The renin-angiotensin system (RAS) in the brain is well recognized as an important determinant of cardiovascular regulation, through its actions on arterial pressure, fluid homeostasis and sympathetic nerve activity, and has been implicated in hypertension. Growing evidence has advanced the concept that the RAS, both in the brain and periphery also regulates energy expenditure. However, the precise central and peripheral mechanisms by which angiotensin II (ANG) regulates energy homeostasis, its sites of production and action in the brain, the neural circuitry involved, and its integration with other pathways controlling feeding and energy homeostasis remain undefined. Similarly, it remains unclear if the mechanisms and efferent pathways regulating the cardiovascular versus metabolic actions of ANG are similar or distinct. During the previous funding period we reported compelling data advancing the concept that activation of angiotensinergic signaling in the brain results in increased energy expenditure. Our overall hypothesis is that there are differential central mechanisms controlling the cardiovascular and metabolic outputs following brain RAS activation, and that local synthesis of ANG in the brain controls arterial pressure, water intake, and energy expenditure through overiapping yet discrete ANG-dependent mechanisms and efferent pathways. We further hypothesize that the adipose RAS through AT2R modulates the actions of the brain RAS on adipose tissue, and that diet-induced obesity (DIO) blunts the effects of brain RAS activation on energy expenditure by stimulating the adipose RAS acting through an AT2R-dependent mechanism.
The aims ofthe proposal are to address the following hypotheses. 1) ANG production and angiotensinergic signaling in the SFO and PVN are critical mediators of the arterial pressure, water intake, and energy expenditure responses to exogenous and endogenous brain RAS activation;2) The effects of increased brain RAS activity are modulated by the activity ofthe adipose RAS induced by DIO and mediated by an AT2R-dependent mechanism;3) Endoplasmic reticulum (ER) stress in the SFO and PVN plays an important role in the arterial pressure, water intake, and energy expenditure responses to increased brain RAS activity. We will capitalize on exciting new preliminary data, and leverage conceptual advances and the unique expertise of the investigators in this program in genetics, neural control mechanisms, neuroanatomy, and sophisticated cardiovascular and metabolic phenotyping. A distinctive strength is the extensive intellectual and technical interactions with the other projects.

Public Health Relevance

(See Instructions): These studies are significant in advancing the concepts of a) differential central mechanisms by which the brain RAS regulates arterial pressure, water intake, and energy expenditure, b) novel integration between the central and adipose RAS, and c) ER stress as a novel signaling modality in the brain. The studies are innovative in employing state-of-the-art genetic models and techniques for gene ablation in the brain, and advanced cardiovascular, metabolic and ER stress monitoring

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Program Projects (P01)
Project #
2P01HL084207-06A1
Application #
8524230
Study Section
Special Emphasis Panel (ZHL1-PPG-J (F1))
Project Start
Project End
Budget Start
2013-04-01
Budget End
2014-03-31
Support Year
6
Fiscal Year
2013
Total Cost
$502,914
Indirect Cost
$169,577
Name
University of Iowa
Department
Type
DUNS #
062761671
City
Iowa City
State
IA
Country
United States
Zip Code
52242
Littlejohn, Nicole K; Keen, Henry L; Weidemann, Benjamin J et al. (2016) Suppression of Resting Metabolism by the Angiotensin AT2 Receptor. Cell Rep 16:1548-60
Mukohda, Masashi; Stump, Madeliene; Ketsawatsomkron, Pimonrat et al. (2016) Endothelial PPAR-γ provides vascular protection from IL-1β-induced oxidative stress. Am J Physiol Heart Circ Physiol 310:H39-48
von Holstein-Rathlou, Stephanie; BonDurant, Lucas D; Peltekian, Lila et al. (2016) FGF21 Mediates Endocrine Control of Simple Sugar Intake and Sweet Taste Preference by the Liver. Cell Metab 23:335-43
Lu, Ko-Ting; Keen, Henry L; Weatherford, Eric T et al. (2016) Estrogen Receptor α Is Required for Maintaining Baseline Renin Expression. Hypertension 67:992-9
Guo, Deng-Fu; Cui, Huxing; Zhang, Qihong et al. (2016) The BBSome Controls Energy Homeostasis by Mediating the Transport of the Leptin Receptor to the Plasma Membrane. PLoS Genet 12:e1005890
Shinohara, Keisuke; Liu, Xuebo; Morgan, Donald A et al. (2016) Selective Deletion of the Brain-Specific Isoform of Renin Causes Neurogenic Hypertension. Hypertension 68:1385-1392
Hu, Chunyan; Lu, Ko-Ting; Mukohda, Masashi et al. (2016) Interference with PPARγ in endothelium accelerates angiotensin II-induced endothelial dysfunction. Physiol Genomics 48:124-34
Chapleau, Mark W; Rotella, Diane L; Reho, John J et al. (2016) Chronic vagal nerve stimulation prevents high-salt diet-induced endothelial dysfunction and aortic stiffening in stroke-prone spontaneously hypertensive rats. Am J Physiol Heart Circ Physiol 311:H276-85
Mark, Allyn L; Somers, Virend K (2016) Obesity, Hypoxemia, and Hypertension: Mechanistic Insights and Therapeutic Implications. Hypertension 68:24-6
Bell, Balyssa B; Rahmouni, Kamal (2016) Leptin as a Mediator of Obesity-Induced Hypertension. Curr Obes Rep 5:397-404

Showing the most recent 10 out of 162 publications