Enhanced browning of adipose tissue by mirabegron-microspheres

Area of Science:

• Adipose tissue biology
• Pharmacology
• Biomaterials

Background:

• Thermogenic brown adipose tissue (BAT) activation is a promising strategy for obesity treatment.
• Pharmacological approaches targeting BAT and white adipose tissue (WAT) browning are limited by cardiovascular side effects.

Purpose of the Study:

• To develop a localized drug delivery system for sustained activation of thermogenic adipocytes.
• To mitigate cardiovascular risks associated with beta-3 adrenergic receptor (ADRB3) agonists.

Main Methods:

• Development of polylactide-co-glycolide acid (PLGA) microspheres loaded with mirabegron (MIR), a selective ADRB3 agonist.
• In vitro and in vivo studies in isolated white adipose tissue (WAT) and mice.
• Assessment of thermogenic markers, lipolysis, and cardiovascular parameters (systolic blood pressure, heart rate).
• Evaluation of MIR-loaded microsphere (MIR-MS) efficacy in human subcutaneous WAT.

Main Results:

• MIR-MS effectively activated brown adipocytes and induced thermogenic programs in white adipocytes.
• Local MIR-MS treatment increased WAT browning markers and lipolysis via ADRB3.
• In mice, MIR-MS induced iWAT browning at the injection site and mitigated cardiovascular risks compared to systemic MIR.
• MIR-MS treatment in human subcutaneous WAT increased lipolysis and uncoupling protein 1 (UCP1) expression.

Conclusions:

• MIR-MS serve as an effective local drug delivery system for inducing WAT browning.
• This approach successfully activates thermogenic adipocytes in both murine and human tissues.
• MIR-MS mitigate adverse cardiovascular effects associated with systemic administration of ADRB3 agonists.