title: Circulating Follistatin Is Liver-Derived and Regulated by the Glucagon-to-Insulin Ratio.
abstract: BACKGROUND
  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.
  
  
  METHODS
  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.
authors.affiliation: 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.
authors.forename: Jakob S
authors.initials: JS
authors.lastname: Hansen
authors.affiliation: 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.
authors.forename: Sabine
authors.initials: S
authors.lastname: Rutti
authors.affiliation: 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.
authors.forename: Caroline
authors.initials: C
authors.lastname: Arous
authors.affiliation: 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.
authors.forename: Jens O
authors.initials: JO
authors.lastname: Clemmesen
authors.affiliation: 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.
authors.forename: Niels H
authors.initials: NH
authors.lastname: Secher
authors.affiliation: 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.
authors.forename: Andrea
authors.initials: A
authors.lastname: Drescher
authors.affiliation: 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.
authors.forename: Carmen
authors.initials: C
authors.lastname: Gonelle-Gispert
authors.affiliation: 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.
authors.forename: Philippe A
authors.initials: PA
authors.lastname: Halban
authors.affiliation: 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.
authors.forename: Bente K
authors.initials: BK
authors.lastname: Pedersen
authors.affiliation: 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.
authors.forename: Cora
authors.initials: C
authors.lastname: Weigert
authors.affiliation: 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.
authors.forename: Karim
authors.initials: K
authors.lastname: Bouzakri
authors.affiliation: 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.
authors.forename: Peter
authors.initials: P
authors.lastname: Plomgaard
mesh_terms: D000818:Animals; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D002478:Cells, Cultured; D000242:Cyclic AMP / Q000378:metabolism; D004655:Emulsions / Q000494:pharmacology; D015444:Exercise; D038681:Follistatin / Q000097:blood*; D005934:Glucagon / Q000378:metabolism* / Q000494:pharmacology; D022781:Hepatocytes / Q000187:drug effects / Q000378:metabolism; D006801:Humans; D007328:Insulin / Q000378:metabolism* / Q000494:pharmacology; D050417:Insulin-Secreting Cells / Q000187:drug effects; D007515:Islets of Langerhans / Q000187:drug effects / Q000378:metabolism; D008099:Liver / Q000378:metabolism*; D008297:Male; D010743:Phospholipids / Q000494:pharmacology; D051381:Rats; D013024:Soybean Oil / Q000494:pharmacology; D055815:Young Adult
chemical_list: D004655:Emulsions; C503233:FST protein, human; D038681:Follistatin; D007328:Insulin; D010743:Phospholipids; C545823:soybean oil, phospholipid emulsion; D013024:Soybean Oil; D005934:Glucagon; D000242:Cyclic AMP