LAUSR

Objectives Sweetened beverage (SB) consumption is highly associated with obesity, but the mechanism underlying this correlation is not understood. Our objective was to examine metabolomic links between SB intake and obesity to understand metabolic mechanisms. Methods We examined the association of plasma metabolomic profiles with SB intake and obesity risk in 782 participants, aged 45-75y, in the Boston Puerto Rican Health Study (BPRHS) using linear regression models, controlling for potential confounding factors. Based on identified metabolites, we conducted pathway enrichment analysis to identify potential metabolic pathways that link SB intake and obesity risk. Genetic variants in identified metabolic pathways were examined for their interaction with SB intake on metabolites of interest and obesity. Interactions between SB and genotypes on obesity were evaluated for replication in the Framingham Heart Study (FHS). Results In BPRHS, SB intake was highly correlated with BMI (β = 0.455, P < 0.05). Among 526 measurable metabolites, 109 metabolites showed significant correlation with SB intake and 170 metabolites with BMI (P < 0.05); and 43 were correlated with both SB intake and BMI. Pathway enrichment analysis identified two metabolic pathways: phosphatidylethanolamine (PE) and lysophospholipid pathways linking SB intake and obesity, after correction for multiple testing. Focusing on the PE pathway, we identified 12 SNPs in nine genes that were significantly associated with BMI. At least four genetic variants showed suggestive interaction with SB intake on obesity risk and obesity-associated metabolites. In particular, CC carriers of rs4646360 in the PEMT (Phosphatidylethanolamine N-Methyltransferase) gene had increased risk of obesity when consuming SB. We replicated this finding in the FHS study. Conclusions We identified two key metabolic pathways linking SB intake to obesity, revealing potential mechanisms by which SB intake increases the risk of obesity. The interaction between genetic variants in the identified pathway and SB intake on obesity and obesity-associated metabolites further supports the mechanism. Funding Sources This work was funded by the US Department of Agriculture, under agreement no. 8050-51,000-098-00D, and NIH grants P01 AG023394, P50 HL105185, and R01 AG027087.