Novel mechanisms regulating inflammatory gene expression in adipocytes

UNCG Author/Contributor (non-UNCG co-authors, if there are any, appear on document)
Heesun Nam (Creator)
Institution
The University of North Carolina at Greensboro (UNCG )
Web Site: http://library.uncg.edu/
Advisor
Ron Morrison

Abstract: Obesity and diabetes are major public health concerns worldwide that contribute to cardiovascular disease, hypertension, and stroke. Research over the last two decades has revealed an important role for adipose tissue (AT) in the regulation and control of whole-body metabolic homeostasis and that chronic AT inflammation is an important pathogenic mechanism that links obesity and diabetes. While it is now recognized that inflammation is increased in AT with obesity, studies are underway to identify key inflammatory mediators and their downstream pathways that contribute to adipocyte inflammation. Therefore, data presented in this dissertation demonstrate that three novel mechanisms that may mediate obesity-induced inflammation in adipocytes. Interleukin (IL)-12 family cytokines are heterodimeric proteins mostly expressed in classic immune cells and play critical roles in innate and adaptive immunity. However, recent evidence has shown that plasma levels of IL-12 family cytokines are elevated in obesity and diabetes, yet little has addressed a role for IL-12 family cytokines in adipocytes under any condition. Data presented in this dissertation demonstrate that various IL-12 family members are highly induced in AT under conditions of genetic and diet-induced obesity that is associated with increased inflammation and IR. Subsequently, we show that both preadipocytes (PAs) and adipocytes (ADs) secrete IL-27 in response to inflammatory stress and demonstrate a novel function of IL-27 in adipocytes that is dependent on environmental cues. While PAs and ADs both secrete IL-27 protein, divergent mRNA regulation of the IL-27 subunits (i.e., p28 and EBI3) was observed in response to tumor necrosis factor a (TNFa) in adipocytes. As our data indicated a role for epigenetic modifications in differential IL-27 mRNA expression, we further determined that histone deacetylases (HDACs) play a key role in TNFa-induced p28 gene expression. Thus, these data demonstrate that epigenetic modification of histones potentially regulates the divergent outcomes observed with p28 and EBI3 gene expression during inflammatory stress. While extensive studies have identified TNFa as a master cytokine involved in AT inflammation, questions regarding its inflammatory actions on gene expression remain unclear. Emerging evidence highlights an important role for the Golgi apparatus (GA) in TNFa-induced inflammation, in part, through TNF receptor (TNFR) storage and secretion to the cell-surface, thus allowing for TNFa signaling. Our findings demonstrate a critical role for the GA in TNFR cell-surface expression and TNFa signaling as well as suggest a novel mechanism for the GA in TNFa-induced inflammation that potentially involves Golgi-localized co-factor(s) necessary for transcriptional gene expression. Collectively, data presented in this dissertation provide seminal evidence for novel mechanisms regulating adipocyte inflammation, potentially linking obesity with metabolic diseases.

Additional Information

Publication
Dissertation
Language: English
Date: 2012
Keywords
Adipocyte, Golgi apparatus, HDAC, IL-12 family cytokine, Inflammation, Obesity
Subjects
Adipose tissues $x Pathophysiology
Obesity $x Physiological aspects
Obesity x Pathophysiology
Gene expression
Inflammation $x Pathophysiology

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