Metabolism
Increased Dynamics of Tricarboxylic Acid Cycle and Glutamate Synthesis in Obese Adipose Tissue: IN VIVO METABOLIC TURNOVER ANALYSIS*

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Obesity is closely associated with various metabolic disorders. However, little is known about abnormalities in the metabolic change of obese adipose tissue. Here we use static metabolic analysis and in vivo metabolic turnover analysis to assess metabolic dynamics in obese mice. The static metabolic analyses showed that glutamate and constitutive metabolites of the TCA cycle were increased in the white adipose tissue (WAT) of ob/ob and diet-induced obesity mice but not in the liver or skeletal muscle of these obese mice. Moreover, in vivo metabolic turnover analyses demonstrated that these glucose-derived metabolites were dynamically and specifically produced in obese WAT compared with lean WAT. Glutamate rise in obese WAT was associated with down-regulation of glutamate aspartate transporter (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 a high intra-adipocyte glutamate level potentially relates to adipocyte dysfunction in obesity. This study provides novel insights into metabolic dysfunction in obesity through comprehensive application of in vivo metabolic turnover analysis in two obese animal models.

adipocyte
adipose tissue metabolism
glutamate
metabolomics
obesity

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*

This work was supported in part by Grant-in-Aid for Scientific Research (C) 15K09412 (to H. Nishizawa), Grant-in-Aid for Scientific Research (B) 26293221 (to T. F.), Grant-in-Aid for Scientific Research Innovative Areas “HD Physiology” 25136714 (to S. N.) from the Ministry of Education, Culture, Sports, Science, and Technology of Japan and Core Research for Evolutional Science and Technology (CREST) program of Japan Science and Technology Agency (JST) (to E. F and I. S.). S. K., T. F., and N. M. are members of the Department of Metabolism and Atherosclerosis, a sponsored course endowed by Kowa Co. Ltd. The company has a scientific officer who oversees the program.

This article contains supplemental Figs. S1–S4 and Tables S1 and S2.