Thesis (Ph. D.)--Ohio State University, 2004. / Title from first page of PDF file. Document formatted into pages; contains xvii, 258 p.; also includes graphics. Includes bibliographical references (p. 223-258).

Thesis (doctoral)--Groningen, 1982.

Thesis (M Nursing)--Montana State University--Bozeman, 2010. / Typescript. Chairperson, Graduate Committee: Elizabeth S. Kinion. Includes bibliographical references (leaves 50-58).

Thesis (Ph.D.)--University of Melbourne, Dept. of Veterinary Science, 2010. / Typescript. Includes bibliographical references.

Thesis (Ph.D.)--Aberdeen University, 2008. / Title from web page (viewed on Mar. 2, 2009). Includes bibliographical references.

Thesis (M.S.)--University of Hong Kong, 1999. / Includes bibliographical references (leaves 140-168) Also available in print.

Thesis (Ph. D.)--Ohio State University, 2007. / Title from first page of PDF file. Includes bibliographical references (p. 114-137).

Th. 3e cycle--Pharmacol. et pharmacocinétique exp. et clini.--Montpellier 1, 1981.

The global rise in the prevalence of obesity has been labeled a pandemic. The increasing rates of overweight and obese persons across the world is discerning, as obesity is a risk factor for many life-threatening and debilitating diseases including type two diabetes mellitus (T2DM), a disease that decreases insulin sensitivity of skeletal muscle, adipose tissue and liver, and insulin secretion in pancreatic beta cells. Despite its pervasiveness, the mechanism by which obesity causes T2DM remains elusive. Adipose tissue is known to contribute to whole body glucose metabolism and as a result has been implicated in T2DM. Obesity causes changes in the physiology of adipose tissue, including hypertrophy of adipocytes, rendering them stressed and dysfunctional. The result is an increase in free fatty acids in the blood, due to increased lipolysis and decreased triglyceride storage. Free fatty acids have been shown to cause insulin resistance in insulin sensitive tissues. It has also been observed that in some patients, obesity results in inflammation of adipose tissue. As adipocytes enlarge, they not only secrete increasing amounts of free fatty acids, they also secrete chemoattractant proteins like MCP-1, which attract macrophages. These macrophages secrete inflammatory cytokines such as Tumor Necrosis Factor- alpha, Interleukin-1beta and Interleukin-6, among others, which have been shown to alter adipose tissue metabolism by increasing lipolysis and decreasing triglyceride storage. In addition, inflammatory cytokines have been suspected to play a role in insulin resistance, although the exact mechanisms remain elusive. The present study explored the possibility that Interleukin-1beta and Interleukin-6 affect insulin signaling in human adipocytes by increasing lipolysis, thus increasing free fatty acids in the blood. Recent studies have emphasized the role of fat specific protein 27 (FSP27) in the regulation of lipolysis in adipocytes whereby, FSP27 controls lipolysis by regulating the lipolytic capacity as well as transcription of the primary lipase ATGL. In the present study we used FSP27 as a tool to investigate if managing lipolysis could protect human adipocytes from the impairment of insulin signaling caused by the presence of inflammatory cytokines. We found that Interleukin-1beta and Interleukin-6 increase lipolysis in human adipocytes by depression of endogenous FSP27 protein levels and that the rate of lipolysis can be rescued by adenoviral expression of FSP27. In addition, we found that interleukin-1beta decreased insulin signaling by decreasing phosphorylation of AKT and that adenoviral expression of FSP27 has a protective effect over Interleukin-1beta - induced impairment of insulin signaling in human adipocytes. Our experiments regarding the effect of Interleukin-6 on insulin signaling were inconclusive and need further experimentation. These results suggest that the inflammatory cytokine Interleukin-1beta indirectly suppresses insulin signaling, by increasing lipolysis and that maintenance of FSP27 protein levels in obese patients could prevent patients from developing insulin resistance and T2DM.

Peritoneal adhesions pose a considerable postoperative burden. The mechanisms underlying adhesion formation remain poorly understood but relate principally to inflammation and fibrinolysis. The peritoneum may coordinate the inflammatory response that leads to adhesion formation but human adhesion formation cannot be studied directly so most research has employed animal models and individual transformed cell lines. Furthermore, the specific roles of the visceral or parietal peritoneum in adhesion formation are unclear. The aims of the studies undertaken in this thesis are to investigate the regulation of a gut bacteria-driven inflammatory response in human visceral peritoneum. A novel ex vivo model was designed using human small bowel visceral peritoneum, cultured with E. coli derived LPS, for 18 to 48 hours. ELISA and rtPCR were used to analyse supernatant protein concentration and gene expression respectively for key inflammatory mediators associated with adhesion formation including cytokines (IL-6, IL-10, TNFalpha), transforming growth factor-β1 (TGF-β1) and fibrinolytic factors (tPA and PAI-1) as well as the signalling receptors thought to be involved in LPS-mediated inflammation (TLR2 and 4). LPS exposure resulted in stimulation of IL-6, IL-10 and TNFalpha production from human visceral peritoneum at 18 hours. These increases correlated with increased gene expression for IL-6 and TNFalpha but not IL-10. TGF-β1 production and gene expression were unchanged at 18 & 24 hours but increased at 48 hours when co-incubated with IL-1β. PAI-1 was increased but tPA was unchanged following LPS stimulation, suggesting a reduction in peritoneal fibrinolytic activity. Peritoneal tissue expressed the signalling receptors TLR 2 and 4. However, inhibition of TLR 2 or 4 failed to abrogate production of cytokines in cultured primary mesothelial cells or peritoneal tissue post-LPS exposure. TLR 4 inhibition did reduce mesothelial cell production of chemokines, CCL2 and CXCL1. These novel findings demonstrated that human visceral peritoneum actively participates in LPS-induced peritoneal inflammatory responses and reduced fibrinolysis which may account for the visceral peritoneum's affinity to form adhesions. Ex vivo human peritoneal culture is a novel, feasible and reproducible method of investigating the role of the peritoneum in inflammation.