Effect of Sustaining Dietary Ketosis on the Hippocampal and Serum Metabolome of Sprague‐Dawley Rats

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The ketogenic diet (KD) has been successfully used to treat pediatric refractory epilepsy since the 1920s and is currently being investigated as an adjunct treatment for many disease states. The therapeutic efficacy of the KD results from an elevation of blood ketones. We previously reported that oral administration of ketone supplements produced nutritional ketosis (>0.5 mM) without carbohydrate restriction and the effects of a 28-day administration of five ketone supplements on blood glucose, ketones, and lipids in male Sprague-Dawley rats. We hypothesized that the 28-day administration would affect metabolomic markers. Serum (~300 μL) and hippocampal tissues for ketone supplements 1,3 butanediol acetoacetate diester (KE) and (1:1 mixture of sodium/potassium beta-hydroxybutyrate mineral salt solution (BMS) and medium chain triglyceride oil (MCT)) BMS+MCT were collected on day 28 at 4 hours post-intragastric gavage (peak ketone elevation). Metabolon analyzed samples by gas and liquid chromatography in tandem with mass spectrometry. Both ketone supplements significantly increased serum TCA cycle intermediates: citrate, fumarate and malate. KE supplement significantly increased alpha-ketoglutarate and BMS+MCT supplement significantly increased succinate in the rat serum. Additionally, both supplements affected medium chain fatty acids, dicarboxylic acids, adenosine, inflammatory mediators, antioxidants, and bile acids in both serum and hippocampal tissue. Although both forms of ketone supplementation increased brain and blood ketone levels, the global metabolic profiles were different.