Objective. Ciliary neurotrophic factor (CNTF) reverses muscle insulin resistance by increasing fatty acid oxidation via gp130/LIF receptor signaling to the AMP-activated protein kinase (AMPK). CNTF also increases Akt signaling in neurons and adipocytes. As both Akt and AMPK regulate glucose uptake, we investigated muscle glucose uptake in response to CNTF signaling in lean and obese mice. Research Design and Methods. Mice were injected intraperitoneally with saline or CNTF and blood glucose monitored. The effects of CNTF on skeletal muscle glucose uptake and AMPK/Akt signaling were investigated in incubated soleus and EDL muscles from muscle specific AMPKalpha2 kinase-dead (KD), gp130DeltaSTAT, and lean and obese ob/ob and high-fat fed mice. The effect of C2-ceramide on glucose uptake and gp130-signaling was also examined. Results. CNTF reduced blood glucose, and increased glucose uptake in isolated muscles in a time and dose dependent manner with maximal effects after 30 min with 100 ng.ml(-1). CNTF increased Akt-S473 phosphorylation in soleus and EDL however; AMPK-T172 phosphorylation was only increased in soleus. Incubation of muscles from AMPK-KD and wild-type littermates with the PI3-kinase inhibitor LY-294002 demonstrated that PI3-kinase, but not AMPK, was essential for CNTF-stimulated glucose uptake. CNTF-stimulated glucose uptake and Akt-phosphorylation were substantially reduced in obesity (HFD and ob/ob) despite normal induction of gp130/AMPK signaling, effects also observed when treating myotubes with C2-ceramide. Conclusions. CNTF acutely increases muscle glucose uptake by a mechanism involving the PI3-kinase/Akt pathway, that does not require AMPK. CNTF stimulated glucose uptake is impaired in obesity induced insulin resistance and by ceramide.