Mechanistically, we unraveled that while TLR4 in BM-derived immune cells mediates the hyperglycemia-improving effect of r-mS100A9 within the SkM, TLR4 in KCs underlies the hyperketonemia- and hypertriglyceridemia-lowering action of S100A9 in the liver. Here, TLR4 is linked to Hyperglycemia.