investigation (ESCI), celebrada en Barcelona, del miércoles, 30 de mayo de 2018 hasta el viernes, 1 de junio de 2018