Abstract
Nutritional ketosis may enhance cerebral energy metabolism and has received increased interest as a way to improve or preserve performance and resilience. Most studies to date have focused on metabolic or neurological disorders while anecdotal evidence suggests that ketosis may enhance performance in the absence of underlying dysfunction. Moreover, decreased availability of glucose in the brain following stressful events is associated with impaired cognition, suggesting the need for more efficient energy sources. We tested the hypotheses that ketosis induced by endogenous or exogenous ketones could: (a) augment cognitive outcomes in healthy subjects; and (b) prevent stress-induced detriments in cognitive parameters. Adult, male, Sprague Dawley rats were used to investigate metabolic and behavioral outcomes in 3 dietary conditions: ketogenic (KD), ketone supplemented (KS), or NIH-31 control diet in both control or chronic stress conditions. Acute administration of exogenous ketones resulted in reduction in blood glucose and sustained ketosis. Chronic experiments showed that in control conditions, only KD resulted in pronounced metabolic alterations and improved performance in the novel object recognition test. The hypothalamic-pituitary-adrenal (HPA) axis response revealed that KD-fed rats maintained peripheral ketosis despite increases in glucose whereas no diet effects were observed in ACTH or CORT levels. Both KD and KS-fed rats decreased escape latencies on the third day of water maze, whereas only KD prevented stress-induced deficits on the last testing day and improved probe test performance. Stress-induced decrease in hippocampal levels of β-hydroxybutyrate was attenuated in KD group while both KD and KS prevented stress effects on BDNF levels. Mitochondrial enzymes associated with ketogenesis were increased in both KD and KS hippocampal samples and both endothelial and neuronal glucose transporters were affected by stress but only in the control diet group. Our results highlight the complex relationship between peripheral metabolism, behavioral performance and biochemical changes in the hippocampus. Endogenous ketosis improved behavioral and metabolic parameters associated with energy metabolism and cognition while ketone supplementation replicated the biochemical effects within the hippocampus but only showed modest effects on behavioral improvements.
Highlights
In creased abundance of food choices has resulted in widespread consumption of convenient meals that often lack nutritional value, contributing to the epidemics of obesity, diabetes and metabolic disorders
Administration of exogenous ketones by oral gavage reduced blood glucose within the first 30 min (95.3 mg/dl; two-way repeated measures (RM) ANOVA treatment and time interaction, p = 0.02, Figure 2A), when compared to animals gavaged with water (116.0 mg/dl)
We investigated the effects of a ketogenic (KD) or ketone supplemented (KS) diet on metabolic, behavioral and biochemical outcomes associated with cognitive performance
Summary
In creased abundance of food choices has resulted in widespread consumption of convenient meals that often lack nutritional value, contributing to the epidemics of obesity, diabetes and metabolic disorders. Clinical studies indicate a strong association between stressful events with adiposity, increased body mass index and weight gain (Dallman et al, 2005; Block et al, 2009). These metabolic changes are due, in part, to higher circulating levels of glucose, insulin and insulin resistance induced by cumulative stress (Sinha and Jastreboff, 2013). Nutrient availability and the inability to effectively utilize alternative fuel sources may contribute to deteriorating performance during physically and cognitively taxing settings This underscores the importance of optimizing metabolic interventions targeting the homeostatic control of brain networks involved in efficient energy utilization
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