Molecular Interaction between Adipose Function and Metabolic Syndrome

一系列小鼠实验表明，脂肪组织内细胞内糖皮质激素重新激活的减少有助于保护代谢表型，支持其作为代谢综合征的治疗靶点的作用。在这种背景下，目前的研究重点是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胞内糖皮质激素再活化酶11β-HSD1的表达和氧化还原酶活性。11β-HSD1的激活增强了肿瘤坏死因子α、IL-6、血管紧张素原和抵抗素的表达，而降低了脂联素的表达。这种失调的表型被一系列11种β-hsd1抑制剂的小分子所纠正。脂肪组织由多种类型的细胞组成。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…在肥胖的脂肪组织中，有超过1个β-hsd1升高。因此，我们测试了一种假设，即各种代谢应激可以失调人和小鼠前脂肪细胞中的11个β-hsd1。当去血清或细胞通透性神经酰胺类似物C2神经酰胺、细菌鞘磷脂酶和1-磷酸鞘氨醇处理细胞时，11β-HSD1的表达被强烈地诱导。此外，5-氨基咪唑-4-甲酰胺核糖核苷诱导的AMPK激活增强了11β-HSD1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，这介导了11β-HSD1的强劲诱导。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/EBPββ显著增强前脂肪细胞中11β-HSD1的表达和活性，从而突出了11β-HSD1的代谢应激相关调节。另一方面，巨噬细胞在肥胖脂肪组织中的渗透会引发局部炎症和胰岛素抵抗。然而，11β-HSD1在巨噬细胞中的潜在作用仍不清楚。我们证实巨噬细胞表达11B-HSD1mRNA，这种表达被内毒素诱导的细胞激活所增强。抑制11β-HSD1显著抑制IL-1β、α或MCP-1的表达和分泌，从而突出了116-HSD1在活化巨噬细胞促炎特性中的新作用。较少

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