TY - JOUR
T1 - Increased dynamics of tricarboxylic acid cycle and glutamate synthesis in obese adipose tissue
T2 - In vivo metabolic turnover analysis
AU - Nagao, Hirofumi
AU - Nishizawa, Hitoshi
AU - Bamba, Takeshi
AU - Nakayama, Yasumune
AU - Isozumi, Noriyoshi
AU - Nagamori, Shushi
AU - Kanai, Yoshikatsu
AU - Tanaka, Yoshimitsu
AU - Kita, Shunbun
AU - Fukuda, Shiro
AU - Funahashi, Tohru
AU - Maeda, Norikazu
AU - Fukusaki, Eiichiro
AU - Shimomura, Iichiro
N1 - Funding Information:
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. We thank Yu Tsushima for helpful discussions and technical advice. We also thank Kayoko Ohashi (Department of Metabolic Medicine, Graduate School of Medicine, Osaka University), Takanori Kobayashi, and Satori Matsumoto (Department of Bio-system Pharmacology, Graduate School of Medicine, Osaka University) for excellent technical assistance and all members of the IIIrd laboratory (Adiposcience Laboratory), Department of Metabolic Medicine, Osaka University, for helpful discussions.
Publisher Copyright:
© 2017 by The American Society for Biochemistry and Molecular Biology, Inc.
PY - 2017/3/17
Y1 - 2017/3/17
N2 - 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.
AB - 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.
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U2 - 10.1074/jbc.M116.770172
DO - 10.1074/jbc.M116.770172
M3 - Article
C2 - 28119455
AN - SCOPUS:85015337862
VL - 292
SP - 4469
EP - 4483
JO - Journal of Biological Chemistry
JF - Journal of Biological Chemistry
SN - 0021-9258
IS - 11
ER -