2006 Fiscal Year Final Research Report Summary
Molecular Interaction between Adipose Function and Metabolic Syndrome
| Project/Area Number |
16390267
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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, Graduate School of Medicine, Assistant Professor, 医学研究科, 助手 (00291899)
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| Co-Investigator(Kenkyū-buntansha) |
HOSODA Kiminori Kyoto UniVersity, Graduate School of Medicine, Lecturer Professor, 医学研究科, 講師 (40271598)
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| Project Period (FY) |
2004 – 2006
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| Keywords | metabolic syndrome / adipose dysfunction / therapy / diabetes / cardiovascular risk / 11β-HSD1 / glucocorticoid / visceral fat |
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| Research Abstract |
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
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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
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