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The Renin-Angiotensin System and the Neuroendocrine Regulation of Energy Balance

de Kloet, Annette D.
http://rave.ohiolink.edu/etdc/view?acc_num=ucin1312292019

Abstract Details

2011, PhD, University of Cincinnati, Medicine: Neuroscience/Medical Science Scholars Interdisciplinary.
The renin-angiotensin system (RAS) is best-known as an endocrine system that regulates hydromineral balance and cardiovascular function. More recently, it has become evident that the RAS acts in an autocrine or paracrine fashion within many tissues to influence obesity and its comorbidities. The goal of these studies was to test specific hypotheses relating to how angiotensin-II (Ang-II; an end-product of the RAS) influences energy and glucose homeostasis. The overall hypothesis is that Ang-II acts in the brain to promote negative energy balance and peripherally to enhance energy storage. To assess the role of the RAS in energy and glucose homeostasis, body weight and composition, food intake and glucose tolerance were examined in rats given captopril. Captopril is an angiotensin-converting enzyme (ACE) inhibitor that prevents circulating Ang-II from being formed but does not readily access the brain. Rats fed either high-fat or low-fat diet and given captopril weighed less, had less body fat, and had improved glucose tolerance relative to controls. Rats given captopril also ate significantly less than free-fed controls, and comparisons to pair-fed controls indicated that the reduced weight gain and adiposity and improved glucose tolerance were due primarily to decreased food intake. Because systemic captopril elevates plasma and consequently brain angiotensin-I (Ang-I; the precursor for Ang-II and substrate for ACE), but does not itself enter the brain, we further hypothesized that still-active brain ACE would convert the increased Ang-I into Ang-II, and that the increased central Ang-II would contribute to systemic captopril-induced negative energy balance. Consistent with this, the reduction in food intake elicited by peripheral captopril was reversed by co-administration of the ACE inhibitor into the brain. These results suggest that captopril protects against diet-induced obesity, in part by elevating central Ang-II levels. These studies were extended by directly evaluating the role of RAS in the CNS regulation of energy balance. Osmotic minipumps were used to chronically administer Ang-II to rats in order to examine the effect of increased brain Ang-II signaling on energy balance. Chronic elevation of central Ang-II signaling resulted in reduced food intake, body weight gain and adiposity. The decrease in body weight and adiposity occurred relative to free-fed and pair-fed controls, implying that reduced food intake, in and of itself, does not underlie all of these effects. Consistent with this, rats administered Ang-II exhibited increased energy expenditure and enhanced expression of indices of adipose tissue sympathetic activation. Moreover, chronic icv Ang-II increased the anorectic corticotrophin-releasing and thyroid-releasing hormones within the hypothalamus. This hypothalamic gene expression profile coupled with the abundant angiotensin type-1 receptor expression within the paraventricular nucleus of the hypothalamus (PVN) led to the hypothesis that the PVN angiotensin type-1 receptor population may contribute to some of these processes. This hypothesis is discussed in the final chapter. Collectively, the experiments included in this dissertation support the overall hypothesis that Ang-II acts within the CNS to promote negative energy balance, and suggest that some contributing mechanisms include reduced food intake, elevated energy expenditure and enhanced sympathetic activation of adipose tissue.
Stephen Woods, PhD (Committee Chair)
James Herman, PhD (Committee Member)
Silvana Obici, MD (Committee Member)
Randall Sakai, PhD (Committee Member)
Randy Seeley, PhD (Committee Member)
153 p.
Neurology
Angiotensin; Obesity; Adipose; Neural

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Citations

  • de Kloet, A. D. (2011). The Renin-Angiotensin System and the Neuroendocrine Regulation of Energy Balance [Doctoral dissertation, University of Cincinnati]. OhioLINK Electronic Theses and Dissertations Center. http://rave.ohiolink.edu/etdc/view?acc_num=ucin1312292019

    APA Style (7th edition)

  • de Kloet, Annette. The Renin-Angiotensin System and the Neuroendocrine Regulation of Energy Balance. 2011. University of Cincinnati, Doctoral dissertation. OhioLINK Electronic Theses and Dissertations Center, http://rave.ohiolink.edu/etdc/view?acc_num=ucin1312292019.

    MLA Style (8th edition)

  • de Kloet, Annette. "The Renin-Angiotensin System and the Neuroendocrine Regulation of Energy Balance." Doctoral dissertation, University of Cincinnati, 2011. http://rave.ohiolink.edu/etdc/view?acc_num=ucin1312292019

    Chicago Manual of Style (17th edition)

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© 2011, all rights reserved.
This open access ETD is published by University of Cincinnati and OhioLINK.