Molecular Interaction between Adipose Function and Metabolic Syndrome

脂肪功能与代谢综合征之间的分子相互作用

• 批准号: 16390267
• 负责人: MASUZAKI Hiroaki
• 金额: $ 9.02万
• 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: 2004
• 资助国家: 日本
• 起止时间: 2004 至 2006
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-16390267/
• 关键词: metabolic syndrome; adipose dysfunction; therapy; diabetes; cardiovascular risk; 11β-HSD1; glucocorticoid; visceral fat; 脂肪細胞; ヒト検体; バオプシー; PPARγ; 分子連関; 病態連関

A series of mouse experiments demonstrated that reduction of intracellular glucocorticoid reactivation within adipose tissue contributes to a protective metabolic phenotype, supporting its role as a therapeutic target for the metabolic syndrome. In this context, the present study has been focused on molecular interaction between adipose function and the metabolic syndrome. The present study demonstrated that a series of inflammatory cytokines markedly augment the expression and oxo-reductase activity of intracellular glucocorticoid reactivating enzyme, 11β-HSD1 in cultured adipocytes. The activation of 11β-HSD1 enhances the expression of TNFα, IL-6, angiotensinogen and resistin, whereas decreases that of adiponectin. Such a dysregulated phenotype was corrected by a line of small molecules of 11β-HSD1 inhibitors. Adipose tissue comprises of a variety of cell types. Pathophysiologic interaction among matured adipocytes, preadipocytes and macrophages is involved in the mechanism whereby 1 … More 1β-HSD1 is elevated in obese adipose tissue. We thus tested the hypothesis that a variety of metabolic stresses could dysregulate 11β-HSD1 in human and mouse preadipocytes. Expression of 11β-HSD1 was robustly induced when cells were serum-deprived or treated with cell-permeable ceramide analogue C_2 ceramide, bacterial sphingomyelinase and sphingosine 1-phosphate. Furthermore, 5-aminoimidazole-4-carboxamide ribonucleoside-induced activation of AMPK augmented the expression and oxo-reductase activity of 11β-HSD1. Notably, ceramide and AICAR markedly induced the expression of CCAAT/enhancer-binding protein (C/EBP) β, which mediated the robust induction of 11β-HSD1. Our data provide novel evidence that ceramide and AMPK-mediated signaling pathways substantially augment the expression and activity of 11β-HSD1 in preadipocytes via C/EBPβ, thereby highlighting metabolic stress-related regulation of 11β-HSD1. On the other hand, macrophage infiltration in obese adipose tissue provokes local inflammation and insulin resistance. However, the potential role of 11β-HSD1 in macrophages still remains unclear. We demonstrated that macrophages expresses 11B-HSD1 mRNA, which were augmented by LPS-induced cell activation. Inhibition of 11β-HSD1 significantly suppressed the expression and secretion of IL-1β, TNF-α or MCP-1, thereby highlighting a novel role of 116-HSD 1 in pro-inflammatory properties of activated macrophages. Less

一系列小鼠实验表明，脂肪组织内细胞内糖皮质激素再活化的减少有助于保护性代谢表型，支持其作为代谢综合征治疗靶点的作用。在这种情况下，本研究一直集中在脂肪功能和代谢综合征之间的分子相互作用。本研究表明，一系列炎性细胞因子显著增强培养的脂肪细胞中细胞内糖皮质激素再活化酶11β-HSD 1的表达和氧化还原酶活性。11β-HSD 1的激活可增强TNFα、IL-6、血管紧张素原和β-内酰胺酶的表达，而降低脂联素的表达。这种失调的表型通过一系列11β-HSD 1抑制剂的小分子来纠正。脂肪组织由多种细胞类型组成。成熟脂肪细胞、前脂肪细胞和巨噬细胞之间的病理生理相互作用参与了1 ...更多信息 1β-HSD 1在肥胖脂肪组织中升高。因此，我们测试了一种假设，即各种代谢应激可以在人类和小鼠前脂肪细胞中失调11β-HSD 1。11β-HSD 1的表达在去血清或用细胞可渗透的神经酰胺类似物C_2神经酰胺、细菌鞘磷脂酶和1-磷酸鞘氨醇处理的细胞中被强烈诱导。此外，5-氨基咪唑-4-甲酰胺核苷诱导的AMPK活化增强了11β-HSD 1的表达和氧化还原酶活性。值得注意的是，神经酰胺和AICAR显著诱导CCAAT/增强子结合蛋白（C/EBP）β的表达，其介导11β-HSD 1的稳健诱导。我们的数据提供了新的证据，表明神经酰胺和AMPK介导的信号通路通过C/EBPβ显著增加了前脂肪细胞中11β-HSD 1的表达和活性，从而突出了11β-HSD 1的代谢应激相关调节。另一方面，肥胖脂肪组织中的巨噬细胞浸润引起局部炎症和胰岛素抵抗。然而，11β-HSD 1在巨噬细胞中的潜在作用仍不清楚。我们证明，巨噬细胞表达11B-HSD 1 mRNA，这是由LPS诱导的细胞活化增强。11β-HSD 1的抑制显著抑制了IL-1β、TNF-α或MCP-1的表达和分泌，从而突出了116-HSD 1在活化的巨噬细胞的促炎特性中的新作用。少

项目成果

Augmentation of 11β-hydroxysteroid dehydrogenase type 1 in LPS-activated J774.1 macrophages? Role of 11β-HSD1 in pro-inflammatory properties in macrophages.

LPS 激活的 J774.1 巨噬细胞中 11β-羟基类固醇脱氢酶 1 型的增强？11β-HSD1 在巨噬细胞促炎特性中的作用。

• 发表时间: 2007
• 期刊: FEBS Lett. 6;581(3)
• 作者: T. Ishii;K. Nakao;et. al.
• 通讯作者: et. al.

Novel adipose tissue-mediated resistance to diet-induced visceral obesity in 11β-hydroxysteroid dehydrogenase type 1-deficient mice

• DOI: 10.2337/diabetes.53.4.931
• 发表时间: 2004-04-01
• 期刊: DIABETES
• 影响因子: 7.7
• 作者: Morton, NM;Paterson, JM;Seckl, JR
• 通讯作者: Seckl, JR

Notch/Rbp-j signaling prevents premature endocrine and ductal cell differentiation in the pancreas

• DOI: 10.1016/j.cmet.2005.12.005
• 发表时间: 2006-01-01
• 期刊: CELL METABOLISM
• 影响因子: 29
• 作者: Fujikura, J;Hosoda, K;Nakao, K
• 通讯作者: Nakao, K

Central melanocortin signaling restores skeletal muscle AMP-activated protein kinase phosphoylation in mice fed a high fat diet

中枢黑皮质素信号传导可恢复高脂肪饮食小鼠骨骼肌 AMP 激活的蛋白激酶磷酸化

• 发表时间: 2007
• 期刊: Cell Metabolism 5
• 作者: Motoshima H;Goldstein BJ;Igata M;Araki E;西川 武志 他;Toshihito Tanahashi;荒木 栄一 他;Kodama S et al.;Senokuchi T et al.;Satoshi Tsutsumi;T.Ishii etal.;Mitsuo Itakura;K.Ebihara et al.;T.Tanaka et al.
• 通讯作者: T.Tanaka et al.

Expression of the gene for a membrane-bound fatty acid receptor in the pancreas and islet cell tumors in humans : evidence for GPR40 expression in pancreatic beta cells and implications for insulin secretion

人类胰腺和胰岛细胞肿瘤中膜结合脂肪酸受体基因的表达：胰腺β细胞中GPR40表达的证据及其对胰岛素分泌的影响

• 发表时间: 2006
• 期刊: Diabetofogia 49
• 作者: T.Ishii;H.Masuzaki (corresponding author);T.Tanaka;N.Arai;S.Yasue;N.Kobayashi;M.Noguchi;J.Fujikura;K.Ebihara;K.Hosoda;K.Nakao.;T.Tomita et al.
• 通讯作者: T.Tomita et al.