Year of Publication

2011

Degree Name

Doctor of Philosophy (PhD)

Document Type

Dissertation

College

Medicine

Department

Nutritional Sciences

First Advisor

Dr. Lisa Cassis

Abstract

The purpose of this research was to determine whether adipocytes express ACE2 and its role in obesity-associated hypertension with diet-induced obesity.

To determine if ACE2 was expressed in adipose tissue and its regulation in the setting of diet-induced obesity, we fed male mice either a low fat (LF) or high fat (HF) diet acutely (1 week) or chronically ( 4 months). We demonstrated that ACE2 was regulated specifically in adipose tissue with consumption of a HF diet. However, with chronic HF feeding adipose ACE2 was dysregulated resulting in activation of the systemic RAS and increased blood pressure.

To determine the role of ACE2 in obesity-associated hypertension, we used ACE2 deficient male and female mice. Wild type and ACE2 deficient mice were chronically fed either a LF or HF diet. Metabolic parameters were measured during the entire course of the study and blood pressure was measured by telemetry at the end of the study. Results from these studies demonstrate that HF diet promotes obesity-associated hypertension in male mice which is further augmented with ACE2 deficiency. Further, ACE2 deficiency resulted in marked glucose intolerance suggesting that stimulation of ACE2 may blunt the progression of obesity-associated diabetes.

In contrast to the males, females are protected against obesity-associated hypertension. However, this protection in the females is lost with ovariectomy and ACE2 deficiency. These results suggest that female sex hormones protect the females against obesity-associated hypertension by regulating ACE2.

To define mechanisms for HF diet-induced regulation of ACE2 in adipose tissue we examined various fatty acids for their ability to regulate ACE2 mRNA abundance in 3T3-L1 adipocytes. We revealed that omega-3 fatty acids, known regulators of PPARγ, increased ACE2 mRNA abundance in adipocytes. Therefore, we examined in vitro and in vivo regulation of ACE2 in 3T3-L1 cells and adipose tissue by PPARγ receptor ligands (TZDs). Results demonstrate regulatory effects of PPARγ to promote ACE2 gene transcription. These effects were associated with changes in glucose tolerance.

Taken together, these results demonstrate that adipose ACE2 plays a protective role against obesity-associated hypertension in male and female mice and is regulated by natural and synthetic ligands of PPARγ.

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