Deciphering the Roles of Interferon Regulatory Factors in Metabolism

One of the critical advances in the field of adipose biology over the past few decades is the realization that overnutrition causes a state of meta-inflammation, with infiltration of M1-like (i.e., classically activated) macrophages and other pro-inflammatory cell types into the fat pad. This has consequences for local and systemic metabolism, causing insulin resistance, lipolysis, and suppression of thermogenesis. We have been interested in identifying the transcription factors and pathways that mediate these effects, and have focused on members of the interferon regulatory factor (IRF) family. The nine mammalian IRFs have been implicated in almost every aspect of immunity, from macrophage formation and lymphopoieisis to T cell activation, but our lab was the first to define a role for IRFs in adipose biology and metabolic function. Most of our work has focused on IRF3 and IRF4, which are highly expressed in adipocytes and which we have shown are regulators of adipogenesis (PMID: 18177728). IRF3 is a pro-inflammatory factor that promotes insulin resistance and obesity on a high fat diet, related at least in part to its anti-thermogenic properties (PMID: 27400129). IRF4 on the other hand, is pro-thermogenic, and is the natural DNA binding partner of PGC-1a in brown fat (PMID: 24995979). We have also shown that IRF4 in brown fat regulates the expression of myostatin, which in turn controls skeletal muscle function. Thus, animals lacking IRF4 in BAT have an unusual form of myopathy and diminished exercise capacity (PMID: 30078553), which is pretty cool. We are currently pursuing several lines of investigation related to the actions of IRFs, including: (a) What are the tissue-specific roles of IRF3 in macrophages vs. adipocytes? (b) Is IRF3 required for the development of fatty liver (spoiler alert: Yes!) (c) What are the critical downstream target genes of IRF3 and IRF4 in fat and liver, and how do they impact upon metabolic function in those tissues? (d) What are the key post-translational modifications and interacting partners of IRFs in fat and liver? (e) What other IRFs are important metabolic regulators in fat and other tissues?