The renin-angiotensin system (RAS) exists as a circulating hormone system but also as a local autocrine/paracrine signaling mechanism in tissues such as the brain. The RAS is active in regions of the brain which are recognized contributors to blood pressure control, including the subfornical organ, paraventricular nucleus, area postrema, medulla, and others. Although generally considered a major contributor to metabolic but not cardiovascular control, the arcuate nucleus (ARC) also exhibits expression of the RAS. We and others have determined that the brain RAS strongly contributes to energy balance, especially through the control of sympathetic nervous activity (SNA) and subsequently, resting metabolic rate (RMR). Together these data led to the general hypothesis that the RAS within the ARC may differentially contribute to metabolic versus cardiovascular control. The overall objective of the current proposal is therefore to understand the role of the RAS in the neurocircuitry of the ARC which contributes to metabolic versus cardiovascular control physiology. New unpublished data from our group demonstrate that that the angiotensin II type 1A receptor (AT1A) specifically localized to cells that express the leptin receptor (LepR) are critically involved in the control of RMR and thereby weight gain in response to high fat diet. Importantly AT1A expressed in LepR-expressing cells are also involved in the RMR, but not blood pressure (BP) responses to deoxycorticosterone acetate (DOCA)-salt treatment. Localization and gene profiling studies indicate that AT1A are only expressed in the subset of LepR-expressing cells which also express agouti related peptide (AgRP), but not proopiomelanocortin (POMC). These data lead us to propose three aims.
Aim 1 will evaluate the cardiovascular and metabolic consequences of selectively disrupting AT1A expression within AgRP-expressing cells.
Aim 2 will examine the role of AT1A in the AgRP neuron in the pathogenesis of selective leptin resistance (SLR). SLR describes the selective loss of metabolic, but not cardiovascular, responses to leptin which occur after prolonged obesity. SLR has been proposed as a possible explanation for the high comorbidity of hypertension and obesity (i.e. ? obesity-associated hypertension). Our discovery that the ARC RAS specifically acts to modulate metabolic (but not cardiovascular) sensitivity therefore supports the novel concept that AT1A receptor modulation within AgRP cells may explain the molecular mechanism of SLR.
Aim 3 will examine a novel hypothesis that LepR activation in AgRP cells activates a RAS-mediated autocrine signaling pathway, which may represent the molecular mechanism of the cross-talk between the LepR and AT1A in these cells. We will use an array of newly-developed genetically-modified animal models, state-of-the-art methods for the measurement of BP, SNA, and RMR, and well-established collaborations with recognized experts in leptin, SLR and SNA assessments to accomplish the proposed studies. Completion of the project will expand our knowledge of neurocircuitry that controls RMR vs BP and our understanding of obesity-hypertension.
The metabolic rate of an organism at rest is tightly regulated by specific pathways and genes within the brain, and minor dysfunctions of these mechanisms over a lifetime are thought to majorly contribute to obesity and high blood pressure. The current project explores the cross-talk of leptin and angiotensin in these brain mechanisms, with the ultimate goal of identifying new molecular targets to treat or prevent obesity-associated hypertension.
|Sandgren, Jeremy A; Deng, Guorui; Linggonegoro, Danny W et al. (2018) Arginine vasopressin infusion is sufficient to model clinical features of preeclampsia in mice. JCI Insight 3:|
|Morselli, Lisa L; Claflin, Kristin E; Cui, Huxing et al. (2018) Control of Energy Expenditure by AgRP Neurons of the Arcuate Nucleus: Neurocircuitry, Signaling Pathways, and Angiotensin. Curr Hypertens Rep 20:25|
|Scroggins, Sabrina M; Santillan, Donna A; Lund, Jenna M et al. (2018) Elevated vasopressin in pregnant mice induces T-helper subset alterations consistent with human preeclampsia. Clin Sci (Lond) 132:419-436|
|Shinohara, Keisuke; Nakagawa, Pablo; Gomez, Javier et al. (2017) Selective Deletion of Renin-b in the Brain Alters Drinking and Metabolism. Hypertension 70:990-997|
|Sapouckey, Sarah A; Deng, Guorui; Sigmund, Curt D et al. (2017) Potential mechanisms of hypothalamic renin-angiotensin system activation by leptin and DOCA-salt for the control of resting metabolism. Physiol Genomics 49:722-732|
|Grobe, Justin L (2017) Comprehensive Assessments of Energy Balance in Mice. Methods Mol Biol 1614:123-146|
|Srisai, Dollada; Yin, Terry C; Lee, Abigail A et al. (2017) MRAP2 regulates ghrelin receptor signaling and hunger sensing. Nat Commun 8:713|
|Riedl, Ruth A; Atkinson, Samantha N; Burnett, Colin M L et al. (2017) The Gut Microbiome, Energy Homeostasis, and Implications for Hypertension. Curr Hypertens Rep 19:27|
|Agassandian, Khristofor; Grobe, Justin L; Liu, Xuebo et al. (2017) Evidence for intraventricular secretion of angiotensinogen and angiotensin by the subfornical organ using transgenic mice. Am J Physiol Regul Integr Comp Physiol 312:R973-R981|
|Claflin, Kristin E; Sandgren, Jeremy A; Lambertz, Allyn M et al. (2017) Angiotensin AT1A receptors on leptin receptor-expressing cells control resting metabolism. J Clin Invest 127:1414-1424|