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 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.

[1]  N. Secher,et al.  Glucagon-to-insulin ratio is pivotal for splanchnic regulation of FGF-21 in humans , 2015, Molecular metabolism.

[2]  Ruhang Tang,et al.  Overcoming Insulin Insufficiency by Forced Follistatin Expression in β-cells of db/db Mice. , 2015, Molecular therapy : the journal of the American Society of Gene Therapy.

[3]  B. Thorens.  GLUT2, glucose sensing and glucose homeostasis , 2015, Diabetologia.

[4]  E. Dermitzakis,et al.  Fractalkine (CX3CL1), a new factor protecting β-cells against TNFα , 2014, Molecular metabolism.

[5]  J. Andrews,et al.  Follistatin: A Novel Therapeutic for the Improvement of Muscle Regeneration , 2014, The Journal of Pharmacology and Experimental Therapeutics.

[6]  A. S. Andreasen,et al.  Plasma follistatin is elevated in patients with type 2 diabetes: relationship to hyperglycemia, hyperinsulinemia, and systemic low‐grade inflammation , 2013, Diabetes/metabolism research and reviews.

[7]  M. Hedger,et al.  The activins and their binding protein, follistatin-Diagnostic and therapeutic targets in inflammatory disease and fibrosis. , 2013, Cytokine & growth factor reviews.

[8]  S. Woods,et al.  Fibroblast Growth Factor 21 Mediates Specific Glucagon Actions , 2013, Diabetes.

[9]  A. Schneyer,et al.  Increased activin bioavailability enhances hepatic insulin sensitivity while inducing hepatic steatosis in male mice. , 2013, Endocrinology.

[10]  D. Drucker,et al.  Liver-Specific Disruption of the Murine Glucagon Receptor Produces α-Cell Hyperplasia , 2013, Diabetes.

[11]  A. Pfeiffer,et al.  Glucagon increases circulating fibroblast growth factor 21 independently of endogenous insulin levels: a novel mechanism of glucagon-stimulated lipolysis? , 2013, Diabetologia.

[12]  A. Wagers,et al.  Liver-derived systemic factors drive β cell hyperplasia in insulin-resistant states. , 2013, Cell reports.

[13]  N. Stefan,et al.  The role of hepatokines in metabolism , 2013, Nature Reviews Endocrinology.

[14]  X. Chen,et al.  Injection of duck recombinant follistatin fusion protein into duck muscle tissues stimulates satellite cell proliferation and muscle fiber hypertrophy , 2012, Applied Microbiology and Biotechnology.

[15]  A. Mukherjee,et al.  Follistatin and Follistatin Like‐3 Differentially Regulate Adiposity and Glucose Homeostasis , 2011, Obesity.

[16]  C. Mantzoros,et al.  Energy deprivation alters in a leptin- and cortisol-independent manner circulating levels of activin A and follistatin but not myostatin in healthy males. , 2011, The Journal of clinical endocrinology and metabolism.

[17]  D. Edgerton,et al.  Physiologic action of glucagon on liver glucose metabolism , 2011, Diabetes, obesity & metabolism.

[18]  M. Febbraio,et al.  Exercise induces a marked increase in plasma follistatin: evidence that follistatin is a contraction-induced hepatokine. , 2011, Endocrinology.

[19]  P. Halban,et al.  Bimodal Effect on Pancreatic β-Cells of Secretory Products From Normal or Insulin-Resistant Human Skeletal Muscle , 2011, Diabetes.

[20]  K. Tsuchida,et al.  Follistatin-derived peptide expression in muscle decreases adipose tissue mass and prevents hepatic steatosis. , 2011, American journal of physiology. Endocrinology and metabolism.

[21]  O. Ljungqvist.  Metabolic Regulation: A Human Perspective , 2011 .

[22]  M. Tschöp,et al.  The metabolic actions of glucagon revisited , 2010, Nature Reviews Endocrinology.

[23]  J. Piret,et al.  Reciprocal modulation of adult beta cell maturity by activin A and follistatin , 2010, Diabetologia.

[24]  K. Birkeland,et al.  A Complex Role of Activin A in Non-Alcoholic Fatty Liver Disease , 2009, The American Journal of Gastroenterology.

[25]  P. Halban,et al.  Silencing Mitogen-activated Protein 4 Kinase 4 (MAP4K4) Protects Beta Cells from Tumor Necrosis Factor-α-induced Decrease of IRS-2 and Inhibition of Glucose-stimulated Insulin Secretion* , 2009, The Journal of Biological Chemistry.

[26]  S. Arver,et al.  Role of follistatin in promoting adipogenesis in women. , 2009, Journal of Clinical Endocrinology and Metabolism.

[27]  S. Keiding,et al.  Methodological problems in the use of indocyanine green to estimate hepatic blood flow and ICG clearance in man. , 2008, Liver.

[28]  B. Pedersen,et al.  Effect of short-term intralipid infusion on the immune response during low-dose endotoxemia in humans. , 2008, American journal of physiology. Endocrinology and metabolism.

[29]  M. Hedger,et al.  Activin A is a critical component of the inflammatory response, and its binding protein, follistatin, reduces mortality in endotoxemia , 2007, Proceedings of the National Academy of Sciences.

[30]  T. Jardetzky,et al.  Structural and Biophysical Coupling of Heparin and Activin Binding to Follistatin Isoform Functions* , 2007, Journal of Biological Chemistry.

[31]  C. Robinson,et al.  Structural basis for the inhibition of activin signalling by follistatin , 2006, The EMBO journal.

[32]  D. Trono,et al.  Treatment of fulminant liver failure by transplantation of microencapsulated primary or immortalized xenogeneic hepatocytes , 2005, Transplantation proceedings.

[33]  C. Donaldson,et al.  Autocrine/paracrine regulation of pituitary function by activin, inhibin and follistatin , 2004, Molecular and Cellular Endocrinology.

[34]  P. Sluss,et al.  Differential distribution of follistatin isoforms: application of a new FS315-specific immunoassay. , 2004, The Journal of clinical endocrinology and metabolism.

[35]  K. Patel,et al.  Follistatin complexes Myostatin and antagonises Myostatin-mediated inhibition of myogenesis. , 2004, Developmental biology.

[36]  P. Morel,et al.  Highly efficient lentiviral vector-mediated transduction of nondividing, fully reimplantable primary hepatocytes. , 2002, Molecular therapy : the journal of the American Society of Gene Therapy.

[37]  Se-Jin Lee,et al.  Regulation of myostatin activity and muscle growth , 2001, Proceedings of the National Academy of Sciences of the United States of America.

[38]  H. Uchiyama,et al.  Direct binding of follistatin to a complex of bone-morphogenetic protein and its receptor inhibits ventral and epidermal cell fates in early Xenopus embryo. , 1998, Proceedings of the National Academy of Sciences of the United States of America.

[39]  M. Kanzaki,et al.  Regulation of the expression of follistatin in rat hepatocytes. , 1997, Biochimica et biophysica acta.

[40]  K. Miyanaga,et al.  Structural and functional characterization of the rat follistatin (activin-binding protein) gene promoter , 1993, Molecular and Cellular Endocrinology.

[41]  P. Halban,et al.  Uvomorulin mediates calcium-dependent aggregation of islet cells, whereas calcium-independent cell adhesion molecules distinguish between islet cell types. , 1991, Developmental biology.

[42]  K. Titani,et al.  Immunohistochemical localization of follistatin in rat tissues. , 1991, Endocrinologia japonica.

[43]  K. Titani,et al.  Activin-binding protein from rat ovary is follistatin. , 1990, Science.

[44]  J. Watanabe,et al.  Glucagon receptors in endothelial and Kupffer cells of mouse liver. , 1988, The journal of histochemistry and cytochemistry : official journal of the Histochemistry Society.

[45]  N. Ling,et al.  Primary structure of the human follistatin precursor and its genomic organization. , 1988, Proceedings of the National Academy of Sciences of the United States of America.

[46]  E. Marliss,et al.  The effects of prolonged fasting on plasma triglyceride kinetics in man. , 1977, Metabolism: clinical and experimental.

[47]  D. Drucker,et al.  Liver-Speci fi c Disruption of the Murine Glucagon Receptor Produces a -Cell Hyperplasia: Evidence for a Circulating a -Cell Growth Factor , 2012 .

[48]  J. Philippe,et al.  Activin A Decreases glucagon and arx Gene Expression in α-Cell Lines , 2007 .

[49]  J. Philippe,et al.  Activin A decreases glucagon and arx gene expression in alpha-cell lines. , 2007, Molecular endocrinology.

[50]  A. Jeukendrup,et al.  Fat Metabolism During Exercise: A Review. Part I: Fatty Acid Mobilization and Muscle Metabolism , 1998, International journal of sports medicine.

[51]  D. Allmann,et al.  Effect of sodium fluoride on cyclic AMP production in rat hepatocytes. , 1979, Journal of cyclic nucleotide research.