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Ciliary Neurotrophic Factor_Ax15 Alters Energy Homeostasis, Decreases Body Weight, and Improves Metabolic Control in Diet-Induced Obese and UCP1-DTA Mice

¹ Department of Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts
² Joslin Diabetes Center, Harvard Medical School, Research Division, Boston, Massachusetts
³ Regeneron Pharmaceuticals, Tarrytown, New York

Ciliary neurotrophic factor (CNTF) potently reduces appetite and body weight in rodents and humans. We studied the short- and long-term effects of CNTF_Ax15, 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. CNTF_Ax15 administration (0.1, 0.3, or 1.0 µg · g^–1 · day^–1 s.c.) for 3 or 7 days reduced food intake and body weight (mainly body fat mass). The effect of CNTF_Ax15 on food intake and body weight was more pronounced in CNTF_Ax15-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, CNTF_Ax15 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-CNTF_Ax15 treatment of CNTF_Ax15-treated but not pair-fed mice, followed by a gradual regain in body weight over 28 days. Finally, CNTF_Ax15 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 CNTF_Ax15-treated UCP1-DTA compared with pair-fed mice of similar body weight. These data suggest that CNTF_Ax15 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. CNTF_Ax15 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.

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