Increased Dynamics of Tricarboxylic Acid Cycle and Glutamate Synthesis in Obese Adipose Tissue: In vivo Metabolic Turnover Analysis

Abstract Obesity locates upstream of various metabolic disorders. However, little is known about abnormalities in metabolic change of obese adipose tissue. Here, we use static metabolic analysis and in vivo metabolic turn over analysis to assess metabolic dynamics in obese mice. The static metabolic analyses showed that glutamate and constitutive metabolites of tricarboxylic acid (TCA) cycle were increased in white adipose tissue (WAT) of ob/ob and diet-induced obesity (DIO) mice, but not in liver or skeletal muscle of these obese mice. Moreover, in vivo metabolic turnover analyses demonstrated that glucose-derived these metabolites were dynamically and specifically produced in obese WAT, compared to lean WAT. Glutamate rise in obese WAT was associated with downregulation of GLAST, a major glutamate transporter for adipocytes, and low uptake of glutamate into adipose tissue. In adipocytes, glutamate treatment reduced adiponectin secretion and insulin-mediated glucose uptake and phosphorylation of Akt. These data suggest that high intra-adipocytes glutamate level potentially relates to adipocyte dysfunction in obesity. The study provides novel insight of metabolic dysfunction in obesity through comprehensive application of in vivo metabolic turnover analysis in two obese animal models.