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Title page for ETD etd-03262012-123545


Type of Document Dissertation
Author Gutierrez, Dario Alejandro
Author's Email Address dario.a.gutierrez@vanderbilt.edu
URN etd-03262012-123545
Title Effects of Leptin Receptor, C-C Chemokine Receptor 2 and Complement Factor 5 Deficiency on Mouse Immunometabolism
Degree PhD
Department Molecular Physiology and Biophysics
Advisory Committee
Advisor Name Title
Richard O'Brien Committee Chair
Amy Major Committee Member
Kate Ellacott Committee Member
Owen McGuinness Committee Member
Keywords
  • Immunometabolism
  • inflammation
  • adipose tissue
  • insulin resistance
  • type 2 diabetes
  • macrophages
  • eosinophils
Date of Defense 2012-03-06
Availability unrestricted
Abstract
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

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