2026-08-21T00:04:24Zhttps://docta.ucm.es/rest/oai/request

oai:docta.ucm.es:20.500.14352/933922025-03-18T13:05:23Zcom_20.500.14352_14col_20.500.14352_15

00925njm 22002777a 4500 dc Raposo López-Pastor, Andrea author Gómez Hernández, María De La Almudena author Díaz Castroverde, Sabela author González-Aseguinolaza Gloria author González Rodríguez, Águeda author García, Gema author Fernández, Silvia author Escribano Illanes, Óscar author Benito, Manuel author 2019 Among the main complications associated to obesity is insulin resistance and an altered glucose and lipid metabolism within the liver. It has been previously described that insulin receptor isoform A (IRA) favors glucose uptake and glycogen storage in hepatocytes as compared to isoform B (IRB) improving glucose homeostasis in mice lacking liver insulin receptor. Thus, we hypothesized that IRA could also improve glucose and lipid metabolism in a mouse model of high fat diet-induced obesity. We addressed the role of insulin receptor isoforms on glucose and lipid metabolism in vivo. We expressed IRA or IRB specifically in the liver by using adeno-associated viruses (AAV) in a mouse model of diet-induced insulin resistance and obesity. IRA expression, but not IRB, induced an increased glucose uptake in the liver and muscle improving insulin tolerance. Regarding lipid metabolism, we found that AAV-mediated IRA expression also ameliorated hepatic steatosis by decreasing the expression of Fasn, Pgc1a, Acaca and Dgat2 and increasing Scd-1. Taking together, our results further unravel the role of insulin receptor isoforms in hepatic glucose and lipid metabolism in an insulin-resistant scenario. Our data strongly suggest that IRA is more efficient than IRB favoring hepatic glucose uptake, improving insulin tolerance and ameliorating hepatic steatosis. Therefore, we conclude that a gene therapy approach for hepatic IRA expression could be a safe and promising tool for the regulation of hepatic glucose consumption and lipid metabolism, two key processes in the development of non-alcoholic fatty liver disease (NAFLD) associated to obesity. Lopez-Pastor AR, Gomez-Hernandez A, Diaz-Castroverde S, Gonzalez-Aseguinolaza G, Gonzalez-Rodriguez A, Garcia G, et al. Liver-specific insulin receptor isoform A expression enhances hepatic glucose uptake and ameliorates liver steatosis in a mouse model of diet-induced obesity. Disease Models & Mechanisms 2019:dmm.036186. https://doi.org/10.1242/dmm.036186. 1754-8403 10.1242/dmm.036186 https://hdl.handle.net/20.500.14352/93392 1754-8411 https://doi.org/10.1242/dmm.036186 Liver-specific insulin receptor isoform A expression enhances hepatic glucose uptake and ameliorates liver steatosis in a mouse model of diet-induced obesity