Gloaguen I, Costa P, Demartis A, Lazzaro D, Di Marco A, Graziani R, Paonessa G, Chen F, Rosenblum C I, Van der Ploeg L H, Cortese R, Ciliberto G, Laufer R
Istituto di Ricerche di Biologia Molecolare P. Angeletti (IRBM), Via Pontina km 30.600, 00040 Pomezia, Rome, Italy.
Proc Natl Acad Sci U S A. 1997 Jun 10;94(12):6456-61. doi: 10.1073/pnas.94.12.6456.
Receptor subunits for the neurocytokine ciliary neurotrophic factor (CNTF) share sequence similarity with the receptor for leptin, an adipocyte-derived cytokine involved in body weight homeostasis. We report here that CNTF and leptin activate a similar pattern of STAT factors in neuronal cells, and that mRNAs for CNTF receptor subunits, similarly to the mRNA of leptin receptor, are localized in mouse hypothalamic nuclei involved in the regulation of energy balance. Systemic administration of CNTF or leptin led to rapid induction of the tis-11 primary response gene in the arcuate nucleus, suggesting that both cytokines can signal to hypothalamic satiety centers. Consistent with this idea, CNTF treatment of ob/ob mice, which lack functional leptin, was found to reduce the adiposity, hyperphagia, and hyperinsulinemia associated with leptin deficiency. Unlike leptin, CNTF also reduced obesity-related phenotypes in db/db mice, which lack functional leptin receptor, and in mice with diet-induced obesity, which are partially resistant to the actions of leptin. The identification of a cytokine-mediated anti-obesity mechanism that acts independently of the leptin system may help to develop strategies for the treatment of obesity associated with leptin resistance.
神经细胞因子睫状神经营养因子（CNTF）的受体亚基与瘦素受体具有序列相似性，瘦素是一种由脂肪细胞产生的细胞因子，参与体重稳态调节。我们在此报告，CNTF和瘦素在神经元细胞中激活相似模式的信号转导和转录激活因子（STAT），并且CNTF受体亚基的信使核糖核酸（mRNA）与瘦素受体的mRNA类似，定位于参与能量平衡调节的小鼠下丘脑核中。全身性给予CNTF或瘦素可导致弓状核中tis-11初级反应基因的快速诱导，这表明这两种细胞因子均可向下丘脑饱食中枢发出信号。与此观点一致，研究发现，对缺乏功能性瘦素的ob/ob小鼠进行CNTF治疗，可减轻与瘦素缺乏相关的肥胖、食欲亢进和高胰岛素血症。与瘦素不同，CNTF还可减轻缺乏功能性瘦素受体的db/db小鼠以及对瘦素作用具有部分抗性的饮食诱导肥胖小鼠的肥胖相关表型。鉴定一种独立于瘦素系统起作用的细胞因子介导的抗肥胖机制，可能有助于制定治疗与瘦素抵抗相关肥胖的策略。
