1999 Fiscal Year Final Research Report Summary
Regulation in obese gene expression and adipocyte differentiation by tumor necrosis factor-α.
| Project/Area Number |
10672093
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| Research Category |
Grant-in-Aid for Scientific Research (C)
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| Allocation Type | Single-year Grants |
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| Section | 一般 |
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| Research Field |
医薬分子機能学
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| Research Institution | Tokyo Women's Medical University |
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Principal Investigator |
UCHIDA Yoko Tokyo Women's Medical University, School of Medicine, Assistant Professor, 医学部, 講師 (30075494)
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| Co-Investigator(Kenkyū-buntansha) |
OGAWA Akira Tokyo Women's Medical University, School of Medicine, Research Associate, 医学部, 助手 (60266715)
OHBA Ken-ichi Tokyo Women's Medical University, School of Medicine, Research Associate, 医学部, 助手 (60256477)
MURAKI Takamura Tokyo Women's Medical University, School of Medicine, Professor, 医学部, 教授 (50051446)
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| Project Period (FY) |
1998 – 1999
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| Keywords | brown adipocytes / tumor necrosis factor-α / obese gene / leptin / protein kinase C / gene expression |
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| Research Abstract |
Previously we showed that tumor necrosis factor-α(TNF-α) inhibits lipoprotein lipase (LPL) activity and its gene expression, an early marker of adipocyte differentiation, in cultured brown adipocytes. To know whether TFN-αalso affects late events in brown adipocyte maturation, we examined the effect of TFN-α on obese gene expression and leptin secretion in mouse brown adipocytes differentiated in culture. TNF-α caused a concentration-dependent decrease in leptin accumulation in culture medium and leptin mRNA abundance in brown adipocytes which constitutively express the ob gene. Time-course study showed that TNF-α significantly suppressed leptin secretion during incubation for 16, 24 and 48 h. Since some effects of TNF-α are mediated by activation of protein kinase C (PKC), the role of PKC in TNF-α-induced down regulation of ob gene expression and leptin secretion was studied. The suppressive effect of TNF-α on both ob gene expression and leptin secretion was blocked by PKC inhibitors such as bisindolylmaleimide I (BIM) and 1-(5-isoquinolinesulfonyl)-2-methylpiperazine dihydrochloride (H-7). Incubation of brown adipocytes with TNF-α(20 ng/ml, 15 min) caused a rapid shift of PKC activity from the cytosol to the membrane fraction, suggesting an activation of PKC by TNF-α in brown adipocytes. This effect of TNF-α was blocked by a selective PKC inhibitor, BIM. These results suggest that TNF-α promotes dedifferentiation of the brown adipocytes as evidenced by a down regulation in ob gene expression and leptin secretion via PKC-dependent mechanisms.
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