GLP-1對(duì)脂肪細(xì)胞及相關(guān)炎癥調(diào)控的研究進(jìn)展

馬振南，劉 源，唐世磊

1.中國醫(yī)科大學(xué)附屬盛京醫(yī)院普通外科，遼寧 沈陽 110022； 2.中國醫(yī)科大學(xué)附屬第四醫(yī)院結(jié)直腸、疝及腹壁外科

GLP-1對(duì)脂肪細(xì)胞及相關(guān)炎癥調(diào)控的研究進(jìn)展

馬振南1，劉 源1，唐世磊2

1.中國醫(yī)科大學(xué)附屬盛京醫(yī)院普通外科，遼寧 沈陽 110022； 2.中國醫(yī)科大學(xué)附屬第四醫(yī)院結(jié)直腸、疝及腹壁外科

通過總結(jié)近年來胰高血糖素樣肽1(Glucagon like peptide1，GLP-1)對(duì)脂肪細(xì)胞及相關(guān)慢性炎癥調(diào)控機(jī)理的最新研究進(jìn)展，進(jìn)一步闡明Roux-en-Y胃旁路手術(shù)治療2型糖尿病(type 2 diabetes mellitus，T2DM)的機(jī)制。GLP-1能調(diào)節(jié)脂肪細(xì)胞代謝紊亂及抑制以巨噬細(xì)胞為主的慢性炎癥的發(fā)展，RYGB術(shù)后GLP-1的升高，可明顯改善多種原因?qū)е碌囊葝u素抵抗，最終長期緩解T2DM患者的高血糖。RYGB術(shù)后GLP-1調(diào)節(jié)脂肪細(xì)胞及相關(guān)慢性炎癥的作用機(jī)理尚未完全清楚，進(jìn)一步認(rèn)識(shí)和研究GLP-1如何發(fā)揮生物學(xué)作用，將可能為開發(fā)用于治療糖尿病的新藥提供理論依據(jù)。

2型糖尿??；胃轉(zhuǎn)流；胰高血糖素樣肽1；脂肪細(xì)胞；炎癥

隨著社會(huì)發(fā)展、人們高能食物攝入及低體力活動(dòng)等生活方式的轉(zhuǎn)變，世界范圍內(nèi)肥胖癥人群的發(fā)病率呈逐年上升趨勢(shì)，已嚴(yán)重威脅人們的身體健康[1-2]。大量臨床觀察和研究已證實(shí)，如T2DM、三高癥、冠心病、阻塞性睡眠呼吸暫停綜合征等與肥胖癥密切相關(guān)，尤其是T2DM人群約占90%以上[3]，已成為威脅人類健康的一大疾病。目前T2DM常用治療手段不僅醫(yī)療費(fèi)用高昂，且長期療效不理想，最終引起一系列身體其他器官的嚴(yán)重并發(fā)癥，因此其治療備受關(guān)注。近年來，源于減肥手術(shù)的突破性進(jìn)展Roux-en-Y胃旁路(Roux-en-Y gastric bypass，RYGB)手術(shù)可迅速緩解糖尿病肥胖患者的高血糖并減輕體質(zhì)量，血糖降至正常的有效率達(dá)84%～98%，并可長期維持[4-6]。而其控制血糖的機(jī)制相對(duì)復(fù)雜，至今仍未完全明確，術(shù)后外周胰高血糖素樣肽1(glucagon like peptide 1，GLP-1)分泌增多對(duì)機(jī)體的作用被認(rèn)為是緩解T2DM的重要機(jī)制之一，現(xiàn)總結(jié)GLP-1水平的變化對(duì)脂肪因子及相關(guān)慢性炎癥調(diào)控方面的研究進(jìn)展，旨在更全面解釋RYGB術(shù)后治療肥胖糖尿病的分子機(jī)理。

1 肥胖與T2DM

肥胖癥表現(xiàn)為體內(nèi)脂肪組織過度堆積和(或)分布異常致體質(zhì)量異常增加的一種慢性代謝性疾病(診斷標(biāo)準(zhǔn)為 BMI>25 kg/m2)[7-9]。該人群機(jī)體代謝紊亂引起的胰島素抵抗(insulin resistance，IR)和(或)分泌缺陷在T2DM的進(jìn)程中起決定作用，IR即機(jī)體脂肪、肌肉和肝細(xì)胞對(duì)胰島素的敏感性降低。眾所周知，肥胖是T2DM最重要的危險(xiǎn)因子，90%以上T2DM患者都伴有肥胖或超重，而肥胖人群中脂肪細(xì)胞的功能紊亂和以巨噬細(xì)胞為主的相關(guān)慢性炎癥是造成T2DM的主要原因[10-11]，且肥胖癥人群與許多疾病密切相關(guān)[9,12]，如：T2DM、非酒精性脂肪肝、心血管疾病、退行性疾病及惡性腫瘤，而脂肪組織不再單是能量儲(chǔ)存器官，也是一種很重要的內(nèi)分泌器官，它分泌的多種脂肪因子參與神經(jīng)-內(nèi)分泌-免疫網(wǎng)絡(luò)的調(diào)節(jié)[13]。肥胖人群中脂肪細(xì)胞的功能紊亂導(dǎo)致脂肪因子和一些炎癥因子的分泌及功能異常，如腫瘤壞死因子α(tumor necrosisfactor-α，TNF-α)、IL-1α、白細(xì)胞介素6(interleukin-6，IL-6)、瘦素、脂聯(lián)素、抵抗素等，以及化學(xué)趨化因子，如單核細(xì)胞趨化蛋白-1(monocyte chemoattractant protein-1，MCP-1)、MCP-1α，以及產(chǎn)生過多的游離脂肪酸(free fatty acid，F(xiàn)FA)等[14]。如脂聯(lián)素是多肽類激素，通過作用腺苷酸活化蛋白激酶和過氧化物酶增殖物激活受體；瘦素是最早發(fā)現(xiàn)的脂肪因子，主要通過抑制食欲、增加能量消耗和抑制脂肪合成等3種調(diào)節(jié)方式，這些脂肪因子可協(xié)同調(diào)節(jié)葡萄糖、脂肪酸代謝及胰島素行為[15-16]。但在病態(tài)下，脂肪-胰島軸的反饋機(jī)制受損，使脂肪因子分泌紊亂、加速炎癥進(jìn)展等變化,引起胰島細(xì)胞去極化，出現(xiàn)IR、敏感性降低等一系列反應(yīng)，最終發(fā)展成為T2DM。研究已證實(shí)，持續(xù)的低度炎癥反應(yīng)也是肥胖、IR和T2DM一個(gè)共同的重要病理特點(diǎn)[17]。肥胖的IR患者炎性因子表達(dá)和(或)分泌增加，如TNF-α、IL-6、C-反應(yīng)蛋白(C-reactive protein，CRP)等，然而許多炎性因子相互作用也可直接導(dǎo)致脂代謝紊亂，如TNF-α和IL-6能促進(jìn)脂肪水解，釋放過多的FFA、聯(lián)素水平下降使脂肪氧化下降，最終導(dǎo)致肝臟和肌肉組織脂肪沉積和IR。胰島素的受體信號(hào)通路與炎性信號(hào)通路存在交叉，TNF-α可促進(jìn)胰島素受體底物(IRS和IRS2)的絲氨酸磷酸化，加重IR,同時(shí)多種細(xì)胞因子通過不同途徑直接或間接作用于胰腺組織，促進(jìn)T2DM的發(fā)生[18]。在肥胖癥發(fā)展過程中，脂肪組織中巨噬細(xì)胞的浸潤進(jìn)行性加重，而巨噬細(xì)胞是分泌炎性因子的主要細(xì)胞，且與IR呈正相關(guān)，在IR的進(jìn)展中，脂肪細(xì)胞和巨噬細(xì)胞的交互作用起著非常重要的作用[19]。此外，如趨化因子MCP-1和MCP-1α也可吸引巨噬細(xì)胞浸潤到脂肪細(xì)胞中，在脂肪、肝和肌肉細(xì)胞中通過活化JNK和NF-κB通路及長期暴露于高FFA環(huán)境下可通過TLR4/TLR2和NF-κB通路活化巨噬細(xì)胞，促進(jìn)炎癥的發(fā)展[20]，使胰島β細(xì)胞下調(diào)及凋亡增加，最終導(dǎo)致T2DM。因此，改善肥胖人群中脂肪因子分泌異常、抑制炎癥因子的生成是改善IR及提高胰島素的敏感性、控制高血糖及肥胖相關(guān)的代謝性紊亂疾病的關(guān)鍵之一，也是目前研究治療T2DM和肥胖癥的新趨勢(shì)。

2 RYGB術(shù)與GLP-1

近年來，隨著臨床上減重代謝外科中心的成立，已證明肥胖合并T2DM的患者RYGB術(shù)后體質(zhì)量明顯下降及糖脂代謝明顯改善，使血糖恢復(fù)至正常并可長期維持且有效率達(dá)84%～98%[5，21]。然而迄今RYGB手術(shù)治療肥胖糖尿病的機(jī)制尚未完全清楚，值得關(guān)注的是，到目前為止大量基礎(chǔ)和臨床實(shí)踐表明，糖脂代謝的改善與RYGB術(shù)后調(diào)節(jié)腸道激素的分泌密切相關(guān)，如GLP-1、Ghrelin、PYY(peptide YY)、抑胃肽(glucose-dependent insulinotropic polypeptide，GIP)等，目前研究表明主要是GLP-1的作用效果，可調(diào)節(jié)脂肪細(xì)胞功能紊亂和相關(guān)慢性炎癥所致的IR，從而直接或間接調(diào)節(jié)機(jī)體的血糖水平至正常范圍。GLP-1是一個(gè)由29～30個(gè)氨基酸構(gòu)成的肽類激素，由胰高血糖素原(preproglucogan)基因編碼，在特定的細(xì)胞中轉(zhuǎn)錄后加工而成。GLP-1由位于回腸末端和結(jié)腸的L細(xì)胞受營養(yǎng)物質(zhì)直接刺激而分泌，生理情況下，餐后機(jī)體產(chǎn)生的GLP-1很快釋放入血參與血糖調(diào)節(jié)，呈現(xiàn)早期(10～15 min)和延遲(30～60 min)兩個(gè)分泌相，不幸的是GLP-1在體內(nèi)常迅速地被二肽基肽酶4(dipeptydil-peptidase-4，DPP-4)降解失活[22]。GLP-1通過與GLP-1R結(jié)合發(fā)揮生物學(xué)作用，而GLP-1R在人體的許多組織中表達(dá)，包括胰島的α、β、δ細(xì)胞，肺，心臟，腎臟，胃腸道及中樞神經(jīng)系統(tǒng)的下丘腦和腦干區(qū)域等。因此，GLP-1的作用很廣泛，可以促進(jìn)糖原合成、脂肪分解，抑制肝糖原的輸出和胰高血糖素分泌，組織對(duì)葡萄糖的利用率增加，提高機(jī)體對(duì)胰島素的敏感性。臨床已證明Ex-4是GLP-1的長效類似物，不易被DPP-4降解，與GLP-1R結(jié)合后在改善糖代謝中起重要作用。RYGB術(shù)后GLP-1分泌增高的機(jī)制中以“后腸學(xué)說”最受關(guān)注且已被證實(shí)，認(rèn)為RYGB術(shù)后消化道重組, 未消化或部分消化的食物早期進(jìn)入后腸(末段回腸及結(jié)腸)，刺激腸 L細(xì)胞后主要影響GLP-1分泌，而空腹時(shí)GLP-1與術(shù)前相比基本一致，但在餐后GLP-1分泌會(huì)急劇增加，有研究表明RYGB術(shù)后2年，甚至更久GLP-1分泌增加持續(xù)存在，且與體質(zhì)量變化無相關(guān)性[23]，其更遠(yuǎn)期效果還有待隨訪研究。此外，末段回腸分泌的其他因子的提高也對(duì)糖代謝的改善有一定關(guān)系，如PYY等[24-26]。機(jī)體經(jīng)過GLP-1的生理作用后，促進(jìn)IR狀態(tài)脂肪細(xì)胞的葡萄糖攝取和脂肪分解增強(qiáng)其對(duì)胰島素的敏感性，增加胰島素mRNA的表達(dá)和胰島素前體合成，促進(jìn)胰島β細(xì)胞增生并抑制其凋亡[27]，在以上“后腸學(xué)說”作用下使血糖恢復(fù)至正常，其已經(jīng)成為治療糖尿病的新方向。

3 GLP-1與脂肪細(xì)胞

GLP-1是由腸L細(xì)胞分泌的目前已知作用最強(qiáng)的腸促胰島素分泌肽。越來越多的研究[28-29]表明，引起糖、脂質(zhì)代謝紊亂及IR的T2DM的肥胖癥人群中，RYGB術(shù)后GLP-1分泌增多并作用其受體可發(fā)揮多種生物學(xué)功能，以明顯改善血糖為代表已應(yīng)用于臨床[30]。但目前對(duì)GLP-1通過調(diào)節(jié)脂肪因子的分泌來改善血糖的機(jī)制尚未完全清楚。通過RYGB術(shù)后GLP-1對(duì)脂肪細(xì)胞的基礎(chǔ)研究顯示，Gao等[31]認(rèn)為脂肪細(xì)胞作為胰島素主要作用的靶器官,GLP-1可促進(jìn)脂肪細(xì)胞的胰島素依賴性葡萄糖攝取，而僅有GLP-1時(shí)則無此效應(yīng)，然而在發(fā)生IR時(shí)，GLP-1還可促進(jìn)脂肪細(xì)胞的葡萄糖攝取，從而增強(qiáng)其對(duì)胰島素的敏感度，進(jìn)而達(dá)到緩解機(jī)體高血糖環(huán)境。在肥胖伴T2DM的人群中，RYGB術(shù)后可使血糖恢復(fù)至正常水平并持續(xù)維持，這與術(shù)后GLP-1升高調(diào)節(jié)脂肪因子表達(dá)的變化有關(guān)，已有研究證實(shí)，術(shù)后GLP-1的分泌增多，通過調(diào)控核因子κB(NF-κB)來調(diào)節(jié)脂肪組織中眾多糖脂代謝基因的表達(dá)，使瘦素和FFA水平降低、保護(hù)性因子脂聯(lián)素的表達(dá)顯著增加,因多種脂肪因子的相互調(diào)節(jié)作用，可顯著改善糖脂代謝、緩解IR及增加外周器官胰島素的敏感性，故GLP-1提高可明顯緩解T2DM及肥胖相關(guān)的代謝障礙性疾病，且到目前為止是現(xiàn)代治愈T2DM被廣泛認(rèn)可的方案。其次，RYGB術(shù)后GLP-1分泌增多可以影響前脂肪細(xì)胞的增殖、分化[32],其機(jī)制與激活ERK、PKC和Akt信號(hào)通路(regulation of adipocyte formation by GLP-1/GLP-1R signaling)有關(guān)，可使小體積脂肪細(xì)胞的數(shù)量增加,而總體脂質(zhì)沒有顯著變化，GLP-1R與PPARr表達(dá)密切相關(guān)，是脂肪細(xì)胞分化的后期階段的標(biāo)志，提示GLP-1R可能與PPARr靶基因直接作用，可調(diào)節(jié)成熟脂肪細(xì)胞的效應(yīng)，Kang等[33-34]研究發(fā)現(xiàn),小體積脂肪細(xì)胞也有助于改善IR和糖脂代謝紊亂,使葡萄糖轉(zhuǎn)運(yùn)子4(GLIJT-4)表達(dá)增加。且術(shù)后GLP-1水平的升高可作用于NF-κB來調(diào)節(jié)脂肪因子的表達(dá)和分泌，NF-κB的激活可引起包括IL-6、C/EBPs、TNF-α、IL-6、CRP等在內(nèi)的多種因子的表達(dá)改變，能抑制脂肪組織中巨噬細(xì)胞浸潤，共同改善肥胖患者脂肪細(xì)胞的調(diào)節(jié)作用。因此，RYGB術(shù)后明顯改善脂肪細(xì)胞的功能紊亂，并有效調(diào)節(jié)脂肪因子發(fā)揮其應(yīng)有的效應(yīng)[35]，其與術(shù)后GLP-1的分泌增加后作用于脂肪細(xì)胞息息相關(guān)，而其作用機(jī)制仍需進(jìn)一步研究。

4 GLP-1與炎癥

目前研究表明，炎癥反應(yīng)與IR、肥胖癥和T2DM密切相關(guān)，且慢性炎癥是肥胖、T2DM的主要特征之一[36]。而這種慢性低度炎癥狀態(tài)主要起源于脂肪組織，脂肪組織不僅是一個(gè)儲(chǔ)存脂質(zhì)的器官，還是一個(gè)內(nèi)分泌器官，可以分泌多種胃腸激素及細(xì)胞因子等，在調(diào)節(jié)糖脂代謝、饑餓及飽腹感等信號(hào)通路中起至關(guān)重要的作用。脂肪組織分泌的細(xì)胞因子及趨化因子，統(tǒng)稱為脂肪因子(adipokines)，如瘦素、脂聯(lián)素、TNF-α、IL-6、CRP及MCP-1等[37-38]。在肥胖癥的IR患者中，其脂肪細(xì)胞中炎性因子的表達(dá)和(或)分泌增加，反之炎性因子也可直接導(dǎo)致脂肪細(xì)胞代謝紊亂，進(jìn)而對(duì)局部及全身產(chǎn)生異常生理效應(yīng)[39]。肥胖癥進(jìn)展過程中，脂肪組織中以巨噬細(xì)胞為主的炎癥細(xì)胞浸潤進(jìn)行性加重，并在其他異常細(xì)胞因子的協(xié)同下，加速β細(xì)胞的功能損傷和破壞，促進(jìn)IR的發(fā)生、發(fā)展，最終導(dǎo)致T2DM[40-41]。有研究[42-47]報(bào)道，RYGB術(shù)后血循環(huán)中促炎性脂肪因子水平明顯降低；而抗炎性脂肪因子水平明顯升高；脂肪組織巨噬細(xì)胞浸潤減少；脂肪組織及肝臟組織中炎性因子mRNA表達(dá)水平下降等，這些變化與體質(zhì)量減輕無明顯相關(guān)性，而受術(shù)后胃腸激素變化的影響，其主要是GLP-1的水平升高。事實(shí)上，越來越多的研究表明GLP-1能抑制炎癥性疾病的發(fā)展。Daousi等[48]研究顯示T2DM患者靜脈注射GLP-1或服用GLP-1類似物后,循環(huán)中炎性細(xì)胞因子如TNF-α、IL-6及IL-1p水平降低，抗炎性脂肪因子脂聯(lián)素水平升高，且其抗炎作用與體質(zhì)量、血糖的變化無關(guān)。Lee等[49]通過給ob/ob小鼠注射產(chǎn)生GLP-1的重組腺病毒(recombinant adenovirus producing GLP-1，rAd-GLP-1)使其GLP-1水平升高，可使ob/ob小鼠脂肪細(xì)胞中炎癥減輕及脂肪組織中浸潤的巨噬細(xì)胞，有直接抑制炎癥信號(hào)通路的作用[50]。如NF-κB的活化和JNK信號(hào)轉(zhuǎn)導(dǎo)通誘導(dǎo)炎性細(xì)胞因子和趨化因子基因的表達(dá)，因此產(chǎn)生的IL-6、TNF-α、MCP-1減少，進(jìn)而改善IR。另外，Terasaki等[51]報(bào)道在自發(fā)性動(dòng)脈粥樣硬化小鼠體內(nèi)持續(xù)注射低劑量GLP-1，可顯著抑制巨噬細(xì)胞的浸潤和降低動(dòng)脈粥樣硬化病變，其作用與GLP-1在巨噬細(xì)胞中介導(dǎo)cAMP活化有關(guān)。同樣，GLP-1還可在培養(yǎng)的人胰島中抑制IFN γ誘導(dǎo)趨化因子和炎癥因子的表達(dá)，應(yīng)用Ex-4治療糖尿病大鼠能明顯抑制黏附分子1(ICAM-1)的表達(dá)和NF-κB的活化，明顯改善糖尿病相關(guān)的腎臟炎癥。然而近期的研究還表明免疫細(xì)胞、T細(xì)胞和巨噬細(xì)胞也可表達(dá)GLP-1R。RYGB術(shù)后機(jī)體炎癥的改善狀態(tài)與胰島素敏感性呈正相關(guān)，使T2DM得到治愈，這些減重術(shù)后變化的效果在已發(fā)表文獻(xiàn)中均有闡述，但其作用機(jī)理仍需深入研究。

綜上所述，鑒于RYGB術(shù)后GL-1釋放明顯增加、減重效果確切及在治愈T2DM方面具有顯著效果，并且GLP-1及其類似物是目前治療T2DM和肥胖癥的藥物治療最有前途的選擇。但是，GLP-1對(duì)身體組織器官的生理學(xué)作用，仍有許多功能機(jī)制尚未完全清楚，仍需深入研究RYGB術(shù)后GLP-1增加是如何改善脂肪細(xì)胞功能紊亂和慢性炎癥的作用機(jī)制，將為開發(fā)治療糖尿病方面的新藥提供理論依據(jù)。因此，對(duì)GLP-1及其類似物藥物的臨床應(yīng)用有效性也需要持續(xù)深入的研究。

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(責(zé)任編輯：李 健)

Research progress of GLP-1 on the regulation of fat cells and related inflammation

MA Zhennan1, LIU Yuan1, TANG Shilei2

1.Department of General Surgery, Shengjing Hospital of China Medical University, Shenyang 110022; 2.Department of Colorectal, Hernia and Abdominal Surgery, the Fourth Affiliated Hospital of China Medical University, China

To further clarify the mechanism of Roux-en-Y gastni bypass(RYGB) in treating type 2 diabetes by summarizing recent research progress of GLP-1 on the regulation of fat cells and related chronic inflammation. GLP-1 can regulate the metabolism disorder of fat cells and inhibit the development of chronic inflammation in macrophages. The improvement of GLP-1 after RYGB operation can significantly improve the insulin resistance (IR) for variety of reasons, and finally help T2DM patients to chronically relieve symptoms caused by hyperglycemia. The mechanism of GLP-1 regulation of fat cells and related chronic inflammation after RYGB operation is not yet fully understood, and further understanding and studying on the biological function of GLP-1 will provide a theoretical basis for the development of new drugs for treating diabetes.

Type 2 diabetes; Gastric bypass; Glucagon like peptide 1; Fat cells; Inflammation

10.3969/j.issn.1006-5709.2016.06.031

遼寧省科學(xué)技術(shù)基金項(xiàng)目(C916)

馬振南，在讀碩士研究生，研究方向：肝膽、胃腸微創(chuàng)外科。E-mail：mazhennan8888@163.com

劉源，副教授、副主任，研究方向：肝膽、胃腸微創(chuàng)外科。E-mail：liuy12@sj-hospital.org

R57

A

1006-5709(2016)06-0711-05

2015-09-22