Abstract

Offspring born to obese and diabetic mothers are prone to metabolic diseases, a phenotype that has been linked to mitochondrial dysfunction and endoplasmic reticulum (ER) stress in oocytes. In addition, metabolic diseases impact the architecture and function of mitochondria-ER contact sites (MERCs), changes which associate with mitofusin 2 (MFN2) repression in muscle, liver and hypothalamic neurons. MFN2 is a potent modulator of mitochondrial metabolism and insulin signaling, with a key role in mitochondrial dynamics and tethering with the ER. Here, we investigated whether offspring born to mice with MFN2-deficient oocytes are prone to obesity and diabetes. Deletion of Mfn2 in oocytes resulted in a profound transcriptomic change, with evidence of impaired mitochondrial and ER function. Moreover, offspring born to females with oocyte-specific deletion of Mfn2 presented increased weight gain and glucose intolerance. This abnormal phenotype was linked to decreased insulinemia and defective insulin signaling, but not mitochondrial and ER defects in offspring liver and skeletal muscle. In conclusion, this study suggests a link between disrupted mitochondrial/ER function in oocytes and increased risk of metabolic diseases in the progeny. Future studies should determine whether MERC architecture and function are altered in oocytes from obese females, which might contribute toward transgenerational transmission of metabolic diseases.

中文翻译：

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具有卵母细胞特异性线粒体融合蛋白 2 缺失的雌性所生小鼠体重增加增加且葡萄糖稳态受损

摘要

肥胖和糖尿病母亲所生的后代容易患代谢疾病，这种表型与卵母细胞的线粒体功能障碍和内质网 (ER) 应激有关。此外，代谢疾病影响线粒体-ER 接触位点 (MERC) 的结构和功能，这些变化与肌肉、肝脏和下丘脑神经元中的线粒体融合蛋白 2 (MFN2) 抑制相关。MFN2 是线粒体代谢和胰岛素信号传导的有效调节剂，在线粒体动力学和与 ER 的束缚中起关键作用。在这里，我们调查了 MFN2 缺陷型卵母细胞小鼠所生的后代是否容易患肥胖症和糖尿病。删除Mfn2在卵母细胞中导致了深刻的转录组变化，有证据表明线粒体和 ER 功能受损。此外，具有卵母细胞特异性Mfn2缺失的女性所生的后代体重增加增加和葡萄糖耐受不良。这种异常表型与胰岛素血症减少和胰岛素信号传导缺陷有关，但与后代肝脏和骨骼肌中的线粒体和内质网缺陷无关。总之，这项研究表明卵母细胞线粒体/ER 功能受损与后代代谢疾病风险增加之间存在联系。未来的研究应确定肥胖女性卵母细胞中的 MERC 结构和功能是否发生改变，这可能有助于代谢疾病的跨代传播。