GDF15 is an exercise-induced hepatokine regulated by glucagon and insulin in humans

Peter Plomgaard*, Jakob S. Hansen, Logan K. Townsend, Anders Gudiksen, Niels H. Secher, Jens O. Clemmesen, Rene K. Støving, Jens P. Goetze, David C. Wright, Henriette Pilegaard

*Corresponding author af dette arbejde

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Abstract

Objective: Growth differentiation factor (GDF)-15 is implicated in regulation of metabolism and circulating GDF15 increases in response to exercise. The source and regulation of the exercise-induced increase in GDF15 is, however not known. Method: Plasma GDF15 was measured by ELISA under the following conditions: 1) Arterial-to-hepatic venous differences sampled before, during, and after exercise in healthy male subjects (n=10); 2) exogenous glucagon infusion compared to saline infusion in resting healthy subjects (n=10); 3) an acute exercise bout with and without a pancreatic clamp (n=6); 4) healthy subjects for 36 hours (n=17), and 5) patients with anorexia nervosa (n=25) were compared to healthy age-matched subjects (n=25). Tissue GDF15 mRNA content was determined in mice in response to exhaustive exercise (n=16). Results: The splanchnic bed released GDF15 to the circulation during exercise and increasing the glucagon-to-insulin ratio in resting humans led to a 2.7-fold (P<0.05) increase in circulating GDF15. Conversely, inhibiting the exercise-induced increase in the glucagon-to-insulin ratio blunted the exercise-induced increase in circulating GDF15. Fasting for 36 hours did not affect circulating GDF15, whereas resting patients with anorexia nervosa displayed elevated plasma concentrations (1.4-fold, P<0.05) compared to controls. In mice, exercise increased GDF15 mRNA contents in liver, muscle, and adipose tissue. Conclusion: In humans, GDF15 is a “hepatokine” which increases during exercise and is at least in part regulated by the glucagon-to-insulin ratio. Moreover, chronic energy deprivation is associated with elevated plasma GDF15, which supports that GDF15 is implicated in metabolic signalling in humans.

OriginalsprogEngelsk
Artikelnummer1037948
TidsskriftFrontiers in Endocrinology
Vol/bind13
ISSN1664-2392
DOI
StatusUdgivet - 2022

Bibliografisk note

Funding Information:
The Centre for Physical Activity Research (CFAS) is supported by TrygFonden (grants ID 101390 and ID 20045). During the study period, the Centre of Inflammation and Metabolism (CIM) was supported by a grant from the Danish National Research Foundation (DNRF55). This study was further supported by a grant from the Augustinus Foundation. LT was supported by the Natural Sciences and Engineering Research Council of Canada. DW is a Tier II Canada Research Chair. Animal work was supported by the Discovery Grant from the Natural Sciences and Engineering Research Council of Canada. Danish Ministry of Culture for Sports Research and Danish Council for Independent Research.

Publisher Copyright:
Copyright © 2022 Plomgaard, Hansen, Townsend, Gudiksen, Secher, Clemmesen, Støving, Goetze, Wright and Pilegaard.

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