Uncoupling protein 1-mediated protective effects of β3-adrenergic receptor agonist on kidney fibrosis via promoting adipose tissue browning in diabetic mice.

Background: Diabetes mellitus (DM) is a global health concern. Diabetic kidney disease (DKD) is a prevalent severe complication of DM and therapy is urgently needed. Adipose tissue (AT) plays a crucial role in the energy mediation through glucolipid metabolism. Mirabegron is a specific β3-adrenergic receptor agonist, which can activate thermogenesis in adipocytes, improve energy consumption, and increase insulin sensitivity and glucose tolerance. Therefore, mirabegron may play a role in DKD pathogenesis. However, its effects and precise mechanisms remain unclear.

Methods: A DKD mouse model based on type 2 DM (T2DM) was constructed and treated with mirabegron. Mice with AT surgically removed and mice with uncoupling protein 1 (Ucp1) knockout were used to confirm whether thermogenesis induced by mirabegron was the key process.

Results: Mirabegron promoted AT browning in DKD mice. Mirabegron increased insulin sensitivity, promoted glucolipid metabolism, reduced inflammatory factor levels in kidney tissue, and improved renal function and fibrosis in DKD mice. Notably, all of these benefits disappeared in AT-removed DKD mice or in Ucp1 knockout DKD mice.

Conclusions: Mirabegron protects against kidney fibrosis in DM mice by activating AT thermogenesis via the UCP1 pathway. Thus, mirabegron may provide a promising potential option for DKD therapy.