Molecular mechanisms for dysfunction of obese adipose tissue focusing on the network of NADPH producing enzymes and intracellular glucocorticoid reactivating enzyme

肥胖脂肪组织功能障碍的分子机制，重点关注 NADPH 产生酶和细胞内糖皮质激素再激活酶网络

• 批准号: 19390248
• 负责人: MASUZAKI Hiroaki
• 金额: $ 11.56万
• 依托单位: Kyoto University
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for Scientific Research (B)
• 财政年份: 2007
• 资助国家: 日本
• 起止时间: 2007 至 2009
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-19390248/
• 关键词: 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

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.

细胞内糖皮质激素再活化酶11 β-羟基类固醇脱氢酶1（11β-HSD 1）的表达和活性升高，导致肥胖脂肪组织功能障碍。虽然11β-HSD 1在肥胖脂肪组织中的病理生理作用已经研究了很长时间，但11β-HSD 1在肥胖脂肪组织中增加的机制仍然不清楚。在这种情况下，在本研究中，我们调查了可能涉及慢性炎症，氧化应激，神经酰胺信号和NADPH提供的酶组成的戊糖途径。在培养的脂肪细胞和来自小鼠肥胖脂肪组织的SVF细胞中，TNFα、IL-1β、LPS和神经酰胺增强了11β-HSD 1的酶活性和表达。11β-HSD 1的药理学抑制和针对11β-HSD 1的RNA干扰减少了一系列促炎分子，并显著减弱了培养的脂肪细胞中的NF-κ β和MAPK炎症信号传导。在人和小鼠中，与肥胖程度成比例的肥胖脂肪组织中包括戊糖途径的酶的表达升高。脂肪细胞中葡萄糖-6-磷酸脱氢酶（G6 PD）（戊糖途径的一个成员）的强制表达增强了细胞内糖皮质激素的再扩增，并导致皮质醇分泌到培养基中，这表明11β-HSA 1和肥胖脂肪组织中的NADPH供应之间存在功能联系。我们的数据强调了再扩增糖皮质激素的意想不到的作用和肥胖脂肪组织中11β-HSD 1扩增的分子基础。

项目成果

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.

人类新鲜尿液中糖皮质激素代谢终产物的系统平衡指数：其在评估肥胖相关疾病中的潜在用途。

• 发表时间: 2009
• 期刊: Obes Res Clin Pract 3
• 作者: 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.
• 通讯作者: K.

17β-Estradiol inhibits 11β-hydroxysteroid dehydrogenase type 1 activity in rodent adipocytes.

17β-Estradiol 抑制啮齿动物脂肪细胞中 11β-羟基类固醇脱氢酶 1 型活性。

• 发表时间: 2009
• 期刊: J Endocrinol 202
• 作者: N. Tagawa;R. Yuda;S. Kubota;M. Wakabayashi;Y. Yamaguchi;N. Mori;E. Minamitani;H. Masuzaki;Y. Kobayashi
• 通讯作者: Y. Kobayashi

細胞内グルココルチコイド活性化酵素を標的とするメタボリックシンドロームの治療展望, 実験医学(特集:メタボリックシンドロームの鍵因子)

靶向细胞内糖皮质激素激活酶治疗代谢综合征的前景，实验医学（专题：代谢综合征的关键因素）

• 发表时间: 2008
• 作者: 益崎裕章;石井崇子;泰江慎太郎;中尾一和
• 通讯作者: 中尾一和

特集:糖尿病と食欲調節の分子基盤肥満者の食欲調節と糖代謝異常

专题：糖尿病和食欲调节的分子基础肥胖人群的食欲调节和糖代谢异常

• 发表时间: 2008
• 作者: 益崎裕章、田中智洋、海老原健、中尾一和;Diabetes Frontier
• 通讯作者: Diabetes Frontier

Glucocorticoid reamplification within cells intensifies NFB and MAPK signaling and reinforces inflammation in activated preadipocytes

细胞内的糖皮质激素再放大增强了 NFB 和 MAPK 信号传导，并增强了活化的前脂肪细胞中的炎症

• 发表时间: 2010
• 期刊: Am J Physiol Endocrinol Metab 299(1)
• 作者: T.Ishii-Yonemoto;H.Masuzaki;S.Yasue;S.Okada;C.Kozuka;T.Tanaka;M.Noguchi;T.Tomita;J.Fujikura;Y.Yamamoto;K.Ebihara;K.Hosoda;K.Nakao
• 通讯作者: K.Nakao