The proposed studies are in response to RFA-HL-02-016 and will address the working hypothesis that a moderately high fat diet (MHF) stimulates the adipose renin-angiotensin system, contributing to obesity-related elevations in blood pressure. Preliminary data demonstrates that rats fed a MHF diet segregate into obesity prone (OP) versus obesity-resistant (OR) populations. In OP rats, blood pressure was increased coincident with activation of the systemic and adipose renin-angiotensin system. The first hypothesis is that a MHF diet activates the adipose renin-angiotensin system, resulting in an increase in circulating angiotensin peptides and blood pressure. Time-dependent regulation of adipose versus non-adipose components of the renin-angiotensin system will be examined in control, OR and OP rats and compared to the time course for elevations in blood pressure. The contribution of various circulating angiotensin peptides to blood pressure elevations in control, OR and OP rats will be determined. The second hypothesis is that adipocytes from OP rats exhibit a redistribution of free cholesterol from the plasma membrane to intracellular triglyceride pools, thereby increasing the activity of sterol regulatory binding protein-2 and stimulating angiotensinogen (Ao) mRNA expression. This would provide an adipocyte-specific mechanism for regulation of Ao gene expression in response to the MHF diet. The intracellular localization of free cholesterol in adipocytes prepared from control, OR and OP rats will be determined and compared to the level of Ao mRNA expression. The effect of depletion of intracellular free cholesterol pools on adipocyte Ao mRNA expression will be determined. The third hypothesis is that elevations in circulating angiotensin peptides increase blood pressure in OP rats by stimulating sympathetic drive. The responsiveness of the baroreceptor reflex and the blood pressure response to ganglionic blockade will be determined in control, OR and OP rats. A second approach will determine the effect of neonatal sympathectomy on blood pressure elevations in diet-induced obesity. In hypothesis 4 a novel animal model will be developed to determine the effect of targeted deficiency of Ao in adipose tissue on blood pressure regulation in diet-induced obesity. The goals of this research are to definitively determine the role of adipose-derived angiotensins and the systemic renin-angiotensin system in blood pressure elevations in diet-induced obesity.
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