β3 adrenergic receptor activation alleviated PM_2.5-induced hepatic lipid deposition in mice

Increasing energy expenditure through activation of hepatocytes is a potential approach to treat fine particulate matter (PM_2.5) induced metabolic-associated fatty liver disease (MAFLD). Beta-3 adrenergic receptor (β3-AR) agonists could stimulate brown adipose tissue (BAT) energy expenditure, but it has never been investigated in MAFLD. The objective of this study is to explore the therapeutic effects of administering CL-316,243, a selective agonist of β3-AR, on hepatic lipid metabolism disturbances induced by PM_2.5. Firstly, C57BL/6 N mice were intraperitoneally injected with CL-316,243 for one week. CL-316,243 significantly upregulated expression of β3-AR in the liver, accompanied with reduced serum triglyceride (TG) and free fatty acids (FFA). Next, mice were subjected to PM_2.5 exposure for 4 weeks, and CL-316,243 was daily intraperitoneally injected in the fourth week of PM_2.5 exposure. Exposure to PM_2.5 led to a significant increase in hepatic TG and monounsaturated fatty acids (MUFAs), accompanied with elevated activity of SCD1, increased levels of TG synthesis enzymes and inhibited COX4 activity. Furthermore, the administration of CL-316,243 alleviated PM_2.5-induced hepatic lipid deposition by enhancing SCD1 activity, TG lipolysis, fatty acid oxidation and TG synthesis via β3-AR/PKA/CREB/PPAR signaling pathway. Therefore, β3-AR activation may serve as a potential therapeutic approach for PM_2.5 exposure-induced MAFLD.