Adiponectin supplementation in pregnant mice prevents the adverse effects of maternal obesity on placental function and fetal growth
Adiponectin supplementation in pregnant mice prevents the adverse effects of maternal obesity on placental function and fetal growth
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DOI：
10.1073/pnas.1515484112
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发表时间：
2015-10-13
影响因子：
11.1
通讯作者：
Janssona, Thomas
中科院分区：
文献类型：
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作者：
Aye, Irving L. M. H.;Rosario, Fredrick J.;Janssona, Thomas
患有肥胖症或妊娠期糖尿病的母亲循环中脂联素（ADN）水平较低，并且经常分娩脂肪量增加的大婴儿，这些婴儿易患围产期并发症，并在以后的生活中发展为代谢综合征。目前尚不清楚母体ADN和胎儿生长之间的负相关是否反映了因果关系。我们测试了肥胖妊娠母鼠补充ADN可改善母体胰岛素敏感性、恢复正常胎盘胰岛素/雷帕霉素复合物1（mTORC 1）信号转导和营养转运机制以及预防胎儿过度生长的假设。与对照饮食的母鼠相比，在交配前和整个妊娠期喂食致肥胖饮食的雌性C57 BL/6 J小鼠在胚胎第18.5天（E）空腹血清瘦素、胰岛素和C肽增加，高分子量ADN减少。胎盘胰岛素和mTORC 1信号被激活，过氧化物酶体增殖物激活受体-a（PPAR α）磷酸化减少，体内葡萄糖和氨基酸的胎盘转运增加，肥胖母鼠的胎儿体重增加29%。从E14.5至E18.5，肥胖母鼠的母体ADN输注使母体胰岛素敏感性、胎盘胰岛素/mTORC 1和PPARa信号传导、营养转运和胎儿生长正常化，而不影响母体脂肪量。使用与肥胖孕妇有惊人相似之处的小鼠模型，我们证明了ADN通过调节胎盘功能在母体脂肪组织和胎儿生长之间起着内分泌联系的作用。重要的是，母体补充ADN逆转了母体肥胖对胎盘功能和胎儿生长的不良影响。提高孕妇ADN水平可能是预防孕妇肥胖引起胎儿过度生长的有效干预策略。
Mothers with obesity or gestational diabetes mellitus have low circulating levels of adiponectin (ADN) and frequently deliver large babies with increased fat mass, who are susceptible to perinatal complications and to development of metabolic syndrome later in life. It is currently unknown if the inverse correlation between maternal ADN and fetal growth reflects a cause-and-effect relationship. We tested the hypothesis that ADN supplementation in obese pregnant dams improves maternal insulin sensitivity, restores normal placental insulin/mechanistic target of rapamycin complex 1 (mTORC1) signaling and nutrient transport, and prevents fetal overgrowth. Compared with dams on a control diet, female C57BL/6J mice fed an obesogenic diet before mating and throughout gestation had increased fasting serum leptin, insulin, and C-peptide, and reduced high-molecular-weight ADN at embryonic day (E) 18.5. Placental insulin and mTORC1 signaling was activated, peroxisome proliferator-activated receptor-a (PPAR alpha) phosphorylation was reduced, placental transport of glucose and amino acids in vivo was increased, and fetal weights were 29% higher in obese dams. Maternal ADN infusion in obese dams from E14.5 to E18.5 normalized maternal insulin sensitivity, placental insulin/mTORC1 and PPARa signaling, nutrient transport, and fetal growth without affecting maternal fat mass. Using a mouse model with striking similarities to obese pregnant women, we demonstrate that ADN functions as an endocrine link between maternal adipose tissue and fetal growth by regulating placental function. Importantly, maternal ADN supplementation reversed the adverse effects of maternal obesity on placental function and fetal growth. Improving maternal ADN levels may serve as an effective intervention strategy to prevent fetal overgrowth caused by maternal obesity.