CNTF reverses obesity-induced insulin resistance by activating skeletal muscle AMPK.
Ciliary neurotrophic factor (CNTF) induces weight loss and improves glucose tolerance in humans and rodents. CNTF is thought to act centrally by inducing hypothalamic neurogenesis to modulate food intake and peripherally by altering hepatic gene expression, in a manner similar to that of leptin. Here, we show that CNTF signals through the CNTFRalpha-IL-6R-gp130beta receptor complex to increase fatty-acid oxidation and reduce insulin resistance in skeletal muscle by activating AMP-activated protein kinase (AMPK), independent of signaling through the brain. Thus, our findings further show that the antiobesogenic effects of CNTF in the periphery result from direct effects on skeletal muscle, and that these peripheral effects are not suppressed by diet-induced or genetic models of obesity, an essential requirement for the therapeutic treatment of obesity-related diseases.
Watt
Matthew J
MJ
Cellular and Molecular Metabolism Laboratory, School of Medical Sciences, Royal Melbourne Institute of Technology, PO Box 71, Bundoora, 3083, Australia.
Dzamko
Nicolas
N
Thomas
Walter G
WG
Rose-John
Stefan
S
Ernst
Matthias
M
Carling
David
D
Kemp
Bruce E
BE
Febbraio
Mark A
MA
Steinberg
Gregory R
GR
D055372:AMP-Activated Protein Kinases; D000818:Animals; D001835:Body Weight; D002478:Cells, Cultured; D020934:Ciliary Neurotrophic Factor / Q000378:metabolism*; D050822:Cytokine Receptor gp130 / Q000378:metabolism; D004789:Enzyme Activation; D005227:Fatty Acids / Q000378:metabolism; D005786:Gene Expression Regulation; D006801:Humans; D007249:Inflammation; D007333:Insulin Resistance / Q000502:physiology*; D053680:Leukemia Inhibitory Factor Receptor alpha Subunit; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009097:Multienzyme Complexes / Q000378:metabolism*; D018482:Muscle, Skeletal / Q000166:cytology / Q000378:metabolism*; D009765:Obesity; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism*; D020801:Receptor, Ciliary Neurotrophic Factor / Q000378:metabolism; D018121:Receptors, Cytokine / Q000378:metabolism; D019947:Receptors, Interleukin-6 / Q000378:metabolism; D053606:Receptors, OSM-LIF; D015398:Signal Transduction / Q000502:physiology; D000071223:Suppressor of Cytokine Signaling 3 Protein; D050826:Suppressor of Cytokine Signaling Proteins / Q000378:metabolism
D020934:Ciliary Neurotrophic Factor; D005227:Fatty Acids; C507840:LIFR protein, human; D053680:Leukemia Inhibitory Factor Receptor alpha Subunit; C507841:Lifr protein, mouse; D009097:Multienzyme Complexes; D020801:Receptor, Ciliary Neurotrophic Factor; D018121:Receptors, Cytokine; D019947:Receptors, Interleukin-6; D053606:Receptors, OSM-LIF; C491411:Socs3 protein, mouse; D000071223:Suppressor of Cytokine Signaling 3 Protein; D050826:Suppressor of Cytokine Signaling Proteins; D050822:Cytokine Receptor gp130; D017346:Protein Serine-Threonine Kinases; D055372:AMP-Activated Protein Kinases