The Strategic Location of Glycogen and Lactate: From Body Energy Reserve to Brain Plasticity

Abstract

Brain energy metabolism has been the object of intense research in recent years. Pioneering work has identified the different cell types involved in energy production and use. Recent evidence has demonstrated a key role of L-Lactate in brain energy metabolism, producing a paradigm-shift in our understanding of the neuronal energy metabolism. At the center of this shift, is the identification of a central role of astrocytes in neuroenergetics. Thanks to their morphological characteristics, they are poised to take up glucose from the circulation and deliver energy substrates to neurons. Astrocyte neuron lactate shuttle (ANLS) model, has shown that the main energy substrate that astrocytes deliver to neurons is L-Lactate, to sustain neuronal oxidative metabolism. L-Lactate can also be produced from glycogen, the storage form of glucose, which is exclusively localized in astrocytes. Inhibition of glycogen metabolism and the ensuing inhibition of L-Lactate production leads to cognitive dysfunction. Experimental evidence indicates that the role of lactate in cognitive function relates not only to its role as a metabolic substrate for neurons but also as a signaling molecule for synaptic plasticity. Interestingly, a similar metabolic uncoupling appears to exist in peripheral tissues plasma, whereby glucose provides L-Lactate as the substrate for cellular oxidative metabolism. In this perspective article, we review the known information on the distribution of glycogen and lactate within brain cells, and how this distribution relates to the energy regime of glial vs. neuronal cells.

Proteomic and Metabolomic Characterization of Human Neurovascular Unit Cells in Response to Methamphetamine

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Astrocyte-neuron crosstalk through Hedgehog signaling mediates cortical circuit assembly

“…We also observed more astrocytes with intensely labeled glycogen granules accumulated in their processes compared to WT ( Figure 6H, 6J, S6G and Table S2). Accumulation of glycogen granules has been shown correlate with astrocytes in reactive states (Cai et al 2020, Dienel and Rothman 2019, Cali, Tauffenberger and Magistretti 2019b. We also observed significantly increased GFAP labeling in astrocytes in all cortical layers of ShhcKOs (Figure S6H and S6I), suggesting that astrocytes become reactive when Shh is deleted in cortical neurons.…”

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“…As the DMH is not adjacent to a circumventricular site it is probable that the astrogliosis in this region is not directly caused solely by peripheral inflammatory changes or constituents of the diet, such as saturated fatty acids, which may modulate the activity of glia. One possible explanation is functional differences between glial cells within the hypothalamus, as regional heterogeneity in glial cell function in the brain is an emerging area of understanding ( Cali et al, 2019 , Masuda et al, 2019 , Polyzos et al, 2019 ). Another likely factor is ‘neurogenic neuroinflammation’ ( Xanthos and Sandkuhler, 2014 ).…”