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

National Institute of Health (NIH)
National Heart, Lung, and Blood Institute (NHLBI)
Research Program Projects (P01)
Project #
Application #
Study Section
Special Emphasis Panel (ZHL1-PPG-J (F1))
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
University of Iowa
Iowa City
United States
Zip Code
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

Showing the most recent 10 out of 183 publications