母代肥胖對(duì)子代的影響及其機(jī)制的研究進(jìn)展

楊 天(綜述) 劉晟驊 胡夢(mèng)博 張立旻 姜昊文(審校) 丁 強(qiáng)

(復(fù)旦大學(xué)附屬華山醫(yī)院泌尿外科-復(fù)旦大學(xué)泌尿外科研究所 上海 200040)

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母代肥胖對(duì)子代的影響及其機(jī)制的研究進(jìn)展

楊 天(綜述) 劉晟驊 胡夢(mèng)博 張立旻 姜昊文△(審校) 丁 強(qiáng)

(復(fù)旦大學(xué)附屬華山醫(yī)院泌尿外科-復(fù)旦大學(xué)泌尿外科研究所 上海 200040)

超重和肥胖是影響現(xiàn)代人健康的一個(gè)重要因素。高脂高糖飲食和不健康的生活習(xí)慣是導(dǎo)致成人肥胖的主要原因,而近年來(lái)許多研究提示母代肥胖及相關(guān)的代謝紊亂也會(huì)影響其子代,提高子代罹患肥胖、糖尿病、哮喘,心血管等疾病的概率。本綜述總結(jié)了這一過(guò)程發(fā)生的相關(guān)機(jī)制,包括一氧化碳(nitric oxide,NO)和前列腺素途徑、高血糖癥和胰島素抵抗、活性氧(reactive oxygen species,ROC)的產(chǎn)生、脂毒性以及瘦素對(duì)下丘腦攝食中樞的調(diào)節(jié)作用。

母代肥胖; 子代; 影響機(jī)制

超重和肥胖是影響現(xiàn)代人健康的一個(gè)重要因素。截止至2010年,全球有15億人超重,5億人肥胖,而其中4 300萬(wàn)是小于5歲的兒童,按照這個(gè)趨勢(shì),預(yù)計(jì)2030年會(huì)有21.6億人超重,11.2億人肥胖[1]。此外,流行病學(xué)資料還發(fā)現(xiàn)20至39歲女性的肥胖比率明顯高于同年齡群的男性[2]。盡管高脂高糖飲食及不健康的生活習(xí)慣是導(dǎo)致成人肥胖的主要原因,近年來(lái)許多研究提示母代肥胖及相關(guān)的代謝紊亂也會(huì)影響其子代,如Lee等[3]研究了1950年至1976年為第一胎出生的18 873名新生兒,發(fā)現(xiàn)母代肥胖會(huì)增加子代成年后心血管事件的發(fā)生率,在一項(xiàng)針對(duì)11 006名孕婦的研究中也得到類(lèi)似的結(jié)論[4]。Hussen等[5]在一個(gè)大樣本隊(duì)列研究中發(fā)現(xiàn)母代肥胖會(huì)增加子代患1型糖尿病的概率。Derraik等[6]研究了26 561對(duì)母女,提出母代肥胖還會(huì)導(dǎo)致其女兒肥胖。此外,一項(xiàng)對(duì)108 312個(gè)樣本的薈萃分析發(fā)現(xiàn),母代肥胖也是子代罹患哮喘等呼吸系統(tǒng)疾病的危險(xiǎn)因素[7]。子代的精神系統(tǒng)疾病也被發(fā)現(xiàn)與其相關(guān)[8]。在動(dòng)物實(shí)驗(yàn)中同樣表明,妊娠期肥胖及高能量飲食的母親,其子代患高血壓、肝臟疾患、胰腺脂肪浸潤(rùn)及代謝性疾病的可能性也會(huì)有所提高[9-12]。

胎兒在圍產(chǎn)期,包括母代妊娠期和哺乳期,其與外界的聯(lián)系主要是通過(guò)母體。 在分娩前,胎兒完全生活在母體的羊水中,并通過(guò)臍動(dòng)靜脈、胎盤(pán)從母體獲取營(yíng)養(yǎng),母體的內(nèi)在環(huán)境與胎兒密切相關(guān)。又由于胎兒在分娩前各系統(tǒng)器官的發(fā)育處于不成熟階段,對(duì)于外界環(huán)境因素較為敏感,此時(shí)母體宮內(nèi)環(huán)境的變化可能對(duì)胎兒造成影響,增加或降低其在出生后及成年后對(duì)某些疾病的易感性。 而當(dāng)胎兒分娩后,在哺乳期其仍然主要是通過(guò)母體的乳汁獲得營(yíng)養(yǎng),此時(shí)母體仍然是胎兒接觸并聯(lián)系最為密切的外界因素,母體的環(huán)境變化仍可能影響其在幼年及成年后對(duì)某些疾病的易感性[13]。母代肥胖,尤其是在妊娠期間高脂高糖飲食及其導(dǎo)致的體重明顯增高,會(huì)影響母體的糖代謝變化,進(jìn)而造成多種病理學(xué)改變,使子代成年后更傾向于發(fā)生代謝異常[14-15]。此外,母代身體質(zhì)量指數(shù)(body mass index,BMI)的升高同樣也會(huì)增加母代及子代產(chǎn)科并發(fā)癥的發(fā)生,Ovesen等[16]對(duì)369 347位孕婦進(jìn)行研究后發(fā)現(xiàn)巨大胎兒的比例隨著母親BMI的升高而遞增,而母代BMI與子代先天畸形的關(guān)系也有多篇文獻(xiàn)報(bào)導(dǎo)[17-18]。相對(duì)地,妊娠期間保持正常體重或適量減少體重的母親,其子代心肌標(biāo)志物水平相比肥胖母親的子代明顯下降[17,19-21]。

近幾年,母代肥胖對(duì)子代影響的研究逐漸成為了研究熱門(mén),Herring等[22]綜述了母代肥胖與子代肥胖和糖尿病的關(guān)系,Ojha等[23]則進(jìn)一步論述了相關(guān)的代謝過(guò)程及分子機(jī)制,但目前的綜述多為從某一個(gè)疾病入手,很少探討疾病與疾病之間的內(nèi)在機(jī)制關(guān)聯(lián)。本綜述從機(jī)制角度切入,在分子層面探討母代肥胖對(duì)胚胎早期發(fā)育發(fā)展及子代的影響,希望能夠找到一些共同的分子通路,為臨床預(yù)防和治療提供理論依據(jù)。

機(jī)制研究進(jìn)展 關(guān)于母代肥胖對(duì)子代產(chǎn)生相關(guān)影響的原因,多項(xiàng)動(dòng)物學(xué)研究中已經(jīng)部分闡明了一些機(jī)制。多細(xì)胞生物在發(fā)育的過(guò)程中,細(xì)胞會(huì)受到一個(gè)短暫的刺激,繼而改變其基因編程,從而分化成另一種細(xì)胞[16],即使在這種刺激去除后很長(zhǎng)一段時(shí)間內(nèi),細(xì)胞在之后多次的分裂中都保持相同的分化選擇,這種現(xiàn)象稱(chēng)之為“細(xì)胞記憶”[24]。肥胖孕婦的宮內(nèi)環(huán)境為一些致病因素的相互作用提供了一個(gè)適宜的場(chǎng)所,這些致病因素通過(guò)干擾發(fā)育過(guò)程中的關(guān)鍵節(jié)點(diǎn),改變細(xì)胞正常分化選擇,從而造成產(chǎn)科并發(fā)癥和錯(cuò)誤遺傳編程的發(fā)生。比如胎兒下丘腦攝食通路上的錯(cuò)誤編程能夠?qū)ζ浯x和攝食活動(dòng)造成持續(xù)影響,使子代在發(fā)育過(guò)程及成年后更傾向于罹患一些代謝性疾病如糖尿病、肥胖等,而這種影響甚至可以持續(xù)至第三代[11,16]。

一氧化氮(nitric oxide ,NO)途徑與前列腺素途徑 NO在前列腺素的生成中起到重要作用。NO的表達(dá)方式有兩種,一種是在血管內(nèi)皮細(xì)胞內(nèi),由內(nèi)皮型一氧化氮合酶(endothelial nitric oxide synthase ,eNOS)組成性表達(dá),另一種需先通過(guò)細(xì)胞因子、脂多糖和其他免疫原激發(fā)后,由免疫細(xì)胞中的誘導(dǎo)型一氧化氮合酶(inducible nitric oxide synthase,iNOS)誘導(dǎo)表達(dá)[25]。NO可以激活含有血紅素的酶如環(huán)氧合酶1和2(cyclo-oxygen-ase-1 & 2,COX-1 & COX-2),而COX-1和COX-2可以通過(guò)多種反應(yīng)將花生四烯酸轉(zhuǎn)化為不同類(lèi)型活躍的前列腺素,因此NO可以促進(jìn)不同組織中前列腺素的合成[26]。

在正常胚胎發(fā)育的過(guò)程中,前列腺素和NO在一些關(guān)鍵的環(huán)節(jié)都起到了重要的作用。前列腺素,尤其是前列腺素E2,會(huì)影響卵泡的成熟和排卵過(guò)程,而NO也參與了卵母細(xì)胞的成熟、排卵、受精和著床[27]。前列腺素和NO產(chǎn)生過(guò)少會(huì)對(duì)胚胎發(fā)育和心血管形成造成不良影響。研究發(fā)現(xiàn),NO可以激活血管平滑肌內(nèi)的鳥(niǎo)苷酸環(huán)化酶,使環(huán)鳥(niǎo)苷酸生成增加、游離鈣離子濃度降低,從而使血管平滑肌舒張、血管擴(kuò)張[28]。因此對(duì)于胚胎而言,NO可以保障胎盤(pán)有充足的血流灌注。而肥胖狀態(tài)會(huì)增加體內(nèi)氧化性低密度脂蛋白(oxygenized low density lipoprotein,oxLDL)和腫瘤壞死因子α(tumor necrosis factor-α,TNF-α)的含量[29-30],它們能夠縮短eNOS信使RNA的半衰期,從而抑制eNOS的表達(dá)[31]。此外,如果孕婦存在胰島素抵抗,則蛋白激酶Cβ會(huì)被激活,進(jìn)而抑制了磷脂酰肌醇-3激酶(phosphatidylinositol 3-kinase,PI3K)和eNOS的活性和表達(dá)[31-32]。這兩方面均會(huì)使NO的分泌減少,抑制前列腺素的功能,使胎盤(pán)血管舒張受限,血管阻力增高,胎盤(pán)灌注降低,影響胎盤(pán)與母體之間氣體和營(yíng)養(yǎng)物質(zhì)的交換,最終影響胚胎發(fā)育,增加子代罹患心血管系統(tǒng)疾病的概率。

高血糖癥與胰島素抵抗 葡萄糖是胚胎最基本的能量來(lái)源,孕婦血糖水平的波動(dòng)會(huì)對(duì)胎兒和胎盤(pán)的發(fā)育造成不良影響[20,33]。研究表明孕婦的血糖水平與其子代的體型和肥胖相關(guān)[34]。孕婦過(guò)高的血糖、高血糖癥或妊娠期間肥胖被認(rèn)為是造成胎兒畸形和發(fā)育異常的主要原因之一[17-18,35]。

在妊娠開(kāi)始的第1～3個(gè)月和第7～9個(gè)月間,由于胰島素敏感性下降,孕婦胰島素的分泌量會(huì)增加至正常人的2倍,以適應(yīng)妊娠期的需要,之后會(huì)引起生理性的胰島素抵抗和高胰島素血癥。這對(duì)于普通孕婦來(lái)說(shuō)是一個(gè)正常的生理過(guò)程,它可以通過(guò)抑制母體對(duì)葡萄糖的利用來(lái)保證胎兒成長(zhǎng)所需的葡萄糖水平[21]。然而對(duì)于肥胖的孕婦,由于其本身就會(huì)產(chǎn)生過(guò)量的胰島素而出現(xiàn)胰島素抵抗,這一過(guò)程便會(huì)造成孕婦的高血糖癥[36]。有關(guān)高血糖對(duì)孕婦和胎兒影響的機(jī)制,目前多數(shù)學(xué)者認(rèn)為由于與胰島素相比,葡萄糖較容易通過(guò)胎盤(pán),因此妊娠期高血糖的母親,葡萄糖會(huì)持續(xù)經(jīng)胎盤(pán)到達(dá)胎兒體內(nèi),引起胎兒的高血糖,高血糖能夠刺激胎兒胰島 β細(xì)胞分泌胰島素,導(dǎo)致高胰島素血癥,最終造成胎兒的胰島素抵抗,氨基酸轉(zhuǎn)移系統(tǒng)被活化,抑制脂肪分解,促進(jìn)蛋白質(zhì)合成,增加胎兒體內(nèi)脂肪堆積和蛋白質(zhì)儲(chǔ)存,導(dǎo)致巨大兒的發(fā)生[37]。此外,胎兒生長(zhǎng)發(fā)育的加速還會(huì)增加器官耗氧量,延遲胎肺成熟,使胎兒出現(xiàn)宮內(nèi)缺氧、新生兒呼吸窘迫綜合征等問(wèn)題[38]。

高脂飲食在肥胖誘導(dǎo)的胰島素抵抗中起到了重要的作用。機(jī)體中TNF-α,iNOS及白介素6(interleukin-6,IL-6)主要是由脂肪組織巨噬細(xì)胞來(lái)表達(dá)的[39]。由于肥胖和高脂飲食的存在,過(guò)多的游離脂肪酸與巨噬細(xì)胞上的先天免疫受體Toll樣受體4結(jié)合[40],使脂肪細(xì)胞分泌較低水平的TNF-α,反過(guò)來(lái)促進(jìn)了前脂肪細(xì)胞、內(nèi)皮細(xì)胞單核細(xì)胞趨化蛋白-1 、IL-6,TNF-α、iNOS、C反應(yīng)蛋白以及可溶性細(xì)胞間黏附分子的釋放[41-42],這些分子進(jìn)一步誘導(dǎo)了促炎和促氧化的發(fā)生,促炎信號(hào)進(jìn)而通過(guò)抑制胰島素信號(hào)造成了胰島素抵抗。也有研究認(rèn)為T(mén)NF-α可以通過(guò)削弱胰島素受體上酪氨酸的磷酸化,促進(jìn)胰島素受體底物1的磷酸化過(guò)程,從而直接降低脂肪細(xì)胞的胰島素敏感性[43]。同時(shí),TNF-α還可以通過(guò)激活絲裂原活化蛋白激酶(mitogen-activated protein kinase,MAPK)和以及提高環(huán)磷酸腺苷(cyclic AMP,cAMP)水平來(lái)促進(jìn)人分化脂肪細(xì)胞的脂溶過(guò)程[43],這在高血糖癥、胰島素抵抗、2型糖尿病等代謝綜合征的發(fā)生發(fā)展中起到重要的作用[40,42]。此外,脂肪細(xì)胞還會(huì)分泌血管內(nèi)皮生長(zhǎng)因子、堿性成纖維細(xì)胞生長(zhǎng)因子、血管生成素等多種生脂和生血管因子,這些因子促進(jìn)了新生血管的形成,加固了脂肪血管系統(tǒng),從而進(jìn)一步提高了游離脂肪酸和細(xì)胞因子的水平,使肥胖、高血糖癥和胰島素抵抗得以繼續(xù)惡化[44]。

瘦素與下丘腦攝食中樞 大量動(dòng)物實(shí)驗(yàn)表明,母代肥胖和高脂飲食可引起子代神經(jīng)內(nèi)分泌系統(tǒng)的改變,這種改變主要集中在控制食欲、代謝和能量消耗的部分,通過(guò)下丘腦的弓狀核(arcuate nucleus of hypothala mus,ARH)和下丘腦室旁核(paraventricular hypothalamic nucleus,PVH)神經(jīng)元網(wǎng)絡(luò)進(jìn)行復(fù)雜調(diào)控。其中最重要的部分是在弓狀核中負(fù)責(zé)分泌阿黑皮素原(proopiomelanocortin,POMC),神經(jīng)肽Y(neusopeptide Y,NPY)和共表達(dá)刺鼠基因相關(guān)蛋白(agouti gene-related protein,AGRP)的神經(jīng)元[36]。POMC可以通過(guò)產(chǎn)生α-黑素細(xì)胞刺激激素有效降低食欲,而NPY/AGRP神經(jīng)元?jiǎng)t可以促進(jìn)食欲,引發(fā)攝食行為[45]。母代肥胖的子代,其N(xiāo)PY/AGRP神經(jīng)元表達(dá)上升而POMC表達(dá)下降,導(dǎo)致了下丘腦攝食通路長(zhǎng)期不平衡以及持續(xù)的食欲過(guò)盛。

瘦素在這一過(guò)程中起著核心的作用[46]。瘦素主要由脂肪組織產(chǎn)生,也可由人胎盤(pán)、乳腺(尤其是在哺乳期的早期階段)等組織產(chǎn)生。瘦素有許多生物學(xué)功能,本文主要關(guān)注瘦素對(duì)于下丘腦的作用及其改變食欲和食物攝入量的過(guò)程。瘦素可以通過(guò)抑制NPY/AGRP神經(jīng)元活性并加強(qiáng)POMC神經(jīng)元活性來(lái)減少饑餓感[46]。而研究發(fā)現(xiàn),肥胖大鼠的新生子代體內(nèi)會(huì)出現(xiàn)一個(gè)明顯的瘦素激增,導(dǎo)致中樞性的瘦素抵抗,減弱了對(duì)NPY/AGRP神經(jīng)元的抑制,并對(duì)ARH、PVH等下丘腦功能區(qū)造成永久影響[47]。這可能是導(dǎo)致子代食欲過(guò)剩和肥胖的主要原因。

瘦素對(duì)NPY/AGRP和POMC神經(jīng)元活性調(diào)節(jié)的本質(zhì)可能與下丘腦啟動(dòng)子區(qū)域DNA甲基化模式的改變有關(guān)[48]。在一項(xiàng)動(dòng)物研究中發(fā)現(xiàn),在圍產(chǎn)期營(yíng)養(yǎng)過(guò)度的母鼠,其子代小鼠NPY的啟動(dòng)子甲基化水平較低而POMC的啟動(dòng)子甲基化水平較高,而這些小鼠在成年后相比對(duì)照組更容易患肥胖、胰島素抵抗和心血管疾病[49]。還有研究發(fā)現(xiàn),母代高脂飲食所誘導(dǎo)的甲基化狀態(tài)改變可以遺傳到之后至少兩代的小鼠[50]。

活性氧(reactive oxygen species,ROS) ROS是生物有氧代謝過(guò)程中的一種副產(chǎn)物,包括氧離子、過(guò)氧化物和含氧自由基等,低水平的ROS有利于蛋白合成,而過(guò)高的ROS水平則會(huì)對(duì)線(xiàn)粒體和DNA結(jié)構(gòu)造成損壞[51]。高血糖癥會(huì)引起線(xiàn)粒體中的ROS慢性增長(zhǎng),造成線(xiàn)粒體DNA損傷、功能下降,甚至細(xì)胞損傷和凋亡[52-53]。ROS可以通過(guò)改變蛋白質(zhì)中心(如Ryanodine受體關(guān)鍵位置上的巰基),直接影響其收縮功能,并通過(guò)氧化Ca2 +-ATP酶抑制肌漿網(wǎng)L型鈣通道對(duì)Ca2 +的吸收利用[54]。ROS還可以激活酪氨酸激酶、GTP結(jié)合蛋白、蛋白激酶C和MAPK等多種與心肌肥大相關(guān)的信號(hào)激酶和轉(zhuǎn)錄因子,從而刺激心肌細(xì)胞生長(zhǎng)和基質(zhì)重建的下游信號(hào)通路,影響心肌的發(fā)育和功能[52-54]。

人類(lèi)和動(dòng)物研究中均發(fā)現(xiàn),肥胖孕婦子代的心血管疾病患病率與正常妊娠相比有明顯的增高[55-57]。在子宮內(nèi),ROS可直接刺激胚胎心臟成纖維細(xì)胞和心肌細(xì)胞的增殖[58-59]。心臟成纖維細(xì)胞占成人心臟細(xì)胞總數(shù)的三分之二[60],它可以提高纖維蛋白、膠原蛋白等細(xì)胞外基質(zhì)蛋白的分布,誘導(dǎo)間質(zhì)纖維化,增加心肌被動(dòng)剛度,從而導(dǎo)致心臟功能障礙[61]。ROS也可以通過(guò)間接方式影響心肌發(fā)育和功能。在成人心臟中,ROS可以刺激炎性因子,激活心肌基質(zhì)金屬蛋白酶,從而促進(jìn)心室重塑[52]。此外有研究發(fā)現(xiàn)[62],在體外培養(yǎng)的大鼠胚胎中添加可清除ROS的超氧化物歧化酶后,高血糖對(duì)大鼠的致畸作用明顯減少。也有研究認(rèn)為,ROS能夠以中間體的方式作用于血管緊張素II受體1,促進(jìn)血管緊張素II誘導(dǎo)心肌肥厚和心肌成纖維細(xì)胞增殖[63]。

脂毒性 在妊娠過(guò)程中,肥胖女性的脂肪會(huì)更多地累積在上半身,而苗條女性的脂肪則更多地累積在下半身[54-55]。脂肪的分布又與內(nèi)臟脂肪代謝異常有關(guān),上半身的脂肪更容易分解,產(chǎn)生大約60%的循環(huán)游離脂肪酸,相比之下,下半身脂肪產(chǎn)生的游離脂肪酸只占了循環(huán)游離脂肪酸的15%～20%[64]。肥胖狀態(tài)會(huì)抑制脂肪酸攝取,增加脂肪分解、炎癥細(xì)胞浸潤(rùn)以及脂肪因子的分泌[65]。多余的脂肪酸于是進(jìn)入血液積聚在組織器官(心、肝、肌肉),導(dǎo)致脂毒性的發(fā)生[66]。當(dāng)細(xì)胞難以處理胞內(nèi)過(guò)多的脂肪酸時(shí),便會(huì)發(fā)生細(xì)胞干擾,如脂肪酸發(fā)生過(guò)氧化產(chǎn)生ROS,細(xì)胞膜磷脂的破壞以及神經(jīng)酰胺信號(hào)和膽固醇含量的變化[67]。血脂水平升高和氧化應(yīng)激會(huì)導(dǎo)致過(guò)氧化脂質(zhì)、氧化脂蛋白和氧化型膽固醇等有害物質(zhì)的產(chǎn)生[65]。此外,與ROS類(lèi)似,游離脂肪酸可以直接抑制NO的生物利用度[31],激活還原型輔酶Ⅱ氧化酶和電子傳遞鏈產(chǎn)生過(guò)氧化物,進(jìn)而損害線(xiàn)粒體等細(xì)胞的細(xì)胞結(jié)構(gòu)[68]。

脂毒狀態(tài)下產(chǎn)生的氧化型膽固醇會(huì)對(duì)胎盤(pán)的發(fā)育和功能產(chǎn)生一定影響[64]。人胎盤(pán)上能夠表達(dá)肝X受體α,β以及過(guò)氧化物酶增殖物激活受體γ,而ox-LDL中含有較多的氧化型膽固醇和磷脂氫過(guò)氧化物衍生物,可為這兩個(gè)受體提供配體[69]。在一項(xiàng)對(duì)綿羊進(jìn)行的動(dòng)物實(shí)驗(yàn)中發(fā)現(xiàn),母羊妊娠中期的肥胖會(huì)增加胎盤(pán)上脂肪酸轉(zhuǎn)運(yùn)蛋白的表達(dá),升高胎羊血三酰甘油水平,增強(qiáng)炎癥信號(hào)通路以及細(xì)胞因子表達(dá)[70]。在臨床研究中同樣發(fā)現(xiàn),肥胖妊娠的孕婦和胎兒血液中的膽固醇及三酰甘油濃度顯著高于正常妊娠的孕婦和胎兒[71]。過(guò)多的游離脂肪酸和脂毒性會(huì)誘導(dǎo)級(jí)聯(lián)反應(yīng),影響細(xì)胞記憶,并通過(guò)NO途徑、ROS等方面對(duì)胎兒發(fā)育過(guò)程產(chǎn)生不良影響。

結(jié)語(yǔ) 孕期肥胖對(duì)母親和孩子都是明確的危險(xiǎn)因素。盡管不良的飲食和生活方式是成人肥胖的主要原因,越來(lái)越多的證據(jù)表明,成人肥胖和相關(guān)疾病的發(fā)病原因也許可以追溯到其胚胎發(fā)育期和出生早期。本文綜述了這一過(guò)程發(fā)生的相關(guān)機(jī)制,包括高血糖癥、胰島素抵抗、NO和前列腺素途徑、ROS的產(chǎn)生、脂毒性以及瘦素對(duì)下丘腦攝食中樞的調(diào)節(jié)作用。這些過(guò)程會(huì)影響胎兒發(fā)育,引起胎盤(pán)、心血管、肌肉骨骼、神經(jīng)系統(tǒng)和代謝系統(tǒng)的發(fā)育異常(圖1)。目前已經(jīng)進(jìn)行了大量的動(dòng)物實(shí)驗(yàn)來(lái)研究母代肥胖對(duì)子代的影響及機(jī)制。研究表明,通過(guò)減少胎兒肥胖相關(guān)因素的暴露,能夠顯著降低兒童及成年后患肥胖和相關(guān)代謝性疾病的風(fēng)險(xiǎn)。因此,肥胖女性在懷孕前應(yīng)當(dāng)建議其減少體重,同時(shí)在懷孕期間也要控制飲食和體重。

雖然臨床實(shí)驗(yàn)有利于進(jìn)一步的機(jī)制研究,但由于臨床實(shí)驗(yàn)存在其倫理和實(shí)際操作的困難性,不適合全面開(kāi)展。因此今后需要繼續(xù)深入研究分子之間的相互關(guān)系,尋找更有效的治療和行為干預(yù)方式,以防止肥胖和相關(guān)疾病的代際循環(huán)。

ROS:Reactive oxygen species; NO:Nitric oxide.

圖1 母代肥胖對(duì)子代的影響及相關(guān)機(jī)制

Fig 1 The influence from maternal obesity to offspring and its mechanisms

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Research progress in the mechanisms of influence from maternal obesity to offspring

YANG Tian, LIU Sheng-hua, HU Meng-bo, ZHANG Li-min, JIANG Hao-wen△, DING Qiang

(DepartmentofUrology,HuashanHospital,FudanUniversity-InstitueofUrology,FudanUniversity,Shanghai200040,China)

Overweight and obesity are seriously impacting the whole population nowadays.Though high-fat or high-sugar diet and an unhealthy life style are the main causes of obesity in adult,recent researches suggest that maternal obesity and related metabolic disorders may affect the offspring,resulting in diseases like obesity,diabetes,asthma and cardiovascular symptoms.This review summarized some mechanisms of influence from maternal obesity to offspring including arachidonic acid-prostaglandin pathway and nitric oxide pathway,hyperglycaemia and insulin resistance,reactive oxygen species,lipotoxicity,and the effect of leptin to hypothalamus.

maternal obesity; offspring; influence mechanisms

國(guó)家自然科學(xué)基金(81272835)

R151.2

B

10.3969/j.issn.1672-8467.2016.06.017

2015-10-20;編輯:張秀峰)

△Corresponding author E-mail:haowenjiang_urol@126.com

* This work was supported by the National Natural Science Foundation of China (81272835).