Stable-isotope tracing reveals the role of corticosteroid receptors in driving cortisol-mediated central and peripheral glucose regulation in zebrafish
Bibliographic record
Abstract
Rationale Corticosteroids play a crucial role in the stress-induced metabolic adjustments, and this stress response is conserved across vertebrates. In teleosts, cortisol is the principal glucocorticoid and regulates metabolic processes predominantly through the activation of the glucocorticoid receptor (GR). In zebrafish (Danio rerio), we recently showed that both the GR and the mineralocorticoid receptor (MR) are essential for stressor perception and metabolic regulation, especially related to glucose production and target-tissue glucose uptake. Here, we tested the hypothesis that GR and MR have distinct roles in modulating the tissue-specific glucose metabolism in response to cortisol stimulation during stress in fish. Methods This was tested using GR knockout (nr3c1−/−) and either wild-type or MR knockout (nr3c2−/−) zebrafish treated with cortisol to mimic a chronic stress condition. Stable isotope-labeled glucose (U-13C-glucose) was injected intraperitoneally, and the labeled intermediates were assessed to investigate the fate of the glucose carbon in the serum, liver, and brain. The metabolites in these tissues were analyzed using LC-MS to investigate the 13C incorporation across the metabolic pathway at a systems level. Results Chronic cortisol stimulation enhanced glucose breakdown and its utilization in the TCA cycle for energy production. The GR and MR activation led to distinct and complementary effects on glucose utilization and the generation of TCA intermediates in the brain and liver, suggesting a tissue-specific role for these receptors in energy substrate partitioning during stress in fish. Conclusion Overall, our results underscore the roles of GR and MR activation in elevating circulating energy substrates and facilitating tissue-level oxidative capacity and biomolecule synthesis from glucose metabolism in response to chronic cortisol stimulation in fish.
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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".