Glycogenolysis in astrocytes supports blood-borne glucose channeling not glycogen-derived lactate shuttling to neurons: evidence from mathematical modeling - PubMed (original) (raw)

Glycogenolysis in astrocytes supports blood-borne glucose channeling not glycogen-derived lactate shuttling to neurons: evidence from mathematical modeling

Mauro DiNuzzo et al. J Cereb Blood Flow Metab. 2010 Dec.

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 (∼1.5:1) neuronal versus astrocytic activation-induced Na(+) influx ratio, ∼12% 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 (∼3:1), 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.

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Figures

Figure 1

Figure 1

Time courses of glycogen synthase (GS) and glycogen phosphorylase (GP) reaction rates. Brain stimulation produces a rapid activation of GP because of increased energy demand, which effect glucosyl equivalents concentration in astrocytes (inset). The GP-catalyzed mobilization of glycogen decreases during the late phase of the stimulation period, and readily returns to basal level after the end of stimulation. The GS-catalyzed incorporation of glucose into glycogen is delayed and much slower than glycogen breakdown; however, it remains significantly elevated during the poststimulus period. Note that, although the resting activity of both GS and GP is very small, substantial synthesis and degradation of glycogen occur simultaneously during activation. The simulated neuron/astrocyte activation ratio is 1.5:1.

Figure 2

Figure 2

Net brain glycogen breakdown as a function of time during the stimulation. The simulated net glycogen breakdown rate (difference between phosphorolysis rate and synthesis rate) shows a transient peak (up to 0.12 _μ_mol/g per min) at 1 to 2 minutes and then reaches a steady-state value of 0.02 _μ_mol/g per min after 6 minutes. Therefore, the mean net glycogen breakdown rate averaged over the stimulation period decreases with increasing duration of the stimulus. As shown in the inset, the amount of mobilized glycogen is 0.67 _μ_mol/g in correspondence of a 20-minute stimulation. The simulated neuron/astrocyte activation ratio is 1.5:1.

Figure 3

Figure 3

Time courses of neuron (A) and astrocyte (B) glucose flow rates (relative to interstitium) for active or inactive glycogenolysis. Under the same activation conditions, astrocytic glucose uptake from the extracellular space is significantly diminished when glycogen is mobilized. This is a result of glucose-6-phosphate-induced inhibition of hexokinase in astrocytes (inset). On average, substrate flow through astrocytic hexokinase is nearly 40% inhibited (65% peak inhibition, values relative to resting conditions), without any change in the activity of neuronal hexokinase (not shown). The increased availability of paracellularly diffused glucose into the interstitium results in increased amount of the sugar taken up by neurons. On the contrary, astrocytes diminish extracellular glucose uptake, which translates to a small, transient gradient-driven release of part of their glucose pool to the interstitium. The glycogenolysis-induced changes in neuronal and astrocytic glucose fluxes shown here are introduced by the breakdown of about 12% of total glycogen content. It is noted that only when hexokinase is inhibited by its product during active glycogenolysis, the rate of glycogen breakdown (see Figure 1) exceeds the rate of glycolysis during early stimulation, consistent with experimental evidence (Subbarao et al, 1995). The simulated neuron/astrocyte activation ratio is 1.5:1.

Figure 4

Figure 4

Time courses of neuron (A) and astrocyte (B) lactate flow rates (relative to interstitium) for active or inactive glycogenolysis. Glycogenolysis affects marginally the lactate trafficking between neurons and astrocytes. In particular, flux changes during the initial phase of stimulation are negligible for both cell types. During the late stimulation period, astrocytes divert glucose to the replenishment of glycogen and thus reduce extracellular lactate release for aerobic energy production. In terms of glucose equivalents, the mean variations of cellular lactate flow rates between active and inactive glycogen metabolism represents only 12% and 20% of the concurrent changes of neuronal and astrocytic glucose flow rates, respectively (see Table 2). The simulated neuron/astrocyte activation ratio is 1.5:1.

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