Angiotensin II Type 1 Receptor Signaling Regulates Feeding Behavior through Anorexigenic Corticotropin-releasing Hormone in Hypothalamus

• Published in: The Journal of biological chemistry 2011-06, Vol.286 (24), p.21458-21465
• Main Authors: Yamamoto, Rie, Akazawa, Hiroshi, Fujihara, Hiroaki, Ozasa, Yukako, Yasuda, Noritaka, Ito, Kaoru, Kudo, Yoko, Qin, Yingjie, Ueta, Yoichi, Komuro, Issei
• Format: Article
• Language: English
• Subjects: Adipose Tissue; Adipose Tissue - metabolism; Animals; Corticotropin-Releasing Hormone - metabolism; Feeding Behavior; Gene Expression; Gene Expression Regulation; HEK293 Cells; Humans; Hypothalamus - physiology; Male; Mice; Mice, Knockout; Molecular Bases of Disease; Neuropeptide; Neuropeptides - chemistry; Obesity; Obesity - metabolism; Oligopeptides - chemistry; Pyrrolidonecarboxylic Acid - analogs & derivatives; Pyrrolidonecarboxylic Acid - chemistry; Receptor, Angiotensin, Type 1 - metabolism; Receptors
• ISSN: 0021-9258; 1083-351X
• DOI: 10.1074/jbc.M110.192260

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 (AT1) receptor signaling regulates the hypothalamic neurocircuit that is involved in the control of food intake. Compared with wild-type Agtr1a+/+ mice, AT1 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 AT1 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 AT1 receptor blockade in feeding disorders.