期刊
CELL REPORTS
卷 18, 期 8, 页码 2030-2044出版社
CELL PRESS
DOI: 10.1016/j.celrep.2017.01.064
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资金
- Platform Project for Support in Drug Discovery and Life Science Research of the Japan Agency for Medical Research and Development (AMED)
- Ministry of Education, Science, Sports and Culture (MEXT)
- Japanese Technology Agency (JST)
- Japan Society for the Promotion of Science (JSPS) [24249015, 90396474, 26893008]
- Takeda Foundation
- Naito Foundation
- Japanese Foundation for Applied Enzymology
- Mochida Pharmaceutical Co., Ltd.
- AMED
- Grants-in-Aid for Scientific Research [26893008, 26111002] Funding Source: KAKEN
The relationship between loss of hypothalamic function and onset of diabetes mellitus remains elusive. Therefore, we generated a targeted oxida-tive- stress murine model utilizing conditional knockout (KO) of selenocysteine- tRNA (Trsp) using rat-insulin-promoter-driven-Cre (RIP-Cre). These Trsp-KO (Trsp RIP KO) mice exhibit deletion of Trsp in both hypothalamic cells and pancreatic beta cells, leading to increased hypothalamic oxidative stress and severe insulin resistance. Leptin signals are suppressed, and numbers of proopiomelanocortin-positive neurons in the hypothalamus are decreased. In contrast, Trsp-KO mice (Trsp(Ins1)KO) expressing Cre specifically in pancreatic b cells, but not in the hypothalamus, do not display insulin and leptin resistance, demonstrating a critical role of the hypothalamus in the onset of diabetes mellitus. Nrf2 (NF-E2-related factor 2) regulates antioxidant gene expression. Increased Nrf2 signaling suppresses hypothalamic oxidative stress and improves insulin and leptin resistance in Trsp(RIP)KO mice. Thus, Nrf2 harbors the potential to prevent the onset of diabetic mellitus by reducing hypothalamic oxidative damage.
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