Journal
MOLECULAR AND CELLULAR ENDOCRINOLOGY
Volume 365, Issue 1, Pages 25-35Publisher
ELSEVIER IRELAND LTD
DOI: 10.1016/j.mce.2012.08.022
Keywords
Serotonin; 5-HT2A receptor; IRS-1 ubiquitination; Low density microsome; Insulin resistance; Sarpogrelate
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Funding
- Ministry of Education, Science, and Culture of Japan
- Tokushima Prefecture, Japan
- Grants-in-Aid for Scientific Research [22616005] Funding Source: KAKEN
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Serotonin (5-hydroxytryptamine, 5-HT) was found to be elevated in the serum of diabetic patients. In this study, we investigate the mechanism of insulin desensitization caused by 5-HT. In 3T3-L1 adipocytes, 5-HT treatment induced the translocation of insulin receptor substrate-1 (IRS-1) from low density microsome (LDM), the important intracellular compartment for its functions, to cytosol, inducing IRS-1 ubiquitination and degradation. Moreover, inhibition of 5-HT-stimulated Akt activation by either ketanserin (a specific 5-HT2A receptor antagonist) or knocking-down the expression of 5-HT2A receptor promoted 5-HT-stimulated IRS-1 dissociation from 14-3-3 beta in LDM, leading to drastic ubiquitination. Interestingly, sarpogrelate, another antagonist of 5-HT2A receptor, protected IRS-1 from degradation through activation of Akt. This implicates the importance of Akt activation in extending IRS-1 life span through maintaining their optimal sub-location into adipocytes. Taken together, this study suggest that activation of Akt may be able to compensate the adverse effects of 5-HT by stabilizing IRS-1 in LDM. (C) 2012 Elsevier Ireland Ltd. All rights reserved.
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