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胃促生长素

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胃促生长素[1][2]（ghrelin，lenomorelin）全名胃生长激素释放肽（growth hormone-releasing peptide）[3]，俗称饥饿素（hunger hormone），是一种主要由胃肠道（尤其是胃）的肠内分泌细胞（英语：Enteroendocrine cell）（P/D1细胞（英语：P/D1 cell））产生的激素，属一种多功能脑肠肽（胃肠道神经肽）[4][5]，能诱导生长激素的释放、胃肠道功能调节、摄食、抑制炎症反应，并维持能量正平衡的作用。

它被称为饥饿素是因为它会增加进食的动力[5]，在餐前饥饿时，饥饿素在血液中浓度最高，进食后恢复到较低水平[5][6]。饥饿素可能透过增加胃的活动性和刺激胃酸分泌来帮助进食准备[5][7]。

饥饿素能够激活脑垂体前叶和下丘脑弓状核中的细胞，[5][8]其中包括可引起食欲的神经肽Y神经元。[5][9]饥饿素能够刺激具有特定受体的大脑结构：饥饿素受体1A（GHSR -1A）。[5][10]饥饿素同时也能够调节神经结构中的犒赏系统[11]、学习和记忆，睡眠-苏醒周期、味觉、犒赏行为和葡萄糖代谢。[5][12][13]

历史与命名

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饥饿素的首次发现是在1999年[5]发现了饥饿素受体（称为生长激素促分泌素受体1A或GHS-R）之后。其命名是以它能够“促生长激素分泌”的功能来命名，源自于原始印欧语中的gʰre，意谓成长。[5]

基因、转录产物与构造

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其GHRL基因产生的mRNA有四个外显子，并产生五种产物：第一种是117个氨基酸的前饥饿素原。（与促胃动素原同源；两者都是促胃动素家族的成员）。将前饥饿素原剪接后产生饥饿素原，再剪接后产生一个具有28个氨基酸的未酰化饥饿素和一个酰化饥饿素（C-Gherlin）。据推测，肥胖抑制素可能从C-ghrelin剪接而成。[14]

饥饿素只有在饥饿素酰基转移酶 （页面存档备份，存于互联网档案馆）（GOAT）的帮助下，结构中的辛酸在翻译后与丝氨酸的3号位连接时才具有活性。它位于胃和胰脏中的饥饿素细胞的细胞膜上[15]，而未辛酰化的形式则称为去酰基饥饿素，其无法激活GHS-R受体，但具有其他作用：心脏方面的功能[16]、刺激食欲[17]和抑制肝脏输出葡萄糖[18]。同时也观察到，辛酰基以外的侧链也可以触发饥饿素受体[19]。 特别的是，已发现癸酰饥饿素在小鼠循环中的饥饿素站了一定比例，但截至2011年，其在人体中的存在尚未确定。[20]

前饥饿素原(蓝色和绿色的部分)及饥饿素(绿色部分)

饥饿素细胞

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别名

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饥饿素细胞也被称为胰脏的A-like cell、X-cell（X意谓功能不明）、小鼠中的X/A-like cell、胰脏中的ε细胞、人体的P/D sub 1 cell、或Gr cell（Gherlin的简称）[21]。

位置

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饥饿素细胞主要存在于胃[22]和十二指肠中，但也存在于空肠、肺、胰岛[23]、性腺、肾上腺皮质、胎盘和肾脏中。最近也有研究显示，饥饿素能够在大脑局部产生[24]。

特色

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饥饿素细胞存在于胃底腺细胞中（占细胞的20％）[25]、幽门和小肠中，是卵圆形的颗粒性细胞[26]，同时具有胃泌素受体[27]，且有一些能够产生脂肪激素nesfatin-1[28]。饥饿素细胞在胰脏中没有终末分化的步骤，它们作为前驱细胞，可以产生A细胞、PP细胞和β细胞。[29]

作用的功能与机制

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饥饿素参与调节能量平衡（英语：Energy_homeostasis）的复杂过程，透过调节饥饿讯号来影响能量输入;调节ATP生产、脂肪储存、肝糖储存及短期热消耗等能量比例调节来影响能量输出。能量平衡的结果最终反映在体重上，并根据代谢信号和需求进行持续监测调整。而胃脑沟通是影响能量平衡的重要途径，有几种沟通路径，其中包括胃细胞内mTOR（英语：mTOR） / S6K1（英语：S6_Kinase_1 S6K1）路径所调节的饥饿素、nesfatin（英语：Nesfatin-1）及内源性大麻素（英语：Endocannabinoid_system）胃系统彼此间的交互作用，[30]及迷走神经的传出入讯号。

饥饿素及合成饥饿素模拟物(生长激素促进剂（英语：Growth_hormone_secretagogue）)透过诱发含神经肽Y(NPY)（英语：Neuropeptide_Y）及刺鼠肽基因相关蛋白(AgRP)（英语：Agouti-related_peptide）[31][9]的弓形核[8]受体来增加体重及脂肪量。[32][33][34]这些对饥饿素反应的神经元对瘦素及胰岛素均敏感。[35]而饥饿素会降低胃迷走神经传入（英语：Afferent_nerve_fiber）的敏感性，导致较低的胃扩张程度。[36]

除了其能量平衡的功能，饥饿素还会激活胆碱能-多巴胺能犒赏回路在腹侧被盖区的输入，以及用来传达自然犒赏的享乐和增强方面的回路，[37]如食物和成瘾性药物[35][38][39]的中脑边缘通路。[40]该回路上可以找到饥饿素的受体。[37][11]而酒精[41]及可口/奖励食物[42][43]是需要下丘脑饥饿素讯号来提供回馈。

饥饿素与诱导食欲及进食行为有关，而血液循环中的饥饿素水平会在饭前最高、饭后最低。[44][45]在人和大鼠注射饥饿素已证明会增加食物摄取，即注射量越多，食物摄取越多[46]，但饥饿素所增加的不是进食量，而是进食的次数。[47]饥饿素的注射还会增加动物觅食行为，同时增加嗅觉寻找能力，倾向搜集囤积食物。由于体重是透过能量平衡来调节的，饥饿素浓度与体重会呈负相关，由此饥饿素可以做为肥胖警讯。[7]

血液中浓度

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饥饿素在血液中的浓度在pmol / l的范围内。具有活性的饥饿素含量和总饥饿素含量都可以被测量出来[48] 。循环中的饥饿素浓度在进食前升高，并在进食后下降[44]，并且对于蛋白质和碳水化合物的反应比对脂质的反应更强烈。[20]

饥饿素受体

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饥饿素受体GHS-R1A（由饥饿素受体剪接而来）可以调节多项饥饿素造成的生物效应，包括：刺激生长激素的释放、增加饥饿感、调节葡萄糖和脂质的代谢、调节肠胃蠕动和分泌、保护神经和心血管细胞以及调节免疫功能。[49]它们大量存在于下丘脑和脑垂体、迷走神经上（在传入的细胞体和传出的神经末梢上）以及整个胃肠道中。[15]

作用地点

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葡萄糖代谢

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整个饥饿素系统（包含dAG、AG、GHS-R、GOAT）皆具有调节葡萄糖的作用。[50]

睡眠

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初步研究表明，饥饿素参与了昼夜规律的调节[5]。虽然有文献表示，没有发现有力的证据显示限制睡眠会影响饥饿素以及瘦素的浓度或能量消耗。[51]

生殖系统

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饥饿素对促性腺激素释放激素（GnRH）的分泌具有抑制作用，可能导致生育力下降。[52]

胎儿和新生儿

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饥饿素在胎儿时期的早期肺脏产生，并具有促进肺生长的功能。[53] 脐带血中饥饿素的浓度也显示，饥饿素浓度和新生儿出生体重之间的相关性。[48]

厌食症和肥胖

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肥胖个体血浆中的饥饿素浓度低于瘦型个体[5][54]，由此显示，饥饿素并不直接造成肥胖，只有在小胖威利综合征引起的肥胖中，高浓度的饥饿素能够造成食物摄入量的增加[55][55]。与体重过轻和正常体重的两个对照组相比，神经性厌食症的血浆饥饿素浓度更高[56][57][58]。体型较为削瘦的人在一天中，从午夜到黎明的这段时间的饥饿素浓度较高，这显示肥胖者的昼夜规律系统存在缺陷[59]。同时，癌症引起的恶体质患者也有高浓度的饥饿素[60]。尚无足够的证据得出支持或反对使用生长素释放肽治疗癌症相关恶体质的结论[61]。

相关疾病的控管与治疗

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胃绕道手术

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与体型瘦削和节食减肥的人相比，进行胃绕道手术的人不仅减少了肠道容量，甚至能够降低体内饥饿素浓度。[5][62]在此方面，尚未有研究阐明，接受胃绕道手术的人，体内的饥饿素浓度是否在减轻的体重稳定下来后就恢复正常浓度。[63]统计也显示，胃绕道的相关手术中，进行袖状胃切除术（英语：Sleeve_gastrectomy）的人从长远来看，体内饥饿素浓度能够降低约60％。[64]

参见

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参考文献

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