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 (
SOCS-3)
mRNA, and
GLUT4 translocation. We found that
resistin at a concentration of 30 ng/ml decreased insulin-stimulated
glucose uptake by 30-40% in
soleus muscle and
myotubes, whereas in EDL
muscle insulin-stimulated
glucose uptake was
impaired at a
resistin concentration of 100 ng/ml.
Impaired insulin-stimulated
glucose uptake was not associated with reduced
Akt phosphorylation or
IRS-1 protein or increased
SOCS-3 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-1-beta-4-ribofuranoside (
AICAR) and found that, although
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 Thr(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
SOCS-3.
