Dynamic alterations in the central glutamatergic status following food and glucose intake: in vivo multimodal assessments in humans and animal models

Abstract

Fluctuations of neuronal activities in the brain may underlie relatively slow components of neurofunctional alterations, which can be modulated by food intake and related systemic metabolic statuses. Glutamatergic neurotransmission plays a major role in the regulation of excitatory tones in the central nervous system, although just how dietary elements contribute to the tuning of this system remains elusive. Here, we provide the first demonstration by bimodal positron emission tomography (PET) and magnetic resonance spectroscopy (MRS) that metabotropic glutamate receptor subtype 5 (mGluR5) ligand binding and glutamate levels in human brains are dynamically altered in a manner dependent on food intake and consequent changes in plasma glucose levels. The brain-wide modulations of central mGluR5 ligand binding and glutamate levels and profound neuronal activations following systemic glucose administration were further proven by PET, MRS, and intravital two-photon microscopy, respectively, in living rodents. The present findings consistently support the notion that food-associated glucose intake is mechanistically linked to glutamatergic tones in the brain, which are translationally accessible in vivo by bimodal PET and MRS measurements in both clinical and non-clinical settings.

Insulin-stimulated brain glucose uptake correlates with brain metabolites in severe obesity: A combined neuroimaging study

“…Taken together, this is the first study to link directly upregulated brain glucose uptake during euglycemic hyperinsulinemia with increased concentrations of glutamine/glutamate, total choline, and total creatine in humans in vivo. This supports the growing evidence in both animal models and humans of altered TCA cycling in the brain associated with obesity and insulin resistance, 54,61,62 with the lower brain glucose concentrations of a previous 1 H-MRS study possibly explained by a higher turnover of glucose into further metabolites. 28 While several of these findings might be attributed to astrocytosis, they do not confirm the existence of central inflammation per se.…”

“…25 The increase also occurs postprandially in rats and healthy human subjects, with the increase in glutamate synthesis possibly being mediated by the increase in plasma glucose. 54 While we observed no effect of severe obesity on fasting Glx levels or changes during hyperinsulinemic euglycemia, brain Glx correlated with insulin-stimulated brain GU. While increased intracellular glucose concentration in astrocytes might stimulate glutamate synthesis, enhanced glycolysis is also required to provide glutathione to maintain the redox status in association with upregulated glutathione/glutamine cycling.…”

Considerations on gradual glutamate accumulation related to cognitive task performance

“… 8 Taken together, adaptations in anaplerosis and pyruvate recycling in astrocytes could explain glutamate/glutamine changes seen with MRS. Glutamate accumulation induced by feeding or glucose infusion was recently reported. 10 Therefore, altered glucose availability in the circulation caused by a stress-related hormonal response during task execution could also contribute to increased brain [Glu].…”