Des-acyl ghrelin induces food intake by a mechanism independent of the growth hormone secretagogue receptor
Des-acyl ghrelin induces food intake by a mechanism independent of the growth hormone secretagogue receptor
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DOI：
10.1210/en.2005-1357
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发表时间：
2006-05-01
期刊：
影响因子：
4.8
通讯作者：
Nakazato, M
中科院分区：
文献类型：
--
作者：
Toshinai, K;Yamaguchi, H;Nakazato, M
胃饥饿素是一种主要在胃中产生的酰化肽，通过与促生长激素1a型受体（GHS-R1a） （GHS-R的功能活性形式）相互作用，刺激摄食和生长激素分泌。胃饥饿素分子以两种主要的内源性形式存在于胃和下丘脑中，一种是丝氨酸3酰化的形式（胃饥饿素），另一种是去酰化的形式（去酰基胃饥饿素）。酰化对于ghrelin与GHS-R1a的结合是必不可少的。Ghrelin通过神经肽Y和食欲素的神经元通路增强摄食，它们在下丘脑中作为食氧肽。我们在此研究了去酰基胃饥饿素对摄食行为的影响。在光照期给大鼠或小鼠自由喂食大鼠去酰基胃饥饿素（deacyl ghrelin）；去酰基胃促生长素对禁食小鼠均无抑制摄食作用。在下丘脑外侧区表达食欲素的神经元中，icv给药能诱导Fos（神经元激活的标志物）的表达，但在弓状核中表达神经肽y的神经元中则不能。大鼠或小鼠外周注射去酰基胃促生长素对摄食没有影响。虽然肠促生长素在ghs - r缺陷小鼠中没有诱导进食，但在食欲素缺乏小鼠中却有。相比之下，静脉注射去酰基胃饥饿素刺激ghs - r缺陷小鼠的摄食，但不刺激食欲素缺陷小鼠的摄食。去-酰基胃饥饿素增加离体食欲素神经元细胞内钙浓度。中枢去酰基胃饥饿素可能激活表达食欲素的神经元，可能通过与不同于GHS-R的靶蛋白相互作用在摄食调节中起作用。
Ghrelin, an acylated peptide produced predominantly in the stomach, stimulates feeding and GH secretion via interactions with the GH secretagogue type 1a receptor (GHS-R1a), the functionally active form of the GHS-R. Ghrelin molecules exist in the stomach and hypothalamus as two major endogenous forms, a form acylated at serine 3 (ghrelin) and a des-acylated form (des-acyl ghrelin). Acylation is indispensable for the binding of ghrelin to the GHS-R1a. Ghrelin enhances feeding via the neuronal pathways of neuropeptide Y and orexin, which act as orexigenic peptides in the hypothalamus. We here studied the effect of des-acyl ghrelin on feeding behavior. Intracerebroventricular (icv) administration of rat des-acyl ghrelin to rats or mice fed ad libitum stimulated feeding during the light phase; neither ip nor icv administration of des-acyl ghrelin to fasting mice suppressed feeding. The icv administration of des-acyl ghrelin induced the expression of Fos, a marker of neuronal activation, in orexin-expressing neurons of the lateral hypothalamic area, but not neuropeptide Y-expressing neurons of the arcuate nucleus. Peripheral administration of des-acyl ghrelin to rats or mice did not affect feeding. Although icv administration of ghrelin did not induce food intake in GHS-R-deficient mice, it did in orexin-deficient mice. In contrast, icv administration of des-acyl ghrelin stimulated feeding in GHS-R-deficient mice, but not orexin-deficient mice. Des-acyl ghrelin increased the intracellular calcium concentrations in isolated orexin neurons. Central desacyl ghrelin may activate orexin-expressing neurons, perhaps functioning in feeding regulation through interactions with a target protein distinct from the GHS-R.