COBRE Pilot Project for Hong Lu: Center of Research in Obesity and Cardiovascular Disease

Grants and Contracts Details


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.
Effective start/end date9/8/087/31/15


  • National Institute of General Medical Sciences


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