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 AMPKalpha2 activity, AMPKalpha2Thr172 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.