{"title":"胎盘mTOR信号与小鼠线粒体功能障碍、营养转运和新生儿β细胞扰动有关。","authors":"Megan Beetch,Eunice Oribamise,Seokwon Jo,Briana Clifton,Sarah Larson,Alex Hausmann,Alicia Wong,Brian Akhaphong,Elizabeth Morgan,Emilyn U Alejandro","doi":"10.1007/s00125-025-06542-z","DOIUrl":null,"url":null,"abstract":"AIMS/HYPOTHESIS\r\nFetal programming of metabolic health is influenced by the in utero environment. The placental nutrient sensor mechanistic target of rapamycin (mTOR) is implicated in regulating fetal growth and programming of offspring metabolic health, but the mechanisms are unknown.\r\n\r\nMETHODS\r\nUsing a placental mTOR deficiency model to induce fetal growth restriction (FGR), we investigated mTOR-modulated placental mitochondrial function, nutrient transport and developmental programming of pancreatic beta cells, which are exquisitely sensitive to nutrient levels in utero.\r\n\r\nRESULTS\r\nWe found defects in placental mitochondria function and morphology that were specific to placentas of mTOR knockout (mTORKO) mice. Despite smaller placentas and FGR in both sexes, nutrient transporter expression and leucine flux were paradoxically increased in female mTORKO placentas. Female fetuses exposed to placental mTOR deficiency (mTORKOpl) displayed significantly reduced circulating insulin without neonatal perturbations in insulin secretion. However, average beta cell size and proliferation were increased in mTORKOpl female fetuses, possibly driven by system A (SNAT) amino acids, suggesting an immature beta cell phenotype. Adult mTORKOpl female offspring exhibit increased susceptibility to diet-induced obesity, insulin resistance and inability to mount a beta cell mass response to a hypernutrient environment.\r\n\r\nCONCLUSIONS/INTERPRETATION\r\nOur novel in vivo model of direct placental mTOR-driven FGR provides strong evidence linking placental dysfunction and amino acid transport to proper programming of beta cells in early life.","PeriodicalId":11164,"journal":{"name":"Diabetologia","volume":"82 1","pages":""},"PeriodicalIF":10.2000,"publicationDate":"2025-10-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":"{\"title\":\"Placental mTOR signalling links mitochondrial dysfunction, nutrient transport and neonatal beta cell perturbations in mice.\",\"authors\":\"Megan Beetch,Eunice Oribamise,Seokwon Jo,Briana Clifton,Sarah Larson,Alex Hausmann,Alicia Wong,Brian Akhaphong,Elizabeth Morgan,Emilyn U Alejandro\",\"doi\":\"10.1007/s00125-025-06542-z\",\"DOIUrl\":null,\"url\":null,\"abstract\":\"AIMS/HYPOTHESIS\\r\\nFetal programming of metabolic health is influenced by the in utero environment. The placental nutrient sensor mechanistic target of rapamycin (mTOR) is implicated in regulating fetal growth and programming of offspring metabolic health, but the mechanisms are unknown.\\r\\n\\r\\nMETHODS\\r\\nUsing a placental mTOR deficiency model to induce fetal growth restriction (FGR), we investigated mTOR-modulated placental mitochondrial function, nutrient transport and developmental programming of pancreatic beta cells, which are exquisitely sensitive to nutrient levels in utero.\\r\\n\\r\\nRESULTS\\r\\nWe found defects in placental mitochondria function and morphology that were specific to placentas of mTOR knockout (mTORKO) mice. Despite smaller placentas and FGR in both sexes, nutrient transporter expression and leucine flux were paradoxically increased in female mTORKO placentas. Female fetuses exposed to placental mTOR deficiency (mTORKOpl) displayed significantly reduced circulating insulin without neonatal perturbations in insulin secretion. However, average beta cell size and proliferation were increased in mTORKOpl female fetuses, possibly driven by system A (SNAT) amino acids, suggesting an immature beta cell phenotype. Adult mTORKOpl female offspring exhibit increased susceptibility to diet-induced obesity, insulin resistance and inability to mount a beta cell mass response to a hypernutrient environment.\\r\\n\\r\\nCONCLUSIONS/INTERPRETATION\\r\\nOur novel in vivo model of direct placental mTOR-driven FGR provides strong evidence linking placental dysfunction and amino acid transport to proper programming of beta cells in early life.\",\"PeriodicalId\":11164,\"journal\":{\"name\":\"Diabetologia\",\"volume\":\"82 1\",\"pages\":\"\"},\"PeriodicalIF\":10.2000,\"publicationDate\":\"2025-10-09\",\"publicationTypes\":\"Journal Article\",\"fieldsOfStudy\":null,\"isOpenAccess\":false,\"openAccessPdf\":\"\",\"citationCount\":\"0\",\"resultStr\":null,\"platform\":\"Semanticscholar\",\"paperid\":null,\"PeriodicalName\":\"Diabetologia\",\"FirstCategoryId\":\"3\",\"ListUrlMain\":\"https://doi.org/10.1007/s00125-025-06542-z\",\"RegionNum\":1,\"RegionCategory\":\"医学\",\"ArticlePicture\":[],\"TitleCN\":null,\"AbstractTextCN\":null,\"PMCID\":null,\"EPubDate\":\"\",\"PubModel\":\"\",\"JCR\":\"Q1\",\"JCRName\":\"ENDOCRINOLOGY & METABOLISM\",\"Score\":null,\"Total\":0}","platform":"Semanticscholar","paperid":null,"PeriodicalName":"Diabetologia","FirstCategoryId":"3","ListUrlMain":"https://doi.org/10.1007/s00125-025-06542-z","RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q1","JCRName":"ENDOCRINOLOGY & METABOLISM","Score":null,"Total":0}
Placental mTOR signalling links mitochondrial dysfunction, nutrient transport and neonatal beta cell perturbations in mice.
AIMS/HYPOTHESIS
Fetal programming of metabolic health is influenced by the in utero environment. The placental nutrient sensor mechanistic target of rapamycin (mTOR) is implicated in regulating fetal growth and programming of offspring metabolic health, but the mechanisms are unknown.
METHODS
Using a placental mTOR deficiency model to induce fetal growth restriction (FGR), we investigated mTOR-modulated placental mitochondrial function, nutrient transport and developmental programming of pancreatic beta cells, which are exquisitely sensitive to nutrient levels in utero.
RESULTS
We found defects in placental mitochondria function and morphology that were specific to placentas of mTOR knockout (mTORKO) mice. Despite smaller placentas and FGR in both sexes, nutrient transporter expression and leucine flux were paradoxically increased in female mTORKO placentas. Female fetuses exposed to placental mTOR deficiency (mTORKOpl) displayed significantly reduced circulating insulin without neonatal perturbations in insulin secretion. However, average beta cell size and proliferation were increased in mTORKOpl female fetuses, possibly driven by system A (SNAT) amino acids, suggesting an immature beta cell phenotype. Adult mTORKOpl female offspring exhibit increased susceptibility to diet-induced obesity, insulin resistance and inability to mount a beta cell mass response to a hypernutrient environment.
CONCLUSIONS/INTERPRETATION
Our novel in vivo model of direct placental mTOR-driven FGR provides strong evidence linking placental dysfunction and amino acid transport to proper programming of beta cells in early life.
期刊介绍:
Diabetologia, the authoritative journal dedicated to diabetes research, holds high visibility through society membership, libraries, and social media. As the official journal of the European Association for the Study of Diabetes, it is ranked in the top quartile of the 2019 JCR Impact Factors in the Endocrinology & Metabolism category. The journal boasts dedicated and expert editorial teams committed to supporting authors throughout the peer review process.