How Energy Metabolism Supports Cerebral Function: Insights from 13C Magnetic Resonance Studies In vivo

Abstract

Cerebral function is associated with exceptionally high metabolic activity, and requires continuous supply of oxygen and nutrients from the blood stream. Since the mid-twentieth century the idea that brain energy metabolism is coupled to neuronal activity has emerged, and a number of studies supported this hypothesis. Moreover, brain energy metabolism was demonstrated to be compartmentalized in neurons and astrocytes, and astrocytic glycolysis was proposed to serve the energetic demands of glutamatergic activity. Shedding light on the role of astrocytes in brain metabolism, the earlier picture of astrocytes being restricted to a scaffold-associated function in the brain is now out of date. With the development and optimization of non-invasive techniques, such as nuclear magnetic resonance spectroscopy (MRS), several groups have worked on assessing cerebral metabolism in vivo. In this context, 1H MRS has allowed the measurements of energy metabolism-related compounds, whose concentrations can vary under different brain activation states. 1H-[13C] MRS, i.e., indirect detection of signals from 13C-coupled 1H, together with infusion of 13C-enriched glucose has provided insights into the coupling between neurotransmission and glucose oxidation. Although these techniques tackle the coupling between neuronal activity and metabolism, they lack chemical specificity and fail in providing information on neuronal and glial metabolic pathways underlying those processes. Currently, the improvement of detection modalities (i.e., direct detection of 13C isotopomers), the progress in building adequate mathematical models along with the increase in magnetic field strength now available render possible detailed compartmentalized metabolic flux characterization. In particular, direct 13C MRS offers more detailed dataset acquisitions and provides information on metabolic interactions between neurons and astrocytes, and their role in supporting neurotransmission. Here, we review state-of-the-art MR methods to study brain function and metabolism in vivo, and their contribution to the current understanding of how astrocytic energy metabolism supports glutamatergic activity and cerebral function. In this context, recent data suggests that astrocytic metabolism has been underestimated. Namely, the rate of oxidative metabolism in astrocytes is about half of that in neurons, and it can increase as much as the rate of neuronal metabolism in response to sensory stimulation.

Glycogen metabolism is impaired in the brain of male type 2 diabetic Goto‐Kakizaki rats

“…Previous 13 C‐MRS studies in rats under light α‐chloralose anesthesia, have estimated similar (Choi, Tkác, Ugurbil, & Gruetter, ) or slightly faster (0.7 µmol/g/h, van Heeswijk, Morgenthaler, Xin, & Gruetter, ) glycogen turnover rates. The discrepancy on the measured turnover rates in our study and these previous publications could be caused by either the deepness of anesthesia that modulates brain activity and metabolism (Sonnay, Gruetter, & Duarte, ), or the brain levels of insulin that might stimulate glycogen synthesis (Fernandez et al, ; Muhič et al, ). Accordingly, administration of insulin to anaesthetized rats was previously reported to increase brain glycogen levels (Morgenthaler et al, ).…”

“…Previous 13 C-MRS studies in rats under light α-chloralose anesthesia, have estimated similar (Choi, Tkác, Ugurbil, & Gruetter, 1999) or slightly faster (0.7 µmol/g/h, van Heeswijk, Morgenthaler, Xin, & Gruetter, 2010) glycogen turnover rates. The discrepancy on the measured turnover rates in our study and these previous publications could be caused by either the deepness of anesthesia that modulates brain activity and metabolism (Sonnay, Gruetter, & Duarte, 2017), or the brain F I G U R E 6 Western blot analysis of GLUT1 detected the highly glycosylated (top band, 55 kDa) and less glycosylated (lower band, 45 kDa) isoforms (a), which are present in endothelial cells and brain parenchyma, respectively. The relation between the normalized immunoreactivity of both GLUT1 forms is plotted together with the line of equality.…”

“…Metabolism of glucose and glycogen is linked to glutamatergic neurotransmission (Gibbs et al, ; Sickmann et al, ; Sonnay et al, ). However, the present results are not sufficient to determine whether brain hypo‐metabolism and reduced glycogen turnover are cause or consequence of the previously reported reduced glutamate‐glutamine cycle rate in the brain of GK rats (Girault et al, ).…”

In vivo 13C and 1H‐[13C] MRS studies of neuroenergetics and neurotransmitter cycling, applications to neurological and psychiatric disease and brain cancer

“…In animal models the rate of the glial TCA cycle and its relationship to the glutamate/GABA/glutamine cycle has mainly been looked at by Gruetter and colleagues as reviewed in references. Analysis of results from these studies, in which the flux was measured at different steady state levels of brain activity from anesthetized to awake found a linear increase in glial glucose oxidation versus the glutamate/GABA/glutamine cycle with a slope of approximately 0.3.…”

A glucose-stimulated BOLD fMRI study of hypothalamic dysfunction in mice fed a high-fat and high-sucrose diet

“…The measured HFHSD-induced dampening of the BOLD fMRI response to glucose cannot be simply attributed to impaired glucose sensing. The neurovascular coupling that underlies the BOLD signal involves tight metabolic interactions between neurons and glial cells, namely astrocytes (Sonnay et al, 2017). The early neuroinflammatory process of the hypothalamus also involves astrogliosis (e.g.…”