Placental mTOR complex 1 regulates fetal programming of obesity and insulin resistance in mice
Placental mTOR complex 1 regulates fetal programming of obesity and insulin resistance in mice
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DOI：
10.1172/jci.insight.149271
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发表时间：
2021-07-08
期刊：
影响因子：
8
通讯作者：
Alejandro, Emilyn U.
中科院分区：
文献类型：
--
作者：
Akhaphong, Brian;Baumann, Daniel C.;Alejandro, Emilyn U.
胎儿生长受限，或低出生体重，是最终肥胖和2型糖尿病的重要决定因素。临床研究表明，胎盘机制靶雷帕霉素（mTOR）信号调节胎儿出生体重和后代的代谢健康轨迹。在目前的研究中，我们使用胎盘mTOR功能缺失的遗传模型（mTOR- ko胎盘）来测试mTOR信号对成年后代出生体重和代谢健康的直接作用。mtor - kol胎盘动物在胚胎日表现出胎盘面积和总重减少，以及胎儿体重(E) 17.5。出生体重和血清胰岛素水平降低；然而，mtor - ko胎盘新生儿的β细胞团正常。与对照组相比，成年mtor - kol胎盘后代在代谢高脂肪挑战下表现出更严重的肥胖和代谢功能障碍。随后，我们测试了在子宫内通过TSC2的基因消融来增强胎盘mTOR复合物1 （mTORC1）信号是否会改善后代的葡萄糖稳态。的确，胎盘mTORC1的增加可以保护后代免受饮食引起的肥胖。总之，胎盘mTORC1在胎盘功能与成年后代肥胖和胰岛素抵抗的编程之间起着机制联系。
Fetal growth restriction, or low birth weight, is a strong determinant for eventual obesity and type 2 diabetes. Clinical studies suggest placental mechanistic target of rapamycin (mTOR) signaling regulates fetal birth weight and the metabolic health trajectory of the offspring. In the current study, we used a genetic model with loss of placental mTOR function (mTOR-KOPlacenta) to test the direct role of mTOR signaling on birth weight and metabolic health in the adult offspring. mTOR-KOPlacenta animals displayed reduced placental area and total weight, as well as fetal body weight at embryonic day (E) 17.5. Birth weight and serum insulin levels were reduced; however, beta cell mass was normal in mTOR-KOPlacenta newborns. Adult mTOR-KOPlacenta offspring, under a metabolic high-fat challenge, displayed exacerbated obesity and metabolic dysfunction compared with littermate controls. Subsequently, we tested whether enhancing placental mTOR complex 1 (mTORC1) signaling, via genetic ablation of TSC2, in utero would improve glucose homeostasis in the offspring. Indeed, increased placental mTORC1 conferred protection from diet-induced obesity in the offspring. In conclusion, placental mTORC1 serves as a mechanistic link between placental function and programming of obesity and insulin resistance in the adult offspring.