Characterizing the physiologic effects of exogenous ketone supplements – an alternative or adjuvant to the ketogenic diet

Abstract

The ketogenic diet (KD) is a high fat, adequate protein, low carbohydrate diet that is used clinically for refractory pediatric epilepsy, and is under investigation as a treatment for a wide variety of disorders, including many neurological diseases, cancer, obesity, and diabetes. Studies suggest that many of the beneficial effects associated with the KD are mechanistically attributable to the ketone bodies, leading our lab and others to develop and test exogenous ketone supplements (KS). KS elevate blood ketones without the need for dietary restriction of carbohydrate. In order to further our understanding of this new technology, we sought to characterize the metabolic effects, safety, and toxicity of KS in healthy rats. KS tested include the R,S‐1,3‐butanediol acetoacetate diester, 1,3‐butanediol, medium chain triglyceride oil, caprylic acid, and beta‐hydroxybutyrate mineral salts, alone and in various combinations. Healthy rats were administered KS by oral gavage or in their food in an acute (once, or 7 days), sub‐chronic (1 month) or chronic (4 months) fashion and analyzed for a variety of metabolic and physiologic biomarkers. KS rapidly elevate blood ketones to therapeutic levels (2–5mM), and simultaneously decrease blood glucose. Some types of KS induce a mild calorie restriction effect, and preliminary evidence suggests ketone ester treatment during CR may preserve lean muscle mass in this catabolic state via a non‐insulin dependent mechanism. Satiety may be increased by KS as demonstrated by an elevation in leptin following KE administration, even when animals were self calorie‐restricting. KS significantly alters the global metabolome, indicating a shift from carbohydrate‐based to fat‐based metabolism. Some markers of this were an elevation in medium chain fatty acids, an increase in acetyl coA and acetylcarnitine suggestive of enhanced mitochondrial LCFA oxidation, and an increase in Kreb's cycle intermediates such as citrate, succinate, and fumarate. Inflammatory profiling following chronic, but not acute, KS administration revealed decreases in many pro‐inflammatory cytokines, including IL‐1β, IL‐6, IFN‐γ, MCP‐1, and RANTES. KS appears safe as there were no signs of toxicity or adverse changes in total cholesterol, HDL, LDL, triglycerides, or markers of liver/kidney function over the chronic treatment protocol. KS may be a useful alternative or adjuvant to the KD for disorders where nutritional ketosis is therapeutic.Support or Funding InformationOffice of Naval Research, Scivation Inc, Disruptive Nutrition, Epigenix FoundationThis abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.