Dissertation
Adipocyte mechanisms mediating metabolic and cardiovascular homeostasis
University of Iowa
Doctor of Philosophy (PhD), University of Iowa
Autumn 2024
DOI: 10.25820/etd.007652
Abstract
Obesity is a major public health issue given its growing rates across the globe which increases the risk of serious health problems including type 2 diabetes, hypertension and other cardiovascular disorders. Adipose tissue plays a crucial role in regulating systemic energy homeostasis. However, the specific contribution of adipose tissue to the development of obesity and related cardiovascular complications remains elusive.
This study delves into the complex interplay between adipose tissue and the progression of obesity and associated metabolic and cardiovascular deregulations. The first part of my thesis research focuses on the role of the adipocyte BBSome, a critical protein complex, in energy and glucose regulation, in controlling metabolic and cardiovascular processes. Here, we show that adipocyte-specific constitutive disruption of the BBSome through selective deletion of the Bbs1 gene (AdipoCre/Bbs1fl/fl mice) does not affect body weight under normal chow or high fat & high sucrose diet (HFHSD) feeding conditions. However, constitutive BBSome deficiency caused impairment in glucose tolerance and insulin sensitivity. Similar phenotypes were observed after inducible adipocyte-specific disruption of the BBSome (AdipoCreERT2/Bbs1fl/fl mice). Interestingly, a significant increase in renal sympathetic nerve activity, measured using multifiber recording in the conscious state, was observed in AdipoCre/Bbs1fl/fl mice fed either chow or HFHSD. Moreover, AdipoCre/Bbs1fl/fl mice had no significant alterations in vascular reactivity. On the other hand, HFHSD-fed AdipoCre/Bbs1fl/fl mice displayed impaired baroreceptor reflex sensitivity. Taken together, these data highlight the relevance of the adipocyte BBSome for the regulation of glucose homeostasis, sympathetic traffic, observed in both normal chow-fed and HFHSD-fed mice, and baroreflex sensitivity only observed in HFHSD-fed mice.
Extracellular Vesicles (EVs) are membrane-bound vesicles secreted by all types of cells. EVs are responsible for intercellular communication between various tissues and organs by delivering bioactive cargos such as proteins, lipids, microRNAs (miRNAs) and DNAs. Adipose tissue-derived EVs (AdEVs) appear to play a significant role in insulin resistance, type II diabetes and other metabolic disorders, as well as the related cardiovascular diseases. The second part of my thesis aims to explore how AdEVs contribute to metabolic dysfunction. Here, we first investigated the impact of obesity on the release of AdEVs and their content through proteomic analysis and miRNA sequencing. We found that obesity leads to alterations in the release and cargos of visceral AdEVs. Differentially enriched proteins and miRNAs between AdEVs isolated from lean and obese adipose tissue were implicated in mitochondrial function and neurodegenerative risks. Importantly, in vitro studies reveal that treatment of hypothalamus N39 cells with visceral AdEVs from obese mice leads to elongated mitochondria, further demonstrating the bioactive capacity of AdEVs. Furthermore, the infusion of visceral AdEVs of obese mice resulted in elevated renal sympathetic nerve activity in lean mice. Collectively, our data suggests that obesity can alter the protein and miRNA content of AdEVs with implication on the control autonomous nervous system.
In summary, our work underscores the importance of the adipocyte BBSome in regulating metabolic and cardiovascular processes and suggest that AdEVs serve as crucial mediators of obesity-related dysfunctions. This research provides an insight into future therapeutic strategies aimed at mitigating the widespread impact of obesity on health.
Details
- Title: Subtitle
- Adipocyte mechanisms mediating metabolic and cardiovascular homeostasis
- Creators
- Yuying Zhao
- Contributors
- Kamal Rahmouni (Advisor)Aloysius Klingelhutz (Committee Member)Ethan Anderson (Committee Member)Ling Yang (Committee Member)Val Sheffield (Committee Member)
- Resource Type
- Dissertation
- Degree Awarded
- Doctor of Philosophy (PhD), University of Iowa
- Degree in
- Human Toxicology
- Date degree season
- Autumn 2024
- DOI
- 10.25820/etd.007652
- Publisher
- University of Iowa
- Number of pages
- xvii, 129 pages
- Copyright
- Copyright 2024 Yuying Zhao
- Language
- English
- Date submitted
- 12/06/2024
- Description illustrations
- Illustrations, tables, graphs, charts
- Description bibliographic
- Includes bibliographical references (pages 119-129).
- Public Abstract (ETD)
Obesity is a major public health issue that can lead to serious health problems like type 2 diabetes and hypertension. Adipose tissue, the main function of which is to store energy in the form of fat, plays an important role in managing energy in the body, but its specific influence in obesity and related health issues is not fully understood.
Previous studies from our lab have shown that a protein complex called the BBSome is necessary for energy and glucose regulation, but the role of the BBSome in fat cells is not well understood. We found that mice bearing specific disruption of the BBSome in adipocytes display poor glucose handling and impaired sensitivity to the hormone insulin. Interestingly, these mice also showed increased activity of the sympathetic nerves that control the renal functions. Notably, when these mice are fed rich-calorie diet and become obese, their baroreflex, which helps regulate blood pressure, becomes less sensitive. The second part of this research explores how tiny particles released from fat cells, known as extracellular vesicles, influence obesity and its related health problems. We show that the amount and content of these vesicles change with obesity. Specifically, the proteins and miRNAs (genetic materials) carried by the vesicles are different in lean versus obese mice, which impacts how mitochondria (the energy producers in cells) function and could increase the risk of neurodegenerative diseases. Tests confirmed that when vesicles from obese mice were used in experiments, they caused changes in the size and function of mitochondria in brain cells and affected the activity of the nervous system in mice.
These studies highlighted the importance of the BBSome in fat cells for controlling metabolism and heart health. Our work also shows how small vesicles released from fat cells are linked to obesity-related problems. These findings could help manage obesity and its many health effects, potentially leading to new treatments in the future.
- Academic Unit
- Interdisciplinary Studies Program
- Record Identifier
- 9984774456702771
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