Regulation of Hepatic Follistatin Expression at Rest and during Exercise in Mice

Introduction: Follistatin (FST) is a protein with numerous biological roles and was recently identified as an exercise-inducible hepatokine; however, the signals that regulate this are not well understood. The purpose of this study was to delineate potential endocrine factors that may regulate hepatic FST at rest and during exercise. Methods: This study used four experiments. First, male and female C57BL/6J mice remained sedentary or were subjected to a single bout of exercise at moderate or exhaustive intensity with liver collected immediately post. Second, mice were injected with glucagon (1 mg.kg(-1), 60 min), epinephrine (2 mg.kg(-1), 30 min), glucagon then epinephrine, or saline. Third, mice were pretreated with propranolol (20-60 mg.kg(-1), 30 min) before epinephrine injection. Fourth, glucagon receptor wild type (Gcgr(+/+)) or knockout (Gcgr(-/-)) mice were pretreated with saline or propranolol (20 mg.kg(-1), 30 min) and were subjected to a single bout of exhaustive exercise with liver collected immediately post or after 2 h recovery. In all experiments liver FSTmRNA expression was measured, and in experiment four FST protein content was measured. Results: A single bout of treadmill exercise performed at an exhaustive but not moderate-intensity increased FST expression, as did injection of glucagon or epinephrine alone and when combined. Pretreatment of mice with propranolol attenuated the epinephrine-induced increase in FST expression. The exercise-induced increase in FST expression was attenuated in Gcgr(-/-) mice, with no effect of propranolol. Gcgr(-/-) mice had higher protein content of FST, but there was no effect of exercise or propranolol. Conclusions: These data suggest that both glucagon and epinephrine regulate hepatic FST expression at rest; however, only glucagon is required for the exercise-induced increase.