Circulating Follistatin Is Liver-Derived and Regulated by the Glucagon-to-Insulin Ratio

Context: Follistatin is a plasma protein recently reported to increase under conditions with negative energy balance, such as exercise and fasting in humans. Currently, the perception is that circulating follistatin is a result of para/autocrine actions from various tissues. The large and acute increase in circulating follistatin in response to exercise suggests that it may function as an endocrine signal. Objective: We assessed origin and regulation of circulating follistatin in humans. Design/Interventions: First, we assessed arterial-to-venous difference of follistatin over the splanchnic bed at rest and during exercise in healthy humans. To evaluate the regulation of plasma follistatin we manipulated glucagon-to-insulin ratio in humans at rest as well as in cultured hepatocytes. Finally, the impact of follistatin on human islets of Langerhans was assessed. Results: We demonstrate that in humans the liver is a major contributor to circulating follistatin both at rest and during exercise. Glucagon increases and insulin inhibits follistatin secretion both in vivo and in vitro, mediated via the secondary messenger cAMP in the hepatocyte. Short-term follistatin treatment reduced glucagon secretion from islets of Langerhans, whereas long-term follistatin treatment prevented apoptosis and induced proliferation of rat beta cells. Conclusions: In conclusion, in humans, the liver secretes follistatin at rest and during exercise, and the glucagon-to-insulin ratio is a key determinant of circulating follistatin levels. Circulating follistatin may be a marker of the glucagon-to-insulin tone on the liver.