Pharmacological but not physiological GDF15 suppresses feeding and the motivation to exercise
- PMID: 33589633
- PMCID: PMC7884842
- DOI: 10.1038/s41467-021-21309-x
Pharmacological but not physiological GDF15 suppresses feeding and the motivation to exercise
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.
Conflict of interest statement
S.B.J., W.L., and B.F. are working for Novo Nordisk A/S, a pharmaceutical company producing and selling medicine for the treatment of chronic diseases including diabetes and obesity. E.L.L. and H.E.P. have received an unrestricted research grant from Boehringer Ingelheim for an unrelated investigator-initiated study. R.J.S. has received research support from Zafgen, Novo Nordisk, Ionis, AstraZeneca, and Pfizer. R.J.S. has served on scientific advisory boards for Novo Nordisk, Sanofi, Scohia, Ionis, Kintai Therapeutics, and GuidePoint Consultants. R.J.S. is a stakeholder of Zafgen and Redesign Health. The other authors have declared that no competing interests exist.
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