Cardiovascular and metabolic disorders are rapidly growing burdens on tiuman hiealth worldwide. Currently approximately one third ofthe adult population ofthe United States is clinically obese, and one third exhibit sustained hypertension. There is also a high overlap of patients who exhibit both obesity and hypertension. Collectively, the economic, social, psychological, and productivity burdens which result from cardiovascular and metabolic disorders costs the United States roughly quarter of a trillion dollars per year. One hormone system involved in the regulation of both metabolism and cardiovascular function is the Renin-Angiotensin System (RAS). This system exists in the circulation as a classic hormone system, and also within individual orgains ofthe body where it acts in a paracrine fashion. While the RAS is found in many tissues throughout the body, we have demonstrated that hyperactivity of the brain RAS is sufficient to cause gross disturbances in blood pressure, fluid balance, and metabolic regulation. We have identified specific, distinct signaling mechanisms that mediate each of these phenotypes. The current proposal will narrowly focus on the mechanism of metabolic regulation by the brain RAS. Guided by our preliminary findings, we hypothesize that the brain RAS stimulates thermogenesis through two mechanisms. First, via activation of the sympathetic nervous system, the brain RAS stimulates thermogenesis within brown adipose tissue. Second, via a vasopressin-mediated hypertension, the brain RAS suppresses the circulating RAS. Suppression ofthe circulating RAS results in reduced angiotensin AT2 receptor signaling within white adipocytes and preadipocytes, which results in increased formation of brown adipocytes and thus increased thermogenic capacity. Together, these mechanisms synergistically act to positively influence metabolic rate. Examination of these mechanisms will likely lead to the identification of novel therapeutic targets for metabolic diseases.

Public Health Relevance

The Renin-Angiotensin System (RAS) is a hormone system involved in the regulation of renal, cardiac, and vascular structure and function, fluid and sodium consummatory behavior, blood pressure, and metabolic rate. In the current proposal, we will evaluate the mechanism through which the brain's RAS regulates metabolism, with the ultimate goal of identifying novel therapeutic targets for obesity and hypertension.

National Institute of Health (NIH)
National Heart, Lung, and Blood Institute (NHLBI)
Research Transition Award (R00)
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Special Emphasis Panel (NSS)
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Galis, Zorina S
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University of Iowa
Schools of Medicine
Iowa City
United States
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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
Santillan, Mark K; Santillan, Donna A; Scroggins, Sabrina M et al. (2014) Vasopressin in preeclampsia: a novel very early human pregnancy biomarker and clinically relevant mouse model. Hypertension 64:852-9
Burnett, Colin M L; Grobe, Justin L (2014) Dietary effects on resting metabolic rate in C57BL/6 mice are differentially detected by indirect (O2/CO2 respirometry) and direct calorimetry. Mol Metab 3:460-4
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
Burnett, Colin M L; Grobe, Justin L (2013) Direct calorimetry identifies deficiencies in respirometry for the determination of resting metabolic rate in C57Bl/6 and FVB mice. Am J Physiol Endocrinol Metab 305:E916-24
Littlejohn, Nicole K; Siel Jr, Rick B; Ketsawatsomkron, Pimonrat et al. (2013) Hypertension in mice with transgenic activation of the brain renin-angiotensin system is vasopressin dependent. Am J Physiol Regul Integr Comp Physiol 304:R818-28
Grobe, Justin L; Rahmouni, Kamal; Liu, Xuebo et al. (2013) Metabolic rate regulation by the renin-angiotensin system: brain vs. body. Pflugers Arch 465:167-75
Hilzendeger, Aline M; Cassell, Martin D; Davis, Deborah R et al. (2013) Angiotensin type 1a receptors in the subfornical organ are required for deoxycorticosterone acetate-salt hypertension. Hypertension 61:716-22