Circulating Follistatin Is Liver-Derived and Regulated by the Glucagon-to-Insulin Ratio
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Circulating Follistatin Is Liver-Derived and Regulated by the Glucagon-to-Insulin Ratio. / Hansen, Jakob S; Rutti, Sabine; Arous, Caroline; Clemmesen, Jens Otto; Secher, Niels H; Drescher, Andrea; Gonelle-Gispert, Carmen; Halban, Philippe A; Pedersen, Bente K; Weigert, Cora; Bouzakri, Karim; Plomgaard, Peter.
In: The Journal of Clinical Endocrinology & Metabolism, Vol. 101, No. 2, 02.2016, p. 550-60.Research output: Contribution to journal › Journal article › Research › peer-review
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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 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.
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 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.
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
VL - 101
SP - 550
EP - 560
JO - Journal of Clinical Endocrinology and Metabolism
JF - Journal of Clinical Endocrinology and Metabolism
SN - 0021-972X
IS - 2
ER -
ID: 164513207