The sympathetic nervous system and angiotensin II (ANG) are implicated in obesity-induced hypertension (HT), but the mechanisms are poorly defined. Our preliminary data support a role for brain ANG signaling in increased arterial pressure (AP) in diet-induced obese (DIO) mice. Additional data reveal striking endoplasmic reticulum (ER) stress in key brain cardiovascular control regions (SFO-PVN axis) in DIO and indicate that chemical manipulation of ER stress influences sympathetic nerve activity (SNA) and AP in this model. Our data also demonstrate that DIO causes oxidative stress in the SFO-PVN axis and this is linked to ER stress. Furthermore, new preliminary data show that both ER stress and oxidative stress in this brain axis are coupled to leptin signaling in DIO mice. Additional new data raise the possibility that DIO-mediated oxidative and ER stress in the brain modulate the facilitatory effect of brain ANG on energy expenditure (EE). Based on these promising, multifaceted preliminary data, we will address four innovative and interrelated concepts: 1) dissociation between central mechanisms controlling energy homeostasis and cardiovascular responses in obesity-HT;2) brain ER stress, a new disease paradigm, as a key underlying mechanism;3) the role of redox signaling, with potential links to ER stress pathways, in obesity-HT and 4) the SFO-PVN axis as a major player in DIO-mediated cardiovascular and metabolic dysregulation. We will address the overall hypothesis that in DIO mice, increased brain ANG and/or leptin signaling promotes ER stress and oxidant stress in the SFO-PVN axis. We postulate that this ER/oxidant stress contributes to the increased renal SNA and AP in DIO mice, but conversely acts in the SFO-PVN axis to blunt or reverse brain ANG- and/or leptin-mediated facilitatory effects on thermogenic SNA and EE in this model of obesity-HTN. To address this innovative hypothesis, we have assembled multiple sophisticated research tools, including 1) genetically engineered mouse models and viral vectors that allow brain site-selective targeting of key ANG, oxidant and ER stress molecules;2) state-of-the-art assays for visualizing and quantifying ER stress;3) sophisticated integrative physiology for evaluating AP, SNA and EE. A notable strength ofthe project is the extensive interfacing, both conceptual and technical, with Projects 2 and 3.

Public Health Relevance

Obesity-induced HT is a major global health problem that involves the sympathetic nervous system. This research has the potential to advance understanding of fundamental molecular and physiologic mechanisms by which the brain triggers sympathetic activation and HT in obesity, and could have implications for novel therapies targeting the neurogenic component of obesity-induced HT and its cardiovascular complications.

National Institute of Health (NIH)
National Heart, Lung, and Blood Institute (NHLBI)
Research Program Projects (P01)
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University of Iowa
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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
Contreras, Cristina; Nogueiras, Rubén; Diéguez, Carlos et al. (2017) Traveling from the hypothalamus to the adipose tissue: The thermogenic pathway. Redox Biol 12:854-863
Jiang, Jingwei; Cui, Huxing; Rahmouni, Kamal (2017) Optogenetics and pharmacogenetics: principles and applications. Am J Physiol Regul Integr Comp Physiol 313:R633-R645
Martínez-Sánchez, Noelia; Seoane-Collazo, Patricia; Contreras, Cristina et al. (2017) Hypothalamic AMPK-ER Stress-JNK1 Axis Mediates the Central Actions of Thyroid Hormones on Energy Balance. Cell Metab 26:212-229.e12
Grobe, Justin L (2017) Comprehensive Assessments of Energy Balance in Mice. Methods Mol Biol 1614:123-146
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
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
Srisai, Dollada; Yin, Terry C; Lee, Abigail A et al. (2017) MRAP2 regulates ghrelin receptor signaling and hunger sensing. Nat Commun 8:713
Chhabra, Kavaljit H; Morgan, Donald A; Tooke, Benjamin P et al. (2017) Reduced renal sympathetic nerve activity contributes to elevated glycosuria and improved glucose tolerance in hypothalamus-specific Pomc knockout mice. Mol Metab 6:1274-1285
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

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