Glycogenolysis in Astrocytes Supports Blood-Borne Glucose Channeling Not Glycogen-Derived Lactate Shuttling to Neurons: Evidence from Mathematical Modeling

Abstract

In this article, we examined theoretically the role of human cerebral glycogen in buffering the metabolic requirement of a 360-second brain stimulation, expanding our previous modeling study of neurometabolic coupling. We found that glycogen synthesis and degradation affects the relative amount of glucose taken up by neurons versus astrocytes. Under conditions of 175:115 mmol/L (B1.5:1) neuronal versus astrocytic activation-induced Na + influx ratio, B12% of astrocytic glycogen is mobilized. This results in the rapid increase of intracellular glucose-6-phosphate level on stimulation and nearly 40% mean decrease of glucose flow through hexokinase (HK) in astrocytes via product inhibition. The suppression of astrocytic glucose phosphorylation, in turn, favors the channeling of glucose from interstitium to nearby activated neurons, without a critical effect on the concurrent intercellular lactate trafficking. Under conditions of increased neuronal versus astrocytic activation-induced Na + influx ratio to 190:65 mmol/L (B3:1), glycogen is not significantly degraded and blood glucose is primarily taken up by neurons. These results support a role for astrocytic glycogen in preserving extracellular glucose for neuronal utilization, rather than providing lactate to neurons as is commonly accepted by the current 'thinking paradigm'. This might be critical in subcellular domains during functional conditions associated with fast energetic demands.

Brain Lactate Metabolism: The Discoveries and the Controversies

“…Astrocytes increase glycogenolysis and oxidative metabolism during activation, besides their presumed use of blood glucose. Glycogenolysis generates glucose-6-phosphate that serves as fuel for astrocytes and can also inhibit astrocytic hexokinase activity, providing a mechanism to divert blood-borne glucose for use by neurons (DiNuzzo et al, 2010b). Small increases in astrocytic oxidative metabolism during activation in vivo produce substantial portion of the total increase in ATP generated in astrocytes during activation.…”

Modeling the contribution of neuron-astrocyte cross talk to slow blood oxygenation level-dependent signal oscillations

“…We have extended our previous kinetic models of functional brain metabolism (DiNuzzo et al 2010a(DiNuzzo et al , 2010b by including Ca 2ϩ dynamics in astrocytes (Lavrentovich and Hemkin 2008) and Ca 2ϩ -dependent astrocytic transmitter release (De Pitta et al 2009;Di Garbo et al 2007). The model incorporates the current biological understanding related to the signaling pathways underlying both the spontaneous and the glutamate-induced generation of Ca 2ϩ oscillations in astrocytes (Fig.…”

Brain Glycogen Content and Metabolism in Subjects with Type 1 Diabetes and Hypoglycemia Unawareness

“…Another potential mechanism to enhance fuel availability during hypoglycemia is to increase brain glycogen content via a phenomenon termed 'supercompensation'. In the adult brain, glycogen is primarily localized in astrocytes (Wiesinger et al, 1997) and may support brain function either by being used locally in astrocytes, which would spare extracellular glucose for neurons, or by being exported to neurons in the form of lactate (Brown et al, 2005;Dienel et al, 2007;DiNuzzo et al, 2010;Sickmann et al, 2009;Swanson et al, 1992;Wender et al, 2000). Glycogen is mobilized during hypoglycemia both in rodents (Canada et al, 2011;Herzog et al, 2008;Suh et al, 2007) and in humans (Ö z et al, 2009).…”