Brain-derived neurotrophic factor (BDNF) has an important role in regulating maintenance, growth and survival of neurons. However, the main source of circulating BDNF in response to exercise is unknown. To identify whether the brain is a source of BDNF during exercise, eight volunteers rowed for 4 h while simultaneous blood samples were obtained from the radial artery and the internal jugular vein. To further identify putative cerebral region(s) responsible for BDNF release, mouse brains were dissected and analysed for BDNF mRNA expression following treadmill exercise. In humans, a BDNF release from the brain was observed at rest (P < 0.05), and increased two-to threefold during exercise (P < 0.05). Both at rest and during exercise, the brain contributed 70-80% of circulating BDNF, while that contribution decreased following 1 h of recovery. In mice, exercise induced a three-to fivefold increase in BDNF mRNA expression in the hippocampus and cortex, peaking 2 h after the termination of exercise. These results suggest that the brain is a major but not the sole contributor to circulating BDNF. Moreover, the importance of the cortex and hippocampus as a source for plasma BDNF becomes even more prominent in response to exercise. Brain-derived neurotrophic factor (BDNF) is a key protein in regulating maintenance, growth and even survival of neurons (Mattson et al. 2004). Brain-derived neurotrophic factor also influences learning and memory (Tyler et al. 2002), and brain tissue from patients with Alzheimer's disease and clinical depression exhibit low expression of BDNF (Connor et al. 1997;Karege et al. 2002). Brainderived neurotrophic factor has also been identified as a key component of the hypothalamic pathway that controls body weight and energy homeostasis (Wisse & Schwartz, 2003). Obese phenotypes are found in BDNFheterozygous mice and are associated with hyperphagia, hyperleptinaemia, hyperinsulinaemia and hyperglycaemia (Lyons et al. 1999). In addition, BDNF reduces food intake and lowers blood glucose in diabetic mice (Nakagawa et al. 2000). In humans, similar symptoms are associated with * P. Rasmussen and P. Brassard contributed equally to the manuscript. the functional loss of one copy of the BDNF gene and with a mutation in the BDNF receptor Ntrk2 gene (Yeo et al. 2004;Gray et al. 2006).Physically and socially more complex housing leads to increased neurogenesis, improved learning and less weight gain in rats (Young et al. 1999;Cao et al. 2004) associated with consistent up-regulation of BDNF expression, and a direct role for BDNF has recently been reported (Cao et al. 2009). A better understanding of therapeutic actions aimed at increasing BDNF levels, such as exercise (Neeper et al. 1995), is of clinical relevance. It is well known that BDNF synthesis is centrally mediated and activity dependent (Johnson & Mitchell, 2003) and that exercise enhances BDNF transcription in the brain (Oliff et al. 1998). In addition, exercise induces brain uptake of insulin-like growth factor 1, which is a prerequisite for ...

The circulating level of brain-derived neurotrophic factor (BDNF) is reduced in patients with major depression and type-2 diabetes. Because acute exercise increases BDNF production in the hippocampus and cerebral cortex, we hypothesized that endurance training would enhance the release of BDNF from the human brain as detected from arterial and internal jugular venous blood samples. In a randomized controlled study, 12 healthy sedentary males carried out 3 mo of endurance training (n = 7) or served as controls (n = 5). Before and after the intervention, blood samples were obtained at rest and during exercise. At baseline, the training group (58 + or - 106 ng x 100 g(-1) x min(-1), means + or - SD) and the control group (12 + or - 17 ng x 100 g(-1) x min(-1)) had a similar release of BDNF from the brain at rest. Three months of endurance training enhanced the resting release of BDNF to 206 + or - 108 ng x 100 g(-1) x min(-1) (P < 0.05), with no significant change in the control subjects, but there was no training-induced increase in the release of BDNF during exercise. Additionally, eight mice completed a 5-wk treadmill running training protocol that increased the BDNF mRNA expression in the hippocampus (4.5 + or - 1.6 vs. 1.4 + or - 1.1 mRNA/ssDNA; P < 0.05), but not in the cerebral cortex (4.0 + or - 1.4 vs. 4.6 + or - 1.4 mRNA/ssDNA) compared with untrained mice. The increased BDNF expression in the hippocampus and the enhanced release of BDNF from the human brain following training suggest that endurance training promotes brain health.

Non-technical summary Exercise is known to stimulate the production of various exercise factors including the well-described muscle-derived interleukin-6 (IL-6). We show that exercise causes a massive expression of the chemokine CXCL-1 in serum, in skeletal muscle and especially in the liver. Furthermore we find that this exercise-induced liver CXCL-1 expression is regulated by IL-6 and that muscle-derived IL-6 is capable of stimulating liver CXCL-1 expression. Such knowledge of the regulation of exercise factors contributes to the understanding of how the liver and muscle communicate in response to exercise. AbstractThe chemokine CXC ligand-1 (CXCL-1) is a small cytokine that elicits effects by signalling through the chemokine receptor CXCR2. CXCL-1 has neutrophil chemoattractant activity, is involved in the processes of angiogenesis, inflammation and wound healing, and may possess neuroprotective effects. The aim of this study was to unravel the mechanisms whereby CXCL-1 is regulated by exercise in mice. After a single bout of exercise, CXCL-1 protein increased in serum (2.4-fold), and CXCL-1 mRNA in muscle (6.5-fold) and liver (41-fold). These increases in CXCL-1 were preceded by increases in serum interleukin-6 (IL-6) and muscle IL-6 mRNA. In contrast, exercise-induced regulation of liver CXCL-1 mRNA expression was completely blunted in IL-6 knockout mice. Based on these findings, we examined the possible existence of a muscle-to-liver axis by overexpressing IL-6 in muscles. This resulted in increases in serum CXCL-1 (5-fold) and liver CXCL-1 mRNA expression (24-fold) compared with control. Because IL-6 expression and release are known to be augmented during exercise in glycogen-depleted animals, CXCL-1 and IL-6 expression were examined after exercise in overnight-fasted mice. We found that fasting significantly augmented serum CXCL-1, and CXCL-1 expression in liver and muscle. Taken together, these data indicate that liver is the main source of serum CXCL-1 during exercise in mice, and that the CXCL-1 expression in the liver is regulated by muscle-derived IL-6. Abbreviations CXCL-1, chemokine ligand 1; IL, interleukin; KO, knockout; WT, wild-type.

The aim of this study was to test whether the transcriptional coactivator peroxisome proliferator-activated receptor (PPAR)-␥ coactivator (PGC)1␣ regulates the content of pyruvate dehydrogenase (PDH)-E1␣ and influences PDH activity through regulation of pyruvate dehydrogenase kinase-4 (PDK4) expression and subsequently PDH phosphorylation. PGC-1␣ whole body knockout (KO), muscle-specific PGC-1␣ overexpressing mice (MCK PGC-1␣), and littermate wild-type (WT) mice underwent two interventions known to affect PDH. Quadriceps muscles were removed from fed and 24-h fasted mice as well as at 6 h of recovery after 1-h running and from mice that did not run acutely. PDH-E1␣ protein content and PDH-E1␣ phosphorylation were lower in PGC-1␣ KO and higher in MCK PGC-1␣ mice at rest, but, while MCK PGC-1␣ had higher PDK4 protein content, KO of PGC-1␣ had no effect on PDK4 protein content. The differences in phosphorylation partly vanished when expressing phosphorylation relative to the PDH-E1␣ content with only a maintained elevated phosphorylation in MCK PGC-1␣ mice. Fasting upregulated PDK4 protein in PGC-1␣ KO, MCK PGC-1␣ and WT mice, but this was not consistently associated with increased PDH-E1␣ phosphorylation. Downregulation of the activity of PDH in the active form (PDHa) at 6-h recovery from exercise in both the PGC-1␣ KO and MCK PGC-1␣ mice and the association between PDH-E1␣ phosphorylation and PDHa activity in PGC-1␣ KO mice indicate that PGC-1␣ is not required for these responses. In conclusion, PGC-1␣ regulates PDH-E1␣ protein content in parallel with mitochondrial oxidative proteins, but does not seem to influence PDH regulation in mouse skeletal muscle in response to fasting and in recovery from exercise. pyruvate dehydrogenase kinase THE TRANSCRIPTIONAL COACTIVATOR peroxisome proliferator-activated receptor (PPAR)-␥ coactivator (PGC)1␣ has been shown to influence the oxidative capacity of skeletal muscle through both regulation of mitochondrial biogenesis (24,38) and capillarization of skeletal muscle (1,22). Thus, PGC-1␣ knockout (KO) mice have reduced capillarization and decreased expression of proteins in oxidative metabolism in skeletal muscle (23,25), while PGC-1␣ overexpression mice have increased capillarization and increased expression of oxidative enzymes in skeletal muscle (24,47). In accordance with these effects on skeletal muscle oxidative capacity, PGC-1␣ KO mice have lower endurance exercise capacity and muscle-specific PGC-1␣ overexpression (MCK PGC-1␣) mice have improved endurance exercise capacity relative to wildtype (WT) mice (5,11,23). These effects on exercise performance may, however, not only be due to PGC-1␣-induced effects on oxidative capacity, but also in part be due to PGC-1␣-mediated regulation of substrate choice. This possibility is supported by the findings that MCK PGC-1␣ overexpression mice exhibit lower respiratory exchange ratio during treadmill running reflecting higher fat oxidation (5). The molecular mechanisms behind this have, however, not yet been clarified.The pyruv...