Abstract 272: Divergent Neural Control of Blood Pressure vs Resting Metabolic Rate by Angiotensin: The Role of AT 1A Signaling in Leptin-Sensitive Cells

Abstract

The renin-angiotensin system (RAS) and leptin both contribute to resting metabolic rate (RMR) and blood pressure control, and thus may contribute to obesity-hypertension. Previously we demonstrated a required role for angiotensin AT 1A receptors in the brain in RMR, and renal and sympathetic nerve activity (SNA) responses to leptin. Here we tested the hypothesis that AT 1A receptors, specifically localized to leptin-sensitive cells, are required for the blood pressure and RMR effects of brain ANG. The AT 1A gene was conditionally disrupted in cells that express the long (b) form of the leptin receptor (ObRb-Cre x AT 1A flox mice; “KO”), and blood pressure was assessed by radiotelemetry under baseline and deoxycorticosterone (DOCA)-salt stimulated conditions. While 24-hr blood pressure (MAP; control n=10, 115 ± 4, vs KO n=9, 115 ± 6 mmHg) and heart rate (control n=10, 561 ± 9, vs KO 563 ± 11 BPM) were not different between control and KO mice, baroreflex sensitivity was significantly increased in KO mice at baseline (control n=6, 3.4 ± 0.7, vs KO n=6, 5.6 ± 0.5 msec/mmHg, P<0.05). DOCA-salt significantly increased MAP (control=8, 130 ± 4, vs KO n=7, 129 ± 3) and decreased baroreflex sensitivity (control=6, 3.0 ± 0.5, vs KO n=5, 2.8 ± 0.5, P<0.05 vs baseline) in all mice. In contrast, RMR responses to DOCA-salt were abolished in KO mice (baseline n=2, 0.2 ± 0.01, vs DOCA-salt n=2, 0.2 ± 0.02). We conclude that AT 1A signaling specifically in leptin-sensitive cells is critically involved in RMR control, but is relatively dispensable for cardiovascular control. To further characterize the cells that mediate the leptin-AT 1A interaction critical for RMR control, we performed immunohistochemical staining for adrenocorticotropin (ACTH) in the arcuate nucleus of mice that express GFP via the AT 1A promoter (“NZ44”). Complete lack of colocalization supports the conclusion that AT 1A are not expressed by proopiomelanocortin (POMC) neurons. In contrast, KO mice exhibit a baseline increase in glutamate decarboxylase mRNA in the arcuate nucleus, consistent with a possible localization of AT 1A upon agouti related peptide (AgRP) neurons. AT 1A may therefore suppress AgRP neuron γ-aminobutyric acid production and thus disinhibit POMC neuronal activity, to ultimately stimulate RMR.