Study the signaling crosstalk between IL-6 and TNF-α in regulating inflammation and insulin resistance under the influence of obesity/overnutrition

The role of metabolic inflammation in Type 2 diabetes (T2D) and its co-morbidities is well established. However, the pathways that promote and sustain the inflammatory process remain unclear. Cytokines play a vital role in the pathogenesis of a wide variety of inflammatory diseases and metabolic syndrome, including obesity, T2D, cardiovascular disease, and hyperlipidemia associated with hepatic steatosis. Several lines of evidence suggest that during the development of obesity and associated metabolic stress, adipose tissue develops a state of chronic low-grade inflammation. Inflammation in adipose tissue is characterized by increased production of proinflammatory cytokines, such as IL-1β, IL-6 and TNF-α and an increase in macrophage numbers. Although IL-6 and TNF-α play critical role in the regulation of metabolic inflammation and insulin resistance, it is not clear which mechanisms are involved. Interestingly, we found co-treatment of monocytes/macrophages with IL-6 and TNF-α gave a dramatically enhanced gene expression response. Thus, we hypothesize that IL-6/TNF-α induced potentiation in gene expression can be thought of as a form of “licensing”, in which one cytokine enables another to exert its full response. Central query: Does interaction between IL-6 and TNF-α sustain and promote inflammation in state of obesity? Our Goal of the study is to explore how IL-6 signal mechanistically interacts with adipokine TNF-α under the challenge of high fat diet and aggravate inflammation/insulin resistance. Approaches & Methodology: We will use both murine and human cell culture models along with global knock-out mice for in vivo studies. Gain and loss of function approaches in vitro and in vivo studies will be used. Conditional knock-out murine models will be used to further elaborate the effect of the target genes. Mice will be metabolically and immunologically characterized. Acetylation/methylation mapping for specific gene promoters and chromatin immunoprecipitation sequencing (ChIP-seq) analysis will be performed. Inflammatory and metabolic repertoire will be determined by RNASeq. Significance: This study could explain some of the complex and contradictory data surrounding the role of IL-6 in immunometabolism. Our findings will provide a deep knowledge about the role of IL-6/TNF-α in metabolic inflammation and insulin resistance that could be a potential therapeutic target for combating diabetes and associated complications.