The Role of Skeletal Muscle Tribbles 3 (TRB3) on Endoplasmic Reticulum (ER) stress‐ and high fat diet‐induced insulin resistance

Abstract

ER stress has been linked to insulin resistance in multiple tissues; however, whether ER stress causes insulin resistance in skeletal muscle has not been explored. ER stress has also been reported to increase TRB3 expression in multiple cell lines. Here, we report that high fat feeding in mice for 6 weeks, and obesity and type 2 diabetes in humans, significantly increased TRB3 expression (1.9‐fold in mice; 1.7‐ and 1.9‐fold in human) and ER stress markers in skeletal muscle. Overexpression of TRB3 in C2C12 muscle cells and mouse tibialis anterior muscles significantly impaired insulin‐stimulated IRS1 Y612 (67% and 22%) and Akt T308 (27% and 23%) phosphorylation. Incubation of C2C12 cells and extensor digitorum longus muscles with ER stressors thapsigargin and tunicamycin increased TRB3 expression and impaired insulin‐stimulated IRS1 Y612 (30–46%) and Akt T308 (35–37%) phosphorylation and glucose uptake (23–36% and 45%), effects reversed in cells with TRB3 RNAi and muscles from TRB3KO mice. Furthermore, TRB3KO mice were protected from high fat diet‐induced insulin resistance in skeletal muscle as TRB3KO mice showed lower body weights (11%) and fasting blood glucose concentration, improved glucose tolerance test (35%), and increased insulin‐stimulated glucose uptake and signaling after 8 weeks on a high fat diet. These data demonstrate that TRB3 mediates ER stress‐induced insulin resistance in skeletal muscle.