Cerebral Ketone Body Oxidation Is Facilitated by a High Fat Diet Enriched with Advanced Glycation End Products in Normal and Diabetic Rats

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.

β hydroxybutyrate levels in serum and cerebrospinal fluid under ketone body metabolism in rats

“…Therefore, the CSF βOHB level may be affected by MCT upregulation or inhibition, and a high level of plasma ketones may increase the protein expression of MCTs [2]. Iriki et al [7] found that the CSF βOHB level was 13% to 28% of the serum βOHB level in calves that received intraruminal administered of butyrate (11–44 g), while the value was 22% in the control.…”

“…In ketone body metabolism, βOHB, the main component of ketone bodies, is carried by several MCTs across the blood-brain barrier [ 2 , 11 ] and used as an energy source by the brain and spinal cord during ketone body metabolism. Therefore, the CSF βOHB level may be affected by MCT upregulation or inhibition, and a high level of plasma ketones may increase the protein expression of MCTs [ 2 ]. Iriki et al [ 7 ] found that the CSF βOHB level was 13% to 28% of the serum βOHB level in calves that received intraruminal administered of butyrate (11–44 g), while the value was 22% in the control.…”