Grants and Contracts Details
Western countries are experiencing an epidemic of obesity and face increasing rates of related complications such as diabetes mellitus, elevated lipid levels and hypertension. A variety of mechanisms have been proposed to link obesity to the high prevalence of hypertension, including activation of the Renin Angiotensin system (RAS). Adipocytes express components of the RAS with elevation in adipose derived Angll potentially contributing to obesity associated hypertension. The mono-carboxypeptidase, ACE2, is a homolog of ACE that cleaves the potent vasoconstrictor angiotensin II (Angll) as a substrate for the production of the vasodilator peptide, angiotensin 1-7 (Angi-7). Preliminary data demonstrate that ACE2 mRNA, protein and enzymatic activity are present in 3T3-Ll adipocytes and in mouse adipose tissue. To determine if adipocyte ACE2 exhibits nutritional regulation, C57BL/6 mice were fed low fat (LF) or high fat (HF) diets acutely or chronically. Initially, ACE2 mRNA expression increased in adipose tissue, but not in kidney, of HF-fed mice. Interestingly, despite continued elevations in ACE2 mRNA expression in adipose tissue with chronic HF feeding, ACE2 activity declined, systemic Angli increased and mice exhibited obesity-hypertension We hypothesize that dysregulated ACE2 in adipose tissue contributes to the development of HF diet-induced obesity and obesity-related hypertension. Moreover, we hypothesize that fatty acids are the mechanistic mediators of HF-regulation of adipocyte ACE2. In Aim 1, we will define effects of ACE2 deficiency in mice on the development of obesity and obesity hypertension. In Aim 2, we will determine the effects of specific fatty acids, on the expression of ACE2 mRNA, protein and activity in 313-Li adipocytes. A focus will be on regulation of ACE2 shedding from adipocytes by specific fatty acids. Fatty acids resulting in an increase in ACE2 expression and activity in adipocytes will then be enriched in the diet of C57BL/6 and ACE2 deficient mice to determine their effects on obesity and obesity-related hypertension. Results from these studies will identify novel mechanisms contributing to the development of obesity and obesity-hypertension.
|Effective start/end date||7/1/08 → 6/30/10|
- American Heart Association Great Rivers Affiliate: $42,000.00
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