TY - JOUR
T1 - Pharmacological but not physiological GDF15 suppresses feeding and the motivation to exercise
AU - Klein, Anders B
AU - Nicolaisen, Trine S
AU - Ørtenblad, Niels
AU - Gejl, Kasper D
AU - Jensen, Rasmus
AU - Fritzen, Andreas M
AU - Larsen, Emil L
AU - Karstoft, Kristian
AU - Poulsen, Henrik E
AU - Morville, Thomas
AU - Sahl, Ronni E
AU - Helge, Jørn W
AU - Lund, Jens
AU - Falk, Sarah
AU - Lyngbæk, Mark
AU - Ellingsgaard, Helga
AU - Pedersen, Bente K
AU - Lu, Wei
AU - Finan, Brian
AU - Jørgensen, Sebastian B
AU - Seeley, Randy J
AU - Kleinert, Maximilian
AU - Kiens, Bente
AU - Richter, Erik A
AU - Clemmensen, Christoffer
PY - 2021/2/15
Y1 - 2021/2/15
N2 - 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.
AB - 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.
KW - Adult
KW - Animals
KW - Appetite Regulation/physiology
KW - Creatine Kinase/blood
KW - Exercise/physiology
KW - Feeding Behavior/physiology
KW - Gene Expression Regulation
KW - Glial Cell Line-Derived Neurotrophic Factor Receptors/deficiency
KW - Growth Differentiation Factor 15/blood
KW - Humans
KW - Interleukin-10/blood
KW - Interleukin-6/administration & dosage
KW - Leptin/blood
KW - Liver/drug effects
KW - Male
KW - Mice
KW - Mice, Knockout
KW - Motivation/physiology
KW - Muscle, Skeletal/drug effects
KW - Myocardium/metabolism
KW - Physical Conditioning, Animal
KW - Physical Endurance/physiology
KW - Time Factors
UR - http://www.scopus.com/inward/record.url?scp=85101481595&partnerID=8YFLogxK
U2 - 10.1038/s41467-021-21309-x
DO - 10.1038/s41467-021-21309-x
M3 - Journal article
C2 - 33589633
SN - 2041-1723
VL - 12
SP - 1041
JO - Nature Communications
JF - Nature Communications
IS - 1
M1 - 1041
ER -