Obesity has been associated with a low-grade systemic inflammation, termed metaflammation, characterized by increased IL-6 interleukin levels that mainly originate from macrophages. Our data show that increased systemic IL-6 level during obesity impair acute IL-6 responsiveness in the liver, a condition that we define as hepatic IL-6 resistance. Data from the first funding period revealed that hepatic IL-6 resistance (in dietary and genetic models) provokes hepatic fibrosis and the development of insulin resistance, at least in part, via Csf1 that promotes accumulation/differentiation of monocyte-derived Cx3cR1-expressing macrophages. Inducible Csf1r inactivation in monocyte-derived macrophages ameliorated fibrosis and insulin resistance in both models of hepatic IL-6 resistance by abrogating macrophage polarization towards fibrotic phenotype. Furthermore, concomitant with fibrosis progression, we observed dramatic upregulation of IL1R1 in IL-6-resistant hepatocytes and also in infiltrating macrophages. IL-1 downstream signaling activates Ikk/NFkB and Jnk/cJun pathways that have been shown to impair insulin action and to promote liver diseases. However, the cell type-specific function of IL-1 signaling in macrophages has not been addressed yet. Here. In the second funding period, we aim to elucidate the cell type-specific functions of IL-1R1 signaling in the development of IL-6 resistance and fibrosis during obesity. To this end, we will: 1) identify the origin of IL1b expression in IL-6 resistance, 2) therapeutically block IL1R1 in IL-6 resistance, and 3) examine the hepatocyte- and macrophage-specific role of IL1R1 signaling in IL-6 resistance. Collectively, this approach will unravel the function of IL1R1 signaling in IL-6 resistance induced fibrosis and development of insulin resistance.

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