Nutritional Ketosis Affects Metabolism and Behavior in Sprague-Dawley Rats in Both Control and Chronic Stress Environments

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.

Modulation of cerebral ketone metabolism following traumatic brain injury in humans

“…Lactate/pyruvate ratio (27 [17-44] vs. 27 vs. 28 ), brain tissue PO 2 (29 [19-39] vs. 29.5 [19][20][21][22][23][24][25][26][27][28][29][30][31][32][33][34][35][36] vs. 29 [21][22][23][24][25][26][27][28][29][30][31][32][33][34][35] mm Hg) and ICP (10 [3-20] vs. 11 [5][6][7][8][9][10][11][12][13][14][15][16][17] (Figure 3(a)), representing a median 4.7-fold decrease of blood KB from fasting to stable nutrition state. Median individual plasma/brain KB ratio was 11.…”

“…15,16 Increasing KB metabolism through fasting or diet-induced ketosis promotes brain resistance to stress and injury 2 and attenuates acute cerebral damage. [16][17][18] Ketone body supplementation, e.g. with the use of medium-chain triglycerides (MCTs) ketogenic diets, has therefore emerged as a potential non-pharmacological neuroprotective therapy.…”

Ketone ester supplementation blunts overreaching symptoms during endurance training overload

“…; Brownlow et al . ; Leckey et al . ), but ketone esters allow blood ketones to reach ∼3‐fold higher levels than salts, with less incidence of gastrointestinal problems (Stubbs et al .…”

“…However, exogenous ketone supplements recently emerged as a novel approach to induce ketosis. Exogenous supplements are available either in the form of ketone salts or ketone esters (Cox et al 2016;Brownlow et al 2017;Leckey et al 2017), but ketone esters allow blood ketones to reach ß3-fold higher levels than salts, with less incidence of gastrointestinal problems (Stubbs et al 2017;Sansone et al 2018). Recent studies in our and other laboratories have shown that post-exercise ingestion of the ketone monoester (R)-3-hydroxybutyl (R)-3-hydroxybutyrate (KE) stimulates markers of protein synthesis and potentially also muscle glycogen repletion following exercise (Holdsworth et al 2017;Vandoorne et al 2017).…”

Ketogenic diet effects on 52 children with pharmacoresistant epileptic encephalopathy: A clinical prospective study

“…KD treatment is a relatively safe treatment method, which can play a role in cognitive and motor function of children, and a large number of tests have confirmed that KD can control the onset of pharmacoresistant epileptic encephalopathy and improve cognition, which may be reflect a reduction in memory impairment caused by seizures in KD‐treated children (Jiang et al., ). The mechanism underlying KD treatment may be related to neuroprotection (Hallböök, Ji, Maudsley, & Martin, ), a reduction in clinical seizure activity, improved energy metabolism, and a reduction in stress‐induced biochemical effects within the hippocampus, thus improving the internal environment and improving cognitive and behavioral function (Brownlow, Jung, Moore, Bechmann, & Jankord, ).…”