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.
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.
|Contreras, Cristina; González-García, Ismael; Martínez-Sánchez, Noelia et al. (2014) Central ceramide-induced hypothalamic lipotoxicity and ER stress regulate energy balance. Cell Rep 9:366-77|
|Borges, Giulianna R; Morgan, Donald A; Ketsawatsomkron, Pimonrat et al. (2014) Interference with peroxisome proliferator-activated receptor-? in vascular smooth muscle causes baroreflex impairment and autonomic dysfunction. Hypertension 64:590-6|
|Li, Wencheng; Peng, Hua; Mehaffey, Eamonn P et al. (2014) Neuron-specific (pro)renin receptor knockout prevents the development of salt-sensitive hypertension. Hypertension 63:316-23|
|Rahmouni, Kamal (2014) Obesity-associated hypertension: recent progress in deciphering the pathogenesis. Hypertension 64:215-21|
|Sones, Jenny L; Lob, Heinrich E; Isroff, Catherine E et al. (2014) Role of decidual natural killer cells, interleukin-15, and interferon-? in placental development and preeclampsia. Am J Physiol Regul Integr Comp Physiol 307:R490-2|
|Coble, Jeffrey P; Johnson, Ralph F; Cassell, Martin D et al. (2014) Activity of protein kinase C-? within the subfornical organ is necessary for fluid intake in response to brain angiotensin. Hypertension 64:141-8|
|Ramkumar, Nirupama; Stuart, Deborah; Rees, Sara et al. (2014) Collecting duct-specific knockout of renin attenuates angiotensin II-induced hypertension. Am J Physiol Renal Physiol 307:F931-8|
|Owen, Bryn M; Ding, Xunshan; Morgan, Donald A et al. (2014) FGF21 acts centrally to induce sympathetic nerve activity, energy expenditure, and weight loss. Cell Metab 20:670-7|
|Grobe, Justin L; Sigmund, Curt D (2014) Another reason to eat your greens: cardiopulmonary protection by dietary delivery of angiotensin-converting enzyme-2 and angiotensin-(1-7) made in plants. Hypertension 64:1182-3|
|Shi, Peng; Grobe, Justin L; Desland, Fiona A et al. (2014) Direct pro-inflammatory effects of prorenin on microglia. PLoS One 9:e92937|
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