{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,8]],"date-time":"2026-10-08T15:52:05Z","timestamp":1791474725131,"version":"4.3.4"},"reference-count":58,"publisher":"MDPI AG","issue":"1","license":[{"start":{"date-parts":[[2025,1,3]],"date-time":"2025-01-03T00:00:00Z","timestamp":1735862400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100000038","name":"Natural Sciences and Engineering Research Council of Canada","doi-asserted-by":"publisher","award":["RGPIN\/6516-2014"],"award-info":[{"award-number":["RGPIN\/6516-2014"]}],"id":[{"id":"10.13039\/501100000038","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100000038","name":"Natural Sciences and Engineering Research Council of Canada","doi-asserted-by":"publisher","award":["RGPIN-386602-2011"],"award-info":[{"award-number":["RGPIN-386602-2011"]}],"id":[{"id":"10.13039\/501100000038","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100000038","name":"Natural Sciences and Engineering Research Council of Canada","doi-asserted-by":"publisher","award":["RGPIN\/06778-2019"],"award-info":[{"award-number":["RGPIN\/06778-2019"]}],"id":[{"id":"10.13039\/501100000038","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100000038","name":"Natural Sciences and Engineering Research Council of Canada","doi-asserted-by":"publisher","award":["2018-RS4-203214"],"award-info":[{"award-number":["2018-RS4-203214"]}],"id":[{"id":"10.13039\/501100000038","id-type":"DOI","asserted-by":"publisher"}]},{"name":"Fonds Qu\u00e9b\u00e9cois de la Recherche sur la Nature et les Technologies-R\u00e9seau Qu\u00e9b\u00e9cois en Reproduction","award":["RGPIN\/6516-2014"],"award-info":[{"award-number":["RGPIN\/6516-2014"]}]},{"name":"Fonds Qu\u00e9b\u00e9cois de la Recherche sur la Nature et les Technologies-R\u00e9seau Qu\u00e9b\u00e9cois en Reproduction","award":["RGPIN-386602-2011"],"award-info":[{"award-number":["RGPIN-386602-2011"]}]},{"name":"Fonds Qu\u00e9b\u00e9cois de la Recherche sur la Nature et les Technologies-R\u00e9seau Qu\u00e9b\u00e9cois en Reproduction","award":["RGPIN\/06778-2019"],"award-info":[{"award-number":["RGPIN\/06778-2019"]}]},{"name":"Fonds Qu\u00e9b\u00e9cois de la Recherche sur la Nature et les Technologies-R\u00e9seau Qu\u00e9b\u00e9cois en Reproduction","award":["2018-RS4-203214"],"award-info":[{"award-number":["2018-RS4-203214"]}]},{"name":"NSERC and the RQR-CREATE scholarships programs","award":["RGPIN\/6516-2014"],"award-info":[{"award-number":["RGPIN\/6516-2014"]}]},{"name":"NSERC and the RQR-CREATE scholarships programs","award":["RGPIN-386602-2011"],"award-info":[{"award-number":["RGPIN-386602-2011"]}]},{"name":"NSERC and the RQR-CREATE scholarships programs","award":["RGPIN\/06778-2019"],"award-info":[{"award-number":["RGPIN\/06778-2019"]}]},{"name":"NSERC and the RQR-CREATE scholarships programs","award":["2018-RS4-203214"],"award-info":[{"award-number":["2018-RS4-203214"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Cells"],"abstract":"<jats:p>Elevated glucose levels at the fetal\u2013maternal interface are associated with placental trophoblast dysfunction and increased incidence of pregnancy complications. Trophoblast cells predominantly utilize glucose as an energy source, metabolizing it through glycolysis in the cytoplasm and oxidative respiration in the mitochondria to produce ATP. The TGF\u03b21\/SMAD2 signaling pathway and the transcription factors PPAR\u03b3, HIF1\u03b1, and AMPK are key regulators of cell metabolism and are known to play critical roles in extravillous trophoblast cell differentiation and function. While HIF1\u03b1 promotes glycolysis over mitochondrial respiration, PPAR\u03b3 and AMPK encourage the opposite. However, the interplay between TGF\u03b21 and these energy-sensing regulators in trophoblast cell glucose metabolism remains unclear. This study aimed to investigate whether and how TGF\u03b21 regulates energy metabolism in trophoblast cells exposed to normal and high glucose conditions. The trophoblast JEG-3 cells were incubated in normal (5 mM) and high (25 mM) glucose conditions for 24 h in the absence and the presence of TGF\u03b21. The protein expression levels of phosphor (p)-SMAD2, GLUT1\/3, HIF1\u03b1, PPAR\u03b3, p-AMPK, and specific OXPHOS protein subunits were determined by western blotting, and ATP and lactate production by bioluminescent assay kits. JEG-3 cells exposed to 25 mM glucose decreased ATP production but did not affect lactate production. These changes led to a reduction in the expression levels of GLUT1\/3, mitochondrial respiratory chain proteins, and PPAR\u03b3, coinciding with an increase in HIF1\u03b1 expression. Conversely, TGF\u03b21 treatment at 25 mM glucose reduced HIF1\u03b1 expression while enhancing the expression levels of GLUT1\/3, PPAR\u03b3, p-AMPK, and mitochondrial respiratory chain proteins, thereby rejuvenating ATP production. Our findings reveal that high glucose conditions disrupt cellular glucose metabolism in trophoblast cells by perturbing mitochondrial oxidative respiration and decreasing ATP production. Treatment with TGF\u03b21 appears to counteract this trend, probably by enhancing both glycolytic and mitochondrial metabolism, suggesting a potential regulatory role of TGF\u03b21 in placental trophoblast cell glucose metabolism.<\/jats:p>","DOI":"10.3390\/cells14010045","type":"journal-article","created":{"date-parts":[[2025,1,3]],"date-time":"2025-01-03T10:17:23Z","timestamp":1735899443000},"page":"45","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":8,"title":["TGF\u03b21 Restores Energy Homeostasis of Human Trophoblast Cells Under Hyperglycemia In Vitro by Inducing PPAR\u03b3 Expression, AMPK Activation, and HIF1\u03b1 Degradation"],"prefix":"10.3390","volume":"14","author":[{"given":"Nihad","family":"Khiat","sequence":"first","affiliation":[{"name":"Groupe de Recherche en Signalisation Cellulaire (GRSC), D\u00e9partement de Biologie M\u00e9dicale, Universit\u00e9 du Qu\u00e9bec \u00e0 Trois-Rivi\u00e8res, 3351 Boulevard des Forges, Trois-Rivi\u00e8res, QC G8Z 4M3, Canada"},{"name":"Centre de Recherche Interuniversitaire en Reproduction et D\u00e9veloppement-R\u00e9seau Qu\u00e9b\u00e9cois en Reproduction (CIRD-RQR), Universit\u00e9 de Montr\u00e9al, St-Hyacinthe, QC J2S 2M2, Canada"},{"name":"Regroupement Intersectoriel de Recherche en Sant\u00e9 de l\u2019Universit\u00e9 du Qu\u00e9bec (RISUQ), Universit\u00e9 du Qu\u00e9bec, Qu\u00e9bec, QC G1K 9H7, Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Julie","family":"Girouard","sequence":"additional","affiliation":[{"name":"Groupe de Recherche en Signalisation Cellulaire (GRSC), D\u00e9partement de Biologie M\u00e9dicale, Universit\u00e9 du Qu\u00e9bec \u00e0 Trois-Rivi\u00e8res, 3351 Boulevard des Forges, Trois-Rivi\u00e8res, QC G8Z 4M3, Canada"},{"name":"Centre de Recherche Interuniversitaire en Reproduction et D\u00e9veloppement-R\u00e9seau Qu\u00e9b\u00e9cois en Reproduction (CIRD-RQR), Universit\u00e9 de Montr\u00e9al, St-Hyacinthe, QC J2S 2M2, Canada"},{"name":"Regroupement Intersectoriel de Recherche en Sant\u00e9 de l\u2019Universit\u00e9 du Qu\u00e9bec (RISUQ), Universit\u00e9 du Qu\u00e9bec, Qu\u00e9bec, QC G1K 9H7, Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Emmanuelle Stella","family":"Kana Tsapi","sequence":"additional","affiliation":[{"name":"Groupe de Recherche en Signalisation Cellulaire (GRSC), D\u00e9partement de Biologie M\u00e9dicale, Universit\u00e9 du Qu\u00e9bec \u00e0 Trois-Rivi\u00e8res, 3351 Boulevard des Forges, Trois-Rivi\u00e8res, QC G8Z 4M3, Canada"},{"name":"Centre de Recherche Interuniversitaire en Reproduction et D\u00e9veloppement-R\u00e9seau Qu\u00e9b\u00e9cois en Reproduction (CIRD-RQR), Universit\u00e9 de Montr\u00e9al, St-Hyacinthe, QC J2S 2M2, Canada"},{"name":"Regroupement Intersectoriel de Recherche en Sant\u00e9 de l\u2019Universit\u00e9 du Qu\u00e9bec (RISUQ), Universit\u00e9 du Qu\u00e9bec, Qu\u00e9bec, QC G1K 9H7, Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0543-6244","authenticated-orcid":false,"given":"Cathy","family":"Vaillancourt","sequence":"additional","affiliation":[{"name":"Centre de Recherche Interuniversitaire en Reproduction et D\u00e9veloppement-R\u00e9seau Qu\u00e9b\u00e9cois en Reproduction (CIRD-RQR), Universit\u00e9 de Montr\u00e9al, St-Hyacinthe, QC J2S 2M2, Canada"},{"name":"Regroupement Intersectoriel de Recherche en Sant\u00e9 de l\u2019Universit\u00e9 du Qu\u00e9bec (RISUQ), Universit\u00e9 du Qu\u00e9bec, Qu\u00e9bec, QC G1K 9H7, Canada"},{"name":"Institut National de la Recherche Scientifique (INRS)-Centre Armand Frappier Sant\u00e9 Biotechnologie and Research Centre CIUSSS-Nord-de-l\u2019\u00eele-de-Montr\u00e9al, Laval, QC H7V 1B7, Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"C\u00e9line","family":"Van Themsche","sequence":"additional","affiliation":[{"name":"Groupe de Recherche en Signalisation Cellulaire (GRSC), D\u00e9partement de Biologie M\u00e9dicale, Universit\u00e9 du Qu\u00e9bec \u00e0 Trois-Rivi\u00e8res, 3351 Boulevard des Forges, Trois-Rivi\u00e8res, QC G8Z 4M3, Canada"},{"name":"Centre de Recherche Interuniversitaire en Reproduction et D\u00e9veloppement-R\u00e9seau Qu\u00e9b\u00e9cois en Reproduction (CIRD-RQR), Universit\u00e9 de Montr\u00e9al, St-Hyacinthe, QC J2S 2M2, Canada"},{"name":"Regroupement Intersectoriel de Recherche en Sant\u00e9 de l\u2019Universit\u00e9 du Qu\u00e9bec (RISUQ), Universit\u00e9 du Qu\u00e9bec, Qu\u00e9bec, QC G1K 9H7, Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4665-7070","authenticated-orcid":false,"given":"Carlos","family":"Reyes-Moreno","sequence":"additional","affiliation":[{"name":"Groupe de Recherche en Signalisation Cellulaire (GRSC), D\u00e9partement de Biologie M\u00e9dicale, Universit\u00e9 du Qu\u00e9bec \u00e0 Trois-Rivi\u00e8res, 3351 Boulevard des 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