Abstract 272: Divergent Neural Control of Blood Pressure vs Resting Metabolic Rate by Angiotensin: The Role of AT1A Signaling in Leptin-Sensitive Cells
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 AT1A receptors in the brain in RMR, and renal and sympathetic nerve activity (SNA) responses to leptin. Here we tested the hypothesis that AT1A receptors, specifically localized to leptin-sensitive cells, are required for the blood pressure and RMR effects of brain ANG. The AT1A gene was conditionally disrupted in cells that express the long (b) form of the leptin receptor (ObRb-Cre x AT1Aflox 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 AT1A 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-AT1A interaction critical for RMR control, we performed immunohistochemical staining for adrenocorticotropin (ACTH) in the arcuate nucleus of mice that express GFP via the AT1A promoter (“NZ44”). Complete lack of colocalization supports the conclusion that AT1A 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 AT1A upon agouti related peptide (AgRP) neurons. AT1A may therefore suppress AgRP neuron γ-aminobutyric acid production and thus disinhibit POMC neuronal activity, to ultimately stimulate RMR.
Author Disclosures: K.E. Claflin: None. H.M. Stauss: None. J.L. Grobe: B. Research Grant (includes principal investigator, collaborator, or consultant and pending grants as well as grants already received); Significant; NIH, AHA, ADA.
- © 2014 by American Heart Association, Inc.