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 mechanisms1,2. Conversely, the endogenous regulation and secretion of GDF15 and its physiological effects on energy homeostasis and behavior remain elusive. Here we show, in four independent studies that prolonged, moderate- to high-intensity endurance exercise substantially increases circulating GDF15, in a time-dependent and reversible fashion, to peak levels otherwise only observed in pathophysiological conditions. This exercise-induced increase can be recapitulated in mice following forced treadmill running and is accompanied by increased Gdf15 expression in the liver, skeletal muscle, and heart muscle. Compared to other metabolic stressors, like fasting, acute high-fat diet feeding, severe caloric excess and temperature changes, exercise has a greater impact on circulating GDF15 levels. However, whereas pharmacological GDF15 inhibits appetite and suppresses wheel running activity via GFRAL, in response to exercise, the physiological induction of GDF15 does not. In summary, exercise-induced circulating GDF15 correlates with the duration of endurance exercise. However, higher GDF15 levels after exercise are not sufficient to evoke canonical pharmacological GDF15 effects on appetite or responsible for exercise aversion/fatigue. Thus, the physiological effects of GDF15 as an exerkine remain elusive.
Competing Interest Statement
SBJ, WL and BF are working for Novo Nordisk A/S, a pharmaceutical company producing and selling medicine for the treatment of chronic diseases including diabetes and obesity. ELL and HEP have received an unrestricted research grant from Boehringer Ingelheim for an unrelated investigator-initiated study. RJS has received research support from Zafgen, Novo Nordisk, Ionis, AstraZeneca, and Pfizer. RJS has served on scientific advisory boards for Novo Nordisk, Sanofi, Scohia, Ionis, Kintai Therapeutics, and GuidePoint Consultants. RJS is a stakeholder of Zafgen and Redesign Health. The other authors have declared that no competing interests exist.
Footnotes
↵* Co-first author