Neuregulin 4 Downregulation Induces Insulin Resistance in 3T3-L1 Adipocytes through Inflammation and Autophagic Degradation of GLUT4 Vesicles.

Autor: Díaz-Sáez F; Department of Biochemistry and Molecular Biomedicine, Faculty of Biology, University of Barcelona, Av. Diagonal, 643, 08028 Barcelona, Spain.; Institute of Biomedicine, University of Barcelona, 08028 Barcelona, Spain., Blanco-Sinfreu C; Department of Biochemistry and Molecular Biomedicine, Faculty of Biology, University of Barcelona, Av. Diagonal, 643, 08028 Barcelona, Spain., Archilla-Ortega A; Department of Biochemistry and Molecular Biomedicine, Faculty of Biology, University of Barcelona, Av. Diagonal, 643, 08028 Barcelona, Spain., Sebastian D; Department of Biochemistry and Molecular Biomedicine, Faculty of Biology, University of Barcelona, Av. Diagonal, 643, 08028 Barcelona, Spain.; Centro de Investigación Biomèdica en Red Diabetes y Enfermedades Metabólicas Asociadas (CIBERDEM), Carlos III Health Institute, 28029 Madrid, Spain.; Institute for Research in Biomedicine (IRB Barcelona), Barcelona Institute of Science and Technology (BIST), 08028 Barcelona, Spain., Romero M; Department of Biochemistry and Molecular Biomedicine, Faculty of Biology, University of Barcelona, Av. Diagonal, 643, 08028 Barcelona, Spain.; Centro de Investigación Biomèdica en Red Diabetes y Enfermedades Metabólicas Asociadas (CIBERDEM), Carlos III Health Institute, 28029 Madrid, Spain.; Institute for Research in Biomedicine (IRB Barcelona), Barcelona Institute of Science and Technology (BIST), 08028 Barcelona, Spain., Hernández-Alvarez MI; Department of Biochemistry and Molecular Biomedicine, Faculty of Biology, University of Barcelona, Av. Diagonal, 643, 08028 Barcelona, Spain.; Institute of Biomedicine, University of Barcelona, 08028 Barcelona, Spain.; Centro de Investigación Biomèdica en Red Diabetes y Enfermedades Metabólicas Asociadas (CIBERDEM), Carlos III Health Institute, 28029 Madrid, Spain., Mora S; Department of Biochemistry and Molecular Biomedicine, Faculty of Biology, University of Barcelona, Av. Diagonal, 643, 08028 Barcelona, Spain.; Institute of Biomedicine, University of Barcelona, 08028 Barcelona, Spain., Testar X; Department of Biochemistry and Molecular Biomedicine, Faculty of Biology, University of Barcelona, Av. Diagonal, 643, 08028 Barcelona, Spain.; Institute of Biomedicine, University of Barcelona, 08028 Barcelona, Spain.; Centro de Investigación Biomèdica en Red Diabetes y Enfermedades Metabólicas Asociadas (CIBERDEM), Carlos III Health Institute, 28029 Madrid, Spain., Ricart W; Department of Medicine, Universitat de Girona, Carrer Emili Grahit, 77, 17071 Girona, Spain.; Department of Diabetes, Endocrinology and Nutrition, Institut d'Investigació Biomèdica de Girona (IDIBGI), Carrer del Dr. Castany, s/n, 17190 Salt, Spain.; Centro de Investigación Biomèdica en Red Fisiopatología de la Obesidad y Nutrición (CIBEROBN), Carlos III Health Institute, 28029 Madrid, Spain., Fernández-Real JM; Department of Medicine, Universitat de Girona, Carrer Emili Grahit, 77, 17071 Girona, Spain.; Department of Diabetes, Endocrinology and Nutrition, Institut d'Investigació Biomèdica de Girona (IDIBGI), Carrer del Dr. Castany, s/n, 17190 Salt, Spain.; Centro de Investigación Biomèdica en Red Fisiopatología de la Obesidad y Nutrición (CIBEROBN), Carlos III Health Institute, 28029 Madrid, Spain., Moreno-Navarrete JM; Department of Medicine, Universitat de Girona, Carrer Emili Grahit, 77, 17071 Girona, Spain.; Department of Diabetes, Endocrinology and Nutrition, Institut d'Investigació Biomèdica de Girona (IDIBGI), Carrer del Dr. Castany, s/n, 17190 Salt, Spain.; Centro de Investigación Biomèdica en Red Fisiopatología de la Obesidad y Nutrición (CIBEROBN), Carlos III Health Institute, 28029 Madrid, Spain., Aragonés J; Research Unit, Hospital of Santa Cristina, Research Institute Princesa, Autonomous University of Madrid, c/Maestro Vives, 2, 28009 Madrid, Spain.; Centro de Investigación Biomédica en Red Enfermedades Cardiovasculares, Carlos III Health Institute, 28029 Madrid, Spain., Camps M; Department of Biochemistry and Molecular Biomedicine, Faculty of Biology, University of Barcelona, Av. Diagonal, 643, 08028 Barcelona, Spain.; Institute of Biomedicine, University of Barcelona, 08028 Barcelona, Spain.; Centro de Investigación Biomèdica en Red Diabetes y Enfermedades Metabólicas Asociadas (CIBERDEM), Carlos III Health Institute, 28029 Madrid, Spain., Zorzano A; Department of Biochemistry and Molecular Biomedicine, Faculty of Biology, University of Barcelona, Av. Diagonal, 643, 08028 Barcelona, Spain.; Centro de Investigación Biomèdica en Red Diabetes y Enfermedades Metabólicas Asociadas (CIBERDEM), Carlos III Health Institute, 28029 Madrid, Spain.; Institute for Research in Biomedicine (IRB Barcelona), Barcelona Institute of Science and Technology (BIST), 08028 Barcelona, Spain., Gumà A; Department of Biochemistry and Molecular Biomedicine, Faculty of Biology, University of Barcelona, Av. Diagonal, 643, 08028 Barcelona, Spain.; Institute of Biomedicine, University of Barcelona, 08028 Barcelona, Spain.; Centro de Investigación Biomèdica en Red Diabetes y Enfermedades Metabólicas Asociadas (CIBERDEM), Carlos III Health Institute, 28029 Madrid, Spain.
Jazyk: angličtina
Zdroj: International journal of molecular sciences [Int J Mol Sci] 2021 Nov 30; Vol. 22 (23). Date of Electronic Publication: 2021 Nov 30.
DOI: 10.3390/ijms222312960
Abstrakt: 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.
Databáze: MEDLINE
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