脑源性神经营养因子对糖尿病能量代谢及神经病变的影响

李小华，冷锦红

（辽宁中医药大学,辽宁 沈阳110032；辽宁中医药大学附属医院，辽宁 沈阳110032）

摘要：脑源性神经营养因子( brain-derived neurotrophic factor，BDNF)是神经营养因子家族的成员之一，是一种非常重要的神经营养因子，可以促进神经元生长、分化与存活，影响突触的生长和可塑性。BDNF能够通过控制摄食和增加饱腹感、改善胰岛素分泌以及增加胰岛素敏感性、影响机体能量代谢的多个方面来改善糖尿病，并且与糖尿病的并发症神经病变相关。能够支持中枢和外周神经系统中某些神经元群体的存活。成熟期的BDNF被认为是突触可塑性的重要调节剂，并且其在炎性和神经性疼痛模型中调节表达。

关键词：脑源性神经营养因子；糖尿病；能量代谢；胰岛素；神经病变

  糖尿病是一种以高血糖症为特征的复杂的代谢性疾病，会对各种器官造成严重损害。高血糖是由于胰岛素分泌缺陷或其生物学效应受损或两者兼而有之。糖尿病中长期存在的高血糖会导致各种组织的慢性损伤和功能障碍。脑源性神经营养因子( brain-derived neurotrophic factor，BDNF)是神经营养因子家族的成员之一，是一种非常重要的神经营养因子，促进神经元分化和存活，影响突触增长和突触可塑性^[1,2,3]。现在已知BDNF及其高亲和力受体TrkB（原肌球蛋白相关激酶B）的表达广泛，其存在于整个中枢和外周神经系统以及骨骼肌，心脏，肝脏和脂肪细胞中的神经元中。^[4]BDNF在饮食，学习和记忆，运动，压力反应和情感行为中都有作用^[5]。在中枢神经系统，全身或外周炎性疾病如急性冠状动脉综合征和2型糖尿病（T2DM）中发挥重要作用。^[6]关于BDNF 改善糖尿病的机制，在这里，我们对BDNF在糖尿病及其并发症中的研究进展予以综述。

 1 内源性BDNF的变化

 与糖尿病1型（DM1）绝对缺乏胰岛素但体重正常且无胰岛素抵抗的患者相比，DM2的特征是肥胖，胰岛素抵抗和高血糖，尽管它们具有不同的潜在发病机制，但DM1和DM2均显示与血浆葡萄糖水平负相关的BDNF血浆水平降低，而非胰岛素^[7,17]。说明人体大脑的BDNF输出在血糖高时被抑制，但当胰岛素水平高时则不被抑制。^[8]在鼠糖尿病模型中，BDNF受体TrkB的水平也降低。^[9] 

在一项对233名受试者的研究中，血浆BDNF水平与空腹血浆葡萄糖水平呈负相关，有趣的是，大脑BDNF输出的测量表明，升高的葡萄糖水平降低了从大脑产生并释放到血液中的BDNF的量。^[10]

2 能量代谢

来自动物模型研究的数据以及在某些情况下的人类受试者的数据表明，BDNF可通过抑制食欲，增加胰岛素敏感性等来预防代谢综合征和肥胖症。^[4]

2.1 饮食控制

基础能量消耗，摄食和饱腹感的代谢调节受到许多激素的影响，包括来自传统内分泌器官如肠，脂肪组织，甲状腺和胰腺的激素。另外，从神经元释放的激素也可以影响体重，食欲和饱腹感。更好的特征包括直接向大脑发出“充满”信号的胃迷走神经牵张受体^[11]。尽管迷走神经感觉机制在饱腹感的神经机制中起着至关重要的作用，但几乎没有证据表明在长期能量稳态中有重要作用。与此形成鲜明对比的是，一系列神经内分泌激素已被证明能显着影响能量代谢，并有助于中枢控制食物摄入量和体重。^[8]

BDNF与这种神经内分泌轴严重相关。BDNF行为通过其高亲和力受体TrkB ^[12]，两者都在成年大脑内与能量平衡有关的核内 - 下丘脑和后脑共表达。^[13] 

受损BDNF / TrkB信号传导的小鼠遗传模型显示食欲过盛和肥胖^[14]，而用BDNF或其他TrkB激动剂进行中枢或外周治疗可减少食物摄入和体重增加^[15]。BDNF的中枢给药^[13,16]触发了食欲不振和体重减轻。同样，在小鼠背部和中下丘脑中BDNF的靶向缺失导致食物摄入量增加和肥胖^[18] BDNF中的自发性人缺失或破坏突变也与食欲过盛和肥胖相关，并且通过BDNF施用是可逆的^[15,19]。值得注意的是，Prader-Willi综合征是一种伴随不断食欲的儿童病态肥胖综合征，与对照相比，BDNF的水平明显较低^[20]，突出了BDNF在人体能量平衡中的重要作用。人类基因组范围的研究发现与BDNF基因座和肥胖风险^[21,22,23]以及黑皮质素-4受体（MC4R ）也在脑和下丘脑中高度表达。 BDNF似乎在瘦素黑皮素信号通路的下游起作用以控制能量平衡^[24]。MC4R是食物摄取，体重和葡萄糖体内平衡的主要调节剂^[25]，所以发现BDNF及其上游MC4R作为肥胖的独立危险因素具有高度相关性。

2.2 胰岛素

2型糖尿病是一种复杂的代谢疾病，会对各种器官造成严重损害。它是一种慢性疾病，由于葡萄糖和脂质代谢的稳态改变，其特征在于胰岛素抵抗，并且通常随后是胰腺b细胞产生胰岛素的渐进性不足^[26]。

由于BDNF的脑室内输注可增加正常啮齿类动物的外周胰岛素敏感性^[27]并改善小鼠的糖尿病^[28]出生后脑BDNF消除的小鼠对压力过敏，血糖和胰岛素水平升高，并且肥胖^[29]。

BDNF对肥胖的人类DM2的肥胖的胰岛素抵抗和肥胖糖尿病啮齿动物模型的全身性日常施用增强了胰岛素敏感性，降低了血糖，并且似乎增加了基础代谢率体重减轻^{[30,16,31,32]}并减轻了小鼠的空腹高血糖症^[33]。治疗效果在停止BDNF治疗后持续数周。即使治疗前驱糖尿病动物，也能防止DM2动物出现明显的DM2并保留了胰腺胰岛素和胰高血糖素的分泌^[31]。 DM1的胰岛素依赖性鼠模型也受益于BDNF的治疗。

2.3 全身能量代谢

BDNF不仅是神经元适应有活力挑战的主要调节者，而且在通过大脑，外周神经元和包括胰腺，肝脏，骨骼肌和心脏的靶器官中的作用来控制外周能量代谢中具有深远的作用。^[4]BDNF +/-小鼠的研究所证实的，BDNF抑制摄食并且改善葡萄糖代谢^[34,35]，通过控制喂养和身体活动模式以及通过调节外周组织中的葡萄糖代谢而在调节能量稳态中起广泛的作用。^[4]有趣的是，BDNF可通过骨骼肌代谢对葡萄糖控制产生积极作用，因为葡萄糖转运蛋白GLUT4的表达响应于BDNF而增加，由此允许血清葡萄糖更容易转运至靶细胞中^[36]。

虽然抑制食欲是中枢神经系统BDNF信号传导影响全身能量代谢的机制之一，但最近的研究结果表明BDNF对神经内分泌途径和参与能量代谢的器官更具直接的能量调节作用。独立于食物摄取的影响，中枢神经系统给予BDNF可降低血糖水平并增加瘦素受体突变体（db / db）小鼠的能量消耗^[37]。中枢神经系统BDNF改善外周糖代谢的机制包括调节胰岛素信号传导途径，因为ICV BDNF处理可增强糖尿病小鼠肝脏中胰岛素受体的酪氨酸磷酸化，同时增加PI3K信号传导^[38]。

新发现的结果表明BDNF是能量稳态的主要调节剂，其作用位点和作用机制远远超出胰岛素和瘦素等激素。^[4]在大鼠脑室内注射BDNF可诱导剂量依赖性食欲抑制和体重减轻^[39]，而小鼠Bdnf基因的条件性缺失会导致饮食过量和肥胖以及瘦素，胰岛素，葡萄糖和胆固醇水平升高^[40]。

后一研究进一步显示胰高血糖素样肽1（GLP-1）的门静脉内给药增加胰腺中的BDNF水平并降低胰高血糖素分泌。 GLP-1受体在胰腺细胞，肌肉和肝细胞以及整个脑中的神经元中表达。 GLP-1受体的激活导致已知诱导BDNF表达的cAMP产生和CREB活化。与GLP-1相似，BDNF信号增加肝脏和骨骼肌和心肌细胞对葡萄糖的摄取^[41]。 BDNF和TrkB均在骨骼肌细胞中表达，运动可诱导BDNF在肌肉中表达。离体和体内研究表明，BDNF处理增加AMPK及其下游靶乙酰辅酶A羧化酶（ACCb）的磷酸化，导致骨骼肌脂肪氧化增强^[42]。

BDNF受体TrkB的激活通过刺激葡萄糖转运和线粒体生物发生来增强神经元生物能量，同时增加对代谢，氧化和兴奋毒性应激的神经元耐受性，保护神经元免受损伤和疾病。^[4]

3 神经病变

神经病变是导致糖尿病患者发病率的主要并发症之一。糖尿病导致广泛的周围神经元缺陷，包括运动神经传导速度减慢，坐骨神经再生受损，神经丝递送减少的轴突缩小以及顺行轴突运输不足等^[43,44,45]。

有关于神经病变并发症的发展和进展的机制尚不完全清楚。外周运动和感觉神经的改变是最常见的，临床上为明显的进行性糖尿病外周多发性神经病（DPN），下肢不敏感或痛觉过敏，后期肌肉力量减少。自主神经病变也可能在糖尿病中发生，并且在临床上表现为非典型出汗，胃轻瘫，缺乏心率变异性，直立性低血压或膀胱功能障碍。目前尚不清楚常见的病理过程是否同等地影响所有神经元类型（运动，感觉和自主），因为大多数器官和组织在疾病过程中会形成某种形式的神经病变。最近的一些见解已被纳入这些机制的几个关键方面，包括高血糖对神经元反应和神经营养因子水平的分子效应，以及对神经营养因子传递的相互有益代谢反应，可能对糖尿病控制产生积极影响，并降低并发症率。^[8]

在发育期间，脑源性神经营养因子（BDNF）支持中枢和外周神经系统中某些神经元群体的存活。在成年期，BDNF被认为是突触可塑性的重要调节剂。BDNF在初级感觉神经元（突触前神经元）的细胞体中合成，并且其表达在炎性和神经性疼痛模型中被调节。^[46]行为学数据表明，BDNF的拮抗作用减弱福尔马林诱导的第二阶段痛觉过敏（在神经生长因子处理的动物中）和角叉菜胶诱导的热痛觉过敏，表明BDNF参与了外周炎症条件下中枢致敏的某些方面。^[46]动物研究揭示了BDNF在DPN诱导的神经传导和髓鞘损伤中的作用。^[47]

缺乏神经营养因子被认为是糖尿病诱发神经病变的重要原因之一^[48,49]。目标神经元中合成了神经营养因子，包括神经生长因子（NGF），脑源性神经营养因子（BDNF），神经营养因子-3（NT-3）和NT-4/5。 BDNF影响培养的运动神经元^[50]，中脑多巴胺能神经元^[51]和中隔胆碱能神经元^[51的存活和分化。在成年大鼠中，BDNF mRNA在全脑中的分布比NGF和NT-3的mRNA更广泛^[52]，并受谷氨酸或γ-氨基丁酸神经传递的调节^[53]。此外，增强的表达可以在建立长时程增强后发现^[53]。因此BDNF似乎参与各种活动依赖性事件，包括突触可塑性。在糖尿病大鼠的坐骨神经中，BDNF的表达降低^[54]。我们先前对我们的研究表明，4-甲基儿茶酚是BDNF合成的刺激物^[55]，能够抵抗糖尿病引起的周围神经病变^[56,57]。这些结果表明BDNF有助于糖尿病神经系统的神经发生。

BDNF对哺乳动物脑中GABA突触的结构修饰和功能可塑性具有许多营养作用^[58,59,60]。它在炎症和神经病理性疼痛反应中起着很好的记忆作用，作用于脑干下行疼痛通路，包括中脑导水管周围灰质（PAG），延髓腹内侧髓质（RVM）和脊髓^[61,62]。在PAG和RVM中观察到高水平的BDNF mRNA和蛋白质^[63,64]。郭等人的一项研究。表明RVM中的BDNF可能来源于PAG中含有BDNF的神经元，并且RVM中BDNF高亲和力受体TrkB信号的BDNF激活诱导下行疼痛促进作用，这表明RVM电路中BDNF-TrkB受体的信号级联起关键作用在炎症后持续性疼痛的发展中^[65]。

尽管人类信息还很少，但动物模型已经确立了神经营养素和多种其他生长因子作为DN的治疗剂的潜力。^[8]

4 .结语

目前，没有特别理想的治疗糖尿病及其并发症的药物。如果能明确BDNF对糖尿病及其并发症的作用机制，则可将该药应用于糖尿病，使血液中维持稳定的BDNF浓度，就可以有效控制血糖。因此，BDNF有希望成为治疗糖尿病，防治糖尿病并发症的新一代的有效的药物。

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