Access Type

Open Access Dissertation

Date of Award

January 2016

Degree Type

Dissertation

Degree Name

Ph.D.

Department

Pathology

First Advisor

Menq-Jer Lee

Abstract

Adipose lipolysis triggers pro-inflammatory responses that play critical roles in insulin resistance and associated metabolic syndrome. However, pro-inflammatory mediators generated by adipose lipolysis, particularly in the context of lipid mediators, are poorly defined. In this study, the activation of the beta-3 adrenergic receptor (ADRB3)/hormone sensitive lipase (HSL) pathway, a well-employed model system, was utilized to characterize the pro-inflammatory lipid mediators generated by adipose lipolysis. Cultured adipocytes were treated with an ADRB3 agonist and the media was analyzed for eicosanoids using the LC-MS/MS lipidomic method. Among the characterized eicosanoids, I found that approximately 43 metabolites generated by cyclooxygenase (COX), lipoxygenase, and cytochrome P450 enzymes were significantly produced in response to ADRB3/HSL-stimulated lipolysis in adipocytes. Mechanistically, I observed that lipolysis induced cyclooxygenase 2 (COX-2), not COX-1, expression in an HSL-dependent manner in adipocytes and in the epididymal white adipose tissue (EWAT) of C57BL/6 mice that were injected with a specific ADRB3 agonist, CL-316243 (CL). Additionally, JNK and NFκB are activated by ADRB3-mediated lipolysis and regulate the increased COX-2 expression. Moreover, treatment with a pharmacological COX-2 inhibitor, celecoxib, decreased the COX metabolites in the media of ADRB3-stimulated adipocytes. Inflamed adipose tissue involves the increased presence and activation of macrophages that are recruited to the tissue by the pro-inflammatory cytokine, MCP-1/CCL2. Interestingly, not only was MCP-1/CCL2 expression significantly increased in ADRB3/HSL-mediated lipolysis, but its expression was also dependent on JNK/NFκB/COX-2 activation. Furthermore, I observed that celecoxib pretreatment significantly blocked macrophage infiltration in the EWAT of mice treated with CL. In summary, I have shown for the first time that ADRB3/HSL signaling activates a pro-inflammatory cyclooxygenase pathway via COX-2, in adipose tissue.

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