Hoffman, Nolan J.Penque, Brent A.Habegger, Kirk M.Sealls, WhitneyTackett, LixuanElmendorf, Jeffrey S.2016-02-032016-02-032014-05Hoffman, N. J., Penque, B. A., Habegger, K. M., Sealls, W., Tackett, L., & Elmendorf, J. S. (2014). Chromium Enhances Insulin Responsiveness via AMPK. The Journal of Nutritional Biochemistry, 25(5), 565–572. http://doi.org/10.1016/j.jnutbio.2014.01.0070955-2863https://hdl.handle.net/1805/8238Trivalent chromium (Cr3+) is known to improve glucose homeostasis. Cr3+ has been shown to improve plasma membrane-based aspects of glucose transporter GLUT4 regulation and increase activity of the cellular energy sensor 5′ AMP-activated protein kinase (AMPK). However, the mechanism(s) by which Cr3+ improves insulin responsiveness and whether AMPK mediates this action is not known. In this study we tested if Cr3+ protected against physiological hyperinsulinemia-induced plasma membrane cholesterol accumulation, cortical filamentous actin (F-actin) loss and insulin resistance in L6 skeletal muscle myotubes. In addition, we performed mechanistic studies to test our hypothesis that AMPK mediates the effects of Cr3+ on GLUT4 and glucose transport regulation. Hyperinsulinemia-induced insulin-resistant L6 myotubes displayed excess membrane cholesterol and diminished cortical F-actin essential for effective glucose transport regulation. These membrane and cytoskeletal abnormalities were associated with defects in insulin-stimulated GLUT4 translocation and glucose transport. Supplementing the culture medium with pharmacologically relevant doses of Cr3+ in the picolinate form (CrPic) protected against membrane cholesterol accumulation, F-actin loss, GLUT4 dysregulation and glucose transport dysfunction. Insulin signaling was neither impaired by hyperinsulinemic conditions nor enhanced by CrPic, whereas CrPic increased AMPK signaling. Mechanistically, siRNA-mediated depletion of AMPK abolished the protective effects of CrPic against GLUT4 and glucose transport dysregulation. Together these findings suggest that the micronutrient Cr3+, via increasing AMPK activity, positively impacts skeletal muscle cell insulin sensitivity and glucose transport regulation.en-USPublisher PolicyAMP-Activated Protein KinasesmetabolismChromiumpharmacologyMuscle Fibers, Skeletaldrug effectsCholesterolGLUT4InsulinArticle