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 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.

GDF15 is an exercise-induced hepatokine regulated by glucagon and insulin in humans

“…Besides exercise, a physiological increase of plasma GDF15 is observed during pregnancy ( 3 , 48 ), which also seems contradictory with a suppression in appetite, in the light of the increased energy requirements during development and growth of the fetus. Interestingly at least in mice, physiologically elevated GDF15 by exercise does not inhibit appetite or suppress wheel running activity whereas pharmacologically elevated GDF15 in mice does ( 49 ). This suggests that the role of physiological elevated GDF15 in human physiology is unclear and has yet to be identified.…”

Growth differentiation factor 15 increases in both cerebrospinal fluid and serum during pregnancy

“…(1-3) GDF15 has for example been shown to induce weight loss (probably through appetite suppression and decreased food intake), affect energy expenditure and motivation to exercise, and improve glucose tolerance. (4)(5)(6)(7)(8)(9) Research interest has recently grown regarding GDF15 during pregnancy as substantial and progressive increases in serum GDF15 have been shown from early to late pregnancy, ending up with serum levels much higher than in any other physiological or pathophysiological state. (10)(11)(12)) Pregnancy is marked by major metabolic and physiological changes, such as increases in appetite, body weight, insulin resistance and inflammation.…”

“…(1–3) GDF15 has for example been shown to induce weight loss (probably through appetite suppression and decreased food intake), affect energy expenditure and motivation to exercise, and improve glucose tolerance. (4–9)…”