PPARß/d upregulates the insulin receptor ß subunit in skeletal muscle by reducing lysosomal activity and EphB4 levels
Por:
Wang JR, Jurado-Aguilar J, Barroso E, Rodríguez-Calvo R, Camins A, Wahli W, Palomer FX and Vazquez M
Publicada:
18 dic 2024
Ahead of Print:
18 dic 2024
Resumen:
BackgroundThe increased degradation of the insulin receptor beta subunit (InsR beta) in lysosomes contributes to the development of insulin resistance and type 2 diabetes mellitus. Endoplasmic reticulum (ER) stress contributes to insulin resistance through several mechanisms, including the reduction of InsR beta levels. Here, we examined how peroxisome proliferator-activated receptor (PPAR)beta/delta regulates InsR beta levels in mouse skeletal muscle and C2C12 myotubes exposed to the ER stressor tunicamycin.MethodsWild-type (WT) and Ppard-/- mice, WT mice treated with vehicle or the PPAR beta/delta agonist GW501516, and C2C12 myotubes treated with the ER stressor tunicamycin or different activators or inhibitors were used.ResultsPpard-/- mice displayed reduced InsR beta protein levels in their skeletal muscle compared to wild-type (WT) mice, while the PPAR beta/delta agonist GW501516 increased its levels in WT mice. Co-incubation of tunicamycin-exposed C2C12 myotubes with GW501516 partially reversed the decrease in InsR beta protein levels, attenuating both ER stress and the increase in lysosomal activity. In addition, the protein levels of the tyrosine kinase ephrin receptor B4 (EphB4), which binds to the InsR beta and facilitates its endocytosis and degradation in lysosomes, were increased in the skeletal muscle of Ppard-/- mice, with GW501516 reducing its levels in the skeletal muscle of WT mice.ConclusionsOverall, these findings reveal that PPAR beta/delta activation increases InsR beta levels by alleviating ER stress and lysosomal degradation.
Filiaciones:
Wang JR:
Department of Pharmacology, Toxicology and Therapeutic Chemistry, Faculty of Pharmacy and Food Sciences, Institute of Biomedicine of the University of Barcelona (IBUB), University of Barcelona, Barcelona, 08028, Spain
Spanish Biomedical Research Center in Diabetes and Associated Metabolic Diseases (CIBERDEM)-Instituto de Salud Carlos III, Madrid, 28029, Spain
Pediatric Research Institute-Hospital Sant Joan de Déu, Esplugues de Llobregat, Spain
Jurado-Aguilar J:
Department of Pharmacology, Toxicology and Therapeutic Chemistry, Faculty of Pharmacy and Food Sciences, Institute of Biomedicine of the University of Barcelona (IBUB), University of Barcelona, Barcelona, 08028, Spain
Spanish Biomedical Research Center in Diabetes and Associated Metabolic Diseases (CIBERDEM)-Instituto de Salud Carlos III, Madrid, 28029, Spain
Pediatric Research Institute-Hospital Sant Joan de Déu, Esplugues de Llobregat, Spain
Barroso E:
Department of Pharmacology, Toxicology and Therapeutic Chemistry, Faculty of Pharmacy and Food Sciences, Institute of Biomedicine of the University of Barcelona (IBUB), University of Barcelona, Barcelona, 08028, Spain
Spanish Biomedical Research Center in Diabetes and Associated Metabolic Diseases (CIBERDEM)-Instituto de Salud Carlos III, Madrid, 28029, Spain
Pediatric Research Institute-Hospital Sant Joan de Déu, Esplugues de Llobregat, Spain
Rodríguez-Calvo R:
Spanish Biomedical Research Center in Diabetes and Associated Metabolic Diseases (CIBERDEM)-Instituto de Salud Carlos III, Madrid, 28029, Spain
Vascular Medicine and Metabolism Unit, Research Unit on Lipids and Atherosclerosis, "Sant Joan" University Hospital, Universitat Rovira i Virgili, Pere Virgili Health Research Institute (IISPV), Reus, 43201, Spain
Camins A:
Department of Pharmacology, Toxicology and Therapeutic Chemistry, Faculty of Pharmacy and Food Sciences, Institute of Biomedicine of the University of Barcelona (IBUB), University of Barcelona, Barcelona, 08028, Spain
Biomedical Research Networking Centre in Neurodegenerative Diseases (CIBERNED), Madrid, Spain
Institute of Neuroscience, University of Barcelona, Barcelona, Spain
Wahli W:
Center for Integrative Genomics, University of Lausanne, Lausanne, CH-1015, Switzerland
INRAE ToxAlim, UMR1331, Chemin de Tournefeuille, Toulouse Cedex 3, F-31027, France
Palomer FX:
Department of Pharmacology, Toxicology and Therapeutic Chemistry, Faculty of Pharmacy and Food Sciences, Institute of Biomedicine of the University of Barcelona (IBUB), University of Barcelona, Barcelona, 08028, Spain
Spanish Biomedical Research Center in Diabetes and Associated Metabolic Diseases (CIBERDEM)-Instituto de Salud Carlos III, Madrid, 28029, Spain
Pediatric Research Institute-Hospital Sant Joan de Déu, Esplugues de Llobregat, Spain
Vazquez M:
Department of Pharmacology, Toxicology and Therapeutic Chemistry, Faculty of Pharmacy and Food Sciences, Institute of Biomedicine of the University of Barcelona (IBUB), University of Barcelona, Barcelona, 08028, Spain
Spanish Biomedical Research Center in Diabetes and Associated Metabolic Diseases (CIBERDEM)-Instituto de Salud Carlos III, Madrid, 28029, Spain
Pediatric Research Institute-Hospital Sant Joan de Déu, Esplugues de Llobregat, Spain
Unitat de Farmacologia, Facultat de Farmàcia i Ciències de l'Alimentació, Av. Joan XXIII 27-31, Barcelona, E-08028, Spain
Green Submitted, gold
|