Abstract 1337: Attenuation of the Leptin-Induced Hypertrophy by NF-kB Inhibition Requires Activation of AMPK in Neonatal Cardiomyocytes
Bibliographic record
Abstract
Introduction: Leptin, a 16 kDa product of the obesity gene, has been shown to be elevated in patients with heart failure. Recently we demonstrated that leptin induces hypertrophy in cultured cardiomyocytes, however the molecular mechanisms underlying the hypertrophic effect of leptin remain to be elucidated. In the present study we investigated whether nuclear factor-kB (NF-kB) and adenosine monophosphate-activated kinase (AMPK) are key mediators in leptin-induced cardiac hypertrophy. Methods and Results: Leptin (3.1 nM) treatment for 24 hrs increased cell surface area by 40% (P<0.002) as measured by Sigma scan software. The increase in cell surface area was completely blocked by NF-kB activation inhibitor (1μM) and AICAR (1 mM), the AMPK activator (P<0.001). Incubation with leptin for 24 hrs had no effect on PRKA-α (α-subunit of AMPK) but upregulated the PRKAβ2 (β-subunit of AMPK) gene by 85% (P<0.04) as determined by real-time PCR. In contrast, AICAR treatment increased the PRKA-α by 256% (P<0.02) but not the PRKA-β gene. The leptin-dependent 90% increase in α-skeletal actin, a hypertrophic marker gene was inhibited by AICAR (P<0.01). Western blot analysis revealed that leptin treatment for 5 min increased the phosphorylation of IkBs, a group of cytoplasmic NF-kB inhibitors by 51% (P<0.03). Phosphorylation triggers their degradation and allows NF-kB to translocate into the nucleus. Leptin-induced IkB-α phosphorylation was associated with significant activation of NF-kB p65 by phosphorylation at Ser536 which is important for translocation into the nucleus. Inhibition of NF-kB induced upregulation of P-Thr172-AMPK but not P-Ser485 AMPK levels. Cglitazone (5 μM), a potent and selective PPAR-γ ligand, or AICAR treatment for 30 min significantly upregulated the expression of P-Thr172-AMPK while leptin had no effect. In addition, AICAR treatment for 24 hrs increased the expression of PPAR-γ by 450% (P<0.006), FATCD36 by 35% (P<0.03) and GLUT1 by 220% (P<0.03). Conclusion : Attenuation of leptin-induced hypertrophy by NF-kB inhibition is mediated by AMPK activation. The anti-hypertrophic effect of AMPK activation is mediated through upregulation of PPAR-γ, FATCD36 and GLUT1 genes expression responsible for maintaining energy homeostasis.
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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 | 0.000 |
| 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) | 0.008 | 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".