Ciliary neurotrophic factor AX15 alters energy homeostasis, decreases body weight, and improves metabolic control in diet-induced obese and UCP1-DTA mice

Ciliary neurotrophic factor (CNTF) potently reduces appetite and body weight in rodents and humans. We studied the short- and long-term effects of CNTFAx15, a second-generation CNTF analog, in diet-induced obese C57BL/6J mice and brown adipose tissue (BAT)-deficient obese UCP1-DTA (uncoupling protein 1-diphtheria toxin A) mice. CNTFAx15 administration (0.1, 0.3, or 1.0 mug (.) g(-1) (.) day(-1) s.c.) for 3 or 7 days reduced food intake and body weight (mainly body fat mass). The effect of CNTFAx15 on food intake and body weight was more pronounced in CNTFAx15-treated diet-induced obese C57BL/6J mice compared with pair-fed controls and was associated with suppressed expression of hypothalamic neuropeptide Y and agouti gene-related protein. Moreover, CNTFAx15 increased uncoupling protein 1 mRNA expression in BAT and energy expenditure in diet-induced obese C57BL/6J mice. Longitudinal observations revealed a sustained reduction in body weight for several days post-CNTFAx15 treatment of CNTFAx15-treated but not pair-fed mice, followed by a gradual regain in body weight over 28 days. Finally, CNTFAx15 administration improved the metabolic profile in both diet-induced obese C57BL/6J and UCP1-DTA mice and resulted in a significantly improved glycemic response to oral glucose tolerance tests in CNTFAx15-treated UCP1-DTA compared with pair-fed mice of similar body weight. These data suggest that CNTFAx15 may act through a pathway downstream of the putative point responsible for leptin resistance in diet-induced obese C57BL/6J and UCP1-DTA mice to alter food intake, body weight, body composition, and metabolism. CNTFAx15 has delayed and persistent effects in diet-induced obese C57BL/6J mice, which account for a reduction in body weight over and above what would be expected based on decreased foot intake alone.