Abstract 010: Adipocyte-derived Aldosterone And Cortisol Are Nox1/4 Dependent: Implications In Obesity-associated Vascular Dysfunction.
Bibliographic record
Abstract
We previously demonstrated that aldosterone (aldo) is produced by adipocytes, an effect associated with reactive oxygen species (ROS) production and adipokine production, which influences vascular function. These processes are exaggerated in obesity. Whether ROS themselves play a role in adipocyte-derived aldo is unclear. Studies were performed in db/m (lean) and db/db (obese) mice, treated with low (20mg/kg/day) or high dose (60mg/kg/day) GKT137831 (GKT, Nox1/4 inhibitor, 16 weeks). Epididymal (EVAT) and perivascular (PVAT) fat were collected. Human adipocytes (SW872) were also studied. Aldo and corticosterone levels were measured by ELISA. Gene expression was assessed by qPCR. ROS generation was assessed by chemiluminescence and amplex red. Plasma aldo levels in db/db (pg/mL: 518 vs. 272g) and aldo levels in culture media from db/db adipocytes were increased (pg/mL/μg RNA: 1964 vs. 388), p<0.05. All effects were decreased by high dose GKT. In PVAT, CYP11B2 gene expression was increased in db/db (2.6±0.8 vs control 1.1±0.1, p<0.05), an effect blocked by Nox1/4 inhibition. Corticosterone levels in culture media from db/db adipocytes were also increased. Gene expression of adipocyte differentiation marker, AP2, was increased (3.5±1.1 vs control 1.4±0.4) in obese mice. GKT decreased AP2 levels. In human adipocytes, AngII stimulation increased aldo (6 fold) and cortisol (4 fold) production, as well as superoxide (1 fold) and H2O2 (2 fold) levels (p<0.05 vs vehicle). Increased levels of superoxide by Ang II were blocked by GKT and ML171 (Nox1 inhibitor); while Ang II-induced H2O2 production was inhibited only by GKT. Ang II-induced aldo production was blocked by tempol (SOD mimetic), GKT and ML171. In contrast, cortisol was only blocked by tempol and GKT. In conclusion, aldo production in adipocytes is dependent on ROS formation and involves Nox1 and Nox4. Nox4 also influences adipocyte-derived cortisol. These data suggest that Nox1/4 may play a role in adipocyte-derived aldosterone and cortisol production, effects that are amplified in obesity. Our findings suggest that adipocyte Nox1/4 may be a putative therapeutic target in obesity-associated hyperaldosteronism and cardiovascular damage.
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How this classification was reachedexpand
Full frame distilled prediction
Teacher imitationNot calibrated prevalence, not ground truth. Human validation pending. Learned from the 10,348 direct Codex labels and 10,348 direct Gemma labels. Candidate is the union of thresholded teacher heads; consensus is their intersection. These outputs are machine_predicted_unvalidated and are not human labels or direct frontier model labels.
Codex and Gemma teacher scores by category
| 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 | 0.000 |
| Insufficient payload (model declined to judge) | 0.000 | 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 teacher head, 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".