Abstract
As part of the blood-brain-barrier, astrocytes are ideally positioned between cerebral vasculature and neuronal synapses to mediate nutrient uptake from the systemic circulation. In addition, astrocytes have a robust enzymatic capacity of glycolysis, glycogenesis and lipid metabolism, managing nutrient support in the brain parenchyma for neuronal consumption. Here, we review the plasticity of astrocyte energy metabolism under physiologic and pathologic conditions, highlighting age-dependent brain dysfunctions. In astrocytes, glycolysis and glycogenesis are regulated by noradrenaline and insulin, respectively, while mitochondrial ATP production and fatty acid oxidation are influenced by the thyroid hormone. These regulations are essential for maintaining normal brain activities, and impairments of these processes may lead to neurodegeneration and cognitive decline. Metabolic plasticity is also associated with (re)activation of astrocytes, a process associated with pathologic events. It is likely that the recently described neurodegenerative and neuroprotective subpopulations of reactive astrocytes metabolize distinct energy substrates, and that this preference is supposed to explain some of their impacts on pathologic processes. Importantly, physiologic and pathologic properties of astrocytic metabolic plasticity bear translational potential in defining new potential diagnostic biomarkers and novel therapeutic targets to mitigate neurodegeneration and age-related brain dysfunctions.
Highlights
Astrocyte and Brain Energy MetabolismThe human brain represents merely 2% of body mass; it consumes approximately 20% of energy substrates at rest, and energy consumption by the brain can be further elevated during various tasks [1,2]
In this paper we review the plasticity of astrocytic energy metabolism and its implications in diseases and aging of the brain
Since the main signaling pathway of Ciliary neurotrophic factor (CNTF) involves signal transducer and activator of transcription 3 (STAT3), which is commonly upregulated during astrocyte activation [154], fatty acid oxidation (FAO) may be a common property of reactive astrocytes
Summary
The human brain represents merely 2% of body mass; it consumes approximately 20% of energy substrates at rest, and energy consumption by the brain can be further elevated during various tasks [1,2]. Neuronal ATP production with astrocyte-derived L-lactate was proposed as a model of activity-dependent energy metabolism called astrocyte-neuron L-lactate shuttle (ANLS) [14], and its involvement in cognitive function is experimentally suggested [15,16] This model is criticized by at least the following points, namely, (i) the ANLS is inconsistent with the existing data on stoichiometry of brain metabolism and with the rapid excretion of L-lactate after neuronal activity [17] and (ii) the capacity of neuronal glucose uptake and oxidative metabolism is large enough for maintaining their energy consumption during activities [18]. Revealing the machinery behind the astrocytic metabolic plasticity is expected to lead us to novel strategies for therapeutic treatment of age-related brain diseases, including dementia, and for maintaining a healthy aging
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