Obesity is closely linked to many metabolic diseases such as insulin resistance (IR), type 2 diabetes mellitus and cardiovascular disease. In the past decade, it has been established that immune cells are recruited to adipose tissue (AT), triggering an inflammatory response characterized by abnormal cytokine production and activation of inflammatory signaling pathways that are temporally associated with IR. Nonetheless, there is a gap in our understanding of what triggers and regulates this inflammatory response. During the completion of this dissertation I investigated several factors involved with AT dysfunction, inflammation and IR during obesity: the leptin receptor (LepR), CC-chemokine receptor 2 (CCR2) and complement factor 5 (C5). First, I showed that hematopoeitic LepR deficiency does not affect macrophage recruitment to AT or insulin sensitivity during high fat diet induced obesity. Second, I discovered the aberrant accumulation of eosinophils in the AT of CCR2 deficient mice and showed that these are important in regulating macrophage polarization, AT inflammation and systemic insulin sensitivity. Third, I found that C5 deficiency leads to an inflammation-independent downregulation of the insulin receptor in the liver, AT and muscle, promoting severe systemic IR. Overall, this dissertation made important contributions to the field of immunometabolism by adding to our current knowledge of macrophage recruitment and polarization, eosinophil function in metabolism, and the novel concept of an inflammation-independent modulation of glucose metabolism by the immune system.
Approved: Professor Alyssa H. Hasty
| Identifer | oai:union.ndltd.org:VANDERBILT/oai:VANDERBILTETD:etd-03262012-123545 |
| Date | 29 March 2012 |
| Creators | Gutierrez, Dario Alejandro |
| Contributors | Richard O'Brien, Owen McGuinness, Amy Major, Kate Ellacott |
| 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-03262012-123545/ |
| Rights | restricted, 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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