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

Significance

The prevention of weight gain in adulthood is a public health challenge, particularly given the difficulty of losing weight. Data on freshmen were collected at the beginning and end of the academic year, and baseline blood samples were studied to find markers of incident weight gain. A metabolite, erythritol, was elevated at the beginning of the year in freshmen who went on to gain weight, fat, and abdominal fat compared with freshmen with stable weight. Erythritol is a sugar substitute low-calorie sweetener, and prior studies claimed no endogenous synthesis. We report a previously unrecognized metabolism of glucose to erythritol, and given the association between erythritol and weight gain, research is needed to understand whether and how this pathway contributes to weight gain risk.

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.