Trends in Endocrinology & Metabolism
ReviewBDNF mediates adaptive brain and body responses to energetic challenges
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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