Abstract 18910: Angiotensin Converting Enzyme 2 Deficiency Results in Cardiac Insulin Resistance in Response to High-Fat Diet
Bibliographic record
Abstract
Background: Activation of the renin-angiotensin system (RAS) can alter the cardiac energy substrate preference, thereby contributing to the progression of heart failure. Angiotensin converting enzyme (ACE) 2 is a key negative regulator of the RAS where it metabolizes angiotensin (Ang) II into Ang (1-7). Hypothesis: Myocardial ACE2 was upregulated in response to high-fat diet in wildtype (WT) mice. We hypothesize that ACE2 upregulation is a compensatory response and loss of ACE2 will worsened obesity and its associated cardiomyopathy. Methods and Results: ACE2-null (ACE2-/y; ACE2KO) and WT litter-mate control mice were fed with high-fat diet (HFD; 45 kcal%) or control diet (10 kcal%) and studied at 6-months of age. In contrast to our hypothesis, loss of ACE2 resulted in decreased obesity in response to HFD compared to WT mice (body weight at 6-months: 45.9±4.3 in ACE2KO-HFD vs 51.4±1.55 in WT-HFD; p<0.05). Conversely, ACE2KO-HFD mice showed increased fasting plasma glucose levels (6.76±0.7 in ACE2KO-HFD vs 5.11±0.6 in WT-HFD; p<0.05) with worsened whole-body insulin resistance. We subjected hearts to ex vivo aerobic perfusions to measure cardiac energy metabolism. ACE2KO-HFD hearts showed markedly decreased cardiac work along with reduced insulin response suggesting increased myocardial insulin resistance. ACE2KO-HFD hearts relied predominantly on fat metabolism as the energy source, a feature observed in cardiomyopathy. Pressure-volume analysis showed worsened diastolic dysfunction in the ACE2KO hearts compared to WT hearts in response to HFD, which was primarily due to impaired active relaxation (Tau(Weiss): 7.41±0.4 in ACE2KO-HFD vs 6.26±0.52 in WT-HFD; p<0.05). Metabolic and functional changes in the ACE2KO-HFD were associated with impaired insulin signaling (decreased p-Akt) and decreased phosphorylation of AMPK. ACE2KO-HFD hearts also showed increased pyruvate dehydrogenase kinase 4 expression and phosphorylation of pyruvate dehydrogenase. Conclusions: Renin-angiotensin system plays an important role in cardiac metabolism. We found a novel role of ACE2 in cardiac insulin signaling, where ACE2 negatively regulates obesity and hyperglycemia induced cardiac insulin-resistance and alterations in cardiac metabolism.
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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 | 0.001 |
| Scholarly communication | 0.000 | 0.000 |
| Open science | 0.000 | 0.000 |
| Research integrity | 0.001 | 0.002 |
| Insufficient payload (model declined to judge) | 0.006 | 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; 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".