Fatty acid oxidation and meiotic resumption in mouse oocytes.
Fatty acid oxidation and meiotic resumption in mouse oocytes.
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DOI：
10.1002/mrd.21047
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发表时间：
2009-09
影响因子：
2.5
通讯作者：
Klinger, Jonathan
中科院分区：
文献类型：
--
作者：
Downs, Stephen M.;Mosey, Jessica L.;Klinger, Jonathan
我们提出的证据表明，amp激活的蛋白激酶（AMPK）存在于小鼠卵母细胞中，是减数分裂诱导系统的重要组成部分。在本研究中，我们研究了脂肪酸氧化（FAO）在AMPK诱导的减数分裂成熟中的潜在作用，因为这是AMPK通常激活的途径之一。依托莫西和丙二醇辅酶a是肉碱棕榈酰转移酶-1 （CPT1）的两种抑制剂，因此FAO，阻断了AMPK激活剂AICAR对dbcamp阻滞的积云细胞封闭卵母细胞（CEO）和去角质卵母细胞（DO）的减数分裂诱导。C75是CPT1和FAO的激活剂，刺激了CEO和DO的减数分裂恢复。这种效应对AMPK抑制剂化合物C不敏感，表明其作用于AMPK的下游。棕榈酸或肉碱也能在低浓度AICAR存在的情况下促进DO的减数分裂恢复。由于C75也抑制脂肪酸合成酶（FAS）的活性，我们测试了另一种FAS抑制剂，cerulenin。Cerulenin刺激了冻结卵母细胞的成熟，但在较小程度上，表现出明显较慢的动力学，并且对CEO有效，但对DO无效。此外，依托莫西完全阻断了c75诱导的成熟，但对蓝蛋白处理的卵母细胞无效。这些结果表明，C75的减数分裂诱导作用是通过激活卵母细胞内的FAO来实现的，而蓝紫蛋白的减数分裂诱导作用则不依赖于FAO而作用于积云细胞内。最后，我们确定长链而非短链的脂肪酰基肉碱衍生物，可以进入依托莫西抑制位点下游的FAO通路，刺激卵母细胞成熟。C16衍生物棕榈酰肉碱（PC）刺激了CEO和DO的成熟，并且在DO中具有快速的动力学（在次黄嘌呤补充的培养基中，2小时后成熟度从11%增加到62%）；这种效应对依托莫西不敏感，但被巯基乙酸酯和2-溴辛酸抑制，这两种都是FAO的下游抑制剂。这些结果与AMPK的激活通过消除对FAO的阻断刺激小鼠卵母细胞减数分裂恢复的观点一致。
We have presented evidence that AMP-activated protein kinase (AMPK) is present in mouse oocytes and is an important component of the meiotic induction system. In the present study, we have examined the potential role of fatty acid oxidation (FAO) in AMPK-induced meiotic maturation, because this is one of the pathways commonly activated by AMPK. Etomoxir and malonyl CoA, two inhibitors of carnitine palmitoyl transferase-1 (CPT1), and thus FAO, blocked meiotic induction in dbcAMP-arrested cumulus cell-enclosed oocytes (CEO) and denuded oocytes (DO) by the AMPK activator, AICAR. C75, an activator of CPT1 and FAO, stimulated meiotic resumption in CEO and DO. This effect was insensitive to the AMPK inhibitor, compound C, indicating an action downstream of AMPK. Palmitic acid or carnitine also promoted meiotic resumption in DO in the presence of a low concentration of AICAR. Since C75 also suppresses the activity of fatty acid synthase (FAS), we tested another FAS inhibitor, cerulenin. Cerulenin stimulated maturation in arrested oocytes, but to a lesser extent, exhibited significantly slower kinetics and was effective in CEO but not DO. Moreover, etomoxir completely blocked C75-induced maturation but was ineffective in cerulenin-treated oocytes. These results indicate that the meiosis-inducing action of C75 is through activation of FAO within the oocyte, while that of cerulenin is independent of FAO and acts within the cumulus cells. Finally, we determined that long chain, but not short chain, fatty acyl carnitine derivatives, which can enter the FAO pathway downstream of the site of etomoxir inhibition, were stimulatory to oocyte maturation. The C16 derivative, palmitoyl carnitine (PC), stimulated maturation in both CEO and DO, with rapid kinetics in DO (an increase in maturation after 2 h from 11% to 62% in hypoxanthine-supplemented medium); this effect was insensitive to etomoxir treatment but was inhibited by mercaptoacetate and 2-bromo-octanoic acid, both downstream inhibitors of FAO. These results are consistent with the idea that activation of AMPK stimulates meiotic resumption in mouse oocytes by eliminating a block to FAO.
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