Enhanced browning of adipose tissue by mirabegron-microspheres

Zheming Niu; Staffan Hildebrand; Sebastian Kappes; Mohamed Ehab Ali; Matthias Vogel; Mickel Mikhael; Danli Ran; Jan Kozak; Maria Wiedner; Dirk F Richter; Alf Lamprecht; Alexander Pfeifer

doi:10.1016/j.jconrel.2024.09.025

Enhanced browning of adipose tissue by mirabegron-microspheres

J Control Release. 2024 Sep 13:S0168-3659(24)00635-7. doi: 10.1016/j.jconrel.2024.09.025. Online ahead of print.

Authors

Affiliations

¹ Institute of Pharmacology and Toxicology, University Hospital, University of Bonn, Bonn, Germany.
² Department of Pharmaceutics, Institute of Pharmacy, University of Bonn, Bonn, Germany.
³ Pharmacogenomic, Federal Institute for Drugs and Medical Devices (BfArM), Bonn, Germany.
⁴ Institut ID, Beethoven Clinic, Plastic and Aesthetic Surgery Cologne, Cologne, Germany.
⁵ Department of Pharmaceutics, Institute of Pharmacy, University of Bonn, Bonn, Germany. Electronic address: alf.lamprecht@uni-bonn.de.
⁶ Institute of Pharmacology and Toxicology, University Hospital, University of Bonn, Bonn, Germany. Electronic address: alexander.pfeifer@uni-bonn.de.

PMID: 39278357
DOI: 10.1016/j.jconrel.2024.09.025

Abstract

Thermogenic brown adipose tissue (BAT) has emerged as an attractive target for combating obesity. However, pharmacological activation of energy expenditure by BAT and/or induction of browning of white adipose tissue (WAT) has been hampered by cardiovascular side effects. To address these concerns, we developed polylactide-co-glycolide acid (PLGA) microspheres loaded with mirabegron (MIR), a selective beta-3 adrenergic receptor (ADRB3) agonist, to achieve sustained local induction and activation of thermogenic adipocytes. MIR-loaded PLGA microspheres (MIR-MS) effectively activated brown adipocytes and enhanced the thermogenic program in white adipocytes. Moreover, treating isolated inguinal WAT (iWAT) with MIR-MS resulted in increased expression of browning markers and elevated lipolysis mainly via ADRB3. In mice, injection of MIR-MS over four weeks induced browning of iWAT at the injection site. Importantly, local MIR-MS injection successfully mitigated unwanted cardiovascular risks, including high systolic blood pressure (SBP) and heart rate, as compared to MIR-treated mice. Finally, injecting MIR-MS into human subcutaneous WAT led to a significant induction of lipolysis and an increase in the expression of thermogenic marker uncoupling protein 1 (UCP1). Taken together, our findings indicate that MIR-MS function as a local drug release system that induces browning of human and murine subcutaneous WAT while mitigating undesirable cardiovascular effects.

Keywords: Attenuated cardiovascular side effects; Browning; Local controlled release; Mirabegron; Polylactide-co-glycolide acid (PLGA) microspheres; White adipose tissue (WAT).