Erythritol is a pentose-phosphate pathway metabolite and associated with adiposity gain in young adults

Abstract

Metabolomic markers associated with incident central adiposity gain were investigated in young adults. In a 9-mo prospective study of university freshmen (n = 264). Blood samples and anthropometry measurements were collected in the first 3 d on campus and at the end of the year. Plasma from individuals was pooled by phenotype [incident central adiposity, stable adiposity, baseline hemoglobin A1c (HbA1c) > 5.05%, HbA1c < 4.92%] and assayed using GC-MS, chromatograms were analyzed using MetaboliteDetector software, and normalized metabolite levels were compared using Welch's t test. Assays were repeated using freshly prepared pools, and statistically significant metabolites were quantified in a targeted GC-MS approach. Isotope tracer studies were performed to determine if the potential marker was an endogenous human metabolite in men and in whole blood. Participants with incident central adiposity gain had statistically significantly higher blood erythritol [P < 0.001, false discovery rate (FDR) = 0.0435], and the targeted assay revealed 15-fold [95% confidence interval (CI): 13.27, 16.25] higher blood erythritol compared with participants with stable adiposity. Participants with baseline HbA1c > 5.05% had 21-fold (95% CI: 19.84, 21.41) higher blood erythritol compared with participants with lower HbA1c (P < 0.001, FDR = 0.00016). Erythritol was shown to be synthesized endogenously from glucose via the pentose-phosphate pathway (PPP) in stable isotope-assisted ex vivo blood incubation experiments and through in vivo conversion of erythritol to erythronate in stable isotope-assisted dried blood spot experiments. Therefore, endogenous production of erythritol from glucose may contribute to the association between erythritol and obesity observed in young adults.

Keywords: adiposity; erythritol; metabolomics; pentose-phosphate pathway; weight gain.

Fig. 1.

Quantitative GC-MS measurement of erythritol and erythronate in dried blood spots from three healthy donors. After ingestion of 50 g of erythritol (blue lines), an immediate increase of erythronate concentrations was observed (red lines).

Fig. 2.

M4 erythritol enrichment after supplementing [U¹³C₆]glucose in whole blood. Significant amounts of fully labeled (M4) erythritol were synthesized by endogenous activity in the blood cells 120 min after tracer addition (*P = 0.01 by Welch’s t test). n.s., not significant (P > 0.05).

Fig. 3.

Atom transitions within the PPP and erythritol labeling from glucose. (A) Erythritol (Ery) is synthesized from glucose via the PPP from glucose-6-phosphate (G6P). First, a [1,2-¹³C₂]glucose tracer, which contains stable isotopes at the first two positions, was used. Based on the atom transitions of the oxidative and reductive PPP, no significant isotopic enrichment in erythritol was expected. Second, a [3,4-¹³C₂]glucose tracer was applied; in this case, the synthesis of M2 erythritol isotopologs was predicted. Third, a [6-¹³C₁]glucose tracer was applied. (B) First, incubation of human blood cells with [1,2-¹³C₂]glucose did not produce significant amounts of enriched erythritol. Second, as expected, twofold-labeled (M2) erythritol isotopologs emerged after addition of the [1,2-¹³C₂]glucose tracer to the blood cells. Third, the expected appearance of onefold-labeled (M1) erythritol isotopologs was observed after the [6-¹³C₁]glucose tracer was applied. The amounts of [1,2-¹³C₂]glucose (1,2-¹³C₂ Glc) yielding nonlabeled (M0) erythritol, [3,4-¹³C₂]glucose (3,4-¹³C₂ Glc) yielding M2 erythritol, and [6-¹³C₁]glucose (6-¹³C₁ Glc) yielding M1 erythritol are shown after incubation with the respective tracer for 120 min (**P < 0.01 and ***P < 0.001 by Student’s t test). F6P, fructose 6-phosphate; G3P, glyceraldehyde 3-phosphate; R5P, ribose 5-phosphate; S7P, sedoheptulose 7-phosphate; X5P, xylulose 5-phosphate.