2. 东南大学附属中大医院药学部, 江苏 南京 210009
2. Department of Pharmacy, Zhongda Hospital, Southeast University, Nanjing 210009, China
5-羟色胺 (5-hydroxytryptamine, 5-HT) 是一种在体内广泛分布的小分子单胺物质, 参与调节机体多种生命活动。在中枢神经系统中, 5-HT作为一种神经递质与情绪、行为、食欲等一系列复杂的生理过程密切相关[1-3]。由于早期较多的研究发现增强脑内5-HT信号具有抑制食欲的作用, 因而激动中枢5-HT系统被认为是改善肥胖等代谢性疾病的潜在靶点[4, 5]。然而, 目前作用于中枢5-HT系统的减肥药物 (如西布曲明、氯卡色林) 由于一些严重不良反应使其临床使用受到限制[6, 7], 表明靶向中枢5-HT系统的代谢综合征治疗策略存在较大的风险。此外, 近年来有研究发现, 抑制小鼠中枢5-HT信号并不会导致肥胖甚至会减轻体重[8, 9], 提示中枢5-HT系统与机体能量代谢调节的复杂性。
机体的能量摄入与消耗的平衡是中枢和外周 (如肝脏、肌肉、脂肪) 多环节协同调控的结果。由于机体中枢与外周均存在5-HT合成与代谢酶系, 并且外周来源的5-HT无法通过血脑屏障, 因此5-HT在中枢和外周组织中形成了相对独立的作用和调控体系。近年来, 有关外周5-HT系统在机体能量代谢调节中的作用取得了较大进展[10-12]。外周5-HT信号通路被发现与肥胖、2型糖尿病等代谢性疾病的病理机制密切相关, 成为代谢综合征防治的潜在突破口。本文就5-HT对外周重要能量代谢调节组织 (脂肪、肝脏、胰岛等) 的调控作用进行综述, 并初步探讨对于相关药物研发的启示, 以期为代谢综合征的干预提供新思路。
1 5-HT的分布、代谢及其受体亚型和相关信号通路体内色氨酸在色氨酸羟化酶 (tryptophan hy droxylase, Tph) 催化下生成5-羟色氨酸 (5-hy droxytryptophan, 5-HTP), 再经芳香族氨基酸脱羧酶 (aromatic amino acid decarboxylase, AADC) 合成5-HT[13], 其中Tph是该过程的限速酶。Tph分为Tph1和Tph2两个亚型, Tph1主要表达在肠嗜铬细胞 (enterochromaffin cell, EC cell)、胸腺等外周组织中, 而Tph2几乎全部表达在中枢神经元和肠神经元中[14]。研究发现, 中枢神经系统的5-HT仅占机体总量的约2%, 其余5-HT都存在于外周组织中[15]。超过90%的外周5-HT由EC细胞合成[13], 且主要储存在血小板中。其他组织 (心脏、肺、胰岛、脂肪组织等) 也可以自身合成少量的5-HT并通过自分泌或旁分泌的方式调节相应组织的功能[12, 16-18]。体内5-HT的灭活通过5-HT选择性再摄取转运体 (serotonin-selective reuptake transporter, SERT) 泵入到细胞内或突触内, 主要被线粒体中的单胺氧化酶分解为5-羟基吲哚乙酸 (5-hydroxyindoleacetic acid, 5-HIAA) 并随尿液排出体外[19]。
细胞外或突触间隙的5-HT通过与细胞膜或突触后膜上相应的5-HT受体 (5-HT receptor, 5-HTR) 结合而发挥作用。5-HTR广泛分布于全身各组织中, 包括7个家族超过14个亚型, 其中除了5-HTR3为配体门控离子通道外, 其余均为G蛋白偶联受体 (G-protein-coupled receptor, GPCR)[20]。5-HTR1包括5-HTR1A、5-HTR1B、5-HTR1D、5-HTR1E和5-HTR1F等5种亚型, 均为Gαi/o蛋白偶联受体, 可以抑制腺苷酸环化酶, 降低环磷酸腺苷 (cyclic adenosine mono phosphate, cAMP) 水平; 5-HTR2是Gαq/11蛋白偶联受体, 可以上调三磷酸肌醇和二酰甘油通路, 导致胞内Ca2+释放, 分为5-HTR2A、5-HTR2B和5-HTR2C三个亚型; 5-HTR3是配体门控离子通道受体, 激活该受体可以导致短暂的内向电流, 触发快速膜去极化, 使非选择性阳离子 (Na+、K+、Ca2+) 通道打开; 其余的受体除5-HTR5作用仍不明确外, 均可以升高cAMP[20, 21]。
2 5-HT与外周能量代谢调节 2.1 5-HT与脂肪组织能量代谢白色脂肪组织 (white adipose tissue, WAT) 是能量储存的主要场所, 同时也是内分泌器官。WAT除了参与机体能量平衡调节外, 还分泌各种脂肪因子调节摄食、胰岛素抵抗和免疫应答等过程。脂肪细胞可以自身合成5-HT, 同时表达丰富的5-HTR。5-HTR2A的表达量在3T3-L1前体脂肪细胞的分化过程中明显上调[12]。在大鼠的原代脂肪细胞分化过程中, 5-HTR2A、5-HTR2B和5-HTR2C表达量明显上调[22], 成熟的大鼠原代脂肪细胞中5-HTR1D、5-HTR2A和5-HTR7表达较丰富[23]。近来研究发现, 外周5-HT可以通过选择性作用于脂肪细胞上不同的5-HTR调节脂肪细胞的合成与分解。Sumara等[24]研究表明在禁食状态下, 肠源型5-HT (gut-derived serotonin, GDS) 通过作用于5-HTR2B, 增加激素敏感性脂肪酶 (hormone sensitive lipase, HSL) 的磷酸化来诱导脂肪分解。S hle等[25]发现对人原代脂肪细胞使用5-HTR2B拮抗剂 (RS127445) 处理后, 可以增加脂肪的累积, 提示5-HT可以通过激动5-HTR2B诱导脂肪分解。而使用5-HTR2A激动剂处理3T3-L1脂肪细胞可以增加脂肪形成相关基因mRNA的表达, 如脂肪酸合成酶基因 (fatty acid synthase, Fasn)、二酯酰甘油酰基转移酶2基因 (diacylglycerol acyltransferase 2, Dgat2) 等[12], 使用5-HTR2A拮抗剂 (酮色林)[12, 26]或5-HTR2C拮抗剂 (SB-242084)[26]则可减少脂肪细胞的脂肪累积, 抑制脂肪形成, 提示5-HT可以通过激动5-HTR2A和5-HTR2C诱导脂肪细胞形成。此外, 5-HT还可以加强胰岛素抗脂质分解作用, 其机制可能与5-HT抑制cAMP/蛋白激酶A (protein kinase A, PKA) 介导的信号通路, 减少HSL的磷酸化、降低脂滴包被蛋白和PKA依赖的底物有关[23]。5-HT这种诱导脂肪形成的作用也得到了体内研究的证实:在高脂饮食 (high-fat diet, HFD) 条件下, 抑制外周5-HT的合成可以改善小鼠脂肪堆积, 降低脂肪细胞大小, 并且减少脂肪形成相关基因mRNA (Fasn、Dgat2等) 的表达[10, 12]。这些研究结果与Sumara等[24]的结果相反, 可能与实验动物所处的代谢状态不同有关。此外, 一些研究发现, 脂肪细胞中5-HIAA也可以直接结合过氧化物酶体增殖物激活受体γ (peroxisome proliferator-activated receptor γ, PPAR-γ) 核受体的配体区结合域, 迅速上调与脂质代谢和脂肪形成相关的PPAR-γ响应基因的表达, 如脂肪酸结合蛋白4基因 (fatty acid binding protein 4, aP2/FABP4)、磷酸烯醇式丙酮酸羧激酶基因 (phosphoenolpyruvate carboxykinase, PEPCK)、脂肪酸转位酶基因 (fatty acid translocase, FAT/CD36) 等, 从而促进甘油三酯 (triglyceride, TG) 的合成和脂质储存[27-29]。
棕色脂肪组织 (brown adipose tissue, BAT) 可维持机体核心体温以抵御寒冷及燃烧过多的能量[30]。BAT分为两种类型, 一种是分布在成人颈部、锁骨上、脊柱旁和肾周等部位的典型的棕色脂肪组织; 另一种是分布在白色脂肪组织中的米色脂肪。米色脂肪在正常状态下或能量过剩时作为储能组织, 当受到相应刺激后 (如冷应激、β肾上腺素能刺激) 可以向典型的BAT转化 (browning), 消耗多余能量发挥产热的作用[31]。近年来, 米色脂肪的browning被认为在阻止肥胖及相关代谢性疾病进展中起着重要作用[31-33]。Crane等[10]研究显示抑制外周5-HT可以增加HFD诱导的小鼠BAT线粒体中解偶联蛋白1 (uncoupling protein 1, UCP1) 的表达, 提升BAT对β肾上腺素能刺激的敏感性, 增加BAT葡萄糖摄入量, 升高基础代谢率。Oh等[12]使用5-HTR3A基因敲除 (Htr3a-/-) 小鼠证明脂肪源性的5-HT对BAT能量消耗的抑制作用是通过5-HTR3A介导完成的。
2.2 5-HT与胰岛β细胞功能胰岛各类型细胞均可以表达5-HT合成、装配和分泌的所有基因, 并且同时表达Tph1和Tph2[18, 34]。人[35, 36]和啮齿类动物[37, 38]的胰岛组织中可表达多种亚型的5-HTR。到目前为止, 5-HT对胰岛素分泌的调节仍存在争议。一些研究发现, 5-HT可以抑制胰岛素的释放[39, 40], 例如选择性5-HT再摄取抑制剂 (selective 5-HT reuptake inhibitor, SSRI) 舍曲林可抑制Min6细胞的经葡萄糖刺激的胰岛素分泌 (glucose stimulated insulin secretion, GSIS)[41]。Zhang等[42]报道5-HTR2C激动剂可抑制小鼠胰岛组织和Min-6细胞GSIS。Paulmann等[43]发现细胞外的5-HT可能是通过激活5-HTR1A来抑制胰岛素的释放。此外, 一项对正常人胰岛组织的研究[44]表明, 5-HT可以抑制正常人胰岛组织GSIS。而另外一些研究则认为5-HT可以刺激胰岛素的释放[45, 46], 例如Paulmann等[43]发现β细胞内的5-HT可以与胰岛素分泌相关的Rab蛋白 (Rab3a和Rab27a) 发生共价结合 (se rotonylation), 从而增加胰岛素的释放。Bennet等[44]认为5-HT可以增加2型糖尿病患者的胰岛组织GSIS, 这可能与糖尿病患者5-HTR1D和5-HTR2A的表达上调有关。在一项HFD诱导的小鼠研究中[11], 特异性β细胞Tph1基因敲除 (Tph1-/-) 以及Htr3a-/-的小鼠血清胰岛素水平较野生型 (wild type, WT) 小鼠均有明显下降。分离这些小鼠的胰岛组织发现GSIS明显减少, 表明β细胞源性的5-HT可以通过激活β细胞上5-HTR3A来调节胰岛素释放。Ohara-Imaizumi等[38]认为可能的机制是5-HTR3A激活可以降低细胞静息膜电位, 降低Ca2+入胞的阈值, 增加高反应性β细胞的比例, 从而增加胰岛素的释放。
妊娠期胰岛β细胞质量与大小均有明显的增加[47]。近年来的研究发现, 5-HT作为胎盘催乳素的下游分子可调节妊娠期β细胞的功能[37]。妊娠期间, 小鼠胰岛细胞中Tph1和Tph2表达均显著增加, 5-HT水平显著增高[34, 37]。5-HT可以通过自分泌或者旁分泌的方式激动5-HTR3增加GSIS[38]。在妊娠中期, 胰岛β细胞上5-HTR2B表达增加, 刺激β细胞增殖, 直到妊娠末期, 5-HTR2B表达减少, 5-HTR1D表达增加, 产生抑制β细胞增殖的信号[37]。也有研究显示, 妊娠期胰岛细胞中5-HT和胰岛素含量增加的时相、对葡萄糖刺激的反应程度以及储存的颗粒池存在差异[34]。此外, 糖皮质激素还可抑制胰岛β细胞内Tph1和Tph2的表达, 并能抵消催乳素和胰高血糖素样肽-1 (glucagon-likepeptide-1, GLP-1) 对5-HT合成的促进作用, 从而降低胰岛β细胞内5-HT水平[48]。
2.3 5-HT与肝脏糖脂代谢5-HT系统对肝脏糖代谢的调节是一个复杂的过程。一系列的犬肝门静脉灌注实验表明, 在高血糖和高胰岛素条件下, 5-HT和SSRI均可以增加肝脏葡萄糖摄取和肝糖原的沉积[49, 50]。而在禁食状态下, 5-HT可以通过5-HTR2B抑制小鼠肝脏葡萄糖摄取, 并增加肝脏糖异生[24], 同样的结果也出现在妊娠期和哺乳期大鼠饮食补充5-HTP后[51]。在体外研究中, 5-HT在微摩尔浓度下可以抑制大鼠肝细胞糖原合成, 而在纳摩尔浓度下却表现出刺激肝糖原合成[52]。这种双向调节的现象可能是由不同5-HTR介导完成的, 激活5-HTR1和5-HTR2A表现出促进糖原合成、抑制糖原分解的作用, 而激活5-HTR2B和5-HTR2C则完全相反[53]。这些差异提示在不同物种、不同代谢状态下, 靶器官的优势表达受体不同, 5-HT的水平及分布也不同, 其对机体能量代谢调节作用的净效应可不同或相反。此外, SERT缺陷小鼠也表现出肝脏蛋白激酶B (protein kinase B, PKB/AKT) 和c-Jun氨基末端激酶 (c-Jun N-terminal kinase, JNK) 活性增高, 胰岛素刺激的磷脂酰肌醇3-激酶 (phos photidylinositol 3-kinase, PI3K) 信号通路减弱, 导致肝脏葡萄糖利用和储存减少[54]。也有研究显示5-HT通过上调肝脏果糖磷酸激酶 (phosphofructokinase, PFK) 的活性从而影响糖酵解过程[55]。
5-HT在肝脏脂肪代谢中也发挥重要的调节作用。Crane等[10]研究发现, Tph1-/-小鼠或使用外周Tph1抑制剂 (LP533401) 均可以减轻HFD条件下肝脏的脂肪累积。另一项研究也表明外周5-HT可以导致肝脏TG和脂肪酸 (fatty acid, FA) 的合成增加, 促进极低密度脂蛋白 (very low density lipoprotein, VLDL) 装配, 其可能机制是5-HT通过肝脏5-HTR2激活了哺乳动物雷帕霉素靶蛋白 (mammalian target of rapamycin, mTOR) 通路[56]。此外, 有研究发现SERT缺陷小鼠在正常饲养条件下会出现脂肪肝[54]。然而, 在一项大鼠和其肝细胞的实验中, 使用5-HTR6拮抗剂却出现肝脏脂肪累积[57], 其作用机制仍待进一步研究。
2.4 5-HT与肠道代谢调控肠道5-HT系统表达SERT和多种5-HTR[58, 59], 在肠道运动、分泌、炎症反应和通透性等方面有着重要作用[60]。研究发现, 机体的代谢状态可以影响肠道5-HT系统。在HFD诱导的肥胖大鼠中, 肠道5-HT水平增加, SERT表达降低, 肠道5-HT系统被高度激活[61]。在瘦素缺陷的肥胖小鼠中, 十二指肠5-HTR3A表达明显增加[62]。有研究认为肥胖小鼠肠道5-HT系统的改变可能存在性别差异[63]。另一方面, 肠道5-HT系统也可以间接影响机体的能量代谢。Weber等[64]的研究发现, 在高糖饮水状态下, 5-HTR3拮抗剂托烷司琼可以明显增加小鼠十二指肠的钠-葡萄糖共转运载体 (sodium-dependent glucose cotransporter 1, SGLT1) 和葡萄糖转运体2 (glucose transporter 2, GLUT2) 表达, 增加葡萄糖的摄取; 同时可以改变肝脏葡萄糖代谢途径, 阻止葡萄糖代谢为TG, 减轻高糖状态下肝脏TG的增加。此外, 5-HT可以导致小鼠或大鼠肠道内毒素移位, 增加肝门静脉内毒素水平[62, 65], 这种改变可能由5-HTR3介导[65, 66]并且与非酒精性脂肪肝的发病有关[67]。
2.5 5-HT与骨骼肌能量代谢5-HT还可以影响骨骼肌的能量代谢。Hajduch等[68]发现使用5-HT和5-HTR2A激动剂 (α-甲基5-HT) 可以迅速增加大鼠骨骼肌细胞葡萄糖摄取量, 同时发现5-HTR2A激动剂还可以增加L6肌细胞膜上GLUT1、GLUT3和GLUT4等3种葡萄糖转运体的聚集。也有研究发现, 5-HT可以通过5-HTR2A增加小鼠骨骼肌PFK的活性, 从而增加骨骼肌糖酵解[69]。Watanabe等[70]通过整体动物模型研究发现, 5-HT通过激活5-HTR2A和5-HTR7, 增加慢肌纤维比例, 减少快肌纤维比例, 改变骨骼肌能量代谢方式, 这可能与增加小鼠骨骼肌过氧化物酶体增殖物激活受体共激活因子1 (peroxisome pro liferator-activated receptor coactivator 1, PGC-1) 的表达有关, 同时该研究还发现5-HT可以增加骨骼肌相关能量代谢基因的表达, 如UCP3、2型碘化甲腺氨酸脱碘酶基因 (type 2 iodothyronine deiodinase, D2) 等, 增加骨骼肌能量消耗[70]。但该研究所使用的饮食诱导条件与大多数HFD条件[10-12]有很大不同, 其结论有待进一步证实。
3 展望代谢综合征是机体多组织能量代谢紊乱的复杂性疾病。外周5-HT系统对各重要能量代谢组织的调节作用使其成为肥胖及相关代谢性疾病研究的新热点。近年来的研究结果较多地表明在高脂饮食诱导的肥胖状态下, 抑制外周5-HT可以阻止肥胖进展、改善糖耐量、增加胰岛素敏感性[10, 12, 24], 这些临床前研究结果为靶向外周5-HT系统开发代谢综合征的治疗药物提供了理论基础。当然, 由于目前的药效学研究大多来源于小动物模型, 其临床相关性还需要深入的论证。此外, 虽然文献[10]报道Tph1-/-小鼠与WT小鼠在行为学及生命特征方面无明显差异, 但由于5-HT系统的生理作用广泛, 且目前应用的多数5-HTR拮抗剂均能透过血脑屏障, 因此, 药物对外周5-HT系统的选择性、长期使用的安全性以及种属差异性仍有待进一步研究。未来的研究应当关注在代谢性疾病模型下, 选择性调控外周能量代谢组织中5-HT的优势表达受体亚型, 同时研究该干预策略的安全性, 以避免或降低中枢及外周不良反应。
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