2005 Fiscal Year Final Research Report Summary
Identification and functional analysis of intrinsic and extrinsic key regulators of adipocyte differentiation.
| Project/Area Number |
15370061
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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 |
Functional biochemistry
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| Research Institution | University of Hyogo (2004-2005)
Himeji Institute of Technology (2003) |
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Principal Investigator |
OSUMI Takashi University of Hyogo, Graduate School of Life Science, Professor, 大学院生命理学研究科, 教授 (50111787)
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| Co-Investigator(Kenkyū-buntansha) |
HIROSE Fumiko University of Hyogo, Graduate School of Life Science, Associate Professor, 大学院生命理学研究科, 助教授 (60208882)
YAMAGUCHI Tomohiro University of Hyogo, Graduate School of Life Science, Assistant Professor, 大学院生命理学研究科, 助手 (50347530)
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| Project Period (FY) |
2003 – 2005
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| Keywords | Adipocytes / Differentiation / PPARγ / PPARα / Perilipin / Lipid droplet / Nuclear receptor / Human mesenchymal stem cells |
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| Research Abstract |
(1)Regulatory mechanism of perilipin gene expression by PPARγ : A PPAR-binding motif was found between the mouse perilipin and PEX11α genes. We showed that PPARγ activates the perilipin gene in the adipocytes, whereas in the liver, PPARα activates the PEX11α gene, respectively, both by binding to this site. Hence, we presented a novel type of eukaryotic gene regulation, where two genes are regulated tissue-specifically through a common protein-binding site.
(2)Role of JNK in the differentiation of human mesenchymal stem cells : We found that JNK regulates the differentiation of multipotent human mesenchymal stem cells into adipocytes negatively, whereas that into osteoblasts positively. This was possibly through negative actions of JNK on CREB and IRS-1 activities.
(3)Identification and characterization of novel lipid droplet-binding proteins : CGI-58, a lipid droplet protein interacting with perilipin, was identified. The CGI-58 mutant proteins carrying the amino acid substitutions same
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as those of Chanarin-Dorfman syndrome patients bound to neither perilipin nor lipid droplets. CGI-58 was suggested to activate lipases, and hence promotes lipid degradation on the lipid droplet surfaces. Next, we identified MLDP, a new member of PAT family, in which perilipin is also included. MLDP was found to be a lipid droplet-binding protein particularly enriched in the heart. MLDP was induced during fasting, the expression being dependent on PPARα. We suggest that MLDP contributes to the characteristically rapid turnover of lipids in the heart.
(4)Investigation of nuclear receptors involved in adipocyte differentiation : We showed that PPARγ is negatively regulated by SUMO conjugation in the N-terminal region. We also found that NGFI-B, acutely induced in the initial stage of adipogenesis of 3T3-L1 cells, exerts a stimulatory effect on the differentiation, through the action on the cell growth in the initial stage. Furthermore, we found that ERRα and γ have extraordinarily broad specificities of sequence recognition. Less
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