Content area
Full Text
OBJECTIVE- Ciliary neurotrophic factor (CNTF) reverses muscle insulin resistance by increasing fatty acid oxidation through gpl30-LIF receptor signaling to the AMP-activated protein kinase (AMPK). CNTF also increases Akt signaling in neurons and adipocytes. Because 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 was monitored. The effects of CNTF on skeletal muscle glucose uptake and AMPK/Akt signaling were investigated in incubated soleus and extensor digitorum longus (EDL) muscles from muscle-specific AMPKα2 kinase-dead, gpl30^sup ΔSTAT^, and lean and obese ob/ob and high-fat-fed mice. The effect of C2-ceramide on glucose uptake and gpl30 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. CNTF increased Akt-S473 phosphorylation in soleus and EDL; however, AMPK-T172 phosphorylation was only increased in soleus. Incubation of muscles from AMPK kinase dead (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 (high-fat diet and ob/ob) despite normal induction of gpl30/AMPK signaling - effects also observed when treating myotubes with C2ceramide.
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.
Diabetes 58:829-839, 2009
Skeletal muscle glucose uptake is regulated by both intrinsic and circulating factors involving the phosphatidylinositol (PI3)-kinase/Akt and the AMP-activated protein kinase (AMPK) signaling pathways (1). The regulation of muscle glucose uptake by both pathways converges on AS160 (TBC1D4) and TBClDl where phosphorylation inhibits the negative regulation of GLUT4 vesicle translocation (2-4) to the plasma membrane (5,6). In insulin-resistant skeletal muscle, reduced insulin receptor substrate (IRS) and Akt activation results in reduced skeletal muscle glucose uptake (7,8). In contrast, activation of AMPK by endogenous circulating factors, including adiponectin (9,10) and interleuken (IL)-6 (11-13), and by pharmacological agents such as 5-aminoimidazole4-carboxamide riboside (AICAR) (14,15) increases muscle glucose uptake, and this response is maintained in muscle from diabetic...