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Mechanisms of vascular dysfunction in obesity and type 2 diabetes: role of the gut microbiota and endoplasmic reticulum stress

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dc.contributor.authorBattson, Micah Lee, author
dc.contributor.authorGentile, Christopher, advisor
dc.contributor.authorCox-York, Kimberly, advisor
dc.contributor.authorWeir, Tiffany, committee member
dc.contributor.authorPagliassotti, Michael, committee member
dc.contributor.authorChicco, Adam, committee member
dc.date.accessioned2018-06-12T16:14:10Z
dc.date.available2019-06-07T16:14:10Z
dc.date.issued2018
dc.description.abstractVascular dysfunction, characterized by arterial stiffness and endothelial dysfunction, is a key antecedent to overt cardiovascular disease in obesity and type 2 diabetes. Although the mechanisms underlying the development of vascular dysfunction in obese and type 2 diabetic individuals are not fully known, a growing body of evidence suggest that adverse cellular processes, including endoplasmic reticulum (ER) stress, inflammation and oxidative stress, are primarily responsible for the disruption of normal vascular function in these two metabolic diseases. Therefore, identifying effective strategies to mitigate one or more of these adverse processes may lead to novel therapies for the treatment of vascular dysfunction in obesity and/or type 2 diabetes. In addition, ascertaining the initial triggering factor(s) that promote these adverse processes will inform innovative ways to prevent or control the progression of vascular dysfunction. The goals of this dissertation research were to 1) examine the underlying causes of vascular dysfunction in obesity and type 2 diabetes and 2) identify potential strategies to mitigate vascular dysfunction in these metabolic diseases. To this end, we conducted three separate studies in murine models of obesity and/or type 2 diabetes aimed to modulate key factors that can affect vascular function. In all three studies, we measured aortic pulse wave velocity and endothelium-dependent dilation as clinically relevant indices of arterial stiffness and endothelial dysfunction, respectively. We also conducted various biochemical analyses to explore the potential mechanisms by which our experimental interventions altered vascular function. In our first study (Chapter 2), we examined the role of ER stress in diabetic vascular dysfunction. In type 2 diabetic (db/db) mice, we found that chronic administration of the ER stress inhibitor, tauroursodeoxycholic acid (TUDCA), significantly reduced arterial stiffness and endothelial dysfunction. These vascular improvements were associated with reduced expression of ER stress-related genes within the aorta and surrounding perivascular adipose tissue (PVAT). Next (Chapter 3), we examined the role of the gut microbiota in the development of vascular dysfunction in obesity. We found that Western diet (WD)-induced obesity increased arterial stiffness, impaired endothelial function, and promoted endotoxemia-related inflammation. Antibiotic treatment to suppress the gut microbiota in WD-fed mice reduced arterial stiffness, improved endothelial function, and attenuated systemic and vascular inflammation. In our final study (Chapter 4), we examined whether gut dysbiosis represents a causal factor in the development of obesity-related vascular dysfunction. We found that transplant of gut microbiota from obese (ob/ob) to control mice promoted the development of arterial stiffness, and this was associated with reduced abundance of a symbiotic bacterium, Akkermansia muciniphila, decreased short-chain fatty acid levels, and increased gut permeability. In contrast, transplant of control microbiota to obese mice did not attenuate arterial stiffness. Collectively, these studies in mice provided evidence that 1) mitigation of ER stress improves vascular function in type 2 diabetes, 2) gut dysbiosis contributes to vascular dysfunction in WD-induced obesity, and 3) an obese-type microbiota can promote arterial stiffening independent of body weight. Future clinical trials and mechanistic studies are needed to translate our findings to humans and to further examine the molecular mechanisms linking gut dysbiosis to vascular dysfunction.
dc.format.mediumborn digital
dc.format.mediumdoctoral dissertations
dc.identifierBattson_colostate_0053A_14751.pdf
dc.identifier.urihttps://hdl.handle.net/10217/189369
dc.languageEnglish
dc.language.isoeng
dc.publisherColorado State University. Libraries
dc.relation.ispartof2000-2019
dc.rightsCopyright and other restrictions may apply. User is responsible for compliance with all applicable laws. For information about copyright law, please see https://libguides.colostate.edu/copyright.
dc.titleMechanisms of vascular dysfunction in obesity and type 2 diabetes: role of the gut microbiota and endoplasmic reticulum stress
dc.typeText
dcterms.embargo.expires2019-06-07
dcterms.embargo.terms2019-06-07
dcterms.rights.dplaThis Item is protected by copyright and/or related rights (https://rightsstatements.org/vocab/InC/1.0/). You are free to use this Item in any way that is permitted by the copyright and related rights legislation that applies to your use. For other uses you need to obtain permission from the rights-holder(s).
thesis.degree.disciplineFood Science and Human Nutrition
thesis.degree.grantorColorado State University
thesis.degree.levelDoctoral
thesis.degree.nameDoctor of Philosophy (Ph.D.)

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