TGFβ1 Restores Energy Homeostasis of Human Trophoblast Cells Under Hyperglycemia In Vitro by Inducing PPARγ Expression, AMPK Activation, and HIF1α Degradation
Bibliographic record
Abstract
Elevated glucose levels at the fetal-maternal 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 TGFβ1/SMAD2 signaling pathway and the transcription factors PPARγ, HIF1α, and AMPK are key regulators of cell metabolism and are known to play critical roles in extravillous trophoblast cell differentiation and function. While HIF1α promotes glycolysis over mitochondrial respiration, PPARγ and AMPK encourage the opposite. However, the interplay between TGFβ1 and these energy-sensing regulators in trophoblast cell glucose metabolism remains unclear. This study aimed to investigate whether and how TGFβ1 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 TGFβ1. The protein expression levels of phosphor (p)-SMAD2, GLUT1/3, HIF1α, PPARγ, 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 PPARγ, coinciding with an increase in HIF1α expression. Conversely, TGFβ1 treatment at 25 mM glucose reduced HIF1α expression while enhancing the expression levels of GLUT1/3, PPARγ, 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 TGFβ1 appears to counteract this trend, probably by enhancing both glycolytic and mitochondrial metabolism, suggesting a potential regulatory role of TGFβ1 in placental trophoblast cell glucose metabolism.
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How this classification was reachedexpand
Full frame machine prediction
Teacher imitationNot calibrated prevalence, not ground truth. Human validation pending. The Gemma side is a direct model label for every work in the frame, read from the title-only record. The Codex side is a classifier learned from the 10,348 direct Codex labels and calibrated to design-weighted sample rates; fields without enough sample support carry no Codex call. Candidate is the union of the two sides; consensus is their intersection. These outputs are machine_predicted_unvalidated and are not human labels.
Distilled classifier scores by category (both heads)
| Category | Codex | Gemma |
|---|---|---|
| Metaresearch | 0.000 | 0.000 |
| Meta-epidemiology (narrow) | 0.000 | 0.000 |
| Meta-epidemiology (broad) | 0.000 | 0.000 |
| Bibliometrics | 0.000 | 0.000 |
| Science and technology studies | 0.000 | 0.000 |
| Scholarly communication | 0.000 | 0.000 |
| Open science | 0.000 | 0.000 |
| Research integrity | 0.000 | 0.001 |
| Insufficient payload (model declined to judge) | 0.001 | 0.000 |
Machine scores (provisional)
The two teacher heads of the student model, read on this work. A score orders the frame for review; it never asserts a category, and the validation status ships verbatim with every row.
Baseline scores from an immature model (maturity gate not passed, 7 training rounds). Scores rank; they never assert a category.
score_only:v0-immature-baseline · verbatim from the scoring run: score_only means the number may rank works, and no category label ships from itClassification
machine, unvalidatedMachine predicted; a candidate call from one source (direct Gemma or distilled Codex), not a consensus.
How this classification was reached, model by model and score by score, is at the end of the page under "How this classification was reached".