Postbiotics engage IRF4 in adipocytes to promote sex‐dependent changes in blood glucose during obesity

Postbiotics are microbial-derived components or metabolites that can influence host immunity and metabolism. Some postbiotics can improve blood glucose control and lower inflammation during bacterial or nutritional stress. Bacterial cell wall-derived muramyl dipeptide (MDP) is a potent insulin-sensitizing postbiotic that engages NOD2, RIPK2, and requires interferon regulatory factor 4 (IRF4) to lower inflammation and improve blood glucose. However, the sex-dependent effects of this postbiotic and the cell type required for IRF4 to cause inflammatory versus glycemic responses to MDP were unknown. Here, we measured how MDP injection altered glucose tolerance and adipose tissue inflammation during low-level endotoxemia and high fat diet (HFD)-induced obesity in male and female adipocyte-specific IRF4 knockout mice (AdipoIRF4^fl/fl ) compared to WT^fl/fl mice. Adipocyte IRF4 was required for the blood glucose-lowering effects of MDP during endotoxemia and HFD-induced obesity in male mice. However, MDP did not alter blood glucose in female WT^fl/fl and AdipoIRF4^fl/f mice during endotoxemia. Unexpectedly, female HFD-fed AdipoIRF4^fl/f mice had lower blood glucose after MDP treatment compared to WT^fl/fl mice. MDP lowered inflammatory gene expression in adipose tissue of HFD-fed WT^fl/fl and AdipoIRF4^fl/fl mice of both sexes. Therefore, MDP-mediated lowering of adipose inflammation does not require adipocyte IRF4 and was independent of sex. Together, these data show that injection of MDP, an insulin-sensitizing postbiotic, lowers adipose tissue inflammation in male and female mice, but lower adipose inflammation is not always associated with improved blood glucose. The blood glucose-lowering effect of the postbiotic MDP and dependence on adipocyte IRF4 is sex-dependent.