Evidence for a release of brain‐derived neurotrophic factor from the brain during exercise

Abstract

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 ...

Chronic treadmill exercise in rats delicately alters the Purkinje cell structure to improve motor performance and toxin resistance in the cerebellum

“…Our laboratory's previous studies have shown that exercise not only transiently elevates BDNF mRNA and protein levels in the hippocampus (13), but also persistently upregulates the hippocampal BDNF receptor TrkB (20,21). Although acute severe exercise in mice failed to increase the BDNF mRNA level in the cerebellum (25), whether chronic moderate exercise has any effect in this regard remains to be clarified. Interestingly, acute and gradual increases in BDNF concentration elicit distinct signaling in cultured neurons and lead to differential effects on neurite morphology (14).…”

Myokines in insulin resistance and type 2 diabetes

“…While in patients with type 2 diabetes circulating levels of BDNF are decreased independently of obesity [47], exercise has been demonstrated to increase serum BDNF levels and BDNF mRNA and protein expression in human skeletal muscle [46]. However, it has been shown in humans that 70-80% of circulating BDNF originates from the brain during both rest and after exercise, suggesting the brain as the major source of this factor [48]. In vitro studies using C2C12 cells have shown that BDNF increases fatty acid oxidation (Table 1) via activation of AMPK and phosphorylation of acetyl-CoA carboxylase [46].…”

Expression of NGF, BDNF and their receptors in subcutaneous adipose tissue of lactating cows

“…In fact, leptin increases the BDNF mRNA expression in VMN, DMN and in other brain areas where BDNF is widely expressed (Komori et al, 2006). According to Pardridge et al (1994) in the rat the mature form of BDNF does not cross the blood-brain barrier, suggesting a paracrine/autocrine activity of this protein in scAT, although other studies reported that about 70% of the BDNF collected from the jugular vein of humans is of brain origin (Rasmussen et al, 2009). It is known that central BDNF enhances energy expenditure through the activation of the sympathetic nervous in rodents (Pelleymounter et al, 1995), however, the central and peripheral activations of the TrkB receptor in reducing the food intake and obesity observed in rodents is not maintained across all species, as monkeys and human (Noble et al, 2011).…”