Central Renin-Angiotensin System: Metabolism, Fluid Balance, and Hypertension

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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.