DOI

10.17077/etd.p2z22sc4

Document Type

Dissertation

Date of Degree

Fall 2015

Degree Name

PhD (Doctor of Philosophy)

Degree In

Pharmacology

First Advisor

Justin L. Grobe

First Committee Member

Allyn L Mark

Second Committee Member

Matthew J Potthoff

Third Committee Member

Kamal Rahmouni

Fourth Committee Member

Curt D Sigmund

Abstract

The renin-angiotensin system (RAS) greatly contributes to energy homeostasis through opposing actions in the brain and adipose. We hypothesize that site- and receptor-specific effects of the RAS may represent a novel therapeutic target for obesity, a concept which is fully reviewed in chapter 1. Transgenic “sRA” mice exhibit brain-specific RAS hyperactivity, and a suppressed circulating RAS presumably secondary to the chronic hypertension exhibited by these animals. In chapter 2, we demonstrated that the hypertension observed with elevated brain RAS is mediated by increased vasopressin signaling. In chapter 3, we investigated how suppressed circulating RAS activity contributes to the elevated resting metabolic rate (RMR) of sRA mice. Despite having no effect upon energy intake, chronic angiotensin II type 2 (AT2) receptor activation suppressed energy expenditure and caused weight gain in sRA mice. The AT2 receptor alters inguinal white adipose tissue to contribute to obesity through the suppression of RMR. Lastly, in chapter 4, we documented moderately-improved glycemic control with elevated brain RAS/reduced circulating RAS activity, though the mechanism behind this remains unknown. Taken together, we determined that low circulating RAS activity is metabolically beneficial due to reduced activation of the AT2 receptor. Thus, specific inhibition of the systemic RAS may ultimately stimulate energy expenditure and thus may be a viable anti-obesity pharmaceutical approach. Overall, our data highlight the importance of site-specific effects of the RAS on energy homeostasis.

Public Abstract

Obesity is a major health risk for cardiovascular disease, cancer, and diabetes, and 1 out of 3 Americans are now obese. Currently, obesity is generally treated with exercise and an improved diet. However, this is not always sufficient to induce and maintain weight loss over a long period of time. One possible method of fighting obesity is to increase the amount of energy expended by the body at rest. A hormone system called the renin-angiotensin system is known to modulate all aspects of energy balance including the amount of calories eaten and absorbed into the body, physical activity, and metabolism. Changes in metabolism are due in part to the conversion of white fat, which primarily stores fat, to brown fat, which can use stored energy to produce body heat.

Genetically altered mice with overactivity of the renin-angiotensin system specifically in the brain have a decreased body mass. This is due to increased energy expenditure, specifically an elevated metabolism, and due to a white-to-brown fat conversion. Activation of a target of the renin-angiotensin system (the AT2 receptor) reduces the conversion of white fat to brown fat, which resulted in a decreased metabolism and ultimately caused body weight gain. Our studies therefore underline the potential beneficial metabolic effects of long-term adipose AT2 blockade. A better understanding of this process could lead to the identification of new drug targets for the treatment of obesity.

Pages

xi, 155 pages

Bibliography

Includes bibliographical references (pages 133-155).

Copyright

Copyright © 2015 Nicole Kathryn Littlejohn

Included in

Pharmacology Commons

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