Dissertation
Neural mechanisms of stress and metabolism
University of Iowa
Doctor of Philosophy (PhD), University of Iowa
Autumn 2024
DOI: 10.25820/etd.007576
Abstract
Obesity imposes tremendous health and economic burdens by increasing the risk of numerous comorbidities. Despite the ever-rising prevalence, we lack a clear understanding of effective therapeutics to manage obesity comorbidities. Hypertension in obesity increases the risk for cardiovascular morbidity and mortality. Overwhelming evidence indicates that the adipose-derived hormone, leptin, mediates obesity-induced hypertension by activating sympathetic nerves. The work herein reviews our understanding of the molecular and neural substrates underpinning leptin’s cardiovascular function and speculates on fundamental advances important for treating obesity-induced hypertension. While preclinical studies have revealed therapeutic targets for managing obesity comorbidities, weight loss remains the most effective treatment. Thus, it is critical to understand the environmental and genetic factors that drive obesity. Chronic stress can lead to overeating and promote obesity, but the underlying neural pathways where stress and appetite information converges are unresolved. We found that an orexigenic adrenergic circuit functions as a general sensor resulting in inhibition of hypothalamic melanocortin neurons to promote negative valence. These results illustrate an integrative role for stress and appetite encoding by an adrenergic-melanocortin circuit which may contribute to stress-induced obesity. In addition to environmental factors, animal models of monogenic obesity provide insight into fundamental metabolic processes. Individuals with Bardet-Biedl Syndrome (BBS) harbor mutations in one of several Bbs genes which disrupts a receptor trafficking complex, the BBSome, and leads to obesity and type 2 diabetes. Here, we generated a conditional knockout mouse model with BBSome dysfunction selectively in brainstem and vagal neurons. In contrast to studies showing that hypothalamic BBSome disruption causes obesity and glucose dysregulation, we found that the brainstem/vagal BBSome plays a negligible role in body weight. However, these lean mice developed marked glucose intolerance coupled with impaired hepatic insulin signaling. These findings reveal complex roles of the BBSome in the central nervous system and indicates that type 2 diabetes in BBS is independent of obesity. Collectively, the work presented here advances our understanding of neuronal mechanisms involved in stress and metabolic homeostasis.
Details
- Title: Subtitle
- Neural mechanisms of stress and metabolism
- Creators
- Connor Laule
- Contributors
- Kamal Rahmouni (Advisor)Deniz Atasoy (Advisor)Rory Fisher (Committee Member)Yuriy Usachev (Committee Member)
- Resource Type
- Dissertation
- Degree Awarded
- Doctor of Philosophy (PhD), University of Iowa
- Degree in
- Biomedical Science (Pharmacology)
- Date degree season
- Autumn 2024
- DOI
- 10.25820/etd.007576
- Publisher
- University of Iowa
- Number of pages
- ix, 147 pages
- Copyright
- Copyright 2024 Connor Laule
- Language
- English
- Date submitted
- 11/29/2024
- Description illustrations
- illustrations, tables, graphs
- Description bibliographic
- Includes bibliographical references (pages 122-147).
- Public Abstract (ETD)
- Obesity leads to many other diseases that decrease life quality and length. High blood pressure caused by obesity is especially dangerous because it can cause organ damage which can be deadly. Fat cells release the hormone, leptin, into the bloodstream which travels into the brain to decrease body weight and increase blood pressure. In obesity, leptin signaling in the brain becomes abnormal. Specifically, leptin is unable to decrease body weight, but it can still increase blood pressure. We review how leptin works in the brain to increase blood pressure and introduce questions that need to be answered to decrease blood pressure in obesity. Because weight loss is the best way to treat health complications associated with obesity, we also studied fundamental brain systems that cause obesity. Stress can increase appetite and lead to obesity but why this happens is not clear. By recording and manipulating brain activity in mice, we found that a hunger circuit is activated by stress. These findings suggest that these parts of the brain might be involved in overeating and obesity caused by stress. Lastly, humans with mutations that cause obesity can be studied in mice genetically engineered with the same mutations. We studied a rare genetic condition that causes obesity and diabetes. Our results show that this mutation in a specific brain region does not impact body weight but is important for controlling blood sugar. These findings help to understand why people with BBS have diabetes.
- Academic Unit
- Biomedical Science Program
- Record Identifier
- 9984774548602771
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