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1,3‐Butanediol at 5% v/v best mimics the systemic and urinary concentrations of β‐hydroxybutyrate after a 24 h fast in adult rats

Ketogenic diets are trendy in the nutrition community as promoters of rapid weight loss for improved cardiometabolic health. In the absence of carbohydrates and increased consumption of fats, ketone bodies become the primary energy source via free fatty acid oxidation, and this state of ketosis mimics what occurs during starvation. β‐hydroxybutyrate (βHB) is the most abundant circulating ketone body. βHB is synthesized in the liver and transported to the peripheral tissues for conversion into energy. To study the long‐term consequences of enhanced βHB bioavailability, the secondary alcohol, 1,3‐butanediol (1,3‐BD), is commonly administered in drinking water as a precursor. After consumption, 1,3‐BD is catabolized by the liver into βHB. However, the concentration of 1,3‐BD that best represents the circulating concentration of βHB after fasting is currently unknown. The objective of the current work was to determine what concentration of 1,3‐BD best mimics the concentration of βHB after a 24 h fast in male adult rats. To test this objective, 40‐week old Wistar‐Kyoto rats were administered with or without 5%, 10%, or 20% v/v 1,3‐BD in drinking water. All rats had free access to food throughout the investigation, although some vehicle‐treated rats were fasted for the final 24 h before study termination to serve as a positive control. While 5% and 10% 1,3‐BD increased βHB in the systemic circulation 1.5‐fold (p<0.05), similar to an overnight fast, which was increased 2.0‐fold (p<0.05), 20% 1,3‐BD increased βHB by 4.5‐fold (p<0.05). On the other hand, fasting and 5% 1,3‐BD did not change urinary βHB, whereas 10% and 20% 1,3‐BD increased urinary βHB by 3‐fold and (p<0.05) and 10‐fold (p<0.05), respectively. No difference in fasting blood glucose was observed in any of the 1,3‐BD groups. Rats treated with 20% 1,3‐BD had a dramatic and sustained decrease in body mass as early as one week after treatment commencement (19±4 g, p<0.05). Consumption of normal chow was decreased relative to vehicle in all three groups of 1,3‐BD (p<0.05), but fluid consumption and urine volume was only decreased in the 20% group (p<0.05). The 20% group, similar to the vehicle‐fasting group, also presented with increased red blood cells (1012/L, vehicle‐non‐fasting: 9.24±0.10, vehicle‐fasting: 9.82±0.26*, and 20%: 9.74±0.20*, p<0.05) and hematocrit (%, vehicle‐non‐fasting: 44.00±0.82, vehicle‐fasting: 46.53±1.10*, and 20%: 46.73±0.78*, p<0.05), indicative of dehydration. Finally, the 20% 1,3‐BD group presented with an increased anion gap (p<0.05), a clinically used marker of metabolic acidosis. In summary, our data suggests that 5% 1,3‐BD best represents the circulatory and urinary concentrations of βHB after a 24 h fast, and overall, we recommend this concentration of 1,3‐BD as the most optimal to understand the physiological significance of fasting‐induced βHB.