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

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.