Glucagon-to-insulin ratio is pivotal for splanchnic regulation of FGF-21 in humans.
OBJECTIVE
Fibroblast growth factor 21 (FGF-21) is a liver-derived metabolic regulator induced by energy deprivation. However, its regulation in humans is incompletely understood. We addressed the origin and regulation of FGF-21 secretion in humans.


METHODS
By determination of arterial-to-venous differences over the liver and the leg during exercise, we evaluated the organ-specific secretion of FGF-21 in humans. By four different infusion models manipulating circulating glucagon and insulin, we addressed the interaction of these hormones on FGF-21 secretion in humans.


RESULTS
We demonstrate that the splanchnic circulation secretes FGF-21 at rest and that it is rapidly enhanced during exercise. In contrast, the leg does not contribute to the systemic levels of FGF-21. To unravel the mechanisms underlying the regulation of exercise-induced hepatic release of FGF-21, we manipulated circulating glucagon and insulin. These studies demonstrated that in humans glucagon stimulates splanchnic FGF-21 secretion whereas insulin has an inhibitory effect.


CONCLUSIONS
Collectively, our data reveal that 1) in humans, the splanchnic bed contributes to the systemic FGF-21 levels during rest and exercise; 2) under normo-physiological conditions FGF-21 is not released from the leg; 3) a dynamic interaction of glucagon-to-insulin ratio regulates FGF-21 secretion in humans.
The Centre of Inflammation and Metabolism and the Centre for Physical Activity Research, Department of Infectious Diseases, Rigshospitalet, University of Copenhagen, Denmark ; Department of Clinical Biochemistry, Rigshospitalet, Copenhagen, Denmark.
Jakob Schiøler
JS
Hansen
Department of Hepatology, Rigshospitalet, Copenhagen, Denmark.
Jens Otto
JO
Clemmesen
Department of Anaesthesiology, The Copenhagen Muscle Research Centre, Rigshospitalet, Copenhagen, Denmark.
Niels Henry
NH
Secher
Division of Pathobiochemistry and Clinical Chemistry, University Tuebingen, Germany.
Miriam
M
Hoene
Division of Pathobiochemistry and Clinical Chemistry, University Tuebingen, Germany.
Andrea
A
Drescher
Division of Pathobiochemistry and Clinical Chemistry, University Tuebingen, Germany ; Institute for Diabetes Research and Metabolic Diseases of the Helmholtz Zentrum München at the University of Tuebingen, Tuebingen, Germany ; German Center for Diabetes Research (DZD), Germany.
Cora
C
Weigert
The Centre of Inflammation and Metabolism and the Centre for Physical Activity Research, Department of Infectious Diseases, Rigshospitalet, University of Copenhagen, Denmark.
Bente Klarlund
BK
Pedersen
The Centre of Inflammation and Metabolism and the Centre for Physical Activity Research, Department of Infectious Diseases, Rigshospitalet, University of Copenhagen, Denmark ; Department of Clinical Biochemistry, Rigshospitalet, Copenhagen, Denmark.
Peter
P
Plomgaard
Exercise; FFA, free fatty acids; FGF-21, fibroblast growth factor-21; Hepatic; Hepatokine; Liver; PPAR, peroxisome proliferator-activated receptor