Abstract
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 CNTFRα–IL-6R–gp130β 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.
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Acknowledgements
We thank AMRAD Operations Pty. Ltd (Richmond, Victoria, Australia) and A. Yoshimura (Kyushu University, Japan) for providing the SOCS3 and STAT3 double-negative adenovirus constructs. We also thank G. Rice and G. Barker from the Royal Women's Hospital (Parkville Victoria, Australia) for assistance with cytokine and hormone analyses, S. Ricardo (Monash University) for db/db mice, A. Allen (Melbourne University) for assistance with intracerebroventricular experiments and N. Owens (RMIT University) for assistance with the graphics. This work was supported in part by research grants from the National Health and Medical Research Council (NHMRC) of Australia (M.A.F and B.E.K.), RMIT Faculty of Life Sciences (M.J.W.), and the Australian Research Council (M.A.F. and B.E.K.). M.J.W. is supported by a Peter Doherty Post Doctoral Fellowship and M.A.F. by a Senior Research Fellowship from the NHMRC. B.E.K. is an Australian Research Council Federation Fellow. G.R.S. is supported by a 'Target Obesity' Fellowship from the Canadian Institutes of Health Research and the Heart and Stroke Foundation.
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Supplementary information
Supplementary Fig. 1
The CNTFR, IL-6R and LIFR are expressed in red and white mouse muscle. (PDF 144 kb)
Supplementary Fig. 2
CNTF administration affects STAT signaling and metabolic gene expression in white gastrocnemius muscle. (PDF 168 kb)
Supplementary Fig. 3
High-fat feeding increases food intake body mass, glucose intolerance and insulin resistance. (PDF 165 kb)
Supplementary Fig. 4
CNTF treatment rescues high-fat diet–induced decreases in PGC-1α protein expression. (PDF 125 kb)
Supplementary Fig. 5
The insulin-sensitizing effect of CNTF in muscle cells is dependent upon AMPK activation. (PDF 125 kb)
Supplementary Table 1
Effects of acute CNTF treatment on markers of inflammation. (PDF 21 kb)
Supplementary Table 2
Plasma metabolites and adipokines without or with 7 days of CNTF treatment. (PDF 22 kb)
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Watt, M., Dzamko, N., Thomas, W. et al. CNTF reverses obesity-induced insulin resistance by activating skeletal muscle AMPK. Nat Med 12, 541–548 (2006). https://doi.org/10.1038/nm1383
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DOI: https://doi.org/10.1038/nm1383
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