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

• Published in: Nature communications Vol. 12; no. 1; pp. 1041 - 9
• Main Authors: Klein, Anders B., Nicolaisen, Trine S., Ørtenblad, Niels, Gejl, Kasper D., Jensen, Rasmus, Fritzen, Andreas M., Larsen, Emil L., Karstoft, Kristian, Poulsen, Henrik E., Morville, Thomas, Sahl, Ronni E., Helge, Jørn W., Lund, Jens, Falk, Sarah, Lyngbæk, Mark, Ellingsgaard, Helga, Pedersen, Bente K., Lu, Wei, Finan, Brian, Jørgensen, Sebastian B., Seeley, Randy J., Kleinert, Maximilian, Kiens, Bente, Richter, Erik A., Clemmensen, Christoffer
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 15.02.2021; Nature Publishing Group; Nature Portfolio
• Subjects: 631/443/319/1557; 64/60; 692/4017; Adult; Animals; Appetite; Appetite Regulation - physiology; Cardiac muscle; Creatine Kinase - blood; Creatine Kinase - genetics; Endurance; Energy balance; Exercise - physiology; Feeding Behavior - physiology; Food intake; Gene Expression Regulation; Glial cell line-derived neurotrophic factor; Glial Cell Line-Derived Neurotrophic Factor Receptors - deficiency; Glial Cell Line-Derived Neurotrophic Factor Receptors - genetics; Growth Differentiation Factor 15 - blood; Growth Differentiation Factor 15 - genetics; Growth Differentiation Factor 15 - metabolism; Homeostasis; Humanities and Social Sciences; Humans; Interleukin-10 - blood; Interleukin-10 - genetics; Interleukin-6 - administration & dosage; Leptin - blood; Leptin - genetics; Liver - drug effects; Liver - metabolism; Male; Mice; Mice, Knockout; Motivation; Motivation - physiology; multidisciplinary; Muscle, Skeletal - drug effects; Muscle, Skeletal - metabolism; Muscles; Myocardium - metabolism; Pharmacology; Physical Conditioning, Animal; Physical Endurance - physiology; Physical training; Physiological effects; Physiology; Science; Science (multidisciplinary); Skeletal muscle; Time Factors
• ISSN: 2041-1723; 2041-1723
• DOI: 10.1038/s41467-021-21309-x

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. The physiological role of GDF15 remains poorly defined. Here, the authors show that circulating GDF15 increases in response to prolonged exercise, but that this exercise-induced GDF15, unlike pharmacological GDF15, does not affect post-exercise food intake or exercise motivation.