High-fat high-fructose diet and alpha-ketoglutarate affect mouse behavior that is accompanied by changes in oxidative stress response and energy metabolism in the cerebral cortex.

BACKGROUND: High caloric diets with high amounts of fats and sweeteners such as fructose may predispose organisms to neurodegenerative diseases. METHODS: This study aimed to examine the effects of a high-fat high-fructose diet (HFFD) on the behavior of mice, energy metabolism, and markers of oxidative stress in murine cerebral cortex. Dietary α-ketoglutarate (AKG) was chosen as a treatment which could modulate the putative effects of HFFD. RESULTS: We found that HFFD stimulated locomotion and defecation in mice, whereas an AKG-supplemented diet had a proclivity to promote anxiety-like behavior. HFFD stimulated lipid peroxidation, and in turn, the AKG-supplemented diet led to a higher ratio of reduced to oxidized glutathione, higher activity of NAD(P)H:quinone oxidoreductase 1, and higher mRNA levels of UDP-glucose 6-dehydrogenase and transcription factor EB. Both diets separately, but not in combination, led to a decrease in the activities of glutathione peroxidase, glutathione S-transferase, and phosphofructokinase. All experimental diets resulted in lower levels of transcripts of genes encoding pyruvate dehydrogenase kinase 4 (PDK4), glycine N-methyl transferase, and peroxisome proliferator receptor γ co-activator 1. CONCLUSIONS: Our results show that diet supplemented with AKG resulted in effects similar to those of HFFD on the cerebral cortex, but elicited substantial differences between these two diets with respect to behavior, glutathione-dependent detoxification, and processes related to autophagy. GENERAL SIGNIFICANCE: Our study provides insight into the metabolic effects of HFFD alone and in combination with alpha-ketoglutarate in the mouse brain.

High fat high fructose diet induces mild oxidative stress and reorganizes intermediary metabolism in male mouse liver: Alpha-ketoglutarate effects.

BACKGROUND: Diets rich in fats and/or carbohydrates are used to study obesity and related metabolic complications. We studied the effects of a high fat high fructose diet (HFFD) on intermediary metabolism and the development of oxidative stress in mouse liver and tested the ability of alpha-ketoglutarate to prevent HFFD-induced changes. METHODS: Male mice were fed a standard diet (10% kcal fat) or HFFD (45% kcal fat, 15% kcal fructose) with or without addition of 1% alpha-ketoglutarate (AKG) in drinking water for 8 weeks. RESULTS: The HFFD had no effect on body mass but activated fructolysis and glycolysis and induced inflammation and oxidative stress with a concomitant increase in activity of antioxidant enzymes in the mouse liver. HFFD-fed mice also showed lower mRNA levels of pyruvate dehydrogenase kinase 4 (PDK4) and slightly increased intensity of mitochondrial respiration in liver compared to mice on the standard diet. No significant effects of HFFD on transcription of PDK2 and PGC1α, a peroxisome proliferator-activated receptor co-activator-1α, or protein levels of p-AMPK, an active form of AMP-activated protein kinase, were found. The addition of AKG to HFFD decreased oxidized glutathione levels, did not affect levels of lipid peroxides and PDK4 transcripts but increased activities of hexokinase and phosphofructokinase in mouse liver. CONCLUSIONS: Supplementation with AKG had weak modulating effects on HFFD-induced oxidative stress and changes in energetics in mouse liver. GENERAL SIGNIFICANCE: Our research expands the understanding of diet-induced metabolic switching and elucidates further roles of alpha-ketoglutarate as a metabolic regulator.