| 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 |
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| Section | 一般 |
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| Research Field |
Metabolomics
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| Research Institution | Kyoto University |
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Principal Investigator |
MASUZAKI Hiroaki Kyoto University, 医学部, 教授 (00291899)
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| Co-Investigator(Kenkyū-buntansha) |
田守 義和 神戸大学, 医学系研究科, 助教 (90379397)
箕越 靖彦 生理学研究所, 発達生理学系, 教授 (10200099)
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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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| Project Status |
Completed (Fiscal Year 2009)
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| Budget Amount *help |
¥18,070,000 (Direct Cost: ¥13,900,000、Indirect Cost: ¥4,170,000)
Fiscal Year 2009: ¥6,110,000 (Direct Cost: ¥4,700,000、Indirect Cost: ¥1,410,000)
Fiscal Year 2008: ¥6,110,000 (Direct Cost: ¥4,700,000、Indirect Cost: ¥1,410,000)
Fiscal Year 2007: ¥5,850,000 (Direct Cost: ¥4,500,000、Indirect Cost: ¥1,350,000)
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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 / 肥満 / 酸化ストレス / G6PD / コルチゾル / NADPH / 代謝学 / 糖尿病学 |
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| 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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