Submitted on September 1, 2008
Revised on May 5, 2009
Accepted on May 11, 2009
Oligomeric resistin impairs insulin and AICAR-stimulated glucose uptake in mouse skeletal muscle by inhibiting GLUT4 translocation
Sebastian Beck Jorgensen1*, Jonathan S Oakhill2, Daniel Fazakerley3, Jacqueline Stoeckli3, Bruce E. Kemp4, and Gregory R. Steinberg5
1 University of Copenhagen
2 St. Vincent's Institute of Medical Research and Department of Medicine
3 Garvan Institute of Medical Research
4 CSIRO Health Sciences and Nutrition
5 St. Vincent's Institute of Medical Research and Department of Medicine University of Melbourne
* To whom correspondence should be addressed. E-mail: sbjorgensen{at}ifi.ku.dk.
The hormone resistin is elevated in obesity and impairs glucose homeostasis. Here we examined the effect of oligomerized human resistin on insulin signaling and glucose metabolism in skeletal muscle and myotubes. This was investigated by incubating mouse extensor digitorum longus (EDL) and soleus muscles and L6 myotubes with physiological concentrations of resistin and assessing insulin-stimulated glucose uptake, cellular signaling, suppressor of cytokine signaling 3 (SOCS3) mRNA and GLUT4 translocation. We found that resistin at a concentration of 30ng/ml-1 decreased insulin-stimulated glucose uptake by 30-40% in soleus muscle and myotubes while in EDL muscle insulin-stimulated glucose uptake was impaired at a resistin concentration of 100ng/ml. Impaired insulin-stimulated glucose uptake was not associated with reduced Akt phosphorylation, IRS-1 protein or SOCS3 mRNA expression. To further investigate the site(s) at which resistin impairs glucose uptake we treated myotubes and skeletal muscle with the AMPK activator 5-Aminoimidazole-4-carboxamide riboside (AICAR) and found that while resistin did not impair AMPK activation it reduced AICAR-stimulated glucose uptake. These data suggested that resistin impairs glucose uptake at a point common to insulin and AMPK signaling pathways and we thus measured AS160/TBC1D4 threonine 642 phosphorylation and GLUT4 translocation in myotubes. Resistin did not impair TBC1D4 phosphorylation but did reduce both insulin and AICAR-stimulated GLUT4 plasma membrane translocation. We conclude that resistin impairs insulin-stimulated glucose uptake by mechanisms involving reduced plasma membrane GLUT4 translocation but independent of the proximal insulin signaling cascade, AMPK and SOCS3.
