Palmitate-induced insulin resistance causes actin filament stiffness and GLUT4 mis-sorting without altered Akt signaling.

Skeletal muscle insulin resistance, a major contributor to Type 2 Diabetes, is linked to the consumption of saturated fats. This insulin resistance arises from failure of insulin-induced translocation of glucose transporter type 4 (GLUT4) to the plasma membrane to facilitate glucose uptake into muscle. The mechanisms of defective GLUT4 translocation are poorly understood, limiting development of insulin-sensitizing therapies targeting muscle glucose uptake. While many studies identify early insulin signaling defects and suggest they are responsible for insulin resistance, their cause-effect has been debated. Here, we find that the saturated fat palmitate (PA) causes insulin resistance of GLUT4 translocation in skeletal muscle myoblasts and myotubes without impairing signaling to Akt or AS160. Instead, PA altered two basal-state events: a) the intracellular localization of GLUT4 and its sorting towards a perinuclear storage compartment, and b) actin filament stiffness that prevents Rac1-dependent actin remodeling. These defects were triggered by distinct mechanisms, respectively protein palmitoylation and endoplasmic reticulum (ER) stress. Our findings highlight that saturated fats elicit muscle cell-autonomous dysregulation of the basal-state machinery required for GLUT4 translocation that 'primes' cells for insulin resistance.