Role of exercise‐induced brain‐derived neurotrophic factor production in the regulation of energy homeostasis in mammals

Pedersen, Bente Klarlund; Pedersen, Maria; Krabbe, K. S.; Bruunsgaard, Helle; Matthews, Vance B.; Febbraio, Mark A.

doi:10.1113/expphysiol.2009.048561

Cited by 223 publications

(158 citation statements)

References 52 publications

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“…For example, BDNF/TrkB signaling could contribute to enhanced cardiac performance during exercise. In fact, exercise augments BDNF levels in the brain, the skeletal muscle, and plasma, enhancing function and improving energy metabolism in these organs (21,22). Our present findings may also provide a potential explanation for recent clinical reports showing that in heart failure patients, a correlation exists between low circulating levels of BDNF and worsening of symptoms (23,24).…”

Section: Discussionsupporting

confidence: 58%

Constitutive BDNF/TrkB signaling is required for normal cardiac contraction and relaxation

Feng

Huke

Zhu

et al. 2015

Autonomic Neuroscience

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BDNF and its associated tropomyosin-related kinase receptor B (TrkB) nurture vessels and nerves serving the heart. However, the direct effect of BDNF/TrkB signaling on the myocardium is poorly understood. Here we report that cardiac-specific TrkB knockout mice (TrkB −/− ) display impaired cardiac contraction and relaxation, showing that BDNF/TrkB signaling acts constitutively to sustain in vivo myocardial performance. BDNF enhances normal cardiomyocyte Ca 2+ cycling, contractility, and relaxation via Ca 2+ /calmodulindependent protein kinase II (CaMKII). Conversely, failing myocytes, which have increased truncated TrkB lacking tyrosine kinase activity and chronically activated CaMKII, are insensitive to BDNF. Thus, BDNF/TrkB signaling represents a previously unidentified pathway by which the peripheral nervous system directly and tonically influences myocardial function in parallel with β-adrenergic control. Deficits in this system are likely additional contributors to acute and chronic cardiac dysfunction.BDNF | TrkB receptor | cardiac contractility/relaxation | CaMKII | neurotrophins I n the brain, BDNF has a pleiotropic profile, preserving cell viability and function, preventing neuronal degeneration during stress (1), and acting as an antidepressant (2). BDNF is also expressed in various nonneuronal tissues, including smooth and skeletal muscle cells, where it enhances airway smooth muscle cell contractility (3) and acts as a metabolic enhancer (4), respectively.In the mammalian heart, BDNF is essential for organ development because its genetic deletion leads to the thinning of cardiac chambers, microvascular leakage, and ultimately, early death in mice (5). In adult mammals, BDNF governs autonomic transmission to the heart (6) and exerts prominent angiogenic effects (7). Recent evidence also points to the presence of the BDNF receptor, tropomyosin-related kinase receptor B (TrkB), in the myocardium (8). However, the role of myocardial BDNF/ TrkB signaling in cardiac physiology and myocardial response to pathologic stress, independent from its well-known trophic actions on blood vessels and autonomic efferent neurons (9), is largely unknown.In neurons, BDNF regulates Ca 2+ signaling, and calmodulindependent protein kinase II (CaMKII) is one of the downstream effectors of the BDNF/TrkB signaling pathway. Because CaMKII is one of the important regulators of excitation-contraction coupling, and because BDNF also enhances smooth muscle contraction by augmenting intracellular Ca 2+ signaling, we first determined the effects of BDNF on cardiomyocyte contractility, relaxation, and Ca 2+ dynamics. Then, to establish whether BDNF/ TrkB stimulation is relevant in maintaining basal cardiac function in vivo, we generated cardiac-specific TrkB −/− mice by crossing conditional TrkB −/− mice with MHC promoter-driven Cre mice and subjected these mice and their WT littermates to pressurevolume analysis. We further investigated which signaling pathway mediates the BDNF cardiac effects, and finally, we tested whether modulatio...

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Section: Discussionsupporting

confidence: 58%

Constitutive BDNF/TrkB signaling is required for normal cardiac contraction and relaxation

Feng

Huke

Zhu

et al. 2015

Autonomic Neuroscience

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“…For example, VEGF signalling regulates muscle capillary density, which is a major determinant of maximal aerobic capacity across mammals [51,52]. Second, BDNF and IGF-1 facilitate lipid oxidation in muscles [53] and glucose metabolism [1], which are essential for energy regulation during submaximal activity [54]. Peripheral production of neurotrophins and growth factors can lead to effects on the central nervous system (CNS) because they all cross the blood -brain barrier, resulting in correlated peripheral and CNS concentrations [55].…”

Section: (A) Neurotrophins and Growth Factorsmentioning

confidence: 99%

Linking brains and brawn: exercise and the evolution of human neurobiology

Raichlen

Polk

2013

Proc. R. Soc. B.

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The hunting and gathering lifestyle adopted by human ancestors around 2 Ma required a large increase in aerobic activity. High levels of physical activity altered the shape of the human body, enabling access to new food resources (e.g. animal protein) in a changing environment. Recent experimental work provides strong evidence that both acute bouts of exercise and long-term exercise training increase the size of brain components and improve cognitive performance in humans and other taxa. However, to date, researchers have not explored the possibility that the increases in aerobic capacity and physical activity that occurred during human evolution directly influenced the human brain. Here, we hypothesize that proximate mechanisms linking physical activity and neurobiology in living species may help to explain changes in brain size and cognitive function during human evolution. We review evidence that selection acting on endurance increased baseline neurotrophin and growth factor signalling (compounds responsible for both brain growth and for metabolic regulation during exercise) in some mammals, which in turn led to increased overall brain growth and development. This hypothesis suggests that a significant portion of human neurobiology evolved due to selection acting on features unrelated to cognitive performance.

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“…BDNF treatment to obese and diabetic conditions significantly suppressed the blood glucose, food consumption, and dietary body weight gain, while also enhancing the energy expenditure, glucose and lipid metabolism etc. [17][18][19] BDNF exhibits hypophagic and hypoglycemic effects in obese hyperglycemic conditions indicating its antiobesity and antidiabetic effects [16,20]. However, in humans with type 2 diabetes, levels of BDNF were decreased independent of obesity, suggesting that BDNF may regulate obesity and insulin resistance via different mechanisms, particularly through the insulin-stimulated phosphoinositide 3-kinase(PI3K) pathway important not only to neuronal survival and synaptic plasticity but also to insulin receptor signalling and insulin resistance.…”

Section: Introductionmentioning

confidence: 99%

“…Beyond the importance of BDNF in neurological development and synaptic plasticity and its role in learning and memory [15], there is evidence that demonstrates that it is also essential for body weight control and energy homeostasis. Low levels of BDNF have been found in individuals with obesity and type 2 diabetes [16] . BDNF treatment to obese and diabetic conditions significantly suppressed the blood glucose, food consumption, and dietary body weight gain, while also enhancing the energy expenditure, glucose and lipid metabolism etc.…”

Section: Introductionmentioning

confidence: 99%

Modeling the Interactions between the BDNF Peptides and TrkB Receptor

Devarapalli¹,

Rao²,

Sridhar³

2012

IJCA

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The BDNF\TrkB signaling system which plays a major role in the regulation of neuronal activity. This neuronal regulation influences the potential role of this system in the therapeutic efficacy of many neurological and psychiatric disorders. Despite these roles decreased levels of BDNF are associated with diabetes and obesity which can be regulated by increasing the insulin sensitivity and glucose tolerance. BDNF mediated signaling through phosphoinositide 3-kinase (PI3K) pathway plays a key role in insulin sensitivity. These beneficial effects of BDNF as antidiabetic agents can be enhanced by the activating BDNF\TrkB signaling. These multiple functionality of BDNF\TrkB complex relies on the protein-protein interactions where those interactions are important in designing pharmacological targets. This apporach focus the use of BDNF peptides in place of BDNF protein in binding to the TrkB receptor. Protein-peptide docking studies were performed to know the interactions of the TrkB and BDNF peptides. Docking studies were done using ZDOCK pro (Accerlys Discovery studio). The interacting amino acids residues identified at the binding site were THR 306, LYS 308, CYS 5 ASP 370.

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Role of exercise‐induced brain‐derived neurotrophic factor production in the regulation of energy homeostasis in mammals

Cited by 223 publications

References 52 publications

Constitutive BDNF/TrkB signaling is required for normal cardiac contraction and relaxation

Constitutive BDNF/TrkB signaling is required for normal cardiac contraction and relaxation

Linking brains and brawn: exercise and the evolution of human neurobiology

Modeling the Interactions between the BDNF Peptides and TrkB Receptor

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