Date of Degree
PhD (Doctor of Philosophy)
Grobe, Justin L.
First Committee Member
Mark, Allyn L.
Second Committee Member
Third Committee Member
Roghair, Robert D.
Fourth Committee Member
Sigmund, Curt D.
Leptin acts within the brain to increase resting metabolic rate (RMR) and blood pressure (BP). The renin-angiotensin system (RAS) elicits similar effects in the brain, as reviewed in chapter 1, and it has previously been shown that central angiotensin II type 1 (AT1) receptors are required for leptin-mediated inductions in sympathetic nerve activity to the brown adipose tissue. Thus, we hypothesize that the brain RAS mediates the metabolic effects of leptin. To investigate the interaction between the RAS and leptin, we generated the AT1ALepR-KO mouse which lacks the AT1A receptor in leptin-sensitive cells. In chapter 2, we demonstrated that stimulation of RMR by DOCA-salt and high fat diet requires AT1A receptors in leptin receptor-expressing cells and that these cells expressing both AT1A and the leptin receptor appear to be agouti related-peptide (AgRP) neurons. In chapter 3, we investigated the role of AT1A specifically in AgRP neurons by utilizing AT1AAgRP-KO mice. Similar to AT1ALepR-KO mice, AT1AAgRP-KO mice exhibited deficits in BAT SNA responses to leptin and induction of RMR by alpha melanocyte stimulating hormone. In chapter 4, we utilized a novel transgenic mouse model to demonstrate that microglia do not express the AT1A receptor under chow or high fat diet fed conditions. Taken together, we conclude that a subset of AgRP neurons, which express both the leptin receptor and the AT1A receptor, are critical for the control of sympathetic nerve activity and ultimately RMR.
Obesity is a major health and economic burden in the United States and worldwide, and it represents a major risk factor for cardiovascular disease, diabetes and cancer. Current treatment options for obesity include diet and exercise, bariatric surgery and several drugs that reduce food intake. Although all of these weight loss methods have proven successful with initial use, the chronic, long-term management of obesity remains an issue. Alternative ways to treat obesity are therefore critical as the prevalence of obesity continues to rise. Another possible method to treat obesity is to increase the amount of energy produced by the body at rest. Angiotensin and leptin are two hormones that can act in the brain to increase this resting metabolism and thus promote weight loss.
Through the use of genetically altered mice, we show that the action of angiotensin at AT1A receptors on neurons in the brain is required for leptin to induce resting metabolism and therefore counteract weight gain. Our studies highlight the potential beneficial metabolic effects of activating angiotensin signaling in select regions of the brain. A more complete understanding of the interaction between leptin and angiotensin in the brain could lead to the identification of new drug targets for the treatment of obesity.
Leptin, Obesity, Renin-Angiotensin System, Resting Metabolism
xi, 148 pages
Includes bibliographical references (pages 126-148).
Copyright © 2016 Kristin Elizabeth Claflin
Claflin, Kristin Elizabeth. "The brain renin-angiotensin system in metabolic and cardiovascular regulation." PhD (Doctor of Philosophy) thesis, University of Iowa, 2016.