BDNF (I)rising from exercise

Abstract

Exercise produces many beneficial effects on brain health, in part by increasing hippocampal BDNF levels; however, the mechanism underlying BDNF gene regulation remains unknown. In this issue of Cell Metabolism, Wrann et al. (2013) show that exercise induces hippocampal Bdnf expression by stimulating expression of FNDC5, the precursor of irisin, via the transcriptional complex PGC-1α/Errα.

Figure 1. Biochemical pathways that mediate exercise-induced Bdnf gene expression in the hippocampus

Red arrow pathway: Exercise increases expression of transcriptional co-activator PGC-1α in hippocampal neurons through an unknown mechanism. Elevated PGC-1α levels boost expression of its binding partner ERRα and thus increase the amount of the transcriptional complex PGC-1α/ERRα, which enhances Fndc5 gene expression. FNDC5 is a type I membrane protein, and its proteolytic product, termed exercise factor (EF) here, is released to the extracellular matrix. EF likely binds to its receptor and activates an unidentified signaling cascade via an autocrine or paracrine mode, which induces Bdnf gene expression through an unknown transcription factor. Increased BDNF levels will improve the health and function of the hippocampus. Interestingly, elevated BDNF-TrkB signaling negatively regulates Fndc5 gene expression, thus forming a homeostatic FNDC5/BDNF feedback loop. Green arrow pathway: Exercise also stimulates production and release of EF in skeletal muscle, and the released EF is distributed throughout the body via circulation. The circulating EF can bind to its receptor on hippocampal neurons and induce Bdnf gene expression there. Blue arrow pathway: It is possible that the circulating EF could stimulate expression of PGC-1α and increase Fndc5 gene expression in hippocampal neurons, thus forming an EF amplification loop.