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.

Public Health Relevance

The relevance of this project to public health is the definition of mechanisms contributing to the development of hypertension in obese subjects. Given the epidemic of obesity in the US, results from these studies will define whether an adipocyte renin-angiotensin system is a primary mechanism linking the epidemic of obesity to a growing prevalence of hypertension. Since the principal cause of death in obese patients is cardiovascular disease, results from these studies are clinically significant.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL073085-09
Application #
8288761
Study Section
Hypertension and Microcirculation Study Section (HM)
Program Officer
OH, Youngsuk
Project Start
2003-06-03
Project End
2014-06-30
Budget Start
2012-07-01
Budget End
2014-06-30
Support Year
9
Fiscal Year
2012
Total Cost
$367,538
Indirect Cost
$120,038
Name
University of Kentucky
Department
Nutrition
Type
Schools of Medicine
DUNS #
939017877
City
Lexington
State
KY
Country
United States
Zip Code
40506
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Yiannikouris, Frederique; Karounos, Michael; Charnigo, Richard et al. (2012) Adipocyte-specific deficiency of angiotensinogen decreases plasma angiotensinogen concentration and systolic blood pressure in mice. Am J Physiol Regul Integr Comp Physiol 302:R244-51
Li, Huiping; Weatherford, Eric T; Davis, Deborah R et al. (2011) Renal proximal tubule angiotensin AT1A receptors regulate blood pressure. Am J Physiol Regul Integr Comp Physiol 301:R1067-77
Grobe, Justin L; Grobe, Connie L; Beltz, Terry G et al. (2010) The brain Renin-angiotensin system controls divergent efferent mechanisms to regulate fluid and energy balance. Cell Metab 12:431-42
Yiannikouris, Frederique; Gupte, Manisha; Putnam, Kelly et al. (2010) Adipokines and blood pressure control. Curr Opin Nephrol Hypertens 19:195-200
Police, Sara B; Putnam, Kelly; Thatcher, Sean et al. (2010) Weight loss in obese C57BL/6 mice limits adventitial expansion of established angiotensin II-induced abdominal aortic aneurysms. Am J Physiol Heart Circ Physiol 298:H1932-8

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