240-OR: Mirabegron Treatment Reduces Myofibroblasts and Inflammatory NK Cells in Adipose Tissue in Obesity

• Published in: Diabetes (New York, N.Y.) Vol. 74; no. Supplement_1; p. 1
• Main Authors: FINLIN, BRIAN, MEMETIMIN, HASIYET, WESTGATE, PHILIP, CHEN, JIN, DUPONT-VERSTEEGDEN, ESTHER E., KERN, PHILIP A.
• Format: Journal Article
• Language: English
• Published: New York American Diabetes Association 20.06.2025
• Subjects: Adipocytes; Adipose tissue (brown); Adrenergic receptors; Agonists; Beta cells; Biopsy; Body fat; Body weight loss; Chemotaxis; CXCR2 protein; Fibrosis; Glucose metabolism; Glucose tolerance; Immunohistochemistry; Inflammation; Obesity; Snail protein; Transcriptomes; Weight control
• ISSN: 0012-1797; 1939-327X
• DOI: 10.2337/db25-240-OR

Introduction and Objective: Treatment with the β3-adrenergic receptor (β3AR) agonist mirabegron improves insulin sensitivity, β cell function, and glucose tolerance in individuals with obesity, without weight loss or a change in brown adipose tissue (BAT). The objective of this study was to identify changes in the mRNA transcriptome of subcutaneous white adipose tissue (SC WAT) to identify mechanisms for the beneficial effects of mirabegron treatment. Methods: Adipose biopsies were performed on obese subjects before and after treatment with mirabegron 50 mg/day. We utilized RNA seq and enrichment analysis on SC WAT to identify biological pathways changed by mirabegron treatment. We verified these changes by immunohistochemistry and performed mechanistic studies in differentiated human adipocytes in vitro. Results: Mirabegron treatment reduced myofibroblasts, which are fibrotic, and reduced CXCR2, which is involved in inflammation and chemotaxis, in SC WAT. Adipose tissue myofibroblasts were higher with obesity and negatively correlated with β cell function. Mirabegron inhibited TGFβ induction of the adipocyte mesenchymal transition pathway in differentiated adipocytes in vitro. Furthermore, mirabegron treatment reduced expression of snail, a transcription factor which promotes the mesenchymal transition pathway, in vitro and in vivo. We also found that mirabegron treatment reduced CXCR2 expression in SC WAT. CXCR2 was expressed by NK cells and mirabegron treatment reduced CXCR2 and the inflammation marker NK1.1 on NK cells in SC WAT. Conclusion: Together, these results suggest mechanisms for a β3AR agonist to reduce fibrosis and inflammation in human SC WAT, which improves glucose metabolism.