Obesity has reached epidemic proportions worldwide, with some of the greatest severity in the United States. The most recent data reports ~70% of the American population is overweight (BMI ⥠25 kg/m2) and ~35% obese (BMI â¥30 kg/m2). Obesity is a metabolic disorder leading to increased risk for cardiovascular disease, type 2 diabetes, asthma, certain cancers, and various other diseases. A hallmark of obesity is adipose tissue (AT) inflammation and AT dysfunction. It is important to understand how immune cells accumulate in AT and regulate inflammation. We used CCR2-/- mice to study macrophage chemotaxis to AT, and also discovered CCR2-/- regulates chemotactic factors that upregulate AT eosinophil accumulation. Previous studies suggested that directly manipulating eosinophils (particularly in AT) could impart beneficial effects in obese subjects. Thus we developed an interventional treatment model of restoring obese AT eosinophils to higher levels of lean AT by injection of rIL5. AT eosinophils were successfully increased with rIL5, but there was no reduction in obesity and its comorbidities. Lastly, we discovered that repeated exposure to a foreign substance such as bovine serum albumin (BSA) could greatly increase AT eosinophils. While there were no metabolic improvements in mice chronically exposed to BSA, we have evidence to believe AT is capable of mounting a type 2 allergic response to antigens similar to the lung of an asthmatic, resulting in this large increase in AT eosinophils. Future studies will determine whether the AT eosinophilia following BSA exposure feeds back to the lung in allergic models, increasing both incidence and severity. Such studies will help in explaining the clinical link between obesity and allergic conditions such as asthma. In conclusion, we have found that restoring AT eosinophils to either physiological levels or super-physiological levels during obesity is not able to improve metabolic fitness (e.g. weight gain, glucose intolerance). Furthermore, we may have discovered a novel site of allergy that could offer insights and treatment opportunities for obese subjects that have increased difficulty with allergic disease.
| Identifer | oai:union.ndltd.org:VANDERBILT/oai:VANDERBILTETD:etd-12112017-131106 |
| Date | 12 December 2017 |
| Creators | Bolus, William Reid |
| Contributors | Dr. John Stafford, Dr. Timothy Blackwell, Dr. Richard O'Brien, Dr. David Harrison |
| Publisher | VANDERBILT |
| Source Sets | Vanderbilt University Theses |
| Language | English |
| Detected Language | English |
| Type | text |
| Format | application/pdf |
| Source | http://etd.library.vanderbilt.edu/available/etd-12112017-131106/ |
| Rights | unrestricted, I hereby certify that, if appropriate, I have obtained and attached hereto a written permission statement from the owner(s) of each third party copyrighted matter to be included in my thesis, dissertation, or project report, allowing distribution as specified below. I certify that the version I submitted is the same as that approved by my advisory committee. I hereby grant to Vanderbilt University or its agents the non-exclusive license to archive and make accessible, under the conditions specified below, my thesis, dissertation, or project report in whole or in part in all forms of media, now or hereafter known. I retain all other ownership rights to the copyright of the thesis, dissertation or project report. I also retain the right to use in future works (such as articles or books) all or part of this thesis, dissertation, or project report. |
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