Exercise Induces Hippocampal BDNF through a PGC-1α/FNDC5 Pathway

Abstract

SUMMARY Exercise can improve cognitive function and has been linked to the increased expression of brain-derived neurotrophic factor (BDNF). However, the underlying molecular mechanisms driving the elevation of this neurotrophin remain unknown. Here we show that FNDC5, a previously identified muscle protein that is induced in exercise and is cleaved and secreted as irisin, is also elevated by endurance exercise in the hippocampus of mice. Neuronal Fndc5 gene expression is regulated by PGC-1α and Pgc1a−/− mice show reduced Fndc5 expression in the brain. Forced expression of FNDC5 in primary cortical neurons increases Bdnf expression, whereas RNAi-mediated knockdown of FNDC5 reduces Bdnf. Importantly, peripheral delivery of FNDC5 to the liver via adenoviral vectors, resulting in elevated blood irisin, induces expression of Bdnf and other neuroprotective genes in the hippocampus. Taken together, our findings link endurance exercise and the important metabolic mediators, PGC-1α and FNDC5, with BDNF expression in the brain.

Irisin and FNDC5: effects of 12-week strength training, and relations to muscle phenotype and body mass composition in untrained women

“…This notion is supported in the literature by an elevated expression of FNDC5 in oxidative muscles in rodents (Wrann et al 2013;Roca-Rivada et al 2013). This may be linked to the fact that low-intensity every-day activities such as walking, which preferentially activate type 1 fibers, may lead to increased nuclear translocation of PGC1α, in turn leading to the observed fiber-specific FNDC5 expression.…”

“…In fact, an association with traits such as muscle fiber composition seems likely, as its transcriptional regulator PGC-1α has been suggested to show muscle fiber-specific expression, being associated with slow fibers in rodents (Lin et al 2002) and also in humans (Krämer et al 2006), though the latter remains controversial (Plomgaard et al 2006;Norrbom et al 2004). An association between FNDC5 expression and aerobic fibers has indeed been indicated in rodents (Wrann et al 2013;Roca-Rivada et al 2013). Such an association may shed light on the previously observed individual variation in FNDC5/s-irisin abundances (Timmons et al 2012;Boström et al 2012;Pekkala et al 2013;Huh et al 2012).…”

PPARγ-coactivator-1α gene transfer reduces neuronal loss and amyloid-β generation by reducing β-secretase in an Alzheimer’s disease model

“…In line with our findings was the report showing that exerciseinduced BDNF expression was mediated by PGC-1α regulation of Fndc5 gene expression (20). Moreover, PPARγ and PPARα, the main transcription factors regulated by PGC-1α, induced the transcription of BDNF in cultured neurons and glial cells (21,22).…”

Exercise regulation of adipose tissue

“…While it is clear that increased activation of this pathway (PGC1a/FNDC5/BDNF) results in an increase in beiging of scWAT, it is not clear whether the increase is a result of the increased circulating irisin, or of the resultant increase in BDNF. 60 Taken together, these studies indicate that there are several secreted factors that have been reported to contribute to the exercise-induced beiging of scWAT. How these molecules interact, as well as how they may be regulated in response to exercise in humans, is still a subject of much interest and investigation.…”

“…25 In another study, endurance exercise by 30 d of voluntary wheel-cage running significantly increased Fndc5 expression in the brain, corresponding with in increased hippocampal BDNF. 60 This increase was impaired in Pgc1a -/-mice, 60 indicating that the increase in BDNF was mediated through the PGC1a/FNDC5 pathway. It had been previously shown that increased FNDC5 27 leads to increased irisin, which increases the beiging of scWAT.…”