Is lactate a volume transmitter of metabolic states of the brain?

Abstract

We present the perspective that lactate is a volume transmitter of cellular signals in brain that acutely and chronically regulate the energy metabolism of large neuronal ensembles. From this perspective, we interpret recent evidence to mean that lactate transmission serves the maintenance of network metabolism by two different mechanisms, one by regulating the formation of cAMP via the lactate receptor GPR81, the other by adjusting the NADH/NAD+ redox ratios, both linked to the maintenance of brain energy turnover and possibly cerebral blood flow. The role of lactate as mediator of metabolic information rather than metabolic substrate answers a number of questions raised by the controversial oxidativeness of astrocytic metabolism and its contribution to neuronal function.

Here, we present the perspective that lactate acts as a volume transmitter in brain tissue by distributing cellular signals that are relevant to the metabolic support of large neuronal ensembles. We interpret recent evidence to mean that lactate transmission is involved in the maintenance of network homeostasis by two different mechanisms; one by regulation of neuronal cAMP formation through the lactate receptor GPR81, the other by adjustment of the NADH/NAD+ redox ratio. Lactate is an intermediary metabolite in brain energy metabolism, the role of which is controversial (Dienel, 2011). Traditionally, lactate was considered a waste product with no certain function in the metabolic housekeeping when eukaryotic cells have sufficient oxygen. However, it is also held to be a “preferred” substrate of energy metabolism, in muscle (Brooks, 2009) as well as in brain (Bouzier-Sore et al., 2003; Smith et al., 2003; Wyss et al., 2011). This alleged preference revives an ancient claim of lactate’s service as nutrient for neurons that do not phosphorylate glucose to the extent required by neuronal energy metabolism (Andriezen, 1893; DiNuzzo et al., 2011). A cue to the notion of a signaling role of lactate, irrespective of any role as intermediary metabolite, is the observation that lactate regulates cerebral blood flow (Gordon et al., 2008).