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

Circadian clock genes regulate energy metabolism partly through neurotrophins in the body. The low affinity neurotrophin receptor p75(NTR) is 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 p75(NTR) receptors. This review highlights a novel molecular mechanism by which BDNF via circadian control of p75(NTR) leads 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, p75(NTR) mediates generation of the bioactive lipid ceramide upon stimulation with BDNF and inhibits PKA activation. As ceramide directly activates PKC zeta, we discuss the importance of the TrkB. T1-p75(NTR)-ceramide-PKC zeta signaling axis in the stimulation of glycogen and lipid synthesis and activation of RhoA. Ceramide-PKC zeta-casein kinase 2 signaling activates Nrf2 to support oxidative phosphorylation via upregulation of antioxidant enzymes. In the absence of p75(NTR), TrkB.T1 functionally interacts with adenosine A(2A)R and dopamine D1R receptors to enhance cAMP-PKA signaling and activate Rac1 and NF-kappa B c-Rel, favoring glycogen hydrolysis, gluconeogenesis and aerobic glycolysis. Thus, diurnal changes in p75(NTR) levels in astrocytes resets energy metabolism via BDNF to accommodate their metabolic interaction with neurons.