Glucagon-like peptide-1, corticotropin-releasing hormone, and hypothalamic neuronal histamine interact in the leptin-signaling pathway to regulate feeding behavior
Glucagon-like peptide-1, corticotropin-releasing hormone, and hypothalamic neuronal histamine interact in the leptin-signaling pathway to regulate feeding behavior
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DOI：
10.1096/fj.04-2384fje
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发表时间：
2005-05-01
期刊：
影响因子：
4.8
通讯作者：
Yoshimatsu, H
中科院分区：
文献类型：
--
作者：
Gotoh, K;Fukagawa, K;Yoshimatsu, H
胰高血糖素样肽-1(GLP-1)、促肾上腺皮质激素释放激素(CRH)和下丘脑神经元组胺抑制食物摄入，这是瘦素在大脑中作用的目标。这项研究考察了GLP-1、CRH和瘦素信号通路下游的组胺在调节摄食行为中的相互作用。与磷酸盐缓冲盐水(PBS)对照组相比，向第三脑室(I3vt)注入GLP-1(1mgGLP-1)可显著减少大鼠最初1h的累积摄食量。GLP-1引起的摄食抑制可被组氨酸脱羧酶的特异性自杀性抑制剂α-氟甲基组氨酸(FMH)部分减弱，FMH可耗尽下丘脑神经元组胺。预先给予非选择性CRH拮抗剂α-螺旋CRH(10mUg/只，13vt)，可完全消除GLP-1引起的摄食抑制。~3VT注射GLP-1可增加CRH含量和组胺转换率，以帕吉林诱导的神经元性组胺的主要代谢物--端甲基组胺(t-MH)在下丘脑的积聚来评估。中枢注射CRH也可引起组胺转换率增加，CRH 1型受体定位于组胺神经元胞体。预先给予GLP-1受体激动剂exendin(9-39)可减轻瘦素引起的下丘脑CRH含量的增加。最后，i3vt注射瘦素也增加了下丘脑中组胺的周转。预先给予exendin(9-39)、α-螺旋CRH或两种拮抗剂均可减弱瘦素诱导的下丘脑t-MH水平的反应。这些结果表明，CRH或下丘脑神经元组胺介导了GLP-1对摄食行为的抑制，CRH介导了GLP-1对神经元组胺的信号转导，GLP-1通过CRH与神经元组胺的功能联系构成了调节摄食行为的瘦素信号通路。
Glucagon-like peptide-1 (GLP-1), corticotropin-releasing hormone (CRH), and hypothalamic neuronal histamine suppress food intake,a target of leptin action in the brain. This study examined the interactions of GLP-1, CRH, and histamine downstream from the leptin-signaling pathway in regulating feeding behavior. Infusion of GLP-1 into the third cerebral ventricle (i3vt) at a dose of 1 mu g significantly decreased the initial 1 h cumulative food intake in rats as compared with phosphate-buffered saline (PBS) controls. The GLP-1-induced suppression of feeding was partially attenuated by intraperitoneal pretreatment with alpha-fluoromethylhistidine (FMH), a specific suicide inhibitor of histidine decarboxylase, which depletes hypothalamic neuronal histamine. Pretreatment with alpha-helical CRH (10 mu g/rat, i3vt), a nonselective CRH antagonist, abolished the GLP-1-induced suppression of feeding completely. I3vt infusion of GLP-1 increased the CRH content and histamine turnover assessed using the pargyline-induced accumulation of tele-methyl histamine(t-MH), a major metabolite of neuronal histamine,in the hypothalamus. The central infusion of CRH also induced the increase of histamine turnover and CRH receptor type 1 was localized on the cell body of histamine neuron. Pretreatment with exendin(9-39), a GLP-1 receptor ant agonist, attenuated the leptin-induced increase in CRH content of the hypothalamus. Finally,i3vt infusion of leptin also increased histamine turnover in the hypothalamus. Pretreatment with exendin(9-39), alpha-helical CRH or both antagonists attenuated the leptin-induced responses of t-MH levels in the hypothalamus. These results suggest that CRH or hypothalamic neuronal histamine mediates the GLP-1-induced suppression of feeding behavior, that CRH mediates GLP-1 signaling to neuronal histamine and that a functional link from GLP-1 to neuronal histamine via CRH constitutes the leptin-signaling pathway regulating feeding behavior.