CNTF reverses obesity-induced insulin resistance by activating skeletal muscle AMPK

Matthew J Watt¹, Nicolas Dzamko², Walter G Thomas³, Stefan Rose-John⁴, Matthias Ernst⁵, David Carling⁶, Bruce E Kemp^2, 7, Mark A Febbraio¹ & Gregory R Steinberg²

¹  Cellular and Molecular Metabolism Laboratory, School of Medical Sciences, Royal Melbourne Institute of Technology, PO Box 71, Bundoora, 3083, Australia.

²  St. Vincent's Institute and Department of Medicine, University of Melbourne, 9 Princess St Fitzroy, 3065, Australia.

³  Molecular Endocrinology Laboratory, Baker Heart Research Institute, PO Box 6492 St. Kilda Road Central, Melbourne 3008, Australia.

⁴  Department of Biochemistry, Christian-Albrechts-Universität zu Kiel, Olshausenstrae 40, D-24098 Kiel, Germany.

⁵  Colon Molecular and Cell Biology Laboratory, Ludwig Institute for Cancer Research, PO Box 2008, Royal Melbourne Hospital, Victoria 3050, Australia.

⁶  Medical Research Council Clinical Sciences Centre, Cellular Stress Group, Imperial College London, Hammersmith Hospital Campus, DuCane Road, London W12 0NN, UK.

⁷  Commonwealth Scientific and Industrial Research Organisation Health Sciences and Nutrition, 343 Royal Parade, Parkville, Victoria 3052, Australia.

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 CNTFR–IL-6R–gp130 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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