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, 60 min), epinephrine (2 mg/kg, 30 min), glucagon then epinephrine, or saline. Third, mice were pre-treated with propranolol (20-60 mg/kg, 30 min) prior to epinephrine injection. Fourth, glucagon receptor wild type (Gcgr+/+) or knockout (Gcgr-/-) mice were pre-treated with saline or propranolol (20 mg/kg, 30 min) and were subjected to a single bout of exhaustive exercise with liver collected immediately post or after 2 hours recovery. In all experiments liver FST mRNA 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. Pre-treatment 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. Conclusion These data suggest that both glucagon and epinephrine regulate hepatic FST expression at rest; however, only glucagon is required for the exercise-induced increase. These authors contributed equally, Willem T. Peppler, Laura N. Castellani Corresponding author: David C. Wright, PhD, Rm. 334 Animal Science Nutrition Building, Department of Human Health and Nutritional Sciences, University of Guelph, Guelph, Ontario, Canada, N1G 2W1, Phone: 519 824 4120 ext 56751, Email: dcwright@uoguelph.ca, Fax: 519-763-5902 This work was supported by a Natural Sciences and Engineering Research Council of Canada (NSERC) Discovery Grant (DCW). DCW is a Tier II Canada Research Chair in Lipids, Metabolism, and Health. The Ontario Graduate Scholarship program supported WTP and LNC. An NSERC postgraduate scholarship, Dairy Farmers of Ontario Doctoral Research Assistantship, and the Ontario Graduate Scholarship Program supported LKT. The Ontario Graduate Scholarship program, and subsequently, a NSERC Canada Graduate Scholarship supported SFC. REKM was supported by a post-doctoral fellowship from the Alzheimer's Society of Canada. The results of the present study do not constitute endorsement by ACSM, and the results of the study are presented clearly, honestly, and without fabrication, falsification, or inappropriate data manipulation. Competing Interests: The authors declare no competing interests. Accepted for Publication: 3 January 2019 © 2019 American College of Sports Medicine

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