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

Author:

Klein Anders B.,Nicolaisen Trine S.ORCID,Ørtenblad NielsORCID,Gejl Kasper D.,Jensen RasmusORCID,Fritzen Andreas M.ORCID,Larsen Emil L.ORCID,Karstoft Kristian,Poulsen Henrik E.,Morville Thomas,Sahl Ronni E.ORCID,Helge Jørn W.ORCID,Lund JensORCID,Falk Sarah,Lyngbæk Mark,Ellingsgaard HelgaORCID,Pedersen Bente K.ORCID,Lu Wei,Finan BrianORCID,Jørgensen Sebastian B.ORCID,Seeley Randy J.ORCID,Kleinert Maximilian,Kiens BenteORCID,Richter Erik A.ORCID,Clemmensen ChristofferORCID

Abstract

AbstractGrowing 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.

Funder

Lundbeckfonden

Novo Nordisk Fonden

Det Frie Forskningsråd

Publisher

Springer Science and Business Media LLC

Subject

General Physics and Astronomy,General Biochemistry, Genetics and Molecular Biology,General Chemistry

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