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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 ?-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.

SUBMITTER: Klein AB

PROVIDER: S-EPMC7884842 | biostudies-literature | 2021 Feb

REPOSITORIES: biostudies-literature

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

Klein Anders B AB Nicolaisen Trine S TS Ørtenblad Niels N Gejl Kasper D KD Jensen Rasmus R Fritzen Andreas M AM Larsen Emil L EL Karstoft Kristian K Poulsen Henrik E HE Morville Thomas T Sahl Ronni E RE Helge Jørn W JW Lund Jens J Falk Sarah S Lyngbæk Mark M Ellingsgaard Helga H Pedersen Bente K BK Lu Wei W Finan Brian B Jørgensen Sebastian B SB Seeley Randy J RJ Kleinert Maximilian M Kiens Bente B Richter Erik A EA Clemmensen Christoffer C

Nature communications 20210215 1

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 ...[more]

PMID: 33589633

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Project description:ObjectiveExercise training has several well-established health benefits, including many related to body weight, appetite control, and blood glucose homeostasis. However, the molecular mechanisms and, in particular, the hormonal systems that mediate and integrate these beneficial effects are poorly understood. In the current study, we aimed to investigate the role of the hormone ghrelin and its receptor, the growth hormone secretagogue receptor (GHSR; ghrelin receptor), in mediating the effects of exercise on food intake and blood glucose following exercise as well as in regulating exercise endurance capacity.MethodsWe used two mouse models of treadmill running to characterize the changes in plasma ghrelin with exercise. We also assessed the role of the ghrelin system to influence food intake and blood glucose after exercise, exercise endurance, and parameters potentially linked to responses to exercise. Mice lacking GHSRs (GHSR-null mice) and wild-type littermates were studied.ResultsAn acute bout of exercise transiently elevated plasma acyl-ghrelin. Without the action of this increased ghrelin on GHSRs (as in GHSR-null mice), high intensity interval exercise markedly reduced food intake compared to control mice. The effect of exercise to acutely raise blood glucose remained unmodified in GHSR-null mice. Exercise-induced increases in plasma ghrelin positively correlated with endurance capacity, and time to exhaustion was reduced in GHSR-null mice as compared to wild-type littermates. In an effort to mechanistically explain their reduced exercise endurance, exercised GHSR-null mice exhibited an abrogated sympathoadrenal response, lower overall insulin-like growth factor-1 levels, and altered glycogen utilization.ConclusionsExercise transiently increases plasma ghrelin. GHSR-null mice exhibit decreased food intake following high intensity interval exercise and decreased endurance when submitted to an exercise endurance protocol. These data suggest that an intact ghrelin system limits the capacity of exercise to restrict food intake following exercise, although it enhances exercise endurance.

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

Publications

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

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