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 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.

Fig. 1. Effect of exercise on circulating GDF15 in humans.

a Plasma GDF15 values before and after 1 h of high-intensity resistance (n = 10) or vigorous endurance exercise (n = 10) and at indicated time points during recovery (p < 0.001). b Plasma GDF15 levels were measured in highly trained elite male triathletes (n = 15) bicycling at 73 ± 1% of maximal heart rate (HR_max) for 4 h, with blood sampling as indicated immediately before, during, and in recovery from exercise (p < 0.001), with one missing value at 28 h. c Plasma GDF15 levels measured before and after a marathon (42.195 km); completing time was 243 ±  8 min [mean ± SEM] (4 h on the figure), with additional measurements of GDF15 on day 2–5 (p < 0.001) and day 9–10 after the marathon (on day 4 and day 9) (n = 20). d On three separate occasions, under three different dietary regimes as indicated, subjects performed cycling exercise at 75% of maximal oxygen uptake (VO_2max) until exhaustion. GDF15 plasma levels were measured pre-exercise and at exhaustion on each occasion (n = 11; standard diet, p < 0.001; low-carb diet, p = 0.0064; high-carb diet, p < 0.001; one missing value in the high-carb group post-exercise). e Relationship between change in GDF15 values (ΔGDF15) and time to exhaustion for the diet-exercise interventions presented in d. f Relationship between change in GDF15 values (ΔGDF15) (from c.) and Δcreatine kinase pre vs. post marathon. g Relationship between change in GDF15 values (ΔGDF15) (from c) with ΔIL-10 plasma values pre vs. post marathon. Data are presented as mean ±  SEM, *P < 0.05; **P < 0.01; ***P < 0.001 compared to time-point 0 or as indicated. a Repeated measures two-way ANOVA with Bonferroni multiple comparisons test. b and c Repeated measures One-way ANOVA relative to starting time, d Two-tailed paired t tests for each exercise–diet trial. Source data are provided as a Source Data file.

Fig. 2. Effect of physiological metabolic stressors on circulating GDF15 in mice and humans.

a Plasma GDF15 levels were measured in mice exposed to forced treadmill running until exhaustion (n = 7) compared to cage-matched sedentary controls (n = 8; p < 0.001). b Fold-change in circulating GDF15 after exhaustive endurance running in mice (based on Fig. 2a) vs. humans (based on Fig. 1c). c–e Relative mRNA levels of indicated genes in liver (Aft6, p = 0.0090; Xbp1s, p = 0.0301), heart (Gdf15, p = 0.0375; Aft4, p = 0.0229; Xbp1s, p = 0.0040), and skeletal muscle (soleus) (Atf4, p = 0.0402; Xbp1s, p = 0.0053) after forced treadmill running until exhaustion (n = 8) compared to cage-matched sedentary controls (n = 8; liver, n = 7). f Circulating GDF15 levels in mice following 3 weeks of voluntary running vs. non-running controls (n = 8) measured in plasma sampled 2 h into the dark phase. g Circulating GDF15 levels in mice after 24 h fasting (n = 9; p = 0.0384) compared to ad libitum fed mice (n = 8). h Circulating GDF15 levels in mice in response to 24 h of ad libitum, high-fat diet exposure compared to aged-matched control mice kept on chow diet (n = 6; p = 0.0202). i Circulating GDF15 levels in mice acclimatized to thermoneutrality (30 °C), kept at room temperature (22 °C), or mice exposed to chronic cold (4 °C) for 3 weeks (n = 8; 30 °C, n = 7; 30 °C vs. 22 °C, p = 0.0036; 30 °C vs. 4 °C, p < 0.001). j–m Plasma GDF15, GLP-1 (p = 0.0153), ghrelin (p < 0.001), and leptin (p = 0.0256) concentrations at indicated time points before, during, and after short-term overfeeding (6000 kcal in 14 h) in young healthy male human subjects (n = 5). Data are presented as mean ±  SEM, *P < 0.05; **P < 0.01; ***P < 0.001. a–h Two-tailed unpaired t test, except for Gdf15 in c, where a Mann–Whitney test was applied. i Repeated measures One-way ANOVA. j–m Two-tailed paired t test between peak time-point for OF vs. corresponding ad lib time-point. Source data are provided as a Source Data file.

Fig. 3. Effects of pharmacological GDF15 and exercise-induced GDF15 on food intake and running behavior.

a, b Effect of single subcutaneous injection of rhGDF15 (8 nmol/kg bw, n = 8) or vehicle (n = 7) on forced treadmill running until exhaustion in mice. c Effect of single subcutaneous injection of rhGDF15 (8 nmol/kg bw, n = 16) or vehicle (n = 16) administered at the onset of the dark cycle on voluntary wheel running distance (2 h, p = 0.0210; 4 h, p = 0.0075; 6 h, p = 0.0036). d, e Effect of daily subcutaneous injections (at the onset of the dark cycle) of rhGDF15 (8 nmol/kg bw, n = 14) or vehicle (n = 14) on voluntary wheel running (day 1, p = 0.0140; day 4, p = 0.0042; day 5, p < 0.001; day 6, p < 0.001; day 7, p < 0.001) and food intake (day 1, p = 0.0032). f, g Effect of single subcutaneous injection of rhGDF15 (8 nmol/kg bw) or vehicle on voluntary wheel running in WT (vehicle n = 6; rhGDF15 n = 6, p = 0.0308) and GFRAL KO (vehicle n = 7; rhGDF15 n = 8) mice. h, i Forced treadmill running to exhaustion in WT (n = 8) and GFRAL KO (n = 8) mice. j Voluntary wheel running distance in WT (n = 12) and GFRAL KO (n = 16) mice k Plasma GDF15 values were measured after forced exercise to exhaustion on treadmill in WT (n = 13) and GFRAL KO (n = 11) mice. l Effect of forced exhaustive treadmill exercise on voluntary wheel running (VWR) in WT (n = 4 sedentary vs. n = 4 forced exercise, p = 0.0261) and GFRAL KO (n = 4 sedentary vs. n = 4 forced exercise, p = 0.0134) mice. m Effect of forced exhaustive treadmill exercise on chow in WT (n = 8) and GFRAL KO (n = 8) mice, and n HFD intake in WT (n = 7) and GFRAL KO (n = 7) mice. Data are presented as mean ±  SEM, *P < 0.05; **P < 0.01; ***P < 0.001. b, g, i, j, l, m, n Two-tailed unpaired t test. c, d, e, k, Repeated measures two-way ANOVA with Bonferroni multiple comparisons test. Source data are provided as a Source Data file.