The brain renin-angiotensin system in metabolic and cardiovascular regulation

Leptin acts within the brain to increase resting metabolic rate (RMR) and blood pressure (BP). The renin-angiotensin system (RAS) elicits similar effects in the brain, as reviewed in chapter 1, and it has previously been shown that central angiotensin II type 1 (AT₁) receptors are required for leptin-mediated inductions in sympathetic nerve activity to the brown adipose tissue. Thus, we hypothesize that the brain RAS mediates the metabolic effects of leptin. To investigate the interaction between the RAS and leptin, we generated the AT_1A^LepR-KO mouse which lacks the AT_1A receptor in leptin-sensitive cells. In chapter 2, we demonstrated that stimulation of RMR by DOCA-salt and high fat diet requires AT_1A receptors in leptin receptor-expressing cells and that these cells expressing both AT_1A and the leptin receptor appear to be agouti related-peptide (AgRP) neurons. In chapter 3, we investigated the role of AT_1A specifically in AgRP neurons by utilizing AT_1A^AgRP-KO mice. Similar to AT_1A^LepR-KO mice, AT_1A^AgRP-KO mice exhibited deficits in BAT SNA responses to leptin and induction of RMR by alpha melanocyte stimulating hormone. In chapter 4, we utilized a novel transgenic mouse model to demonstrate that microglia do not express the AT_1A receptor under chow or high fat diet fed conditions. Taken together, we conclude that a subset of AgRP neurons, which express both the leptin receptor and the AT_1A receptor, are critical for the control of sympathetic nerve activity and ultimately RMR.