Obesity-induced insulin resistance develops in the background of a low-grade chronic inflammation caused by myeloid cells where increased TNF and IL-6 impair insulin action in metabolic tissues. Obesity-induced IL-6 derived from white adipose tissue impairs insulin action but the manifold expression of IL-6 in skeletal muscle under acute exercise conditions promotes insulin action. Thus, the discrepancy between acute and chronic IL-6 on insulin sensitivity has to be clarified. We have hypothesized that similarly to the described mechanism of central leptin resistance in obesity, high IL-6 levels cause peripheral IL-6 resistance. Indeed, IL-6 resistance occurs in the context of chronic IL-6-induced Stat3 activation leading to elevated expression of the negative regulator SOCS3. SOCS3 in turn compromises IL-6 signaling. Interestingly, obesity-induced IL-6 resistance develops exclusively in the liver parenchymal cells. However, how hepatic IL-6 resistance impacts on myeloid programming is largely unclear. For this, we will employ single cell examination of hepatic macrophages by scRNA seq and lipidomics derived from mice exposed to control chow and to high fat diet feeding. To decipher the effect of hepatic IL-6 resistance in this context, we have developed mouse models of genetic IL-6 resistance via hepatocyte-specific expression of Lgp130 and SOCS3K6R, respectively, that we aim to investigate in myeloid programming and compare to the diet-induced mouse model. We have identified IL-6-regulated Csf-1 expression in hepatocytes impacting on monocyte-derived macrophage states without largely affecting liver resident Kupffer cells that we are exploring further. Collectively, the molecular understanding of myeloid cell programming in the context of obesity-induced hepatic IL-6 resistance might help to develop individual strategies to interfere with inflammatory cytokine expression to limit obesity-associated metaflammation and ultimately confer insulin sensitivity in obesity.