Abstract
Astrocytes, heterogeneous neuroglial cells, contribute to metabolic homeostasis in the brain by providing energy substrates to neurons. In contrast to predominantly oxidative neurons, astrocytes are considered primarily as glycolytic cells. They take up glucose from the circulation and in the process of aerobic glycolysis (despite the normal oxygen levels) produce L-lactate, which is then released into the extracellular space via lactate transporters and possibly channels. Astroglial L-lactate can enter neurons, where it is used as a metabolic substrate, or exit the brain via the circulation. Recently, L-lactate has also been considered to be a signaling molecule in the brain, but the mechanisms of L-lactate signaling and how it contributes to the brain function remain to be fully elucidated. Here, we provide an overview of L-lactate signaling mechanisms in the brain and present novel insights into the mechanisms of L-lactate signaling via G-protein coupled receptors (GPCRs) with the focus on astrocytes. We discuss how increased extracellular L-lactate upregulates cAMP production in astrocytes, most likely viaL-lactate-sensitive Gs-protein coupled GPCRs. This activates aerobic glycolysis, enhancing L-lactate production and accumulation of lipid droplets, suggesting that L-lactate augments its own production in astrocytes (i.e., metabolic excitability) to provide more L-lactate for neurons and that astrocytes in conditions of increased extracellular L-lactate switch to lipid metabolism.
Highlights
L-lactate was first considered as a cellular waste product of glycolytic metabolism, it was later proposed that l-lactate can act as a supplemental oxidative energy substrate and as a signaling molecule in the brain (Dienel, 2012a; Magistretti and Allaman, 2018)
(1) during exercise, when l-lactate blood levels increase and l-lactate enters the brain from the systemic circulation, as G-protein coupled receptor 81 (GPR81)-mediated effects of exercise on brain function were demonstrated in mice that have been subjected to high-intensity interval exercise or l-lactate injection mimicking exercise-induced increase in blood l-lactate levels (Morland et al, 2017); (2)
The discovery of signaling properties of l-lactate in astrocytes that are manifested as upregulation in intracellular cAMP production, suggests the existence of a new, as yet unidentified, l-lactate sensitive G-protein coupled receptors (GPCRs) coupled to Gs-proteins in astrocytes. l-Lactatetriggered cAMP signals in astrocytes facilitate aerobic glycolysis with more l-lactate production, likely to provide neurons with more l-lactate
Summary
L-lactate was first considered as a cellular waste product of glycolytic metabolism, it was later proposed that l-lactate can act as a supplemental oxidative energy substrate and as a signaling molecule in the brain (Dienel, 2012a; Magistretti and Allaman, 2018). L-Lactate is involved in various cellular processes in the brain, including in the regulation of intracellular Ca2+ signaling (Requardt et al, 2012), cell energy metabolism (Bergersen and Gjedde, 2012; Barros, 2013), activity of various channels and transporters (Gordon et al, 2008; Ohbuchi et al, 2010), myelination (Fünfschilling et al, 2012), and gene expression (Yang et al, 2014; Descalzi et al, 2019). The entry of l-lactate into cells can affect the cell energy status where l-lactate is first metabolized to pyruvate, which is used for generation of ATP in the tricarboxylic acid cycle (TCA) leading to an increased ATP/ADP ratio This was shown to regulate the activity of ATP-sensitive K+ channels in hypothalamic and orexin neurons, which close when cytoplasmic ATP levels increase, leading to depolarization of the membrane (Song and Routh, 2005; Parsons and Hirasawa, 2010; Mosienko et al, 2015). (1) during exercise, when l-lactate blood levels increase and l-lactate enters the brain from the systemic circulation (usually the l-lactate concentration in the brain is lower than in the circulation; Bergersen, 2015), as GPR81-mediated effects of exercise on brain function were demonstrated in mice that have been subjected to high-intensity interval exercise or l-lactate injection mimicking exercise-induced increase in blood l-lactate levels (Morland et al, 2017); (2)
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