2012 Fiscal Year Final Research Report
Molecular mechanism in the regulation of energy metabolism by nuclear hormone receptors
| Project/Area Number |
20591106
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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 |
Endocrinology
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| Research Institution | Department of Clinical Research, National Hospital Organization Kyoto Medical Center |
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Principal Investigator |
TAGAMI Tetsuya 独立行政法人国立病院機構(京都医療センター臨床研究センター), 内分泌代謝高血圧研究部(分子内分泌代謝), 研究室長 (60273439)
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| Co-Investigator(Kenkyū-buntansha) |
MORIYAMA Kenji 武庫川女子大学, 薬学部, 教授 (00301739)
NARUSE Mitsuhide 独立行政法人国立病院機構(京都医療センター臨床研究センター), 内分泌代謝高血圧研究部, 研究部長 (40120018)
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| Co-Investigator(Renkei-kenkyūsha) |
YAMAMOTO Hiroyuki 武庫川女子大学, 薬学部, 助教 (10466295)
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| Project Period (FY) |
2008 – 2012
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| Keywords | 甲状腺ホルモン受容体 / PPAR / 核内受容体 / ミトコンドリア脱共役蛋白 / 転写制御 |
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| Research Abstract |
A novel thyroid hormone receptor β isoform (TR.4), recently we have cloned from human pituitary, may modulate hormone action as an endogenous antagonist in the tissue or cellular context. For example, aberrant expression of TR.4 may partly contribute to the inappropriate secretion of TSH in a TSHoma. Sites for co-repressors (CoR), co-activators (CoA), and RXR binding partially overlapped, but CoR and CoA bindings were well correlated with T3-independent and T3-dependent transcriptional regulations, respectively, while RXR binding was not among TR mutants, suggesting that transcriptional regulation by TR is mainly mediated by an exchange of CoRs and CoAs. Telmisartan, one of angiotensin II receptor blockers, specifically activates PPARγ. Telmisartan and thiazolidinediones (TZDs) had differential effects on the transcriptional control and interaction with cofactors among PPARγ mutants, suggesting that these mutants could be powerful tools for developing novel therapeutic agents that retain the metabolic efficacy of PPARγ activation with fewer adverse effects associated with TZDs. Moreover, we have studied the effects of FFA, fibrates or irbesartan on TR or PPAR mediated transcription, the search for PPAR activators in herb, and the crosstalk between nuclear hormone receptors and transcription factors that mediate GH/IGF-1 action or glucose, lipid and energy metabolism.
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