2009 Fiscal Year Final Research Report
Molecular mechanisms for dysfunction of obese adipose tissue focusing on the network of NADPH producing enzymes and intracellular glucocorticoid reactivating enzyme
Project/Area Number |
19390248
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Research Category |
Grant-in-Aid for Scientific Research (B)
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Allocation Type | Single-year Grants |
Section | 一般 |
Research Field |
Metabolomics
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Research Institution | Kyoto University |
Principal Investigator |
MASUZAKI Hiroaki Kyoto University, 医学部, 教授 (00291899)
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Co-Investigator(Renkei-kenkyūsha) |
TAMORI Yoshikazu 神戸大学, 医学部, 助手 (90379397)
MINOKOSHI Yasuhiko 生理学研究所, 発達生理学系, 教授 (10200099)
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Project Period (FY) |
2007 – 2009
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Keywords | 糖尿病 / 脂肪組織 / グルココルチコイド / 肥満症 / 11β-HSD1 / 炎症 |
Research Abstract |
Elevated expression and activity of the intracellular glucocorticoid reactivating enzyme, 11beta-hydroxysteroid dehydrogenase type 1 (11β-HSD1), contribute to dysfunction of obese adipose tissue. Although the pathophysiologic role of 11β-HSD1 in obese adipose tissue has long been investigated, the mechanism whereby 11β-HSD1 is augmented in obese adipose tissue still remains obscure. In this context, in the present study, we investigated the possible involvement of chronic inflammation, oxidative stress, ceramide signals and NADPH provision from enzymes comprising of pentose pathways. In cultured adipocytes and SVF cells from obese adipose tissue from mice, enzyme activity and expression of 11β-HSD1 was augmented by TNFα, IL-1β, LPS and ceramide. Pharmacological inhibition of 11β-HSD1 and RNA interference against 11β-HSD1 reduced a line of pro-inflammatory molecules as well as substantially attenuated NF-kβ and MAPK inflammatory signaling in cultured adipocytes. Expression of enzymes comprising of pentose pathways was elevated in obese adipose tissue in proportion to the degree of obesity in both humans and mice. Forced expression of glucose-6-phosphate dehydrogenase (G6PD), a member of pentose pathways, in adipocytes augmented intracellular glucocorticoid reamplification and resultant secretion of cortisol into the media, indicating a functional link between 11β-HSD1 and NADPH provision in obese adipose tissue. Our data highlight an unexpected role of reamplified glucocorticoids and molecular basis for augmented 11β-HSD1 in obese adipose tissue.
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Research Products
(61 results)
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[Journal Article] Adipose Tissue-Specific Dysregulation of Angiotensinogen in Obese Humans and Mice-Impact of Nutritional Status and Adipocyte Hypertrophy-.2010
Author(s)
S. Yasue, H. Masuzaki (corresponding author), S. Okada, T. Ishii, C. Kozuka, T. Tanaka, J. Fujikura, K. Ebihara, K. Hosoda, A. Katsurada, N. Ohashi, M. Urushihara, H. Kobori, N. Morimoto, T. Kawazoe, M. Naitoh, M. Okada, H. Sakaue, S. Suzuki, K. Nakao
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Journal Title
Am J Hypertens 23
Pages: 425-431
Peer Reviewed
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[Journal Article] Glucocorticoid Reamplification within Cells Intensifies NF・B and MAPK Signaling and Reinforces Inflammation in Activated Preadipocytes.2010
Author(s)
T. Ishii-Yonemoto, H. Masuzaki (corresponding author), S. Yasue, S. Okada, C. Kozuka, T. Tanaka, M. Noguchi, T. Tomita, J. Fujikura, Y. Yamamoto, K. Ebihara, K. Hosoda, K. Nakao
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Journal Title
Am. J. Physiol 298
Pages: E930-E940
Peer Reviewed
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[Journal Article] Adipose Tissue-Specific Dysregulation of Angiotensinogen by Oxidative Stress in Obesity.2010
Author(s)
S. Okada, C. Kozuka, H. Masuzaki (corresponding author), S. Yasue, T. Ishii-Yonemoto, T. Tanaka, Y. Yamamoto, M. Noguchi, T. Kusakabe, T. Tomita, J. Fujikura, K. Ebihara, K. Hosoda, H. Sakaue, H. Kobori, M. Ham, YS. Lee, JB. Kim, Y. Saito, K. Nakao
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Journal Title
Peer Reviewed
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[Journal Article] Index of Systemic Balance of End Products of Glucocorticoid Metabolism in Fresh Urine from Humans: Its Potential Usefulness in the Evaluation of Obesity-Related Diseases.2009
Author(s)
N. Kobayashi, H. Masuzaki (corresponding author), T. Tanaka, S. Yasue, T. Ishii, N. Arai, T. Tomita, T. Miyawaki, T. Komeda, Y. Fukuda, N. Satoh, T. Kusakabe, M. Noguchi, J. Fujikura, F. Miyanaga, K. Ebihara, M. Hirata, K. Hosoda, H. Miyata, TS. Sato, K. Nakao
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Journal Title
Obes Res Clin Pract 3
Pages: 53-63
Peer Reviewed
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[Journal Article] Beneficial Effects of Leptin on Glycemic and Lipid Control in a Mouse Model of Type 2 Diabetes with Increased Adiposity Induced by Streptozotocin and a High-Fat Diet.2009
Author(s)
T. Kusakabe, H. Tanioka, K. Ebihara, M. Hirata, L. Miyamoto, F. Miyanaga, H. Hige, D. Aotani, T. Fujisawa, H. Masuzaki, K. Hosoda, K. Nakao
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Journal Title
Diabetologia 52
Pages: 675-683
Peer Reviewed
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[Journal Article] A Case of Cortisol Producing Adrenal Adenoma without Phenotype of Cushing's Syndrome due to Impaired 11β-Hydroxysteroid Dehydrogenase 1 Activity.2008
Author(s)
H. Arai, N. Kobayashi, Y. Nakatsuru, H. Masuzaki, T. Nanbu, K. Takaya, Y. Yamanaka, E. Kondo, G. Yamada, T. Fujii, M. Miura, Y. Komatsu, N. Kanamoto, H. Ariyasu, K. Moriyama, A. YasodaK, K. Nakao
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Journal Title
Endocrine J 54
Pages: 709-715
Peer Reviewed
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[Journal Article] Augmentation of 11β-hydroxysteroid dehydrogenase type 1 in LPS-activated J774. 1 macrophages-Role of 11β-HSD1 in pro-inflammatory properties in macrophages-.2007
Author(s)
T. Ishii, H. Masuzaki (corresponding author), T. Tanaka, N. Arai, S. Yasue, N. Kobayashi, M. Noguchi, J. Fujikura, K. Ebihara, K. Hosoda, K. Nakao
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Journal Title
FEBS Lett 581
Pages: 349-354
Peer Reviewed
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[Journal Article] Bezafibrate regulates the expression and enzyme activity of 11β-hydroxysteroid dehydrogenase type 1 in murine adipose tissue and 3T3-L1 adipocytes.2007
Author(s)
S. Nakano, Y. Inada, H. Masuzaki (corresponding author), T. Tanaka, S. Yasue, T. Ishii, N. Arai, K. Ebihara, K. Hosoda, K. Maruyama, Y. Yamazaki, N. Shibata, K. Nakao
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Journal Title
Am. J. Physiol. 292
Pages: E1213-E1222
Peer Reviewed
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[Journal Article] Efficacy and safety of leptin-replacement therapy and possible mechanisms of leptin actions in patients with generalized lipodystrophy.2007
Author(s)
K. Ebihara, T. Kusakabe, M. Hirata, H. Masuzaki, F. Miyanaga, N. Kobayashi, T. Tanaka, H. Chusho, T. Miyazawa, T. Hayashi, K. Hosoda, Y. Ogawa, A.M. Depaoli, M. Fukushima, K. Nakao.
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Journal Title
J. Clin. Endocrinol. Metab. 92
Pages: 532-541
Peer Reviewed
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[Journal Article] Central melanocortin signaling restores skeletal muscle AMP-activated protein kinase phosphoylation in mice fed a high fat diet.2007
Author(s)
T. Tanaka, H. Masuzaki (corresponding author), S. Yasue, K. Ebihara, T. Shiuchi, T. Ishii, N. Arai, M. Hirata, H. Yamamoto, T. Hayashi, K. Hosoda, Y. Minokoshi, K. Nakao
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Journal Title
Cell Metabolism 5
Pages: 395-402
Peer Reviewed
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[Journal Article] Ceramide and AMP-activated Protein Kinase areTwo Novel Regulators of 11β-Hydroxysteroid Dehydrogenase Type 1 Expression and Actovity in Cultured Preadipocytes.2007
Author(s)
N. Arai, H. Masuzaki(corresponding author), T. Tanaka, T. shii, S. Yasue, N. Kobayashi, T. Tomita, M. Noguchi, T. Kusakabe, H. Tanioka, H. Hige, F. Miyanaga, J. Fujikura, K. Ebihara, M. Hirata, K. Hosoda, H. Sawai, Y. Minokoshi, K. Nakao
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Journal Title
Endocrinology 148
Pages: 5268-5277
Peer Reviewed
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[Journal Article] Genetic and Pharmacological Inhibition of Rho-Associated Kinase II Enhances Adipogenesis.2007
Author(s)
M. Noguchi, K. Hosoda, J. Fujikura, M. Fujimoto, H. Iwakura, T. Tomita, T. Ishii, N. Arai, M. Hirata, K. Ebihara, H. Masuzaki, H. Itoh, S. Narumiya, K. Nakao
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Journal Title
J Biol Chem 282
Pages: 29574-29583
Peer Reviewed
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