Inhibition of the beta-1 adrenergic receptor does not potentiate mirabegron-stimulated human brown adipose tissue thermogenesis

Pharmacological stimulation of human brown adipose tissue (BAT) has been hindered by either ineffective activation or undesirable off-target secondary effects. Oral administration of the maximal allowable dose of mirabegron (200 mg), a β3-adrenergic receptor (β3-AR) agonist, has been effective in stimulating BAT thermogenesis and whole-body energy expenditure. However, this too has been accompanied by undesirable cardiovascular effects. Combining mirabegron with a cardio-selective β1-AR antagonist could not only suppress these unwanted effects, but potentially increase the sensitivity of the β3-AR and β2-AR in WAT and BAT. Here we report that co-ingesting a high dose of the β1-AR antagonist bisoprolol with mirabegron suppresses the increase in heart rate, systolic blood pressure and myocardial oxygen consumption. However, it also blunted the mirabegron-stimulated increase in BAT lipolysis, thermogenesis and glucose uptake. Whether the attenuation in BAT blood flow induced by the large dose of bisoprolol limited BAT thermogenesis remains to be determined. [clinicaltrials.gov][1] ([NCT04823442][2]) ### Competing Interest Statement The authors have declared no competing interest. ### Clinical Trial NCT04823442 ### Funding Statement This work was supported by the Quebec Network on Drug Research (RQRM), to A.Caron and D.P.Blondin as well as a grant from the Natural Sciences and Engineering Research Council of Canada (NSERC Canada) to D.P.Blondin (RGPIN-2019-05813). D.P. Blondin holds the GSK Chair in Diabetes of the Universite de Sherbrooke and a Fonds de Recherche du Quebec-Sante (FRQS) J1 salary award. L. Dumont is the recipient of an FRQS doctoral training award. A. Caron is supported by a Canada Research Chair in Neurometabolic Pharmacology and an FRQS J1 salary award. A.C. Carpentier is supported by a Canada Research Chair in the Molecular Imaging of Diabetes ### Author Declarations I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained. Yes The details of the IRB/oversight body that provided approval or exemption for the research described are given below: Ethics committee of the CIUSSS de l'Estrie - CHUS gave ethical approval for this work. I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals. Yes I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as [ClinicalTrials.gov][3]. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance). Yes I have followed all appropriate research reporting guidelines, such as any relevant EQUATOR Network research reporting checklist(s) and other pertinent material, if applicable. Yes All data produced in the present study are available upon reasonable request to the authors. [1]: https://clinicaltrials.gov [2]: /lookup/external-ref?link_type=CLINTRIALGOV&access_num=NCT04823442&atom=%2Fmedrxiv%2Fearly%2F2023%2F03%2F28%2F2023.03.22.23287600.atom [3]: https://ClinicalTrials.gov