脂肪组织是脂质沉积的部位之一，近年来发现其具有内分泌功能[1-3]。脂肪组织能以自分泌、旁分泌或内分泌的方式分泌多种激素或细胞因子，这些细胞因子统称为脂肪细胞因子[4]。目前已发现的脂肪细胞因子主要包括脂联素(adiponectin)、瘦素(leptin)、抵抗素(resistin)、内脂素(visfatin)、白介素-6(interleukin-6, IL-6)和肿瘤坏死因子α (tumor necrosis factor α，TNF-α)等，其中，脂联素是目前发现的与肥胖呈负相关的脂肪细胞因子之一[5]。了解脂联素的结构和组织分布，探究其调控脂质代谢的作用，是营养和能量代谢的研究热点之一。迄今为止，关于脂联素调控动物脂质代谢的研究，主要集中于人和啮齿动物[6-9]，畜禽[10]上的研究相对较少，而水生动物上罕见。本文主要从脂联素的发现、结构、组织分布、信号接头蛋白和调控脂质代谢进行了综述，以期为深入探究脂联素调控脂质代谢的作用机制提供参考。
1 脂联素的发现与结构脂联素曾称为Acrp30、AdipoQ、GBP28或apM1，最初从人和啮齿动物上分离鉴定出来。1995年Scherer等[11]从3T3-L1脂肪细胞筛选出带地高辛标记的cDNA片段，其编码249个氨基酸，且蛋白结构与补体因子C1q相似，将其称为脂肪细胞补体相关蛋白(adipocyte complement-related protein of 30 ku, Acrp30)。Hu等[12]从人、大鼠和小鼠脂肪组织中分离得到一种新的脂肪基因，称其为AdipoQ基因。Meada等[13]在人腹部皮下和内脏脂肪组织中鉴定出一种在脂肪组织中丰富表达的基因，将其称为apM1(adipose most abundant gene transcript 1)。Nakano等[14]从人血浆中分离出一种由apM1编码的大小为28 ku的明胶结合蛋白，称为28 ku明胶结合蛋白(gelatin-binding protein of 28 ku，GBP28)。直到1999年，Arita等[15]才将以上团队发现的物质正式统一命名为脂联素(adiponectin, AdipoQ)。研究者们现已从猪、牛、绵羊、鸡和鸭等畜禽动物[16-20]以及水生动物[21-22]中鉴定出该基因，而爬行类和两栖类上未见报道。
不同物种AdipoQ基因外显子数量、染色体定位、编码核苷酸及氨基酸种类和数量存在差异。哺乳动物AdipoQ包括3个外显子和2个内含子，家禽该基因包含2个外显子和1个内含子，均编码240~250个氨基酸。脂联素主要由N端信号肽、非同源区、胶原结构域和C端球形结构域组成。其中，N端信号肽的存在提示脂联素是一种分泌性蛋白，C端球形结构域相对保守。最近研究发现，脂联素C端球形结构域中包含的小肽片段具有类似脂联素功能[23-27]。在体内，脂联素以全长脂联素(full-length adiponectin, fAd)和球形脂联素(globular adiponectin, gAd)形式存在，gAd具有更强的生物活性。
2 脂联素的组织分布早期研究者发现，哺乳动物AdipoQ是由脂肪组织特异性表达，而随着研究方法和技术的不断更新，发现AdipoQ也在胎盘、肌肉、血液和囊胚细胞中表达[28-29]。非哺乳动物(如鸡、斑马鱼和虹鳟)的AdipoQ还存在于脑、垂体和肝等组织中[19, 21, 30-31]。此外，AdipoQ在组织中的表达量与品种、性别和生长阶段等相关。例如，罗宗刚等[32]利用荧光定量PCR检测发现，长白猪背最长肌和腰大肌AdipoQ的表达量高于荣昌猪，并且在母猪的表达量极显著高于公猪。苗志国等[33]通过ELISA检测发现，淮南猪和长白猪血清中脂联素含量随年龄增长而上升。然而，爬行类、两栖类和鱼类AdipoQ组织分布模式如何，有待进一步研究。AdipoQ在动物中广泛分布，暗示其可能具有多种生物学功能。现已证实，脂联素具有增强胰岛素敏感性[34-35]、抗动脉粥样硬化[36-38]、保护血管内皮细胞[39]、参与摄食调控[40-41]和促进葡萄糖摄取[42]等功能。哺乳动物和鸟类AdipoQ在脂肪组织的高表达提示，AdipoQ可能在脂质代谢中发挥重要作用，大量的研究已报道了脂联素调控脂质代谢的功能[43-45]。
3 脂联素的信号接头蛋白脂联素首先与脂联素受体C端结合后，脂联素受体的N端被相关信号接头蛋白识别，激活下游AMPK和PPAR和等信号因子，从而发挥生物学功能。脂联素受体主要包括脂联素受体1(adiponectin receptor 1，AdipoR1)、脂联素受体2(adiponectin receptor 2, AdipoR2)和T-钙黏蛋白(T-cadherin)。研究表明，AdipoR1和AdipoR2能介导脂联素发挥多种生物学作用，而T-钙黏蛋白主要参与抗动脉粥样硬化。关于T-钙黏蛋白介导脂质代谢的研究较少。
现已发现4种能与AdipoR1和AdipoR2直接作用的信号接头蛋白，即衔接因子蛋白含PH与磷酸酪氨酸结合域和亮氨酸拉链基元1(adaptor protein, phosphotyrosine interacting with PH domain and leucine zipper 1，APPL1)、酪蛋白激酶Ⅱ(casein kinase Ⅱ，CK2)、蛋白激酶C受体1(receptor for activated C kinase 1，RACK1)和内质网蛋白46(endoplasmic reticulum protein 46，ERp46)[46-47]。APPL1能与AdipoR1和AdipoR2结合, 而CK2、RACK1和ERp46仅与AdipoR1结合。在脂联素调节脂质代谢过程中，信号接头蛋白APPL1和CK2发挥着重要的作用。其中，APPL1是首个被鉴定出能与脂联素受体结合的信号接头蛋白，其包含BAR、PH和PTB结构域。在C2C12细胞中，脂联素能通过促进AdipoR1与APPL1的PTB结构域结合，诱导APPL1的BAR结构域(5~270 aa)与肝激酶(LKB1)结合, 进而激活AMPK，促进ACC磷酸化，促进脂肪酸氧化[48-49]。除此以外，在C2C12肌细胞中，信号接头蛋白CK2的调节亚基(CK2β)能与AdipoR1的N端结合，而CK2抑制剂能明显抑制gAd促进ACC磷酸化的作用[50]。此外，是否还存在其它信号接头蛋白介导脂质代谢过程尚不清楚。
4 脂联素调节脂质代谢脂联素对脂质代谢的调控主要通过促进脂肪酸氧化和抑制脂质合成达到降脂的作用。目前，关于脂联素促进脂肪酸氧化的报道很多，而抑制脂质合成的研究较少。
4.1 脂联素促进脂肪酸氧化脂联素能通过促进脂肪酸氧化，降低血浆游离脂肪酸水平(FFAs)。Fruebis等[51]研究显示，单次饲喂高脂高糖日粮能诱导小鼠血浆FFAs升高，而静脉注射fAd和gAd能在数小时内降低血浆FFAs水平。长期饲喂高脂日粮，并持续16 d注射gAd，能显著降低小鼠血浆中FFAs浓度。在大鼠上，持续皮下注射脂联素也具有类似的效应[6]。脂联素的这种降低血浆FFAs的作用，可能是通过促进肌肉脂肪酸氧化来实现的。本文将AdipoQ促进脂肪酸氧化的途径总结如下。
4.1.1 AdipoR1/2-腺苷酸活化蛋白激酶(AMPK)-乙酰辅酶A羧化酶(ACC)AdipoQ能通过AdipoR1和AdipoR2激活AMPK, 进而诱导ACC磷酸化，最终促进脂肪酸氧化。腺苷酸活化蛋白激酶(AMPK)在调节动物能量代谢平衡中发挥重要作用。在哺乳动物上的研究显示，脂联素能通过AdipoR1和AdipoR2介导，激活AMPK信号途径。活化的AMPK能诱导乙酰辅酶A羧化酶(ACC)磷酸化失活，从而促进脂肪酸氧化。在多种组织和细胞中，脂联素能激活AMPK-ACC信号途径。此外，在C1C12细胞、心肌细胞、趾长伸肌和腓肠肌中，体外和体内试验表明，脂联素能快速(1 h内)激活AMPK，显著提高ACC磷酸化水平，从而促进脂肪酸氧化[7, 52-53]。但是，关于脂联素传递至AMPK的信号研究较为缺乏。已有研究表明，在脂联素刺激下，信号接头蛋白(APPL1和CK2)和肝激酶LKB1作为AMPK上游因子，介导AdipoQ激活AMPK信号通路。在肌细胞和肝细胞中，LKB1激酶与APPL1结合后，能激活AMPK信号途径[7, 54]。当沉默LKB1基因表达时，脂联素激活AMPK的效应被抑制。综上，脂联素与脂联素受体结合后，能迅速激活AMPK信号因子，促进ACC磷酸化，最终促进脂肪酸氧化。
4.1.2 AdipoR1/2-腺苷酸活化蛋白激酶(AMPK)-过氧化物酶体增物激活受体α(PPARα)AdipoQ通过脂联素受体(AdipoR1和AdipoR2)作用于相关组织，不仅能激活AMPK, 促进ACC磷酸化, 进而促进脂肪酸氧化，还可能激活PPARα信号转导途径进而促进脂肪酸氧化。PPARα是调控动物脂质代谢的关键转录因子，其下游许多靶基因与脂肪酸氧化有关，包括乙酰辅酶A氧化酶(ACO)、肉毒碱棕榈酰转移酶1(CPT-1)和脂肪酸结合蛋白(FABP3)等。在C1C12细胞中，AdipoQ处理3~24 h以后，激活AMPK，提高PPARα转录活性，并上调其下游靶基因ACO、CPT-1和FABP3的转录表达水平[52]。在犊牛肝细胞中，添加脂联素孵育4 h以后，主要通过AdipoR2介导激活AMPKα，提高PPARα表达和转录活性，促进ACO、CPT-1和CPT-2等表达，从而促进脂肪酸氧化[55]。与上述研究类似，脂联素也能激活兔囊胚细胞中的PPARα[29]。由此可知，脂联素能促进脂肪酸氧化，部分是通过激活AMPK-PPARα途径来实现的。此外，不同细胞中响应AMPK-PPARα信号的靶基因存在差异。脂联素激活的PPARα途径区别于AMPK-ACC信号途径，其促进脂肪酸效应更持久。
4.1.3 AdipoR1/2-沉默信息调节因子1(SIRT1)-腺苷酸活化蛋白激酶(AMPK)在上述途径中机体处于生理状态，然而，在病理状态下，AdipoQ促进脂肪酸氧化的途径存在差异。SIRT1(Sirtuin 1)作为Sirtuins家族成员之一，SIRT1-AMPK轴在酒精性脂肪肝中发挥重要作用[56]。在患酒精性脂肪肝小鼠中，罗格列酮(PPARγ激动剂)提高血浆中AdipoQ表达，促进肝AdipoR1和AdipoR2表达，激活SIRT1-AMPK轴，继而促进脂肪酸氧化。在肝H4ⅡEC3细胞中，fAd能显著提高SIRT1蛋白水平并激活AMPK信号因子，双敲除试验证实AdipoR1和AdipoR2能共同介导SIRT1表达[57]。由上可知，在肝细胞中，fAd能通过AdipoR1和AdipoR2激活SIRT1-AMPK轴，从而影响脂质代谢。然而，研究者们并未探究AdipoQ是如何激活SIRT1-AMPK轴下游因子的。
综上，在肝和肌肉中，AdipoQ主要与AdipoR1或AdipoR2结合，激活AMPK相关信号途径，从而促进脂肪酸氧化。APPL1、CK2和LKB1作为AMPK信号途径的重要上游因子，此途径还可能涉及其它上游因子(如1-磷酸鞘氨醇(S1P))。此外，ACC和PPARα作为AMPK信号途径的下游因子，参与脂联素增强脂肪酸氧化的作用。
4.2 脂联素抑制脂质合成除了促进脂肪酸氧化以外，脂联素还能通过抑制脂质合成，降低血液中三酰甘油(TG)或胆固醇含量。在鼠上，注射脂联素能降低血浆中TG或胆固醇含量[6, 51]。脂联素的这种效应可能与脂联素结构有关，如gAd的降脂作用较fAd更强。本文主要综述了以下相关途径。
4.2.1 AdipoR1-肝激酶B1(LKB1)-腺苷酸活化蛋白激酶(AMPK)-固醇调节原件结合蛋白-1c (SREBP-1c)脂联素能激活AMPK信号途径，抑制其下游因子SREBP-1c的转录活性，从而抑制脂质合成。SREBP-1c作为重要的脂肪形成转录因子，其下游靶基因具有调节脂肪合成的作用，如乙酰辅酶A羧化酶α(ACCα)、硬脂酰辅酶A去饱和酶1(SCD1)和脂肪酸合成酶(FAS)。已有的研究显示，脂联素能通过抑制SREBP-1c及其靶基因的表达，抑制脂质合成。在LepR-/-小鼠肝中，利用腺病毒介导AdipoR1基因超表达使SREBP-1c的表达显著降低，而AdipoR2没有类似效应, 提示脂联素可能主要通过AdipoR1介导抑制SREBP-1c表达[58]。LKB1作为AMPK上游因子，在该途径中发挥重要的作用。体内体外试验均证实，脂联素能抑制SREBP-1c表达。在小鼠上，腹腔注射fAd能显著降低肝SREBP-1c及靶基因(ACCα和SCD1)的表达[59]。在牛肝细胞中，脂联素能显著降低SREBP-1c及其下游靶基因(ACCα、SCD-1和FAS等)表达[60]。这种效应与脂联素剂量呈正相关。以上研究提示，脂联素可能主要通过AdipoR1作用于肝，激活AMPK信号途径，抑制SREBP-1c及其靶基因(ACCα、SCD-1和FAS等)表达，进而抑制脂质合成。
4.2.2 AdipoR1-钙调素依赖蛋白激酶(CaMKK)-腺苷酸活化蛋白激酶(AMPK)-沉默信息调节因子1(SIRTI)-过氧化物酶体增殖物激活受体辅助活化因子1α(PGC-1α)过氧化物酶体增殖物激活受体辅助活化因子1α(PGC-1α)与脂质代谢密切相关[61]。在C2C12肌细胞中，脂联素通过AdipoR1诱导细胞外Ca2+内流，激活CaMKKB、AMPK和SIRT1，促进PGC-1α表达并抑制PGC-1α乙酰化[62]。尽管研究者们未探究其对脂质代谢的影响，但是已有的研究显示，PGC-1α能影响胆固醇7α羟化酶(CYP7A1)基因的表达，从而调节机体内胆固醇平衡[63]。据此推测，脂联素可能通过AdipoR1调节AMPK/SIRT1相关途径，促进PGC-1α的表达，调节胆固醇合成，从而抑制脂质合成。
4.2.3 AdipoR2-过氧化物酶体增物激活受体α(PPARα)脂联素不仅能通过AdipoR1介导激活AMPK信号途径，还能通过AdipoR2调节PPARα的活性，从而抑制脂质合成。在LepR-/-小鼠肝中，AdipoR2超表达能显著抑制PPARα的转录活性，降低其靶基因(Acox1和Ucp2)转录表达水平，从而抑制三酰甘油生成[58]。此外，载脂蛋白A5(ApoA5)作为调控三酰甘油合成上游的关键靶点，是一种新发现的能降低血浆TG含量的超家族成员，可能与脂联素抑制脂质合成的作用有关。在人HepG2肝细胞中，AdipoQ能显著提高PPARα和ApoA5的转录表达水平和蛋白表达水平，从而抑制三酰甘油合成[64]。据此推测，脂联素的降脂作用可能是通过上调PPARα和ApoA5表达实现，然而，具体的作用机制尚不清楚。
综上，脂联素能通过AdipoR1和AdipoR2作用，激活AMPK和PPARα信号途径，影响下游因子SREBP-1c、Acox1和Ucp2等表达，抑制脂质合成。最近研究者们还发现一些因子(如ATGL和HSL)能作为AMPK下游，介导AdipoQ发挥降脂作用[65]。此外，上述关于AdipoQ调节脂质代谢的研究主要集中于肌肉和肝，而部分研究显示，AdipoQ也能调控其它组织或细胞的脂质沉积，如肾、巨噬细胞和血管平滑肌[66-68]。但是相关的调控机制尚不清楚，有待进一步探究。
5 总结与展望综上所述，脂联素主要通过与其受体结合，促进脂肪酸氧化，抑制脂质合成，从而调节脂质代谢。AdipoQ对动物脂质代谢的影响与物种、组织和生理状态(包括病理状态)等因素密切相关。关于脂联素基因调控脂质代谢的分子机制，尽管已经开展了大量研究工作，但还存在许多问题需要解决。在未来的畜禽养殖业中，AdipoQ通过何种途径提高生产性能和饲料利用率、抗病能力、改善肉质等问题均亟待深入研究。
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