Signaling specificity of interleukin-6 action on glucose and lipid metabolism in skeletal muscle.
We identified signaling pathways by which IL-6 regulates skeletal muscle differentiation and metabolism. Primary human skeletal muscle cells were exposed to IL-6 (25 ng/ml either acutely or for several days), and small interfering RNA gene silencing was applied to measure glucose and fat metabolism. Chronic IL-6 exposure increased myotube fusion and formation and the mRNA expression of glucose transporter 4, peroxisome proliferator activated receptor (PPAR)alpha, PPARdelta, PPARgamma, PPARgamma coactivator 1, glycogen synthase, myocyte enhancer factor 2D, uncoupling protein 2, fatty acid transporter 4, and IL-6 (P < 0.05), whereas glucose transporter 1, CCAAT/enhancer-binding protein-alpha, and uncoupling protein 3 were decreased. IL-6 increased glucose incorporation into glycogen, glucose uptake, lactate production, and fatty acid uptake and oxidation, concomitant with increased phosphorylation of AMP-activated protein kinase (AMPK), signal transducer and activator of transcription 3, and ERK1/2. IL-6 also increased phosphatidylinositol (PI) 3-kinase activity (450%; P < 0.05), which was blunted by subsequent insulin-stimulation (P < 0.05). IL-6-mediated glucose metabolism was suppressed, but lipid metabolism was unaltered, by inhibition of PI3-kinase with LY294002. The small interfering RNA-directed depletion of AMPK reduced IL-6-mediated fatty acid oxidation and palmitate uptake but did not reduce glycogen synthesis. In summary, IL-6 increases glycogen synthesis via a PI3-kinase-dependent mechanism and enhances lipid oxidation via an AMPK-dependent mechanism in skeletal muscle. Thus, IL-6 directly promotes skeletal muscle differentiation and regulates muscle substrate utilization, promoting glycogen storage and lipid oxidation.
Al-Khalili
Lubna
L
Department of Molecular Medicine and Surgery, Karolinska Institutet, 171 77 Stockholm, Sweden.
Bouzakri
Karim
K
Glund
Stephan
S
Lönnqvist
Fredrik
F
Koistinen
Heikki A
HA
Krook
Anna
A
D055372:AMP-Activated Protein Kinases; D002478:Cells, Cultured; D002867:Chromones / Q000494:pharmacology; D005227:Fatty Acids / Q000378:metabolism; D005947:Glucose / Q000378:metabolism*; D051272:Glucose Transporter Type 1 / Q000235:genetics / Q000378:metabolism; D051275:Glucose Transporter Type 4 / Q000235:genetics / Q000378:metabolism; D006003:Glycogen / Q000096:biosynthesis; D006801:Humans; D015850:Interleukin-6 / Q000494:pharmacology*; D019344:Lactic Acid / Q000378:metabolism; D050356:Lipid Metabolism / Q000187:drug effects*; D009025:Morpholines / Q000494:pharmacology; D009097:Multienzyme Complexes / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D018485:Muscle Fibers, Skeletal / Q000378:metabolism*; D018482:Muscle, Skeletal / Q000187:drug effects* / Q000254:growth & development / Q000648:ultrastructure; D010084:Oxidation-Reduction; D047492:Peroxisome Proliferator-Activated Receptors / Q000235:genetics / Q000378:metabolism; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D000081082:Phosphoinositide-3 Kinase Inhibitors; D010766:Phosphorylation; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D034741:RNA, Small Interfering / Q000494:pharmacology; D015398:Signal Transduction / Q000187:drug effects*
D055372:AMP-Activated Protein Kinases; D002867:Chromones; D005227:Fatty Acids; D005947:Glucose; D051272:Glucose Transporter Type 1; D051275:Glucose Transporter Type 4; D006003:Glycogen; D015850:Interleukin-6; D019344:Lactic Acid; D009025:Morpholines; D009097:Multienzyme Complexes; D047492:Peroxisome Proliferator-Activated Receptors; D019869:Phosphatidylinositol 3-Kinases; D000081082:Phosphoinositide-3 Kinase Inhibitors; D017346:Protein Serine-Threonine Kinases; D034741:RNA, Small Interfering; C085911:2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one