1858-P: P38 MAPK Inhibition Protects against FFA-Induced Insulin Resistance and Hepatic Fat Accumulation
Bibliographic record
Abstract
The liver plays a central role in metabolism. Yet, it is unclear how hepatic metabolic dysregulation promotes insulin resistance and hepatic steatosis. Some studies have investigated the role of hepatic p38, a stress mitogen-activated protein kinase (MAPK), in hepatic fat accumulation and insulin resistance in models of obesity. However, the role of p38 in free fatty acid (FFA) induced hepatic fat accumulation and insulin resistance has not been previously investigated. Moreover, the role that p38 MAPK plays in hepatic glucose and lipid metabolism is still controversial. Here, using both genetic and pharmacological models, we investigated whether the inhibition of p38 MAPK reverses FFA-induced hepatic fat accumulation and insulin resistance. Cannulated Wistar rats were intravenously infused with one of four treatments for 48 hours: Saline (SAL), Intralipid+Heparin (IH), IH+p38 MAPK inhibitor - SB239063 (IH+SB) and SB239063 (SB) alone. After 48hr infusion, the liver was collected and stained with Oil Red O to determine hepatic fat accumulation. IH rats had significantly greater hepatic fat accumulation compared to SAL rats (p<0.05). IH+SB rats were protected from FFA-induced hepatic fat accumulation. To assess the role of p38 on FFA-induced insulin resistance, liver-specific p38 knockout mice and wild type mice were infused with ethyl-oleate and ethyl palmitate (EtOP) or ethanol (control) for 48 hrs. After 46 hours of the infusion, the mice underwent a hyperinsulinemic-euglycemic clamp to determine insulin sensitivity. Results thus far suggest that genetic inhibition of p38 MAPK in the liver protects from FFA-induced insulin resistance in the periphery (p=0.06), consistent with tissue cross-talk also observed by our lab in liver-specific p38 knockout mice using a high fat diet model. In conclusion, our data indicates that both the pharmacological and genetic inhibition of p38 has a protective effect on FFA-induced hepatic fat accumulation and insulin resistance. Disclosure D.Y. Joseph: None. S.L. Rivers: None. A. Giacca: None. Funding Canadian Institutes of Health Research (503010)
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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) | 0.001 | 0.000 |
| Meta-epidemiology (broad) | 0.001 | 0.001 |
| 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 | 0.001 | 0.002 |
| Insufficient payload (model declined to judge) | 0.007 | 0.002 |
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".