Angiotensin II type 1 receptor signaling regulates feeding behavior through anorexigenic corticotropin-releasing hormone in hypothalamus

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.