Inflammation causes insulin resistance via IRF3-mediated reduction in FAHFA levels

Obesity-induced inflammation metabolic dysfunction, but the mechanisms remain elusive. Here we showed that the innate immune factor IRF3 is a direct transcriptional regulator of glucose homeostasis through induction of endogenous FAHFA hydrolase Aig1 in adipocytes. Adipocyte-specific knockout IRF3 protects mice against high-fat diet-induced insulin resistance, whereas overexpression of IRF3 in adipocytes promotes insulin resistance on a high-fat diet. Furthermore, pharmacological inhibition of AIG1 reversed obesity-induced insulin resistance and restored glucose homeostasis in the setting of adipocyte IRF3 overexpression. We therefore, identify the adipocyte IRF3/AIG1 axis as a crucial link between obesity-induced inflammation and insulin resistance and suggest an approach for limiting the metabolic dysfunction accompanying obesity. To identify the downstream genes of IRF3 in adipocytes, we performed two RNA-sequencing experiments: 1) we defined the transcriptional profiles of adipocytes using translating ribosome affinity purification (TRAP) from eWAT of Ad-NuTRAP and FI3KO-Ad-NuTRAP mice after 8 weeks of HFD feeding at thermoneutrality; 2) WT and FI3OE SVF-derived adipocytes by RNA-sequencing.