Obesity and Type 2 diabetes represent states of chronic inflammation, and much has been learned about how the soluble mediators and signaling intermediates of immunity disrupt normal metabolic function. We do not yet understand, however, the transcriptional mechanisms by which immune factors interact with the metabolic machinery. Our laboratory has discovered that interferon regulatory factors (IRFs) are expressed in adipose tissue and that IRF4 in particular plays a major role in adipocyte differentiation, lipolysis and lipogenesis. In the current proposal, we focus on the related molecule IRF3, which is a well-studied pro-inflammatory transcription factor. IRF3 is of particular interest because it is activated by two kinases, TBK1 and IKKe, that are known to be up-regulated in obesity. Furthermore, pharmacological or genetic disruption of IKKe promotes leanness and insulin sensitivity in high-fat fed mice. Interestingly, we have discovered that mice lacking IRF3 appear to phenocopy these effects, and show reduced adiposity with enhanced thermogenesis in white fat (i.e. `browning'). Furthermore, Irf3-/- mice are completely protected from hepatic steatosis. We have now shown that IRF3 binds to and inhibits the transcriptional co-activator PGC-1a, and we hypothesize that the phenotype of the Irf3-/- mice may reflect the acquisition of unchecked PGC-1a activity. Here we describe experiments to determine if IRF3 is activated in liver and fat of obese animals, and to study the mechanisms by which IRF3 acts to inhibit thermogenesis and fatty acid oxidation.
Inflammation and metabolism are tightly linked processes with consequences for human diseases such as obesity and Type 2 diabetes. Despite the identification of many avenues of molecular cross-talk between them, little is known about the transcriptional pathways that underlie the effects of inflammation on metabolic function. We have identified the transcription factor IRF3 as a key mediator by which inflammation promotes fat accumulation and glucose intolerance in vitro and in vivo. Here we propose to identify the mechanisms by which IRF3 exerts its detrimental effects on metabolic health.
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