BDNF mediates adaptive brain and body responses to energetic challenges

doi:10.1016/j.tem.2013.10.006

Trends in Endocrinology & Metabolism

Volume 25, Issue 2, February 2014, Pages 89-98

https://doi.org/10.1016/j.tem.2013.10.006 Get rights and content

Highlights

•
Energetic challenges (e.g., exercise and energy restriction) induce BDNF signaling.
•
BDNF enhances neuronal bioenergetics and promotes optimal brain health.
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BDNF signaling improves peripheral energy metabolism and cardiovascular function.
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Deficits in BDNF may contribute to metabolic morbidity and associated diseases.

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.

Section snippets

BDNF is a central regulator of energy homeostasis

BDNF, a member of the neurotrophin family of proteins, plays crucial roles in the development, maintenance, and plasticity of the central and peripheral nervous systems [1]. BDNF promotes the differentiation of neurons from stem cells, enhances neurite outgrowth and synaptogenesis, and can prevent programmed cell death/apoptosis. BDNF is expressed in neurons throughout the developing and adult mammalian nervous system, wherein it is produced in relatively low amounts but is highly potent,

BDNF synthesis, processing, and signaling

BDNF is synthesized as a pre-proneurotrophin that is cleaved into proBDNF and further processed to mature mBDNF (Figure 1). ProBDNF is converted to biologically active mBDNF by furin and proconvertases within secretory vesicles before release [1]. Neurons also release proBDNF, which is converted by the tissue plasminogen activator (tPA)/plasmin system to mBDNF [1]. The expression and release of BDNF are stimulated by excitatory synaptic activity and by particular neuropeptides and hormones [3].

Linking energy availability and physical activity to cognitive function

BDNF signaling may have evolved to play a role in cognition-enhancing effects of running and intermittent food deprivation [9]. Indeed, rodent and human studies show that cognitive function is enhanced by running and intermittent fasting, and BDNF may play a role in this [10]. Rats and mice will voluntarily run as much as 10–15 km in a 24 h period on a running wheel and, compared to more sedentary rodents, runners exhibit improved performance in tests of spatial learning and memory 11, 12. BDNF

Cellular bioenergetics and neuroplasticity

The activation of synapses and ‘firing’ of action potentials to propagate signals along axons are fundamental mechanisms by which neurons perform their functions; the amount of energy required to support this ongoing activity of neurons is considerably greater than in other cell types [30]. The major energy substrates utilized by neurons to generate the ATP and NAD⁺ required to support their diverse biochemical processes are glucose and ketones. BDNF can enhance neuronal ATP production in

BDNF signaling regulates energy metabolism

Whereas mice lacking BDNF die shortly after birth with severe abnormalities in their nervous system, BDNF haploinsufficient mice are hyperphagic, obese, and diabetic [43], and mice lacking BDNF in hippocampal and forebrain neurons develop obesity and an anxiety disorder [44]. Similarly, targeted deletion in mice of BDNF in the dorso- and ventro-medial hypothalamus results in increased food intake and obesity [45]. By contrast, fasting induces BDNF expression in the brain [46], and BDNF

Potential role for BDNF signaling in the regulation of heart rate

Heart-rate regulation is often linked strongly to metabolic status, such that exercise and energy restriction reduce resting heart rate and blood pressure by increasing parasympathetic tone, whereas obesity promotes elevated heart rate and blood pressure by increasing sympathetic tone. BDNF has emerged as a factor playing a role in the adaptive plasticity of the heart and the regulation of heart rate via the autonomic nervous system (ANS). Yang et al. [63] reported that, when ANS neurons are

Implications for the prevention and treatment of metabolic syndrome and associated diseases

The findings from studies of animal models and human subjects described above suggest roles for BDNF in some of the beneficial effects of exercise and energy restriction on brain and body. Interventions that target BDNF signaling are therefore being developed for a range of metabolic and neurological disorders (Table 1). BDNF or TrkB agonists can be administered peripherally, but this approach risks many adverse side effects because of the widespread pattern of TrkB expression. One example of

Concluding remarks and future perspectives

Emerging findings suggest that BDNF is a crucial player in adaptive responses of the brain and body to metabolic challenges such as intermittent fasting and exercise, as well as to intellectual challenges (see Box 3). Produced in a neuronal activity-dependent manner, BDNF signaling enhances synaptic plasticity and promotes neurogenesis, and may thereby mediate the beneficial effects of intermittent energetic challenges on cognition and mood. Activation of the BDNF receptor TrkB bolsters

Acknowledgments

This work was supported by the intramural research program of the National Institute on Aging. We thank KC (Kristen) Alexander for preparing the illustrations for Figures 1 and 2.

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/Objective. An explosion in global obesity epidemic poses threats to the healthcare system by provoking risks of many debilitating diseases, including cognitive dysfunction. Physical activity has been shown to alleviate the deleterious effects of obesity-associated cognitive deficits across the lifespan. Given the strong neuroprotective role of brain-derived neurotrophic factor (BDNF) and exercise training as a known modulator for its elevation, this systematic review sought to examine the strength of the association between exercise and BDNF levels in healthy people with overweight and obesity.
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Published by Elsevier Inc.

Trends in Endocrinology & Metabolism

ReviewBDNF mediates adaptive brain and body responses to energetic challenges

Highlights

Section snippets

BDNF is a central regulator of energy homeostasis

BDNF synthesis, processing, and signaling

Linking energy availability and physical activity to cognitive function

Cellular bioenergetics and neuroplasticity

BDNF signaling regulates energy metabolism

Potential role for BDNF signaling in the regulation of heart rate

Implications for the prevention and treatment of metabolic syndrome and associated diseases

Concluding remarks and future perspectives

Acknowledgments

Auton. Neurosci.

Ageing Res. Rev.

Cell Metab.

Neuroscience

Neuroscience

Neurobiol. Learn. Mem.

Physiol. Behav.

Brain Res.

Neuroscience

Physiol. Behav.

Neurobiol. Aging

Neuroscience

Cell Metab.

Mol. Brain Res.

Mech. Ageing Dev.

Neuron

Trends Neurosci.

Neuroscience

Exp. Neurol.

Metabolism

Cell Metab.

J. Nutr.

Brain Res.

Neuron

Brain Res.

Neurobiol. Dis.

Neurobiol. Dis.

Lancet

Free Radic. Biol. Med.

Neurotrophin signalling in health and disease

Clin. Sci. (Lond.)

Tissue-specific and neural activity-regulated expression of human BDNF gene in BAC transgenic mice

BMC Neurosci.

Preconditioning and neurotrophins: a model for brain adaptation to seizures, ischemia and other stressful stimuli

Amino Acids

Distinct subsets of Syt-IV/BDNF vesicles are sorted to axons versus dendrites and recruited to synapses by activity

J. Neurosci.

Involvement of PGC-1α in the formation and maintenance of neuronal dendritic spines

Nat. Commun.

Role of neurotrophins in the development and function of neural circuits that regulate energy homeostasis

J. Mol. Neurosci.

Hippocampal BDNF mediates the efficacy of exercise on synaptic plasticity and cognition

Eur. J. Neurosci.

Running induces widespread structural alterations in the hippocampus and entorhinal cortex

Hippocampus

Running is the neurogenic and neurotrophic stimulus in environmental enrichment

Learn. Mem.

Exercise increases BDNF levels in the striatum and decreases depressive-like behavior in chronically stressed rats

Metab. Brain Dis.

Caloric restriction enhances fear extinction learning in mice

Neuropsychopharmacology

Recruiting adaptive cellular stress responses for successful brain ageing

Nat. Rev. Neurosci.

Brain-derived neurotrophic factor uses CREB and Egr3 to regulate NMDA receptor levels in cortical neurons

J. Neurochem.

Brain-derived neurotrophic factor stimulates energy metabolism in developing cortical neurons

J. Neurosci.

Brain-derived neurotrophic factor-mediated effects on mitochondrial respiratory coupling and neuroprotection share the same molecular signalling pathways

Eur. J. Neurosci.

Forkhead transcription factor FOXO3a protects quiescent cells from oxidative stress

Nature

Brain-derived neurotrophic factor enhances the expression of the monocarboxylate transporter 2 through translational activation in mouse cultured cortical neurons

J. Cereb. Blood Flow Metab.

Brain-derived neurotrophic factor induces mammalian target of rapamycin-dependent local activation of translation machinery and protein synthesis in neuronal dendrites

J. Neurosci.

Review
BDNF mediates adaptive brain and body responses to energetic challenges