The 2R, 3R isomer of 2, 3-butanediol prevents weight gain and decreases plasma glucose concentration of mice fed a fat-enriched diet.

BACKGROUND: We have previously shown that, in comparison with wild-type mice, mice that lack a functional flavin-containing monooxygenase 5 gene (Fmo5-/- mice) exhibit reduced weight gain as they age, reduced fat deposition, and lower plasma concentrations of total cholesterol and glucose. We also identified isomers of 2, 3-butanediol as urinary biomarkers of Fmo5-/- mice. Treatment of male, wild-type mice fed a standard chow diet, with a 2, 3-butanediol isomer mix resulted in reduced epidydimal fat deposition and lower plasma cholesterol concentration. In the current study we explored the influence of individual isomers of 2, 3-butanediol on weight gain and plasma metabolite concentrations of wild-type mice fed a fat-enriched diet. We also investigated the effect of 2, 3-butanediol isomers on liver metabolites and gut microbiota.

METHODS: Mice were fed a standard chow or a 16% fat-enriched diet. Mice on the fat-enriched diet were untreated or treated with 2R, 3R-butanediol, 2S, 3S-butanediol, meso-2, 3-butanediol or a mix of the three isomers. Mice were analyzed for weight, plasma and liver metabolite concentrations and gut microbiota composition.

RESULTS: Treatment with 2R, 3R-butanediol prevented weight gain and decreased plasma glucose concentration of mice fed the fat-enriched diet. 2R, 3R-Butanediol increased the concentrations of three of the 693 liver metabolites identified: indolepropionate, N-delta-acetylornithine and 1-myristoyl-2-arachidonoyl-glycerophosphorylcholine (14:0/20:4). In comparison with untreated mice fed the fat-enriched diet, the gut microbiota of mice treated with 2R, 3R-butanediol was depleted in the Bacteroidota (Bacteroidetes) phylum and enriched in the Actinomycetota phylum, particularly in two species of Bifidobacterium, B. globosum and B. 388775.

CONCLUSIONS: We have identified 2R, 3R-butanediol as an effective anti-obesogenic agent that prevents weight gain and decreases plasma glucose of mice fed a fat-enriched diet. The effect of 2R, 3R-butanediol may be due, in part, to its ability to increase the concentration of indolepropionate in the liver and of the proportion of Bifidobacterium species in the gut microbiota, both of which are known to have beneficial effects on weight control and plasma glucose concentration. Our results suggest that 2R, 3R-butanediol may be of value as a therapeutic agent to suppress weight gain in humans.