Dissertation
Novel roles of iRhom2 in the regulation of adiposity and inflammation in diet-induced obesity
University of Iowa
Doctor of Philosophy (PhD), University of Iowa
Summer 2021
DOI: 10.17077/etd.005862
Abstract
Obesity is defined by the excess accumulation of body fat. It is an increasingly common affliction of humans, affecting roughly two billion people worldwide. Chronic low-grade inflammation and a metabolic syndrome characterized by impaired glucose and insulin sensitivity are two of the hallmarks of obesity but the relationship between inflammation and the onset of metabolic syndrome and inflammation is incompletely understood. Murine models of obesity have implicated M1 macrophages and tumor necrosis factor (TNF), but inhibition of TNF alone has failed to mitigate metabolic dysregulation in patients with obesity or diabetes, suggesting that other molecules play a role in the onset of metabolic syndrome.
The release of soluble bioactive TNF from TNF-expressing cells is regulated by a disintegrin and metalloproteinase (ADAM) 17 that also controls the release of epidermal growth factor receptor (EGFR) agonists, has been shown to be dysregulated in the adipose tissue of obese patients. Accordingly, the principal objectives of this dissertation have been to further characterize the regulation and role of the mobilization of TNF and EGFR signaling pathways as triggered by a long-term high-fat diet. Key to our experimental approach has been use of a genetic model of ADAM17 inactivity accomplished by deletion (-/-) of its positive regulator, the inactive rhomboid 2 (iRhom2). This dissertation demonstrates that loss of ADAM17 activity in immune cells leads to decreased adipose tissue inflammation, accelerated adiposity, and exacerbated insulin resistance in a murine model of diet-induced obesity.
In our model, high-fat diet-induced inflammatory and metabolic responses have been decoupled, demonstrating a novel role for iRhom2 as an immuno-metabolic regulator, affecting adipose tissue inflammation and insulin resistance via distinct molecular mechanisms. In support of this conclusion, in vitro and ex vivo studies demonstrated that effects of initially low levels of diverse inflammatory stimuli (simulating low-grade inflammation induced by highfat diet) can be amplified by iRhom2-dependent extracellular mobilization of TNF that drives sustained autocrine/paracrine activation of TNF signal transduction. Conversely, we observed that the loss of iRhom2-mediated EGFR signaling in mesenchymal stem cells leads to decreased adipocyte lineage commitment which can be rescued by the addition of an exogenous EGFR agonist. In differentiated adipocytes, the loss of EGFR signaling leads to hypertrophy accompanied by dysregulated autophagy and lipid metabolism. Taken together, this dissertation establishes iRhom2 as a novel and multi-potent regulator of adipose tissue inflammation, adiposity, and insulin resistance in a murine model of diet-induced obesity.
Details
- Title: Subtitle
- Novel roles of iRhom2 in the regulation of adiposity and inflammation in diet-induced obesity
- Creators
- Joseph Skurski
- Contributors
- Thorsten Maretzky (Advisor)Noah Butler (Committee Member)Prajwal Gurung (Committee Member)Brian O'Neill (Committee Member)Jerrold Weiss (Committee Member)
- Resource Type
- Dissertation
- Degree Awarded
- Doctor of Philosophy (PhD), University of Iowa
- Degree in
- Immunology
- Date degree season
- Summer 2021
- Publisher
- University of Iowa
- DOI
- 10.17077/etd.005862
- Number of pages
- xiv, 143 pages
- Copyright
- Copyright 2021 Joseph Skurski
- Comment
- This thesis has been optimized for improved web viewing. If you require the original version, contact the University Archives at the University of Iowa: https://www.lib.uiowa.edu/sc/contact/
- Language
- English
- Description illustrations
- color illustrations
- Description bibliographic
- Includes bibliographical references (pages 134-143).
- Public Abstract (ETD)
Obesity, defined by excessive weight gain, is a chronic disease which has become increasingly common in recent decades. Obesity is often accompanied by other types of chronic conditions, including inflammation of the fat tissue, and resistance to insulin. Although the development of inflammation and metabolic complications are common consequences of obesity, we do not completely understand the relationship between inflammation and insulin resistance. Data from mouse studies have shown that the inflammation that develops with obesity can be attributed to immune cells (macrophages in particular) that produce a key inflammatory molecule, tumor necrosis factor (TNF). Unfortunately, the elimination of TNF activity alone has not been enough to restore insulin resistance in diabetic patients, suggesting that other factors contribute to disease.
The release of TNF from macrophages is regulated by molecules ADAM17 and iRhom2, which also control the release of tissue growth factors in the epidermal growth factor receptor (EGFR) pathway. The goal of this dissertation is to understand how ADAM17/iRhom2 contribute to inflammation and metabolic dysregulation in obesity. We found that the genetic removal of iRhom2 leads to increased weight gain, but lessened inflammation in mice fed a high-fat diet. Insulin resistance is worsened in these mice, suggesting that inflammation in the fat tissue is not necessary for the development of insulin resistance, and that these two complications are driven by different molecular causes. We also found that TNF can be amplified by iRhom2 when there is very little inflammatory stimulus present, and that other inflammatory molecules can be regulated by TNF. In addition, we observed that EGFR activity driven by iRhom2 plays an important role in the ability of stem cells to become fat cells, and that the fat cells which manage to develop are excessively large. Taken together, this dissertation shows for the first time that iRhom2 activity in immune cells plays a role in weight gain, inflammation in the fat tissue, and the development of insulin resistance in response to a long-term high-fat diet.
- Academic Unit
- Immunology Graduate Program
- Record Identifier
- 9984124359802771
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