Alpha-ketoglutarate promotes anxiety, activates autophagy, and suppresses antioxidant enzymes in the cerebral cortex of female mice on cafeteria diet

Alpha-ketoglutarate (AKG), an intermediate of the tricarboxylic acid cycle, has been found to mitigate oxidative stress and inflammation. In turn, a cafeteria diet (CD), an obesogenic diet, is often associated with oxidative stress and inflammation. This study aimed to determine whether AKG can level the effects of CD on animal behavior, oxidative stress markers, glycolytic flow, and autophagy in the mouse cerebral cortex. Female C57BL/6J mice were divided into two groups and fed either a standard diet or a CD for eight weeks. For the next four weeks, each group continued to be fed the previous diet; however, half of the individuals within each group received drinking water with 1% AKG. Using an open field test, we found that the combination of CD and AKG promoted the development of anxiety signs. Both CD and AKG decreased the exploratory behavior of mice, with a significant additive effect in the combined diet. On diets supplemented with AKG, animals produced fewer fecal boli, a measure of emotionality. On all experimental diets, mice had lower activities of antioxidant and related enzymes, with no significant differences in the activities of glycolytic enzymes. The AKG-supplemented diet induced the transcription of autophagy-related genes and targets of the forkhead box O factor, involved in the regulation of carbohydrate metabolism. Transcriptional changes induced by AKG were partly abrogated by the CD. These findings suggest that AKG, particularly when combined with CD, may modulate behavioral responses and oxidative stress intensity in the brain by altering key metabolic and autophagic pathways.