Mirabegron treatment reduces myofibroblasts and CXCR2 expression in adipose tissue in obesity

Background: Treatment with the β3-adrenergic receptor (AR) 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) (Finlin et al, J Clin Invest. 2020 May 1;130(5):2319-2331). Furthermore, mirabegron treatment increased protein expression of beige adipose markers and the number of anti-inflammatory macrophages, and changed the expression of genes involved in fibrosis and tissue remodeling in subcutaneous white adipose tissue (SC WAT). Methods: We utilized RNA seq and enrichment analysis to identify biological pathways changed by mirabegron treatment in SC WAT thigh biopsies. 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 expression in NK cells in SC WAT. Conclusion: Together, these results suggest new mechanisms for improvement of the human SC WAT phenotype by mirabegron treatment to enhance glucose metabolism. These new mechanisms involve the reduction of myofibroblasts as well as the reduction of CXCR2 expression in NK cells.