Circadian control of p75 neurotrophin receptor leads to alternate activation of Nrf2 and c-Rel to reset energy metabolism in astrocytes via brain-derived neurotrophic factor

Jan 29, 2018Free radical biology & medicine

Daily rhythms of a brain receptor help reset energy use in support cells through brain-derived growth factor by switching on two protective pathways

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Abstract

Circadian clock genes regulate energy metabolism through neurotrophins, notably involving the low affinity neurotrophin receptor p75.

The transcriptional factor Clock:Bmal1 complex directly regulates the p75 receptor.
Brain-derived neurotrophic factor (BDNF) interacts with TrkB and p75 receptors to mediate metabolic signaling.
BDNF facilitates the daily resetting of glucose and glycogen metabolism in brain astrocytes, which interact with neurons.
Astrocytes store glycogen and provide lactate to neurons, with the truncated receptor TrkB.T1 influencing cell morphology.
The p75 receptor generates ceramide in response to BDNF, which activates PKCζ and plays a role in glycogen and lipid synthesis.
TrkB.T1 can enhance cAMP-PKA signaling in the absence of p75, promoting glycogen hydrolysis and gluconeogenesis.

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Circadian clock genes regulate energy metabolism partly through neurotrophins in the body. The low affinity neurotrophin receptor p75is a clock component directly regulated by the transcriptional factor Clock:Bmal1 complex. Brain-derived neurotrophic factor (BDNF) is expressed in the brain and plays a key role in coordinating metabolic interactions between neurons and astrocytes. BDNF transduces signals through TrkB and p75receptors. This review highlights a novel molecular mechanism by which BDNF via circadian control of p75leads to daily resetting of glucose and glycogen metabolism in brain astrocytes to accommodate their functional interaction with neurons. Astrocytes store glycogen as an energy reservoir to provide active neurons with the glycolytic metabolite lactate. Astrocytes predominantly express the truncated receptor TrkB.T1 which lacks an intracellular receptor tyrosine kinase domain. TrkB.T1 retains the capacity to regulate cell morphology through regulation of Rho GTPases. In contrast, p75mediates generation of the bioactive lipid ceramide upon stimulation with BDNF and inhibits PKA activation. As ceramide directly activates PKCζ, we discuss the importance of the TrkB.T1-p75-ceramide-PKCζ signaling axis in the stimulation of glycogen and lipid synthesis and activation of RhoA. Ceramide-PKCζ-casein kinase 2 signaling activates Nrf2 to support oxidative phosphorylation via upregulation of antioxidant enzymes. In the absence of p75, TrkB.T1 functionally interacts with adenosine AR and dopamine D1R receptors to enhance cAMP-PKA signaling and activate Rac1 and NF-κB c-Rel, favoring glycogen hydrolysis, gluconeogenesis and aerobic glycolysis. Thus, diurnal changes in p75levels in astrocytes resets energy metabolism via BDNF to accommodate their metabolic interaction with neurons. NTR NTR NTR NTR NTR NTR NTR2A

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Circadian control of p75 neurotrophin receptor leads to alternate activation of Nrf2 and c-Rel to reset energy metabolism in astrocytes via brain-derived neurotrophic factor

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