The Novo Nordisk Foundation (NNF17OC0026114) and the Lundbeck Foundation (R238-2016-2859).

Highlights d Exercise-mode-specific metabolomes enabled by a randomized crossover design d Temporal information on plasma metabolome dynamics d Cluster and pathway analyses reveal mode-linked changes in plasma metabolites d Metabolites with hormone-like signaling properties are regulated by exercise

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.

No abstract

Aim & Methods: Extreme endurance exercise provides a valuable research model for understanding the adaptive metabolic response of older and younger individuals to intense physical activity. Here, we compare a wide range of metabolic and physiologic parameters in two cohorts of seven trained men, age 30 ± 5 years or age 65 ± 6 years, before and after the participants travelled ≈3000 km by bicycle over 15 days. Results: Over the 15-day exercise intervention, participants lost 2-3 kg fat mass with no significant change in body weight. VȮ 2 max did not change in younger cyclists, but decreased (p = 0.06) in the older cohort. The resting plasma FFA concentration decreased markedly in both groups, and plasma glucose increased See related editorial: Henriksson J. 2022. Extreme duration endurance exercise affects old and younger men differently-Older individuals experience a negative adaptive response affecting cardiovascular function. Acta Physiol (Oxf). e13843.

No abstract

Introduction Maximal fat oxidation rate (MFO) is higher in aerobically fit vs. unfit young men, but this training related increase in MFO is attenuated in middle-aged men. Further, it has also been found that unfit men with obesity may have an elevated MFO compared to unfit normal-weight men. Aim/Hypothesis Based hereupon, we aimed to investigate whether a fitness related higher MFO were attenuated in middle-aged women compared to young women. Also, we aimed to investigate if unfit women with obesity have a higher MFO compared to unfit normal-weight women. We hypothezised that the training related elevated MFO was attenuated in middle-aged women, but that unfit women with obesity would have an elevated MFO compared to unfit normal-weight women. Methods We recruited a total of 70 women stratified into six groups: Young fit (n=12), young unfit (n=12) middle-aged fit (n=12), middle-aged unfit (n=12), unfit young women with obesity (n=12) and unfit middle-aged women with obesity (n=10). Body composition and resting blood samples were obtained and MFO was measured by a graded exercise test on a cycle ergometer via indirect calorimetry. Subsequently, a maximal exercise test was performed to establish V̇O2peak. Results Young and middle-aged fit women had a higher MFO compared to age-matched unfit women, and young fit women had a higher MFO compared to fit middle-aged women. Unfit women with obesity, independent of age, had a higher MFO compared to their normal-weight and unfit counterparts. Conclusion The training related increase in MFO seems maintained in middle-aged women and secondly, we find that unfit women with obesity, independent of age have a higher MFO compared to unfit normal-weight women.

Introduction/Purpose: A number of studies have investigated the effect of training with a moderate exercise dose (3–6 h/weekly) on the inflammatory profile in blood, and the data are inconsistent. Cross-sectional studies indicate a positive effect of physical activity level on inflammation levels and risk of metabolic disease. However, it is not clear whether this may be dose dependent and if very prolonged repeated exercise therefore may be beneficial for low-grade inflammation. Based on this we studied how excessive repeated prolonged exercise influenced low-grade inflammation and adipose tissue anti-inflammatory macrophage content in six older male recreationally trained cyclists. Low-grade inflammation and adipose tissue macrophage content were investigated in six older trained men (age: 61 ± 4 years; VO2peak: 48 ± 2 mL kg−1 min−1) following repeated prolonged exercise.Methods: Cycling was performed daily for 14 days covering in total 2,706 km (1,681 miles). Maximal oxygen uptake (VO2peak) was measured before and after the cycling. Duration and intensity of the exercise were determined from heart rates sampled during cycling. An adipose tissue biopsy from subcutaneous abdominal fat and a blood sample were obtained at rest in the overnight fasted state before and after the cycling. Anti-inflammatory adipose tissue macrophages (ATM) were immunohistochemically stained in cross sectional sections using a CD163 binding antibody. The ATM and adipocyte sizes were analyzed blindly.Results: The cyclists exercised daily for 10 h and 31 ± 37 min and average intensity was 53 ± 1% of VO2peak. Body weight remained unchanged and VO2peak decreased by 6 ± 2% (P = 0.04). Plasma inflammatory cytokines, TNFα and IL-18 remained unchanged, as did hsCRP, but plasma IL-6 increased significantly. CD163 macrophage content remained unchanged, as did adipocyte cell size. The HbA1c was not significantly decreased, but there was a trend (P < 0.07) toward an increased insulin resistance as estimated by the Quicki Index.Conclusion: The regular prolonged exercise did not influence abdominal adipose tissue inflammation, but the higher plasma IL-6 concentration concurrent with a trend toward higher insulin resistance and decreased VO2peak implies that the excessive amount of exercise probably attenuated the possible potential anti-inflammatory effects of exercise.