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

Jakob S Hansen; Sabine Rutti; Caroline Arous; Jens Otto Clemmesen; Niels H Secher; Andrea Drescher; Carmen Gonelle-Gispert; Philippe A Halban; Bente K Pedersen; Cora Weigert; Karim Bouzakri; Peter Plomgaard

doi:10.1210/jc.2015-3668

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

Jakob S Hansen, Sabine Rutti, Caroline Arous, Jens Otto Clemmesen, Niels H Secher, Andrea Drescher, Carmen Gonelle-Gispert, Philippe A Halban, Bente K Pedersen, Cora Weigert, Karim Bouzakri, Peter Plomgaard

Department of Clinical Medicine

53 Citations (Scopus)

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 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.

Original language	English
Journal	The Journal of Clinical Endocrinology & Metabolism
Volume	101
Issue number	2
Pages (from-to)	550-60
Number of pages	11
ISSN	0021-972X
DOIs	https://doi.org/10.1210/jc.2015-3668
Publication status	Published - Feb 2016

Keywords

Animals
Cell Line, Tumor
Cell Proliferation
Cell Survival
Cells, Cultured
Cyclic AMP
Emulsions
Exercise
Follistatin
Glucagon
Hepatocytes
Humans
Insulin
Insulin-Secreting Cells
Islets of Langerhans
Liver
Male
Phospholipids
Rats
Soybean Oil
Young Adult
Journal Article
Research Support, Non-U.S. Gov't

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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10.1210/jc.2015-3668

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Hansen, J. S., Rutti, S., Arous, C., Clemmesen, J. O., Secher, N. H., Drescher, A., Gonelle-Gispert, C., Halban, P. A., Pedersen, B. K., Weigert, C., Bouzakri, K., & Plomgaard, P. (2016). Circulating Follistatin Is Liver-Derived and Regulated by the Glucagon-to-Insulin Ratio. The Journal of Clinical Endocrinology & Metabolism, 101(2), 550-60. https://doi.org/10.1210/jc.2015-3668

Hansen, JS, Rutti, S, Arous, C, Clemmesen, JO, Secher, NH, Drescher, A, Gonelle-Gispert, C, Halban, PA, Pedersen, BK, Weigert, C, Bouzakri, K & Plomgaard, P 2016, 'Circulating Follistatin Is Liver-Derived and Regulated by the Glucagon-to-Insulin Ratio', The Journal of Clinical Endocrinology & Metabolism, vol. 101, no. 2, pp. 550-60. https://doi.org/10.1210/jc.2015-3668

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title = "Circulating Follistatin Is Liver-Derived and Regulated by the Glucagon-to-Insulin Ratio",

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 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.",

keywords = "Animals, Cell Line, Tumor, Cell Proliferation, Cell Survival, Cells, Cultured, Cyclic AMP, Emulsions, Exercise, Follistatin, Glucagon, Hepatocytes, Humans, Insulin, Insulin-Secreting Cells, Islets of Langerhans, Liver, Male, Phospholipids, Rats, Soybean Oil, Young Adult, Journal Article, Research Support, Non-U.S. Gov't",

author = "Hansen, {Jakob S} and Sabine Rutti and Caroline Arous and Clemmesen, {Jens Otto} and Secher, {Niels H} and Andrea Drescher and Carmen Gonelle-Gispert and Halban, {Philippe A} and Pedersen, {Bente K} and Cora Weigert and Karim Bouzakri and Peter Plomgaard",

year = "2016",

month = feb,

doi = "10.1210/jc.2015-3668",

language = "English",

volume = "101",

pages = "550--60",

journal = "The Journal of Clinical Endocrinology & Metabolism",

issn = "0021-972X",

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TY - JOUR

T1 - Circulating Follistatin Is Liver-Derived and Regulated by the Glucagon-to-Insulin Ratio

AU - Hansen, Jakob S

AU - Rutti, Sabine

AU - Arous, Caroline

AU - Clemmesen, Jens Otto

AU - Secher, Niels H

AU - Drescher, Andrea

AU - Gonelle-Gispert, Carmen

AU - Halban, Philippe A

AU - Pedersen, Bente K

AU - Weigert, Cora

AU - Bouzakri, Karim

AU - Plomgaard, Peter

PY - 2016/2

Y1 - 2016/2

N2 - 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 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.

AB - 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 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.

KW - Animals

KW - Cell Line, Tumor

KW - Cell Proliferation

KW - Cell Survival

KW - Cells, Cultured

KW - Cyclic AMP

KW - Emulsions

KW - Exercise

KW - Follistatin

KW - Glucagon

KW - Hepatocytes

KW - Humans

KW - Insulin

KW - Insulin-Secreting Cells

KW - Islets of Langerhans

KW - Liver

KW - Male

KW - Phospholipids

KW - Rats

KW - Soybean Oil

KW - Young Adult

KW - Journal Article

KW - Research Support, Non-U.S. Gov't

U2 - 10.1210/jc.2015-3668

DO - 10.1210/jc.2015-3668

M3 - Journal article

C2 - 26652766

SN - 0021-972X

VL - 101

SP - 550

EP - 560

JO - The Journal of Clinical Endocrinology & Metabolism

JF - The Journal of Clinical Endocrinology & Metabolism

IS - 2

ER -

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

Abstract

Keywords

UN SDGs

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