| Obesity has been identified as an epidemic disease in the world for more than two decades. Nowadays, the prevalence of obesity is increasing rapidly throughout the world. The reported from WHO, it is believe that, among the adult, there will be 2.3 billion people suffer from overweight and 700 million people suffer from obesity in 2015.In our country, the situation of the obesity and overweight has been serious with the ratio of 7.1% for obesity and 22.8% for overweight in 2005.The number was about 60 million and 200 million respectively at that time. Diseases involving obesity such as diabetes, cardiovascular diseases (including hypertension, coronary heart disease, and apoplexy) have grown up to the leading killer in our country and become to a heavy health burden for our government.Obesity is a situation compounding excessive fat or is abnormal in adipose tissue distribution for the body. Systemic chronic inflammation has been proposed to have an important role in the pathogenesis of obesity. Lipocyte can secrete the protein cancer putrescence gene—tumor necrosis factor-α(TNF-α), and the bigger the BMI is, the more the TNF-αwill be secreted, which was found by many researchers including Hotamisligil in 1993, causing the correlation between obesity and inflammation.It has been shown that biomarkers of inflammation, such as TNF-α, IL-6, and C-reactive protein (CRP), are present at increased concentrations in individuals who are insulin resistant and obese, and these biomarkers predict the development of Type 2DM. Furthermore, some research showed that obesity is characterized by macrophage accumulation in white adipose tissue, which has added another dimension to our understanding for the development of adipose tissue inflammation in obesityMacrophages are a major cellular component of all inflammatory sites, and the products of activated macrophages, including the classical pro-inflammatory cytokines such as TNF-α, interleukin (IL)-1, and IL-6, are central to the initiation and maintenance of inflammation. Adipose tissue macrophages (ATMs) are likely to contribute to the production of several of the adipokines as we discussed before. A causative role of ATMs in obesity-associated insulin resistance has been recently supported by many studies showing that inhibition of macrophage recruitment in obesity ameliorates the insulin resistance seen in animal models.Refer to the molecular mechanism of obesity involve inflammation, studies mainly focused on the Toll-like receptor (TLR) family, through which the microorganisms induce the transcription of proinflammatory genes with pathogen pattern recognition receptors. The most studied TLR ligand is the lipopolysaccharide (LPS), a component of the cell wall of gram-negative bacteria, recognition of which requires TLR4. LPS stimulate the macrophages and then initiates a complex signaling cascade reaction. Recruitment of adaptor proteins such as MyD88 to the TLR4 receptor activates a signaling cascade, which culminates in nuclear translocation of the transcription factor complex, nuclear factor NF-κB. Many other pathways, acting in series or in parallel, are required for the complete response to LPS. TLR4 related signal pathway is the key factor for the vascular inflammatory and insulin resistance caused by obese.Our study partially explained the detailed molecular mechanism of TLR4 signaling pathway in the inflammatory induced obesity. In the part one study, we try to explore the role of TLR4 signal transduction system in IL-6 treated human Macrophages—THP-1 cell line, The observation for the expression of TLR4 on cell membrane, the cell cycle and proliferation effect for THP-1, and the change for the specific protein phosphorylation have been down in both with or without specific inhibitors groups. The results show that: when treated with IL-6, the TLR4 receptor on THP-1 cell's surface was activated, the expression increased, and the proliferation of THP-1 cells was increased too, which may be related to the activation of Myd88/ JNK pathway .In the part two study, we studied the role of TLR4 signal transduction system in the co-cultured human monocyte/macrophage cell line THP-1 and human adipose cell system. The expression and distribution of TLR4 receptor during dynamic inflammatory change induced by IL-6, and the effect on cell cycle and associated signal transduction pathway of THP-1 cell have been observed. We found that after the establishment of co-culture system, expression of TLR4 receptor on THP-1 cell surface was increased; at the same time, the proliferation of THP-1 cell was also increased compared with the control group. By adding IL-6, there was a further increase in the expression of TLR4 receptor and the proliferation in THP-1 cell. On the other hand, these changes mentioned above were inhibited significantly after added the JNK inhibitor.In the third part, we explore the effect of palmityl palmitate on the proliferation of human peripheral blood monocytes. Results showed that palmityl palmitate can significantly promote human primary monocytes proliferation in a dose and time-dependent manner, whose maximum effect appears at 20μM and 24 hours. These findings not only provide us the co-culture technology platform of human primary fat cells and human primary monocytes, but also elaborate the abnormal lipid metabolism and inflammation preliminary.For the first time, we used culture of human monocyte/macrophage cell line THP-1, and co-culture of THP-1 and human primary adipose cells as the platform, confirmed that TLR4 signaling pathway and its downstream inflammatory pathway play an important role in the pathogenesis of obesity, and discussed the possible role of inflammation in the cause of obesity. It is useful for us to reveal the pathogenesis of obesity, and provide more effect methods for the prevention, intervention of obesity and obesity-related diseases. According to our evidence, adjust or block the TLR4 signaling pathway and its downstream inflammation pathway is expected to become the new target for the treatment of obesity. At the same time, our study may help us for the early diagnosis, prognosis and guide treatment of obesity. |
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