ABSTRACT Obesity and Type 2 diabetes represent states of chronic inflammation. While we have learned much about how the soluble mediators and signaling intermediates of immunity disrupt normal metabolic function, we do not yet understand the transcriptional mechanisms by which these responses occur. Our laboratory has discovered that interferon regulatory factors (IRFs), a family of immune-related transcription factors, are active in tissues of metabolic relevance. We showed that IRF3 in particular becomes induced during obesity, and mediates many of the adverse effects of overnutrition, including weight gain, suppression of brown fat function, insulin resistance, and hepatic steatosis. We have gone on to show that IRF3 exerts distinct functions in adipocytes and hepatocytes, with differential effects on metabolic parameters. We also identify a key downstream IRF3 target, ISG15, as a mediator of the actions of IRF3 in fat. In the current proposal, we will advance our knowledge of IRF3 and metabolic function by focusing on its actions in macrophages, specifically in adipose tissue macrophages and Kupffer cells of the liver. Furthermore, we will determine the mechanisms by which ISG15 represses adipose browning and thermogenesis. Finally, we will pursue an unbiased analysis of IRF3 target genes in fat, liver, and macrophages, to determine new pathways at the nexus of metabolism and inflammation that may be amenable to therapeutic intervention.