2005 Fiscal Year Final Research Report Summary
A novel mechanism of insulin sensitivity regulation by post-translational mechanisms
| Project/Area Number |
16590867
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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 |
Metabolomics
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| Research Institution | Gunma University |
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Principal Investigator |
SHIBATA Hiroshi GUNMA UNIVERSITY, INSTITUTE FOR MOLECULAR AND CELLULAR REGULATION, ASSISTANT PROFESSOR, 生体調節研究所, 助教授 (20235584)
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| Project Period (FY) |
2004 – 2005
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| Keywords | insulin sensitivity / adipocyte / glucose transport / sumoylation / Ubc9 / GLUT4 |
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| Research Abstract |
SUMO conjugating enzyme Ubc9 has been shown to upregulate GLUT4 in L6 myoblasts although the mechanism of action is undefined. Here we investigated the physiological significance of Ubc9 in GLUT4 turnover and subcellular targeting by adenovirus vector-mediated overexpression and by siRNA-mediated gene silencing of Ubc9 in 3T3-L1 adipocytes. Overexpression of Ubc9 resulted in inhibition of GLUT4 degradation and promotion of its targeting to the GLUT4 storage compartment (GSC), leading to an increase in GLUT4 level and insulin-responsive GLUT4 translocation and glucose transport. While long-term (6 hours and more) insulin stimulation caused GLUT4 downregulation by 40-50%, which was inhibited with lysosomal inhibitors and was associated with a selective reduction in GLUT4 in GSC, overexpression of Ubc9 antagonized these effects of insulin. By contrast, Ubc9 gene silencing with siRNA markedly accelerated the insulin-induced GLUT4 downregulation, whereas overexpression of the catalytically inactive mutant Ubc9-C93A increased GLUT4 and insulin-stimulated glucose transport to the level comparable to that with wild-type Ubc9. These results suggest that Ubc9 upregulates GLUT4 by inhibition of lysosomal sorting and promotes GLUT4 targeting to GSC by a mechanism unrelated to its catalytic activity. Thus, Ubc9 plays a indispensable role in expression and maintenance of the insulin-sensitive glucose transport system in adipocytes.
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Research Products
(6 results)
