{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,23]],"date-time":"2026-10-23T21:06:10Z","timestamp":1792789570653,"version":"4.5.0"},"reference-count":85,"publisher":"MDPI AG","issue":"8","license":[{"start":{"date-parts":[[2023,4,14]],"date-time":"2023-04-14T00:00:00Z","timestamp":1681430400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"NIH","award":["HD071306"],"award-info":[{"award-number":["HD071306"]}]},{"name":"NIH","award":["HD068370"],"award-info":[{"award-number":["HD068370"]}]},{"name":"NIH","award":["HD089980"],"award-info":[{"award-number":["HD089980"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>The mechanisms mediating the restricted growth in intrauterine growth restriction (IUGR) remain to be fully established. Mechanistic target of rapamycin (mTOR) signaling functions as a placental nutrient sensor, indirectly influencing fetal growth by regulating placental function. Increased secretion and the phosphorylation of fetal liver IGFBP-1 are known to markedly decrease the bioavailability of IGF-1, a major fetal growth factor. We hypothesized that an inhibition of trophoblast mTOR increases liver IGFBP-1 secretion and phosphorylation. We collected conditioned media (CM) from cultured primary human trophoblast (PHT) cells with a silenced RAPTOR (specific inhibition of mTOR Complex 1), RICTOR (inhibition of mTOR Complex 2), or DEPTOR (activates both mTOR Complexes). Subsequently, HepG2 cells, a well-established model for human fetal hepatocytes, were cultured in CM from PHT cells, and IGFBP-1 secretion and phosphorylation were determined. CM from PHT cells with either mTORC1 or mTORC2 inhibition caused the marked hyperphosphorylation of IGFBP-1 in HepG2 cells as determined by 2D-immunoblotting while Parallel Reaction Monitoring-Mass Spectrometry (PRM-MS) identified increased dually phosphorylated Ser169 + Ser174. Furthermore, using the same samples, PRM-MS identified multiple CK2 peptides coimmunoprecipitated with IGFBP-1 and greater CK2 autophosphorylation, indicating the activation of CK2, a key enzyme mediating IGFBP-1 phosphorylation. Increased IGFBP-1 phosphorylation inhibited IGF-1 function, as determined by the reduced IGF-1R autophosphorylation. Conversely, CM from PHT cells with mTOR activation decreased IGFBP-1 phosphorylation. CM from non-trophoblast cells with mTORC1 or mTORC2 inhibition had no effect on HepG2 IGFBP-1 phosphorylation. Placental mTOR signaling may regulate fetal growth by the remote control of fetal liver IGFBP-1 phosphorylation.<\/jats:p>","DOI":"10.3390\/ijms24087273","type":"journal-article","created":{"date-parts":[[2023,4,14]],"date-time":"2023-04-14T09:23:43Z","timestamp":1681464223000},"page":"7273","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":11,"title":["Placental Remote Control of Fetal Metabolism: Trophoblast mTOR Signaling Regulates Liver IGFBP-1 Phosphorylation and IGF-1 Bioavailability"],"prefix":"10.3390","volume":"24","author":[{"given":"Fredrick J.","family":"Rosario","sequence":"first","affiliation":[{"name":"Division of Reproductive Sciences, Department of Obstetrics and Gynecology, University of Colorado Anschutz Medical Campus, Aurora, CO 80045, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Anand","family":"Chopra","sequence":"additional","affiliation":[{"name":"Institute of Biochemistry, Carleton University, Ottawa, ON K1S 5B6, Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kyle","family":"Biggar","sequence":"additional","affiliation":[{"name":"Institute of Biochemistry, Carleton University, Ottawa, ON K1S 5B6, Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Theresa L.","family":"Powell","sequence":"additional","affiliation":[{"name":"Division of Reproductive Sciences, Department of Obstetrics and Gynecology, University of Colorado Anschutz Medical Campus, Aurora, CO 80045, USA"},{"name":"Section of Neonatology, Department of Pediatrics, University of Colorado Anschutz Medical Campus, Aurora, CO 80045, USA"},{"name":"Department of Biochemistry, University of Western Ontario, London, ON N6A 3K7, Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9197-0341","authenticated-orcid":false,"given":"Madhulika B.","family":"Gupta","sequence":"additional","affiliation":[{"name":"Department of Biochemistry, University of Western Ontario, London, ON N6A 3K7, Canada"},{"name":"Department of Pediatrics, University of Western Ontario, London, ON N6A 3K7, Canada"},{"name":"Children\u2019s Health Research Institute, University of Western Ontario, London, ON N6A 3K7, Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Thomas","family":"Jansson","sequence":"additional","affiliation":[{"name":"Division of Reproductive Sciences, Department of Obstetrics and Gynecology, University of Colorado Anschutz Medical Campus, Aurora, CO 80045, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2023,4,14]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"1625","DOI":"10.1113\/JP278933","article-title":"Reduced Na(+) K(+) -ATPase activity may reduce amino acid uptake in intrauterine growth restricted fetal sheep muscle despite unchanged ex vivo amino acid transporter activity","volume":"598","author":"Stremming","year":"2020","journal-title":"J. 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