Jakob S Hansen1, Sabine Rutti1, Caroline Arous1, Jens O Clemmesen1, Niels H Secher1, Andrea Drescher1, Carmen Gonelle-Gispert1, Philippe A Halban1, Bente K Pedersen1, Cora Weigert1, Karim Bouzakri1, Peter Plomgaard1. 1. The Centre of Inflammation and Metabolism and the Centre for Physical Activity Research (J.S.H., B.K.P., P.P.), Rigshospitalet, University of Copenhagen, Denmark 2100; Department of Clinical Biochemistry (J.S.H., P.P.), Rigshospitalet, Copenhagen, Denmark 2100; Department of Genetic Medicine and Development (S.R., C.A., P.A.H., K.B.), University Medical Centre, University of Geneva, Geneva, Switzerland 1206; Department of Hepatology (J.O.C.), Rigshospitalet, Copenhagen, Denmark 2100; Department of Anaesthesiology (N.H.S.), The Copenhagen Muscle Research Centre, Rigshospitalet, Copenhagen, Denmark 2100; Division of Pathobiochemistry and Clinical Chemistry (A.D., C.W.), Department of Internal Medicine IV, University Tuebingen, Germany 72076; University Hospitals of Geneva (C.G.-G.), Surgical Research Unit, Geneva, Switzerland 1206; Institute for Diabetes Research and Metabolic Diseases of the Helmholtz Zentrum München (C.W.), University of Tuebingen, Tuebingen, Germany 72076; German Center for Diabetes Research (C.W.), München-Neuherberg, Germany 85764.
Abstract
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 β 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.
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 β 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.
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