Metabolic and endocrine functions of the renin-angiotensin system

Obesity affects roughly 40% of Americans, representing a huge medical and economic burden for the country. There are currently very few options for obese patients outside of lifestyle changes such as increased physical activity and restricted diet. Furthermore, surgeries are often only an option for the morbidly obese. Pharmaceutical options are lacking, with only a handful of FDA approved drugs in use, most of which are only mildly effective at best. Interestingly, all the current FDA approved drugs regulate caloric intake such as appetite suppression or fat absorption. However, there is increasing research supporting a role for resting metabolic rate (RMR) in energy expenditure. RMR can account for up to 70% of daily energy expenditure, yet there exist no safe and efficacious drugs targeting RMR for the treatment of obese patients. Therefore, a greater understanding of the molecular mechanisms governing RMR is needed.

Here, we examine the role of the renin-angiotensin system within the hypothalamus of the brain in the control of energy homeostasis. We hypothesized that the central RAS interacts with leptin, a hormone secreted by adipocytes which acts on the hypothalamus to control energy homeostasis. We have demonstrated that leptin increases mRNA expression of the angiotensin type 1A (AGTR1A, Agtr1a) in vitro, which may be important for leptin’s downstream actions in other brain regions. We also demonstrate that angiotensinogen (AGT, Agt) the prohormone from which the effector peptide angiotensin II (ANG II) is produced, is dispensable for leptin’s metabolic actions. Finally, we unexpectedly demonstrate that AGT, mostly likely derived from the adrenal gland, is important for renal development and proper steroid hormone regulation. These results support our hypothesis that leptin and the central RAS interact, potentially to control energy homeostasis, and implicate a novel role for adrenal derived AGT in development.