Macrophage TCF-4 Coactivates p65 to Potentiate Chronic Inflammation and Insulin Resistance in Mice

TCF-4 was recently identified to be a candidate gene for the cause of type 2 diabetes, with the mechanisms being not fully elucidated. Here in this study, we demonstrated that TCF-4 transgene in macrophages aggravated high fat diet-induced insulin resistance and chronic inflammation, characterized by the elevation of proinflammatory cytokines in the blood, livers and white adipose tissues as well as a proinflammatory profile of immune cells in visceral fats in mice. Mechanistically, TCF-4 functioned as a co-activator of p65 to amplify the saturated free fatty acid-stimulated promoter activity, mRNA transcription and secretion of proinflammatory cytokines in primary macrophages. Blockage of p65 with a specific interfering RNA or inhibitor could prevent TCF-4-enhanced expression of proinflammatory cytokines in free fatty acid/LPS-treated primary macrophages. The p65 inhibitor could abolish macrophage TCF-4 transgene-aggravated systemic inflammation, glucose intolerance and insulin resistance in high fat diet-treated mice. Additionally, we demonstrated that the mRNA expression of TCF-4 in the peripheral blood monocytes from the human subjects was positively correlated to the levels of IL-1β, TNFα, IL-6 and fasting plasma glucose. In summary, we identified TCF-4 as a co-activator of p65 to potentiate proinflammatory cytokine production in macrophages and to aggravate high fat diet-induced chronic inflammation and insulin resistance in mice.

Source: Clinical Science - April 25, 2016 Category: Biomedical Science Authors: Kang, X., hou, a., Wang, R., Liu, D., xiang, w., Xie, Q., Zhang, B., gan, l., Zheng, W., Miao, H. Tags: PublishAheadOfPrint Source Type: research