發(fā)布時(shí)間：2018-07-07 16:39

  本文選題：男性不育 + 脂肪營(yíng)養(yǎng)不良　； 參考：《南京醫(yī)科大學(xué)》2014年博士論文

【摘要】：背景： 近年來(lái),隨著肥胖人群的快速增加,多方臨床數(shù)據(jù)證明肥胖的男性由于機(jī)體脂肪含量過(guò)多,其生育力受到負(fù)面影響,然而,很少有研究關(guān)注機(jī)體脂肪含量過(guò)少對(duì)男性生育力有無(wú)影響。2004年有文獻(xiàn)提及患有遺傳性全身脂肪營(yíng)養(yǎng)不良(Congenital generalized lipodystrophy,CGL)的男性患者生育力正常,但我們前期對(duì)CGL2型致病基因Seipin進(jìn)行研究時(shí),發(fā)現(xiàn)全身敲除Seipin基因的雄性小鼠(簡(jiǎn)稱(chēng)：S-KO)呈現(xiàn)完全不育,這一發(fā)現(xiàn)促使我們重新思考機(jī)體脂肪組織過(guò)少對(duì)雄性生殖力的影響。同時(shí),大量數(shù)據(jù)顯示Seipin基因在脂肪組織以及神經(jīng)系統(tǒng)高表達(dá),Seipin蛋白缺失后導(dǎo)致脂肪分化障礙,Seipin基因突變后出現(xiàn)多種運(yùn)動(dòng)神經(jīng)元病變。本次研究過(guò)程中發(fā)現(xiàn)Seipin蛋白及mRNA在睪丸表達(dá)量明顯高于脂肪組織,而其在睪丸組織中的功能尚未有報(bào)道。 研究方法與結(jié)果： 我們?cè)谂R床募集到一例Seipin基因突變家系,其中針對(duì)男性患者進(jìn)行了體脂比例、激素水平和精液分析。同時(shí),在已有的全身性Seipin基因敲除的小鼠(S-KO)基礎(chǔ)上,進(jìn)一步構(gòu)建了脂肪細(xì)胞特異性Seipin基因敲除小鼠(簡(jiǎn)稱(chēng)：aS-KO)和睪丸生殖細(xì)胞特異性Seipin基因敲除小鼠(gS-KO)。繼而,對(duì)這三種敲除小鼠開(kāi)展了多方面的檢測(cè)：機(jī)體代謝、生育力測(cè)試、精子質(zhì)量評(píng)估等。本次研究結(jié)果如下：1.該男性患者因Seipin基因復(fù)合型突變導(dǎo)致全身脂肪營(yíng)養(yǎng)不良的同時(shí),存在嚴(yán)重畸形精子癥,精子畸形主要包括頭部畸形及多核精子束,且畸形精子內(nèi)存在異常的大脂滴。2.S-KO和gS-KO雄性小鼠因睪丸精子細(xì)胞內(nèi)出現(xiàn)異常的大脂滴,精子變形發(fā)生異常,導(dǎo)致少弱畸形精子癥,呈現(xiàn)雄性完全不育,小鼠畸形精子中也存在典型的多核精子束,小鼠睪丸油紅染色及電鏡觀察結(jié)果與男性患者精子內(nèi)異常脂滴相吻合。3. aS-KO并未因脂肪營(yíng)養(yǎng)不良導(dǎo)致生育力下降,睪丸內(nèi)精子發(fā)生正常。4.脂質(zhì)組學(xué)研究結(jié)果提示：在S-KO、gS-KO睪丸內(nèi),PA增加明顯,且磷脂的多不飽和脂肪酸的比例失衡。5.差異蛋白質(zhì)組學(xué)結(jié)果驗(yàn)證了脂質(zhì)組學(xué)的結(jié)果,提示S-KO睪丸內(nèi)脂代謝相關(guān)蛋白表達(dá)量增加,脂代謝水平處于亢進(jìn)狀態(tài),并且細(xì)胞炎癥反應(yīng)及凋亡相關(guān)蛋白大大增加,與小鼠表型一致。綜上所述：睪丸內(nèi)Seipin基因能夠維持精子變形過(guò)程中磷脂穩(wěn)態(tài),seipin基因突變后導(dǎo)致雄性生殖功能障礙,并且由Seipin突變導(dǎo)致的脂肪營(yíng)養(yǎng)不良并不能對(duì)雄性生育力產(chǎn)生影響,強(qiáng)調(diào)了睪丸生殖細(xì)胞的Seipin;對(duì)維護(hù)雄性生殖能力的重要作用。
[Abstract]:Background: in recent years, with the rapid growth of obese people, various clinical data have shown that obese men suffer negative effects on fertility due to excessive body fat content. Few studies have focused on whether low body fat levels have an impact on male fertility. In 2004, there was a reference to normal fertility in men with inherited generalized lipodystrophytic dystrophy. But when we studied Seipin, the pathogenic gene of CGL2, we found that the male mice with Seipin gene knockout showed complete sterility, which prompted us to rethink the effect of too little fat tissue on male fecundity. At the same time, a large number of data showed that Seipin gene in adipose tissue and nervous system overexpression of Seipin protein deletion led to adipose differentiation disorder Seipin gene mutation after the emergence of a variety of motor neuron lesions. In this study, we found that the expression of Seipin protein and mRNA in testis was significantly higher than that in adipose tissue, but the function of Seipin protein and mRNA in testis was not reported. Methods and results: we recruited a family of Seipin gene mutations in a clinical study, in which body fat ratio, hormone levels and semen analysis were performed on male patients. At the same time, based on the existing Seipin knockout mice (S-KO), adipocyte specific Seipin knockout mice (Seipin gene knockout mice) and testicular germ cell specific Seipin gene knockout mice (gS-KO) were further constructed. Then, the three kinds of knockout mice were tested in many aspects: metabolism, fertility test, sperm quality evaluation, etc. The results of this study are as follows: 1. The male patient suffered from systemic fat dystrophy due to Seipin gene complex mutation and had severe sperm malformation, which mainly included head malformation and polynuclear sperm bundles. There were abnormal lipid droplets in abnormal spermatozoa. 2.S-KO and gS-KO male mice showed abnormal lipid droplets in testicular sperm cells, abnormal sperm deformation, resulting in oligodeformed spermatozoa, which showed male complete sterility. Typical polynuclear sperm bundles were also found in abnormal sperm of mice. The results of testicular oil red staining and electron microscopy were in agreement with abnormal lipid droplets in sperm of male patients. AS-KO did not cause fertility decline due to adipose malnutrition. Testicular spermatogenesis is normal. The results showed that PA increased significantly in the testis of S-KOGS-KO, and the proportion of polyunsaturated fatty acids of phospholipid was out of balance. The results of differential proteomics confirmed the results of lipigraphy, suggesting that the expression of lipid metabolism-related proteins in the testis of S-KO was increased, the level of lipid metabolism was in a hyperactive state, and the cellular inflammatory response and apoptosis-related proteins were significantly increased. It is consistent with the mouse phenotype. In conclusion, the Seipin gene in the testis can maintain the mutation of phospholipin homeostasis during sperm deformation and lead to male reproductive dysfunction, and the fatty malnutrition caused by the Seipin mutation has no effect on male fertility. The important role of Seipinin of testicular germ cells in maintaining male reproductive ability was emphasized.
【學(xué)位授予單位】：南京醫(yī)科大學(xué)
【學(xué)位級(jí)別】：博士
【學(xué)位授予年份】：2014
【分類(lèi)號(hào)】：R698

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