Pharmacological but not physiological GDF15 suppresses feeding and the motivation to exercise

Anders Bue Klein ,Mark Lyngbæk,Bente Kiens,Niels Ørtenblad,Rasmus Jensen,Bente Klarlund Pedersen ,Randy J Seeley,Kasper Degn Gejl ,Helga Ellingsgaard,Sebastian Beck Jørgensen ,T Nicolaisen ,Brian Finan,Ronni Eg Sahl ,Andreas M Fritzen,J W Lund ,Kristian Karstoft,Thomas Morville,Maximilian Kleinert,Jørn Wulff Helge ,Sarah Falk,Emil List Larsen ,Wei Lu,Henrik Enghusen Poulsen ,Christoffer Clemmensen

doi:10.1038/s41467-021-21309-x

Abstract

Growing evidence supports that pharmacological application of growth differentiation factor 15 (GDF15) suppresses appetite but also promotes sickness-like behaviors in rodents via GDNF family receptor α-like (GFRAL)-dependent mechanisms. Conversely, the endogenous regulation of GDF15 and its physiological effects on energy homeostasis and behavior remain elusive. Here we show, in four independent human studies that prolonged endurance exercise increases circulating GDF15 to levels otherwise only observed in pathophysiological conditions. This exercise-induced increase can be recapitulated in mice and is accompanied by increased Gdf15 expression in the liver, skeletal muscle, and heart muscle. However, whereas pharmacological GDF15 inhibits appetite and suppresses voluntary running activity via GFRAL, the physiological induction of GDF15 by exercise does not. In summary, exercise-induced circulating GDF15 correlates with the duration of endurance exercise. Yet, higher GDF15 levels after exercise are not sufficient to evoke canonical pharmacological GDF15 effects on appetite or responsible for diminishing exercise motivation.

Highlights

Growing evidence supports that pharmacological application of growth differentiation factor 15 (GDF15) suppresses appetite and promotes sickness-like behaviors in rodents via GDNF family receptor α-like (GFRAL)-dependent mechanisms
Our work show that prolonged endurance exercise leads to a 4-5-fold increase in circulating GDF15 in mice and humans and that pharmacological GDF15 supresses voluntary running in mice
Given the emerging understanding that the weight-lowering effects of pharmacological GDF15 cannot be dissociated from sickness-like behaviors[9], we experimentally pursued the notion that endogenously-induced GDF15 in response to exercise stress contributes to exercise fatigue as a strategy to protect the organism and preserve energy

Summary

Introduction

Growing evidence supports that pharmacological application of growth differentiation factor 15 (GDF15) suppresses appetite and promotes sickness-like behaviors in rodents via GDNF family receptor α-like (GFRAL)-dependent mechanisms. In four independent human studies that prolonged endurance exercise increases circulating GDF15 to levels otherwise only observed in pathophysiological conditions. This exercise-induced increase can be recapitulated in mice and is accompanied by increased Gdf[15] expression in the liver, skeletal muscle, and heart muscle. Novo Nordisk Foundation Center for Basic Metabolic Research, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark. 2 Section of Molecular Physiology, Department of Nutrition, Exercise and Sports, Faculty of Science, University of Copenhagen, Copenhagen, Denmark. Our work show that prolonged endurance exercise leads to a 4-5-fold increase in circulating GDF15 in mice and humans and that pharmacological GDF15 supresses voluntary running in mice. The exercise-induced increase in endogenous GDF15 does not affect post-exercise food intake, nor does it signal exercise aversion

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Conclusion