2026-04-13T02:51:18Zhttps://recercat.cat/oai/request

oai:recercat.cat:2445/1823622025-12-04T21:16:27Zcom_2072_1057col_2072_478781col_2072_478917

00925njm 22002777a 4500 dc Díaz-Sáez, Francisco author Blanco-Sinfreu, Carla author Archilla Ortega, Adrià author Sebastián Muñoz, David author Romero, Montserrat author Hernández-Alvarez, María Isabel author Mora Fayos, Sílvia author Testar, Xavier author Ricart, Wifredo author Fernández-Real Lemos, José Manuel author Moreno-Navarrete, José María author Aragonés, Julián author Camps Camprubí, Marta author Zorzano Olarte, Antonio author Gumà i Garcia, Anna Maria author 2022-01-13T13:57:05Z 2022-01-13T13:57:05Z 2021-11-30 2022-01-13T13:57:05Z The adipokine Neuregulin 4 (Nrg4) protects against obesity-induced insulin resistance. Here, we analyze how the downregulation of Nrg4 influences insulin action and the underlying mechanisms in adipocytes. Validated shRNA lentiviral vectors were used to generate scramble (Scr) and Nrg4 knockdown (KD) 3T3-L1 adipocytes. Adipogenesis was unaffected in Nrg4 KD adipocytes, but there was a complete impairment of the insulin-induced 2-deoxyglucose uptake, which was likely the result of reduced insulin receptor and Glut4 protein. Downregulation of Nrg4 enhanced the expression of proinflammatory cytokines. Anti-inflammatory agents recovered the insulin receptor, but not Glut4, content. Proteins enriched in Glut4 storage vesicles such as the insulin-responsive aminopeptidase (IRAP) and Syntaxin-6 as well as TBC1D4, a protein involved in the intracellular retention of Glut4 vesicles, also decreased by Nrg4 KD. Insulin failed to reduce autophagy in Nrg4 KD adipocytes, observed by a minor effect on mTOR phosphorylation, at the time that proteins involved in autophagy such as LC3-II, Rab11, and Clathrin were markedly upregulated. The lysosomal activity inhibitor bafilomycin A1 restored Glut4, IRAP, Syntaxin-6, and TBC1D4 content to those found in control adipocytes. Our study reveals that Nrg4 preserves the insulin responsiveness by preventing inflammation and, in turn, benefits the insulin regulation of autophagy. Resistència a la insulina Autofàgia Inflamació Receptors d'insulina Insulin resistance Autophagy Inflammation Insulin receptors Neuregulin 4 Downregulation Induces Insulin Resistance in 3T3-L1 Adipocytes through Inflammation and Autophagic Degradation of GLUT4 Vesicles