期刊
JOURNAL OF BIOLOGICAL CHEMISTRY
卷 286, 期 24, 页码 21458-21465出版社
AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC
DOI: 10.1074/jbc.M110.192260
关键词
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资金
- Japan Society for the Promotion of Science [KAKENHI 20390218, 21229010]
- Takeda Science Foundation
- Astellas Foundation for Research on Metabolic Disorders
- Uehara Memorial Foundation
- Ichiro Kanehara Foundation
- Mochida Memorial Foundation for Medical and Pharmaceutical Research
- Suzuken Memorial Foundation
- Japan Association for the Advancement of Medical Equipment
- Grants-in-Aid for Scientific Research [23790280, 23390213, 21229010] Funding Source: KAKEN
The activation of renin-angiotensin system contributes to the development of metabolic syndrome and diabetes as well as hypertension. However, it remains undetermined how renin-angiotensin system is implicated in feeding behavior. Here, we show that angiotensin II type 1 (AT(1)) receptor signaling regulates the hypothalamic neurocircuit that is involved in the control of food intake. Compared with wild-type Agtr1a(+/+) mice, AT(1) receptor knock-out (Agtr1a(-/-)) mice were hyperphagic and obese with increased adiposity on an ad libitum diet, whereas Agtr1a(-/-) mice were lean with decreased adiposity on a pair-fed diet. In the hypothalamus, mRNA levels of anorexigenic neuropeptide corticotropin-releasing hormone (Crh) were lower in Agtr1a(-/-) mice than in Agtr1a(+/+) mice both on an ad libitum and pair-fed diet. Furthermore, intracerebroventricular administration of CRH suppressed food intake both in Agtr1a(+/+) and Agtr1a(-/-) mice. In addition, the Crh gene promoter was significantly transactivated via the cAMP-responsive element by angiotensin II stimulation. These results thus demonstrate that central AT(1) receptor signaling plays a homeostatic role in the regulation of food intake by maintaining gene expression of Crh in hypothalamus and suggest a therapeutic potential of central AT(1) receptor blockade in feeding disorders.
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