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Ciliary Neurotrophic Factor Suppresses Hypothalamic AMP-Kinase Signaling in Leptin-Resistant Obese Mice

St. Vincent’s Institute (G.R.S., B.E.K.) and Department of Medicine (G.R.S., B.E.K.), St. Vincent’s Hospital, Fitzroy 3065, Australia; Department of Medicine (B.C.F., J.P., S.A.), Heidelberg Repatriation Hospital, 3081 Heidelberg, Germany; Department of Physiology (A.M.A.), University of Melbourne, and Commonwealth Scientific and Industrial Research Organization Molecular and Health Technologies (B.E.K.), Parkville 3052, Australia; and Cellular and Molecular Metabolism Laboratory (M.J.W., M.A.F.), School of Medical Sciences, Royal Melbourne Institute of Technology, Bundoora, Victoria 3083, Australia

Address all correspondence and requests for reprints to: Gregory R. Steinberg, St. Vincent’s Institute, 9 Princes Street, Fitzroy, Victoria 3065, Australia. E-mail: gsteinberg{at}svi.edu.au.

We examined the actions of a second-generation ciliary neurotrophic factor analog (CNTF_Ax15) on AMP-activated protein kinase (AMPK), a known regulator of food intake. Unlike leptin CNTF_Ax15 has been shown to reduce food intake in obese rodents and humans. Intraperitoneal injection of CNTF_Ax15 acutely (45 min) reduced hypothalamic AMPK2 activity, AMPK2Thr172 phosphorylation, and acetyl-coenzyme A carboxylase phosphorylation, effects not observed 2 or 6 h after injection. Intracerebroventricular CNTF_Ax15 reduced food intake, increased arcuate nucleus (ARC) signal transducer and activator of transcription 3 phosphorylation, and reduced AMPK signaling but not in the paraventricular nucleus (PVN), posterior hypothalamus, or cortex. To compare the effects of leptin and CNTF_Ax15 in a diet-induced model of obesity, mice were fed a control carbohydrate or high-fat diet (HFD) for 12 wk. Leptin treatment ip reduced food intake in control mice but not in mice fed a HFD. In contrast, ip CNTF markedly reduced food intake in both control and HFD animals. Both leptin and CNTF reduced AMPK activity and acetyl-coenzyme A carboxylase phosphorylation in the ARC and PVN of control-fed mice. A HFD blunted leptin but not CNTF effects on AMPK signaling in the ARC and PVN. In summary, these data demonstrate that CNTF_Ax15 bypasses diet-induced leptin resistance to reduce hypothalamic AMPK activity.

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