BDNF mediates adaptive brain and body responses to energetic challenges

Abstract

Emerging findings suggest that brain-derived neurotrophic factor (BDNF) serves widespread roles in regulating energy homeostasis by controlling patterns of feeding and physical activity, and by modulating glucose metabolism in peripheral tissues. BDNF mediates the beneficial effects of energetic challenges such as vigorous exercise and fasting on cognition, mood, cardiovascular function, and on peripheral metabolism. By stimulating glucose transport and mitochondrial biogenesis BDNF bolsters cellular bioenergetics and protects neurons against injury and disease. By acting in the brain and periphery, BDNF increases insulin sensitivity and parasympathetic tone. Genetic factors, a 'couch potato' lifestyle, and chronic stress impair BDNF signaling, and this may contribute to the pathogenesis of metabolic syndrome. Novel BDNF-focused interventions are being developed for obesity, diabetes, and neurological disorders.

Keywords: Alzheimer's disease; BDNF; diabetes; exercise; glucocorticoid; insulin resistance; learning and memory; obesity.

Figure 1. Mechanisms for the production and release of BDNF

BDNF mRNA is translated into proBDNF protein in the endoplasmic reticulum. ProBDNF is transported into the Golgi and processed to the mature form of BDNF (mBDNF) by extracellular protein convertase 1 (PC1) within the vesicles. The secretory granules are trafficked to the sites of release in the axonal or dendritic terminals. Neurons secrete both proBDNF and mBDNF in an activity-dependent manner. The tissue-type plasminogen activator (tPA) form mBDNF by activating a plasminogen, which then cleaves the precursor molecule. Alternatively, extracellular metalloproteinases process proBDNF to generate mBDNF.

Figure 2. Biological actions of BDNF

When an axon potential reaches the presynaptic terminal of an axon, Na⁺ influx depolarizes the plasma membrane, which triggers Ca²⁺ influx and release of the excitatory neurotransmitter glutamate into the synaptic cleft. Glutamate binds to AMPA and NMDA receptors at the postsynaptic membrane. Activation of the AMPA receptors results in membrane depolarization and Ca²⁺ influx via NMDA and VDCC. Ca²⁺ engages CaMKs that activates CREB and NF-κB which in turn induce the transcription of the Bdnf gene. mBDNF is released at synpases and activates TrkB receptors resulting in activation of downstream signaling cascades including PLCγ, PI3K and MAPKs and subsequent expression of genes critical for the survival and plasticity of neurons. BDNF signaling also elicits rapid effects on membrane excitability and synaptic transmission via altering the activation kinetics of NMDA receptors and increasing the number of docked synaptic vesicles in the presynaptic terminal. Abbreviations: alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic 689 acid (AMPA); N-methyl-D-aspartate (NMDA) receptors; voltage dependent Ca²⁺ channels (VDCC); Ca^2+/calmodulin-dependent kinases (CaMKs); phospholipase Cγ (PLCγ); phosphatidylinositol 3-kinase (PI3K); mitogen-activated protein kinases (MAPKs).

Figure 3. Mechanisms by which BDNF regulates neuronal bioenergetics

Binding of BDNF to trkB results in the activation of phosphatidylinositol-3 kinase (PI3K) and Akt kinase. Akt can activate the mammalian target of rapamycin (mTOR) to stimulate the translation of mRNAs encoding the neuronal glucose transporter GLUT3 and the monocarboxylic acid transporter 2 (MCT2) to enhance cellular uptake of the fuels glucose and lactate. BDNF can also induce Ca²⁺ influx through transient receptor potential C (TRPC) channels. Ca²⁺ then activates a Ca²⁺/calmodulin-dependent protein kinase (CaMK) resulting in the activation of the transcription factor cyclic AMP response element-binding protein (CREB) which, in turn, induces the expression of peroxisome proliferator receptor γ coactivator 1α (PGC-1α). PGC-1α is a master regulator of mitochondrial biogenesis that increases the number of mitochondria in neurons to provide more energy substrates (ATP and NAD⁺) to support the function and adaptive plasticity of the neurons. One energy status-sensitive enzyme that is supported by NAD⁺ is sirtuin-1 (Sirt1), a deacetylase that can activate the transcription factor FOXO3a resulting in the production of the mitochondrial antioxidant enzyme manganese superoxide dismutase (MnSOD). BDNF production is increased in response to bioenergetic challenges such as exercise, intermittent fasting (IF) and cognitive stimulation. By enhancing the uptake of energy substrates, mitochondrial biogenesis and protein synthesis capabilities of neurons, BDNF signaling plays pivotal roles in the adaptive changes in neuronal circuits including synapse formation/modification and neurogenesis (see text for further information).

Figure 4. BDNF is involved in responses of the autonomic nervous system to energy intake and exercise

By increasing the activity of the parasympathetic outflow from brainstem cholinergic neurons in the dorsal motor nucleus of the vagus (DMNV), regular exercise and intermittent fasting (IF) reduce heart rate and blood pressure, increase heart rate variability, and reduce inflammation in the cardiovascular system. Similarly, activation of the parasympathetic input to the gut can enhance motility and reduce local inflammation. BDNF signaling can enhance the activity of brainstem cholinergic neurons, suggesting possible roles for BDNF in the responses of the cardiovascular and gastrointestinal systems to exercise and IF. On the other hand, a sedentary gluttonous lifestyle can increase activity of sympathetic neurons (SN) and reduce BDNF signaling resulting in a relative in reduced parasympathetic tone. As a consequence heart rate and blood pressure are elevated and gut motility is reduced.