Increased Dynamics of Tricarboxylic Acid Cycle and Glutamate Synthesis in Obese Adipose Tissue

• Published in: The Journal of biological chemistry 2017-03, Vol.292 (11), p.4469-4483
• Main Authors: Nagao, Hirofumi, Nishizawa, Hitoshi, Bamba, Takeshi, Nakayama, Yasumune, Isozumi, Noriyoshi, Nagamori, Shushi, Kanai, Yoshikatsu, Tanaka, Yoshimitsu, Kita, Shunbun, Fukuda, Shiro, Funahashi, Tohru, Maeda, Norikazu, Fukusaki, Eiichiro, Shimomura, Iichiro
• Format: Article
• Language: English
• Subjects: adipocyte; adipose tissue metabolism; glutamate; metabolomics; obesity
• ISSN: 0021-9258; 1083-351X
• DOI: 10.1074/jbc.M116.770172

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.