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Submitted on December 15, 2005
Accepted on April 24, 2006
St Vincent’s Institute Fitzroy, 3065, Department of Medicine, St. Vincent’s Hospital, Fitzroy, 3065, Department of Medicine, Heidelberg Repatriation Hospital, Heidelberg 3081, and Department of Physiology, Parkville 3052, University of Melbourne, CSIRO Molecular and Health Technologies, 343 Royal Parade, Parkville, 3052, Cellular & Molecular Metabolism Laboratory, School of Medical Sciences, Royal Melbourne Institute of Technology, Bundoora, 3083; Victoria Australia
* To whom correspondence should be addressed. E-mail: gsteinberg{at}svi.edu.au.
We have examined the actions of a second generation ciliary neurotrophic factor analog (CNTFAx15) on AMP-activated protein kinase (AMPK)-a known regulator of food intake. Unlike leptin CNTFAx15 has been shown to reduce food intake in obese rodents and humans. Intraperitoneal (ip) injection of CNTFAx15, acutely (45 min) reduced hypothalamic AMPK
2 activity, AMPK2Thr172 phosphorylation and acetyl-CoA carboxylase (ACC) phosphorylation, effects not observed 2 or 6 h post injection. Intracerebroventricular (icv) CNTFAx15 reduced food intake, increased arcuate nucleus (ARC) signal transducer and activator of transcription 3 (STAT3) phosphorylation and reduced AMPK signaling, but not in the paraventricular nucleus (PVN), posterior hypothalamus (PH) or cortex. To compare the effects of leptin and CNTFAx15 in a diet-induced model of obesity mice were fed a control carbohydrate (CON) or high-fat diet (HFD) for 12 weeks. 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 ACC 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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