Abstract P247: APPL1 Transgenic Mice Are Protected from High-Fat Diet--Induced Lipotoxic Cardiomyopathy
Bibliographic record
Abstract
Increased circulating levels of free fatty acid (FA) in obesity and diabetes lead to the accumulation of FA in non-adipose tissue such as myocardium and this is known to be a major contributor to cardiomyopathy. In this present study, we investigated the role of APPL1 (Adaptor protein containing PH domain, PTB domain and Leucine zipper motif-1), an important regulator of insulin signaling, in a model of high fat diet (HFD) induced cardiomyopathy. We fed APPL1 transgenic (Tg) or wild type (wt) mice a high fat (60% kcal) or normal chow diet. After 16 weeks, in wt mice HFD induced hyperinsulinemia and hyperlipidemia, as well as cardiac dysfunction determined by echocardiography system (Vevo 2100). Furthermore, HFD induced cardiac insulin resistance and acetyl CoA carboxylase (ACC) phosphorylation. Lipid analysis using LC/MS/MS showed HFD significantly increased intracellular level of distinct ceramide and diacylglycerol (DAG) species in heart tissue. Interestingly, HFD fed APPL1 Tg mice showed a relatively normal circulating level of FA and improved insulin sensitivity in heart tissue, compared to the wt mice. Lipid analysis indicated that APPL1 Tg mice had approximately 20% reduced intra-myocardial accumulation of ceramides and DAGs after HFD compared to wt mice. APPL1 Tg mice also showed better cardiac performance in ejection fraction and cardiac output under these conditions. In summary, here we demonstrated that APPL1 Tg mice are protected from HFD-induced increases in circulating levels of FA, accumulation of lipotoxic fatty acid derivatives and insulin resistance in myocardial tissue and deterioration in cardiac function.
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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 | 0.001 | 0.000 |
| Meta-epidemiology (narrow) | 0.000 | 0.000 |
| Meta-epidemiology (broad) | 0.000 | 0.000 |
| Bibliometrics | 0.000 | 0.001 |
| 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) | 0.002 | 0.001 |
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; both teacher heads agree on what is shown here.
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".