An adiponectin-S1P axis protects against lipid induced insulin resistance and cardiomyocyte cell death via reduction of oxidative stress
Bibliographic record
Abstract
BACKGROUND: Adiponectin exerts several beneficial cardiovascular effects, however their specific molecular mechanisms require additional understanding. This study investigated the mechanisms of adiponectin action in the heart during high fat diet (HFD) feeding or in palmitate (PA) treated H9c2 cardiomyoblasts. METHODS: 6-week-old male adiponectin knock out (Ad-KO) mice were fed chow or 60% HFD for 6 weeks then received saline or recombinant adiponectin (3μg/g body weight) for an additional 2 weeks. After acute insulin stimulation (4 U/kg), tissue and serum samples were collected for analysis. H9c2 cardiomyocytes were treated ±0.1 mM PA, the adiponectin receptor agonist AdipoRon, or the antioxidant MnTBAP then assays to analyze reactive oxygen species (ROS) production and cell death were conducted. To specifically determine the mechanistic role of S1P, gain and loss of function studies were conducted with adding S1P to cells or the inhibitors THI and SKI-II, respectively. RESULTS: HFD feeding induced cardiac insulin resistance in Ad-KO mice, which was reversed following replenishment of normal circulating adiponectin levels. In addition, myocardial total triglyceride was elevated by HFD and lipidomic analysis showed increased levels of ceramides and sphingosine-1-phosphate (S1P), with only the latter being corrected by adiponectin administration. Similarly, treatment of H9C2 cardiomyoblasts with PA led to a significant increase of intracellular S1P but not in conditioned media whereas AdipoRon significantly increased S1P production and secretion from cells. AdipoRon or the antioxidant MnTBAP significantly reduced PA-induced cell death. Gain and loss of function studies suggested S1P secretion and autocrine receptor activation mediated the effect of AdipoRon to attenuate PA-induced ROS production and cell death. CONCLUSION: Our data establish adiponectin signaling-mediated increase in S1P secretion as a mechanism via which HFD or PA induced cardiomyocyte lipotoxicity, leading to insulin resistance and cell death, is attenuated.
Fetched live from OpenAlex and de-inverted. Abstracts are not stored in this database: the inverted indexes are 8.6 GB of the frame’s 9.3 GB of text, and the host has 13 GB free.
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) | 0.001 | 0.000 |
| Bibliometrics | 0.000 | 0.000 |
| Science and technology studies | 0.000 | 0.000 |
| Scholarly communication | 0.000 | 0.001 |
| 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".