Targeting adrenergic receptors to activate brown fat without cardiovascular effects
Bibliographic record
Abstract
Background: We previously revealed that oral administration of the β3-adrenergic receptor (AR) agonist mirabegron only elicited small increases in brown adipose tissue (BAT) thermogenesis when ingested at the maximal allowable dose (200 mg). This led to off-target binding of the β1- and β2-AR, thereby increasing cardiovascular responses and white adipose tissue lipolysis, respectively. We hypothesize that a balanced activation between β1- and β3-AR is key to stimulating metabolic benefits without cardiovascular side effects. Method: We performed a randomized crossover trial in 8 lean men over two study days. The intervention consisted of oral administration of mirabegron (200 mg) with or without the cardio selective β1-AR antagonist bisoprolol (10 mg). Dynamic [11C]-acetate and 2-deoxy-2-[18F]fluoro-D-glucose ([18F]FDG) PET/CT scans were performed sequentially starting at 210 min after oral administration of mirabegron ± bisoprolol. Results: Compared to baselines measures, mirabegron alone or with bisoprolol increased energy expenditure (EE) by 27% (+18.2±6.7 kcal/h) and 11% (7.4±8.1 kcal/h), respectively. However, EE was significantly lower when mirabegron was co-ingested with bisoprolol (P=0.0402) Compared to room temperature, mirabegron alone increased BAT oxidative metabolism (0.631±0.267 vs 1.695±1.097 min-1 from the [11C]-acetate, P=0.0421), but was not different from mirabegron with bisoprolol (1.273±0.651 min-1). Metabolic rate of glucose in BAT, measured using [18F]FDG PET, was significantly higher with mirabegron than mirabegron combined with bisoprolol (24±10 vs 16±8 nmol/g/min, P=0.0284). Mirabegron also increased systolic blood pressure (+5±5 vs -6±10 mmHg, P=0.0252) and heart rate (6±7 vs -5±6 beats·min-1, P=0.0081) relative to baseline levels, which was prevented with bisoprolol. The glycerolipid-fatty acid cycling was not different between mirabegron without or with bisoprolol treatment (total cycling: 118.1±346.9 vs 168.5±439.5 μmol·min-1, P=0.8023). Conclusion: The administration of a β1-AR antagonist decreases the adverse cardiovascular effects of mirabegron. However, at the provided dose, it also restricts the stimulating effects of mirabegron on the thermogenesis. Public foundation grants This is the full abstract presented at the American Physiology Summit 2023 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.
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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 | 0.001 | 0.000 |
| Meta-epidemiology (narrow) | 0.000 | 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) | 0.002 | 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".