Grants and Contracts Details
Obesity is one of the most serious health problems in the United States, and the most common cause of hypertension. Our laboratory demonstrated that adipocytes express components of the renin-angiotensin system (RAS), and that mice with diet-induced obesity and hypertension exhibit adipose-specific dysregulation of these components favoring an increase in blood pressure. Angiotensinogen (AGT), angiotensin type 1a receptors (AT1aR), and ACE2 are three components of the RAS that were regulated specifically in adipose tissue from mice with hypertension from diet-induced obesity. Preliminary data suggest that fatty acids, enriched in the western high fat (HF) diet, regulate specific RAS components in adipocytes, serving as a mechanism for adipose-specific regulation of the RAS. We hypothesize that the RAS of adipocytes contributes to the development of obesity-induced hypertension. In aim 1, we hypothesize that adipose tissue is a predominant source for increased local and systemic angiotensin II (AngII) in obesity-hypertension. To test this hypothesis, we will feed low fat (LF) or HF diets to mice with adipocyte-specific AGT deletion and determine the impact on the development of obesity-hypertension. In vitro studies will use adipose tissue from adipocyte AGT deficient mice to test the hypothesis that fatty acids regulate oxidative stress and proinflammatory adipokines through an AngII-dependent mechanism. In Aim 2, we hypothesize that adipocyte AT1aR mediate effects of local and/or systemic AngII to increase proinflammatory adipokine expression and promote obesity-hypertension. To test this hypothesis, we will feed LF or HF diets to mice with adipocyte-specific AT1aR deficiency and determine the impact on the development of obesity-hypertension. In vitro studies will test the hypothesis that adipocyte AT1aR mediate effects of AngII to promote oxidative stress and adipokine expression. In Aim 3, we hypothesize that specific fatty acids regulate ACE2 expression and shedding to increase the development of obesity-hypertension. In vitro studies will define effects of specific fatty acids on ACE2 gene transcription and/or shedding in adipocytes, and in vivo approaches will use ACE2 deficient mice to define their susceptibility to the development of obesity-hypertension. Results from these studies will identify dietary or pharmacologic sites for targeted reductions in the adipocyte RAS in the treatment of obesity-hypertension.
|Effective start/end date||6/3/03 → 4/30/14|
- National Heart Lung and Blood Institute: $444,035.00
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