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Mol Metab. 2015 Jun 12;4(8):551-60. doi: 10.1016/j.molmet.2015.06.001. eCollection 2015 Aug.

Glucagon-to-insulin ratio is pivotal for splanchnic regulation of FGF-21 in humans.

Author information

1
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.
2
Department of Hepatology, Rigshospitalet, Copenhagen, Denmark.
3
Department of Anaesthesiology, The Copenhagen Muscle Research Centre, Rigshospitalet, Copenhagen, Denmark.
4
Division of Pathobiochemistry and Clinical Chemistry, University Tuebingen, Germany.
5
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.
6
The Centre of Inflammation and Metabolism and the Centre for Physical Activity Research, Department of Infectious Diseases, Rigshospitalet, University of Copenhagen, Denmark.

Abstract

BACKGROUND & AIMS:

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.

KEYWORDS:

Exercise; FFA, free fatty acids; FGF-21, fibroblast growth factor-21; Hepatic; Hepatokine; Liver; PPAR, peroxisome proliferator-activated receptor

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