Portal vein-enriched metabolites as intermediate regulators of the gut microbiome in insulin resistance

Diet and obesity contribute to insulin resistance and type 2 diabetes, in part via the gut microbiome. To explore the role of gut-derived metabolites in this process, we assessed portal/peripheral blood metabolites in mice with different risks of obesity/diabetes, challenged with a high-fat diet (HFD) + antibiotics. In diabetes/obesity-prone C57BL/6J mice, 111 metabolites were portally enriched and 74 were peripherally enriched, many of which differed in metabolic-syndrome-resistant 129S1/129S6 mice. Vancomycin treatment of HFD-fed C57BL/6J mice modified the microbiome and the portal/peripheral ratio of many metabolites, including upregulating tricarboxylic acid (TCA) cycle-related metabolites, like mesaconate, in portal blood. Treatment of isolated hepatocytes with mesaconate, itaconate, or citraconate improved insulin signaling and transcriptionally regulated genes involved in gluconeogenesis, fatty acid oxidation, and lipogenesis in vitro and in vivo. In humans, citraconate levels are inversely correlated with plasma glucose. Thus, portal versus peripheral metabolites play important roles in mediating effects of the microbiome on hepatic metabolism and the pathogenesis of HFD-related insulin resistance.