Sex-Specific Effects of the β3-Adrenergic Receptor Agonist Mirabegron in a Murine Two-Hit Heart Failure Model with Preserved Ejection Fraction
Bibliographic record
Abstract
Background. In addition to its role in thermogenesis, activation of the brown adipose tissue (BAT) has been shown to produce factors (batokines) that can protect the cardiovascular system, particularly the heart, in pathological situations such as hypertension, atherosclerosis, and ischemia/reperfusion injury, BAT activation is mediated via the β3-adrenergic receptor (β3-AR), which is abundantly expressed in this tissue. In this study, we investigated whether using a specific β3-AR agonist, mirabegron, could slow the development of heart failure with preserved ejection fraction (HFpEF) in C57Bl6/J male and female mice after a metabolic-hypertensive stress (MHS).Methods. Eight-week-old mice of both sexes were divided into four groups. Control, mirabegron (Mira) (2 mg/kg/day), MHS (Angiotensin II [1.5mg/kg/day] + a high-fat diet) or MHS + mirabegron for 28 days. At the end of the protocol, all animals had an echocardiography exam, and the heart, lungs, BAT and liver were collected.Results. After four weeks of MHS, the indexed heart weight was significantly increased in all groups, but to a lesser extent in mice that received Mira. The expected left atrial enlargement following the HFpEF-inducing stress, MHS, was present in all groups, but was less in Mira male mice. Body growth was reduced in males receiving Mira. Echocardiography showed that males receiving Mira had smaller left ventricles (LV) and higher ejection fraction. Following the MHS, an expected increase in the expression of several marker genes associated with cardiac hypertrophy or fibrosis was observed in males, but not in females. Mirabegron treatment increased BAT volume in males but had a lesser effect in females. Uncoupled protein 1 (Ucp1) gene expression in the BAT was also in males but not in females. MHS alone also increased Ucp1 and β3-AR mRNA levels in BAT only in males.Conclusion. Male mouse hearts are more responsive to β3-AR activation by mirabegron, a specific agonist, than female hearts. This translates to a blunted hypertrophic response to the MHS and reduced LV expression of genes commonly increased in pathological cardiac conditions.
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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 | 0.001 | 0.000 |
| Science and technology studies | 0.000 | 0.000 |
| Scholarly communication | 0.000 | 0.000 |
| Open science | 0.000 | 0.000 |
| Research integrity | 0.001 | 0.002 |
| Insufficient payload (model declined to judge) | 0.001 | 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 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".