Ciliary neurotrophic factor suppresses hypothalamic AMP-kinase signaling in leptin-resistant obese mice

We 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 injection of CNTFAx15 acutely (45 min) reduced hypothalamic AMPK{alpha}2 activity, AMPK{alpha}2Thr172 phosphorylation, and acetyl-coenzyme A carboxylase phosphorylation, effects not observed 2 or 6 h after injection. Intracerebroventricular CNTFAx15 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 CNTFAx15 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 CNTFAx15 bypasses diet-induced leptin resistance to reduce hypothalamic AMPK activity.