| Summary: | 博士 === 國立成功大學 === 基礎醫學研究所 === 102 === Obesity is a severe health problem worldwide which leads to multiple comorbidities including type 2 diabetes mellitus (DM) and cardiovascular diseases. Inflammation has been found to be an important characteristic of adipose tissue in obese subjects. However, obesity is also associated with compromised immune responses to infections and the impact of obesity on immune function has not been fully understood. To clarify the role of obesity in the immune responses, I investigated the Toll-like receptor (TLR)-induced cytokine secretion by leukocytes from obese and lean subjects. The relationship between insulin-induced intracellular signaling and cytokine production using peripheral blood mononuclear cells (PBMC) and a monocytic cell line THP-1 was also investigated. I found decreased TLR-induced interferon-gamma, interleukin-6 and tumor necrosis factor-alpha secretions and elevated IL-10 secretion by leukocytes from obese subjects when compared with those in lean controls. PBMCs from obese subjects showed enhanced basal Akt and glycogen synthase kinase 3β (GSK-3β) phosphorylation which did not further increased with insulin and lipopolysaccharide (LPS) stimulation. I also found that LPS-induced IκB degradation was inhibited in PBMCs from obese subjects. By using THP-1 cells with GSK-3β knockdown or cells treated with hyperinsulinemic and high fatty acid conditions, I found that LPS-induced NF-κB activation was inhibited and cAMP response element-binding protein (CREB) activation was enhanced. I also found that bariatric surgery corrected the abnormal TLR-induced cytokine secretions in obese subjects. Moreover, type 2 DM, which may be developed from obesity, also showed abnormal TLR-induced cytokine secretions. These findings indicated that GSK-3β is important in the regulation of NF-κB and CREB activation in leukocytes under the metabolic condition of obesity. Our study hence reveals a key mechanism through which metabolic abnormalities, even before the onset of type 2 DM, compromise leukocyte functions in people with obesity.
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