Physiologic, Metabolic, and Toxicologic Profile of 1,3-Butanediol

Abstract

Ketone bodies are essential energy substrates in the absence of exogenous nutrients, and more recently, they have been suggested to prevent disease and improve longevity. βhydroxybutyrate (βHB) is the most abundant ketone body. The secondary alcohol, 1,3-butanediol (1,3-BD), is commonly administered to raise βHB bioavailability in vivo and in the absence of nutrient deprivation. However, the concentration of 1,3-BD that yields a systemic concentration of βHB similar to that observed after a 24 h fast has yet to be determined. To evaluate this knowledge gap, we administered 5%, 10%, or 20% 1,3-BD via the drinking water to adult, male Wistar-Kyoto rats for four weeks. In addition to systemic and excreted βHB concentration, physiologic, metabolic, and toxicologic parameters were measured. We report that only 20% 1,3-BD significantly elevates the systemic and urinary concentrations of βHB. Rats treated with 20% 1,3-BD had a rapid and sustained reduction in body mass. All concentrations of 1,3-BD decreased food consumption, but only the 20% concentration decreased fluid consumption.Urine volume, red blood cell count, and hematocrit suggested dehydration in the 10% and 20% 1,3-BD treated rats. Finally, 20% 1,3-BD treated rats presented with indicators of metabolic acidosis and sinusoidal dilation, but no evidence of fatty liver or hepatotoxicity. In summary, we report that 20% 1,3-BD, but not 5% or 10%, produces a systemic concentration of βHB similar to that observed after a 24 h fast. However, this concentration is associated with deleterious side effects such as body mass loss, dehydration, metabolic acidosis, and sinusoidal dilation.Significance statement: 1,3-Butanediol (1,3-BD) is often administered to stimulate the biosynthesis of the most abundant ketone body, β-hydroxybutyrate (βHB), and its purported salubrious effects. Here, we report that supra-pharmacological concentrations of 1,3-BD are This article has not been copyedited and formatted. The final version may differ from this version.

Exogenous Ketone Supplements in Athletic Contexts: Past, Present, and Future

“…MCTs contain fatty acids 6-12 carbons in length (i.e. MCFAs), and examples include caproic acid (C6), caprylic acid (C8), capric acid (C10), and lauric acid (C12) [318] Compared with long chain fatty acids (LCFAs) being absorbed via the lymphatic system, MCFAs can be absorbed via hepatic portal circulation and enter the hepatic mitochondria without requiring carnitine transport, where they are rapidly metabolised to acetyl CoA, and subsequently to KBs [195] MCTs and MCFAs are therefore considered ketogenic fats as they result in ketogenesis without requiring dietary CHO restriction Ingestion of MCFA increases circulating [R-βHB] in a dosedependent manner, with ~ 25 to ~ 30 g and ~ 85 g elevating concentrations to ~ 0.5 mM and ~ 0.9 to ~ 1.5 mM during submaximal exercise, respectively [215,216,220] 1,3-butanediol (BD) BD was developed in 1958 as an alternative source of energy intake for manned space travel and provides ~ 6 kcal.g −1 in rodents BD is converted to β-hydroxybutyraldehyde in the liver, and oxidised to R,S-βHB via the action of alcohol and aldehyde dehydrogenase, respectively [18] Ingestion of BD therefore can increase circulating [βHB] in isolation, or can augment increases in circulating [βHB] in response to ketone ester ingestion when present as an esterified component of R-BD R-βHB KME or R,S-BD AcAc KDE with βHB or AcAc, respectively…”

“…Early forms included glycerol monobutyrate [ 9 ], monoacetoacetin, a monoester of glycerol and AcAc [ 10 , 11 ], triesters of glycerol and AcAc, and monoesters and triesters of glycerol and βHB [ 13 ]. As well as glycerol, R,S-1,3-butanediol (BD) can be esterified to βHB or AcAc, with BD itself in turn elevating [βHB] given its action as a ketogenic precursor [ 17 , 18 ].…”

Integrated Metabolomics, Lipidomics, and Genomics Reveal the Presence of a New Biomarker, Butanediol Glucuronide, Associated with the Activation of Liver Ketogenesis and Lipid Oxidation by Tomato-Based Sofrito in Obese Rats

“…It has recently been reported that a decreased mitochondrial fuel supply in the liver may optimize the balance between energy supply and demand in a way that may not decrease steatosis but may decrease tissue damage and insulin resistance [ 46 , 47 ]. Ketogenic diets, in which carbohydrates are absent and calories restricted, generate ketone bodies, the primary source of energy for the oxidation of free fatty acids [ 46 , 48 ]. Recently, ketone bodies have been suggested as a fuel for mitochondria and a prominent activator of mitochondrial bioenergetics in adipose tissue that could be a tool in obesity control [ 49 ].…”

“…Butanediol has been described as a precursor molecule of β-hydroxybutyrate, a ketone body, which plays significant roles in energy homeostasis, being used as an oxidative fuel, lipogenic precursor, and signaling molecule. β-hydroxybutyrate is predominantly synthesized in the liver, being the most abundant ketone body in the circulation, and transported to other tissues for conversion into energy [ 46 , 48 ]. In an established obesity state, insulin resistance can lead to a lack of energy in peripheral tissues and the production of ketone bodies could be a compensatory mechanism.…”

Six Decades of History of Hypertension Research at the University of Toledo: Highlighting Pioneering Contributions in Biochemistry, Genetics, and Host-Microbiota Interactions

“…Yet another significant contribution from the Joe laboratory is the discovery of the strong link between metabolism [ 189 •], especially the inverse relationship between the ketone body, betahydroxybutyrate (BHB), and hypertension [ 190 ]. Both renal and vascular mechanisms have been identified via BHB facilitating the inhibition of the Nlrp3 inflammasome and vasodilatory function, respectively [ 191 – 193 ].…”