Abstract
Diabetes mellitus (DM) causes important modifications in the availability and use of different energy substrates in various organs and tissues. Similarly, dietary manipulations such as high fat diets also affect systemic energy metabolism. However, how the brain adapts to these situations remains unclear. To investigate these issues, control and alloxan-induced type I diabetic rats were fed either a standard or a high fat diet enriched with advanced glycation end products (AGEs) (HAGE diet). The HAGE diet increased their levels of blood ketone bodies, and this effect was exacerbated by DM induction. To determine the effects of diet and/or DM induction on key cerebral bioenergetic parameters, both ketone bodies (β-hydroxybutyric acid) and lactate oxidation were measured. In parallel, the expression of Monocarboxylate Transporter 1 (MCT1) and 2 (MCT2) isoforms in hippocampal and cortical slices from rats submitted to these diets was assessed. Ketone body oxidation increased while lactate oxidation decreased in hippocampal and cortical slices in both control and diabetic rats fed a HAGE diet. In parallel, the expression of both MCT1 and MCT2 increased only in the cerebral cortex in diabetic rats fed a HAGE diet. These results suggest a shift in the preferential cerebral energy substrate utilization in favor of ketone bodies in animals fed a HAGE diet, an effect that, in DM animals, is accompanied by the enhanced expression of the related transporters.
Highlights
Alterations in cognitive functions of patients with Diabetes mellitus (DM) were first described many years ago (Miles and Root, 1922) and have been documented more extensively recently (Frier, 2011; Jacobson et al, 2011; McCrimmon et al, 2012)
The plasmatic BHB levels were not affected by DM induction alone compared to control animals, but they were significantly higher in rats fed with the HAGE diet (∼3.0-fold vs. control, P < 0.05, Table 3) with a stronger effect of the HAGE diet
The main results in this study show that rats fed with a high fat diet enriched with advanced glycation end products (AGEs) presented (i) a simultaneous increase in serum BHB levels and its hippocampal and cortical oxidation rate; (ii) a decrease in lactate oxidation for both structures in the diabetic, HAGE diet-fed group; and (iii) an increase in Monocarboxylate Transporter 1 (MCT1) and MCT2 expression in the cerebral cortex, but only in the diabetic, HAGE diet-fed group
Summary
Alterations in cognitive functions of patients with DM were first described many years ago (Miles and Root, 1922) and have been documented more extensively recently (Frier, 2011; Jacobson et al, 2011; McCrimmon et al, 2012). Frontiers in Neuroscience | www.frontiersin.org de Assis et al. Brain Ketone Body Oxidation recent studies have shown that hippocampal metabolism is affected when glycemia is increased (Mcnay and Recknagel, 2011; Duarte et al, 2012). A unifying mechanism to explain the complications linked to diabetes has been proposed in which an inhibition of glycolysis by Poly-(ADP-ribose)-polymerase (PARP) generates an increase in glycolytic intermediates (Brownlee, 2005). These intermediates are metabolized through four pathways leading to several diabetic complications and one of these pathways is the formation of dicarbonyl compounds that are precursors of AGEs, offering a putative explanation for cognitive impairments associated with diabetes
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