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

Anders B Klein, Trine S Nicolaisen, Niels Ørtenblad, Kasper D Gejl, Rasmus Jensen, Andreas M Fritzen, Emil L Larsen, Kristian Karstoft, Henrik E Poulsen, Thomas Morville, Ronni E Sahl, Jørn W Helge, Jens Lund, Sarah Falk, Mark Lyngbæk, Helga Ellingsgaard, Bente K Pedersen, Wei Lu, Brian Finan, Sebastian B JørgensenRandy J Seeley, Maximilian Kleinert, Bente Kiens, Erik A Richter, Christoffer Clemmensen

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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.

Original languageEnglish
Article number1041
JournalNature Communications
Number of pages9
Publication statusPublished - 15. Feb 2021


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