Tissue-specific roles for the renin-angiotensin system in cardiovascular and metabolic regulation

The renin-angiotensin system (RAS) greatly contributes to energy homeostasis through opposing actions in the brain and adipose. We hypothesize that site- and receptor-specific effects of the RAS may represent a novel therapeutic target for obesity, a concept which is fully reviewed in chapter 1. Transgenic “sRA” mice exhibit brain-specific RAS hyperactivity, and a suppressed circulating RAS presumably secondary to the chronic hypertension exhibited by these animals. In chapter 2, we demonstrated that the hypertension observed with elevated brain RAS is mediated by increased vasopressin signaling. In chapter 3, we investigated how suppressed circulating RAS activity contributes to the elevated resting metabolic rate (RMR) of sRA mice. Despite having no effect upon energy intake, chronic angiotensin II type 2 (AT2) receptor activation suppressed energy expenditure and caused weight gain in sRA mice. The AT2 receptor alters inguinal white adipose tissue to contribute to obesity through the suppression of RMR. Lastly, in chapter 4, we documented moderately-improved glycemic control with elevated brain RAS/reduced circulating RAS activity, though the mechanism behind this remains unknown. Taken together, we determined that low circulating RAS activity is metabolically beneficial due to reduced activation of the AT2 receptor. Thus, specific inhibition of the systemic RAS may ultimately stimulate energy expenditure and thus may be a viable anti-obesity pharmaceutical approach. Overall, our data highlight the importance of site-specific effects of the RAS on energy homeostasis.