A maternal high-fat, high-sucrose diet induces transgenerational cardiac mitochondrial dysfunction independently of maternal mitochondrial inheritance
A maternal high-fat, high-sucrose diet induces transgenerational cardiac mitochondrial dysfunction independently of maternal mitochondrial inheritance
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DOI：
10.1152/ajpheart.00013.2019
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发表时间：
2019-05-01
影响因子：
4.8
通讯作者：
Moley, Kelle H.
中科院分区：
文献类型：
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作者：
Ferey, Jeremie L. A.;Boudoures, Anna L.;Moley, Kelle H.
母亲肥胖与后代的心血管疾病相关，在肥胖女性的后代中观察到的事件增加了1.3倍。我们已经观察到，肥胖暴露的卵母细胞表现出受损的线粒体自噬和传递受损的线粒体给后代。因此，我们假设母体肥胖通过异常卵母细胞线粒体的跨代遗传诱导后代的心脏线粒体功能障碍。我们将喂食高脂肪/高蔗糖（HFS）饮食（或食物）的雌性小鼠与喂食食物的雄性小鼠交配，并评估每一代喂食食物的后代的心脏结构和功能。通过每代雌性繁殖的所有F1至F3后代均不肥胖，并表现出心脏线粒体异常，晶体稀疏和耗氧量减少，表明存在跨代效应，而肥胖F0母鼠的心脏不受影响。此外，F1至F3代的雄性后代以及F1和F2代雌性后代的左心室（LV）质量增加（与普通饲料喂养的对照组相比）。在暴露于肥胖症的卵母细胞体外受精和非肥胖症替代者妊娠产生的后代中也观察到LV质量增加，排除了妊娠环境的影响。与我们的假设相反，雄性F1也将这些影响传递给了它们的后代，排除了母体线粒体作为主要传播模式的可能性。我们的结论是，在卵母细胞核，而不是异常的线粒体肥胖诱导的影响传输的基础上跨代遗传的心脏线粒体缺陷的后代肥胖女性。这些发现将刺激对卵母细胞基因组中表观遗传改变的探索，作为母体肥胖家族史易患人类心血管疾病的潜在机制。
Maternal obesity is correlated with cardiovascular disease in offspring, with a 1.3-fold increase in events observed in offspring of obese women. We have observed that obesity-exposed oocytes demonstrate impaired mitophagy and transmit damaged mitochondria to the offspring. Accordingly, we hypothesized that maternal obesity induces cardiac mitochondrial dysfunction in the offspring via transgenerational inheritance of abnormal oocyte mitochondria. We mated female mice fed a high-fat/high-sucrose (HFS) diet (or chow) with chow-fed males and assessed cardiac structure and function in their descendants that were chow fed in each generation. All F1 to F3 descendants bred via the female in each generation were nonobese and demonstrated cardiac mitochondrial abnormalities with crystal rarefaction and reduced oxygen consumption pointing to a transgenerational effect, while obese F0 dams' hearts were unaffected. Furthermore, male offspring from F1 to F3 generations and female F1 and F2 offspring developed increased left ventricular (LV) mass (vs. chow-fed controls). Increased LV mass was also observed in offspring generated by in vitro fertilization of obesity-exposed oocytes and gestation in nonobese surrogates, ruling out a gestational environment effect. Contrary to our hypothesis, male F1 also transmitted these effects to their offspring, ruling out maternal mitochondria as the primary mode of transmission. We conclude that transmission of obesity-induced effects in the oocyte nucleus rather than abnormal mitochondria underlie transgenerational inheritance of cardiac mitochondrial defects in descendants of obese females. These findings will spur exploration of epigenetic alterations in the oocyte genome as potential mechanisms whereby a family history of maternal obesity predisposes to cardiovascular disease in humans.