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Description
Angiotensinogen (AGT) is the only precursor in the renin angiotensin system (RAS), a pivotal
hormonal system regulating many vascular and metabolic functions. Renin cleavage of AGT leads to
generation of angiotensin (Ang)I and des(AngI)-AGT, and subsequently, angiotensin-converting enzyme
(ACE) cleaves AngI into AngII, which interacts with AT1 receptors to regulate multiple pathophysiological
functions. Our study using both genetic and pharmacological approaches found that inhibition of AGT led to
reductions of blood pressure and atherosclerosis. These two effects are consistent with studies using the 3
available modes of RAS inhibition (renin, ACE, and AT1 receptors). Unexpectedly, we also observed that
inhibition of AGT resulted in resistance to body weight gain and liver steatosis induced by western diet, which
were not observed in mice administered a wide range of doses of the 3 modes of RAS inhibition. Our further
experiments demonstrated that (1) inhibition of AGT in C57BL/6 mice fed the same “western” diet led to
profound reductions of body weight gain; and (2) inhibition of AGT led to reductions of fat mass in LDL
receptor -/- mice fed a high carbohydrate diet. Of clinical significance, AGT inhibition also regressed preexisting
obesity, and diminished hemoglobin A1c (HbA1c) in both LDL receptor -/- mice and leptin -/- mice fed
the western diet. Additionally, as implicated by microarray analysis, AGT inhibition attenuated obesityinduced
inflammatory responses in white adipose tissues and changed profiles of multiple factors including
many microRNAs in brown adipose tissues. Therefore, Aim 1 of this application will determine the molecular
mechanisms by which AGT contributes to diet-induced obesity. On the basis of our microarray data, initial
mechanistic exploration will use in vitro culture system and focus on cells isolated from white (gonadal) and
brown (interscapular) adipose tissues in mice with genetic depletion of AGT and their wild type littermates.
The 3 available modes of pharmacological inhibition (renin, ACE, and AT1 receptors) improve diabetic
nephropathy. However, no studies in humans have reported reductions of body weight by these 3 modes of
the RAS inhibition. Also, we and many other groups did not find effects of these 3 modes of the RAS
inhibition on obesity in animal models. These data infer that improving obesity is a unique feature of AGT
inhibition. Since many diabetic patients are also obese, and obesity augments morbidities and complications
of diabetes, Aim 2 will determine whether AGT inhibition has superior beneficial effects to the 3 available
pharmacological inhibitors of the RAS on improving obesity and diabetic complications. Mice with leptin
receptor deficiency will be used in this aim. We will compare maximal effects of AGT inhibition with the 3
RAS inhibition on the development of obesity and diabetic complications. Data generated in this application
will be used for an NIH R01 submission.
Status | Finished |
---|---|
Effective start/end date | 9/8/08 → 7/31/15 |
Funding
- National Institute of General Medical Sciences
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Projects
- 1 Finished
-
COBRE: Center of Research in Obesity and Cardiovascular Disease
Cassis, L. (PI), Abdel-Latif, A. (CoI), Charnigo, R. (CoI), Daugherty, A. (CoI), Esser, K. (CoI), Finlin, B. (CoI), Fornwalt, B. (CoI), Graf, G. (CoI), Katz, W. (CoI), Kern, P. (CoI), Klyachkin, Y. (CoI), Liu, Z. (CoI), Morris, A. (CoI), Nagareddy, P. (CoI), Park, S. H. (CoI), Pearson, K. (CoI), Powell, D. (CoI), Randall, D. (CoI), Ren, H. (CoI), Smyth, S. (CoI), Tannock, L. (CoI), Van Der Westhuyzen, D. (CoI), Wang, S. (CoI), Webb, N. (CoI), Zhou, C. (CoI), Zhu, J. (CoI), Luo, T. (Former CoI) & Suever, J. (Former CoI)
National Institute of General Medical Sciences
9/8/08 → 7/31/15
Project: Research project