PPARß/d upregulates the insulin receptor ß subunit in skeletal muscle by reducing lysosomal activity and EphB4 levels
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...
| Autores: | , , , , , , , |
|---|---|
| Tipo de recurso: | artículo |
| Estado: | Versión publicada |
| Fecha de publicación: | 2024 |
| País: | España |
| Institución: | Fundació Sant Joan de Déu |
| Repositorio: | r-FSJD. Repositorio Institucional de Producción Científica de la Fundació Sant Joan de Déu |
| OAI Identifier: | oai:fsjd.fundanetsuite.com:p27328 |
| Acceso en línea: | https://fsjd.fundanetsuite.com/Publicaciones/ProdCientif/PublicacionFrw.aspx?id=27328 |
| Access Level: | acceso abierto |
| Palabra clave: | PPAR beta/delta InsR beta EphB4 ER stress GW5101516 |
| Sumario: | 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. |
|---|