Functional imaging and neurochemistry identify in vivo neuroprotection mechanisms counteracting excitotoxicity and neurovascular changes in the hippocampus and visual cortex of obese and type 2 diabetic animal models

Abstract

Functional MRI (fMRI) with 1H‐MRS was combined on the hippocampus and visual cortex of animal models of obesity (high‐fat diet, HFD) and type 2 diabetes (T2D) to identify the involved mechanisms and temporal evolution of neurometabolic changes in these disorders that could serve as potentially reliable clinical biomarkers. HFD rats presented elevated levels of N‐acetylaspartylglutamate (NAAG) (p = 0.0365 vs. standard diet, SD) and glutathione (GSH) (p = 0.0494 vs. SD) in the hippocampus. NAAG and GSH levels in this structure proved to be correlated (r = 0.4652, p = 0.0336). This mechanism was not observed in diabetic rats. Combining MRS and fMRI‐evaluated blood‐oxygen‐level‐dependent (BOLD) response, elevated taurine (p = 0.0326 vs. HFD) and GABA type A receptor (GABAAR) (p = 0.0211 vs. SD and p = 0.0153 vs. HFD) were observed in the visual cortex of only diabetic rats, counteracting the elevated BOLD response and suggesting an adaptative mechanism against hyperexcitability observed in the primary visual cortex (V1) (p = 0.0226 vs. SD). BOLD amplitude was correlated with the glutamate levels (r = 0.4491; p = 0.0316). Therefore, here we found evidence for several biological dichotomies regarding excitotoxicity and neuroprotection in different brain regions, identifying putative markers of their different susceptibility and response to the metabolic and vascular insults of obesity and diabetes.

Non‐invasive in vivo measurements of metabolic alterations in the type 2 diabetic brain by 1H magnetic resonance spectroscopy

“…[1,6-13 C]-glucose infusion uncovers markedly diminished glutamate-glutamine cycling in the brain (encompassing hippocampus, thalamus, striatum, and part of the cortex), along with impaired glutamine synthesis and mitochondrial tricarboxylic acid metabolism, in Goto-Kakizaki versus control rats aged between 6 and 7 months (Girault et al, 2019). Elevated hippocampal glutamine was recorded in T2D HFD-STZ mice versus lean standard-diet fed controls aged 20 weeks following 10 weeks of diet, but no differences were seen in glutamate nor GABA (Caramelo et al, 2023).…”

“…Although there were few studies in the literature that detected elevated taurine in humans, this finding in the db/db mouse brain is much better characterized (Zheng et al, 2016;. A very recent study with a different HFD-STZ-induced T2D model reported elevated cortical taurine in T2D HFD mice compared to obese HFD mice (Caramelo et al, 2023). Brain taurine is also elevated in hyperglycemic STZ-induced T1D rats (Chandrasekaran et al, 2020;Duarte et al, 2009).…”

“…Overall, there is a lack of consensus regarding brain GABA, glutamate, and glutamine levels in the T2D context, possibly arising from analyzed brain area, that is, cortex versus hippocampus or striatum, gray or white matter, diabetes duration, glycemic control, that is, well-controlled (Thielen et al, 2019;van Bussel et al, 2016) (Caramelo et al, 2023;Girault et al, 2019) tissue analysis, acquisition during fasted (Girault et al, 2019;Zheng, Zheng, Wang et al, 2017) versus non-fasted condition, and whether the analysis corrected for brain volume, that is, atrophy.…”

“…Several studies have examined neurochemical profiles across various brain regions in HFD (Caramelo et al, 2023;Lizarbe et al, 2018;Ribeiro et al, 2018) and high-fat and high-sucrose diet (Garcia-Serrano, Mohr et al, 2022) rodent models. HFD rodents develop obesity as well as insulin resistance and elevated blood glucose not meeting the formal criteria for diabetes.…”