Research articleα1-Adrenergic receptor downregulates hepatic FGF21 production and circulating FGF21 levels in mice

•Intraperitoneal injection of phentolamine rapidly increased plasma FGF21 levels.•Intraperitoneal injection of prazosin rapidly increased plasma FGF21 levels.•Prazosin increased hepatic FGF21 expression independently of PPARα and PPARγ.•Despite increased circulating FGF21 levels, prazosin impaired glucose tolerance.•α1-Adrenergic receptor downregulates hepatic FGF21 production.

Fibroblast growth factor 21 (FGF21) is primarily secreted by the liver as an endocrine hormone and is suggested as a promising target for the treatment of metabolic diseases. FGF21 acts centrally to exert its effects on energy expenditure and body weight via the sympathetic nervous system in mice. Here we show that intraperitoneal injection of phentolamine (an α-adrenergic receptor antagonist, 5 mg/kg) significantly increased plasma FGF21 levels compared with the saline controls in C57BL6J mice, whereas alprenolol (a β-adrenergic receptor antagonist, 6 mg/kg) had no effect. In addition, intraperitoneal injection of prazosin (an α1-adrenergic receptor antagonist, 5 mg/kg) significantly increased plasma FGF21 levels compared with the controls, whereas yohimbine (an α2-adrenergic receptor antagonist, 5 mg/kg) had no effect. Moreover, the treatment with prazosin significantly increased the expression of hepatic FGF21, while having no effect on the expression of hepatic PPARα and PPARγ. After a 5-h fast, intraperitoneal injection of prazosin significantly increased plasma FGF21 levels and impaired glucose tolerance compared with controls. These findings suggest that α1-adrenergic receptor downregulates the expression of hepatic FGF21 and plasma FGF21 levels independently of feeding and hepatic PPARα and PPARγ expression in mice, and that the increases in circulating FGF21 levels might be related to impaired glucose tolerance.