代谢相关性肌细胞因子的研究进展

周 珊(综述) 叶红英(审校)

(复旦大学附属华山医院内分泌科 上海 200040)

代谢相关性肌细胞因子的研究进展

周 珊(综述) 叶红英△(审校)

(复旦大学附属华山医院内分泌科 上海 200040)

肌细胞因子(myokines)是由肌细胞合成和释放,发挥自分泌、旁分泌或内分泌功能的细胞因子及多肽类物质。肌细胞因子可作用于骨骼肌自身及脂肪、肝脏、胰腺、骨骼等多种组织器官参与机体物质和能量代谢并影响各组织器官的结构和功能,从而在维持机体的生物学稳态中发挥重要作用。目前已发现的肌细胞因子有数百种,其中鸢尾素(irisin)、肌联素(myonectin)、肌肉抑制素(myostatin)、脑源性神经营养因子(brain-derived neurotrophic factor,BDNF)等对机体糖脂及能量代谢起到重要作用。本文主要阐述上述几种代谢相关性肌细胞因子的合成和分泌、生理作用、作用机制及潜在临床应用。

骨骼肌; 肌细胞因子; 鸢尾素; 肌联素; 肌肉抑制素; 脑源性神经营养因子

2003年,Pedersen等[1]首次提出“肌细胞因子”的概念,将其定义为“肌细胞合成和释放的,发挥自分泌、旁分泌或内分泌功能的细胞因子及多肽类物质”。肌细胞因子的发现为研究骨骼肌与其他组织器官的相互作用提供了基础,从整体水平而言,运动对多种代谢性疾病的防治也有可能(部分)通过肌细胞因子来实现。本文主要针对鸢尾素(irisin)、肌联素(myonectin)、肌肉抑制素(myonstatin)、脑源性神经营养因子(brain-derived neurotrophic factor,BDNF)等与机体代谢密切相关的肌细胞因子作一综述。

鸢尾素:诱导白色脂肪棕色化及增加产热 运动可激活骨骼肌中的过氧化物酶体增殖激活受体γ共激活因子1α (peroxisome proliferator-activated receptor γ co-activator 1α,PGC1α)并产生一系列生物学效应,包括增加骨骼肌线粒体合成、血管生成及肌纤维类型转化等[2]。2012年,Boström等[3]研究发现,将PGC1α基因特异性转入小鼠骨骼肌可诱导其白色脂肪棕色化,将表达PGC1α的肌细胞与脂肪细胞体外混合培养也可引起脂肪细胞棕色化基因表达增加;进一步研究发现骨骼肌中PGC1α激活后可诱发膜蛋白纤维连接蛋白Ⅲ含域蛋白5 (fibronectin type Ⅲ domain-containing protein 5,Fndc5)表达增加,Fndc5经酶切后以一种新的激素形式——鸢尾素(irisin)释放[3]。运动后小鼠血浆Irisin水平显著升高,伴随肌细胞Irisin表达量的显著增加[3];Irisin作用于白色脂肪细胞,通过激活过氧化物酶体增殖激活受体α (peroxisome proliferator-activated receptor α,PPARα)促使其解偶联蛋白1 (uncoupling protein 1,UCP1)及一系列棕色化基因表达,进而增加产热并诱导广泛的棕色样改变[3-4]。

关于人体运动与Irisin的关系,有研究发现短时运动可引起人体血浆Irisin水平显著升高[5-6],而Timmons等[7]则发现无论耐力或阻力训练均不能使正常成年人骨骼肌中Fndc5基因表达增加;Raschke等[8]对离体人骨骼肌进行电刺激亦未见Fndc5基因表达增加;Hecksteden等[9]一项随机对照试验发现,长期运动个体其血浆Irisin水平并无显著性升高,因此,运动对人体Irisin合成分泌的影响目前尚无定论,推测运动所需的阈值(形式、强度、持续时间等)可能是其关键影响因素。此外,关于外源性给予重组Irisin能否诱导人体白色脂肪棕色化,仍缺乏相关实验证据,且人和小鼠的棕色脂肪含量差异显著,因此上述动物实验结果是否适用于人体以及Irisin能否成为治疗肥胖的靶点,仍需进一步临床研究来明确。

多项研究结果显示,血浆Irisin水平与体重、体重指数及体脂含量呈正相关[5,10-12],即肥胖人群具有更高的Irisin水平,这与其潜在的抗肥胖作用相互矛盾,推测Irisin可能作为生理性保护因子通过诱导棕色化对抗肥胖,而病理状态下(肥胖)血浆Irisin水平代偿性升高以对抗体重增长及机体脂肪囤积效应。Polyzos等[13]进一步提出“Irisin抵抗”的概念,用以解释肥胖个体明显的Irisin不适当分泌过多。另有研究发现,糖尿病患者血浆Irisin水平低于正常糖耐量个体[14],而血浆Irisin水平的升高与新诊断2型糖尿病比率降低有关[15],提示Irisin有可能成为2型糖尿病的独立预测因子。

肌联素:联系骨骼肌与脂肪的桥梁 Seldin等[16]在小鼠骨骼肌中发现一种全新的补体1q/肿瘤坏死因子相关蛋白(C1q/TNF-related protein,CTRP)家族成员,并将其命名为CTRP15/Myonectin。Myonectin主要在小鼠骨骼肌中表达,运动使小鼠Myonectin的基因表达和血浆浓度升高[16]。Myonectin的分泌还与小鼠营养状态密切相关:饥饿状态下其合成和分泌明显受抑制,重新进食后又显著升高;进一步实验证实营养物质可直接作用于肌细胞调节Myonectin表达[16]。随后Rodriguez等[17]研究发现瘦素作用于肌细胞可上调其Myonectin基因表达; Peterson等[18]则发现,与正常大鼠相比,瘦素受体缺乏的肥胖鼠Myonectin基因表达增加,而运动后其肌细胞Myonectin mRNA表达量反而降低,这与Seldin等[16]的研究结果并不一致。因此,目前关于运动对Myonectin合成和分泌的影响仍无定论,推测Myonectin基因表达可能受瘦素调控,而蛋白分泌则主要由机体营养状态决定。此外,也有研究提及胰岛素抵抗对Myonectin合成和分泌的影响。Yang等[19]发现,在由棕榈酸诱导的小鼠肌细胞胰岛素抵抗状态下,棕榈酸可通过下调磷酸肌醇-3-激酶(phosphoinositide 3 kinase,PI3K)和上调p38基因表达等多种信号途径降低Myonectin基因的表达水平。

关于Myonectin的生物学作用,Seldin等[16]发现在给予重组Myonectin后,小鼠脂肪细胞和肝细胞对游离脂肪酸的摄取均明显增加,且两者都伴随脂肪酸摄取相关基因白细胞分化抗原36,脂肪酸结合蛋白及脂肪酸转运蛋白表达增加,提示Myonectin可能通过上调这些基因的表达从而促进脂肪细胞和肝细胞摄取游离脂肪酸。此外,饥饿可诱发小鼠肝细胞自噬,而Myonectin通过激活雷帕霉素靶蛋白(mammalian target of rapamycin,mTOR)可抑制其自噬作用,这是骨骼肌和肝脏之间内分泌联系的体现[20]。以上研究初步证实Myonectin在机体脂代谢中的重要作用,未来还需进一步设计Myonectin基因失活/获得性突变等动物模型,从而明确其在不同病理生理状态下的作用及机制。

肌肉抑制素 McPherron等[21]发现一种特异性表达于骨骼肌的转化生长因子β超家族成员生长/分化因子8,又称为肌肉抑制素。定向敲除小鼠骨骼肌Myostatin基因可引起肌肉量显著增加[21],人体骨骼肌Myostatin基因失活突变亦可引起广泛的肌细胞增生肥大[22],而小鼠骨骼肌过表达Myostatin则可导致严重肌萎缩[23],充分证实Myostatin可抑制肌细胞生长。关于Myostatin对肌细胞代谢的影响,有研究发现Myostatin基因缺失型/阻断型小鼠均出现肌肉量增加及肌力增强,但肌耐力显著下降且极易疲劳,提示Myostatin在负性生长调节之外,还可增加肌细胞的有氧代谢和肌耐力[24]。

此外,Myostatin还对机体糖脂代谢具有重要影响。骨骼肌过表达Myostatin可引起小鼠肌肉量减少及附睾脂肪垫增多[23],而特异性阻断Myostatin后,无论高脂饮食或是正常饮食喂养的小鼠均表现为肌肉量增加,脂肪量减少[25]。为明确上述作用靶点,研究者进一步设计实验并发现其抗肥胖效应主要是由于Myostatin受阻后对肌细胞的负性调节减弱所致,其对脂肪的直接作用较小[26],提示Myostatin对脂代谢的影响很可能继发于肌细胞的改变。另有研究发现,接受重组Myostatin注射的小鼠出现胰岛素敏感性降低,而其脂肪和肌肉量均无改变,提示Myostatin可能直接影响骨骼肌对葡萄糖摄取及利用,该效应与Myostatin对肌肉量的影响并无相关[27]。另外,特异性阻断小鼠血浆Myostatin可减少其肝脏葡萄糖产生[25],而给予重组Myostatin后,小鼠体内胰岛素作用于肝脏的Akt信号通路明显受阻[27],提示Myostatin可直接作用于肝脏影响糖代谢。进一步研究发现,特异性阻断Myostatin作用可通过PI3K/Akt/mTOR信号途径改善小鼠胰岛素抵抗[28]。综上所述,Myostatin有望成为肌萎缩及肥胖、2型糖尿病等代谢性疾病的治疗新靶点。

脑源性神经营养因子 BDNF是一种神经营养因子,广泛表达于中枢神经系统并发挥营养神经元的作用[29]。近年研究发现骨骼肌也可表达BDNF[30-31],动物实验证实,无论是运动还是电刺激骨骼肌均可诱导BDNF表达量增加[32-34],提示肌肉收缩对肌细胞BDNF的表达具有重要影响。人体在运动后骨骼肌中BDNF表达量也有一定增加[34],但肌细胞来源的BDNF并未释放入血,而是在局部发挥自分泌/旁分泌作用,经由腺苷酸活化蛋白激酶途径增加骨骼肌自身的脂肪酸氧化[31]。临床研究发现,肥胖及2型糖尿病患者较正常个体的血浆BDNF水平更低[35],但目前尚不明确血浆BDNF的降低是机体代谢异常的原因还是其结果,对此仍需进一步研究。综合BDNF对骨骼肌能量及脂代谢的影响,初步推测运动可能通过BDNF介导对肥胖及2型糖尿病等代谢性疾病的防治作用[30]。

结语 骨骼肌作为人体的重要内分泌器官,可以合成和分泌多种肌细胞因子作用于各组织器官,影响其代谢和功能并维持机体的生物学稳态。肌细胞因子的发现为骨骼肌与其他组织器官的相互作用提供了一种全新模式。本文介绍的Irisin、Myonectin、Myostatin、BDNF这几种因子主要与机体糖脂及能量代谢密切相关,其中仍有许多机制尚未明确,进一步深入研究有望为肌萎缩、肥胖及2型糖尿病等代谢性疾病的治疗提供新思路。

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A research progress on metabolism-associated myokines

ZHOU Shan, YE Hong-ying△

(DepartmentofEndocrinology,HuashanHospital,FudanUniversity,Shanghai200040,China)

Cytokines and peptides produced and released by muscle cells and exert either autocrine,paracrine or endocrine effects are defined as myokines.Myokines are capable of exerting specific endocrine effects on organs such as adipose tissue,liver,pancreas and bone,thereby impacting the structure and function of numerous organs and tissues,as well as playing an important role in the maintenance of biological homeostasis.So far,researches have confirmed hundreds of different myokines,including irisin,myonectin,myostatin and brain-derived neurotrophic factor (BDNF),which can affect glucose and lipid metabolism,as well as energy equilibrium.The generation、physiology、mechanism of action and potential clinical value of these metabolism-associated myokines will be reviewed in this article.

sketelal muscle; myokines; irisin; myonectin; myostatin; brain-derived neurotrophic factor

R586.2+4

B

10.3969/j.issn.1672-8467.2017.02.019

2016-07-15;编辑:王蔚)

△Corresponding author E-mail:janeyhy@163.com