Adiponectin, an insulin-sensitizing hormone, and resistin, known to promote insulin resistance, constitute a potential link between obesity and type2 diabetes. In addition, Fibroblast growth factor 21 (FGF21) has similar effects as adiponectin in regulating glucose/lipid metabolism and insulin sensitivity. However, the interplay between adiponectin, FGF21 and resistin signaling pathways during the onset of insulin resistance is unknown. Here, we investigated whether central resistin promotes insulin resistance through the impairment of adiponectin and FGF21 signaling.We showed that chronic ICV resistin infusion down-regulated both hypothalamic and hepatic APPL1, a key protein in adiponectin signaling, associated with decreased Akt/APPL1 interaction and an increased Akt association with its endogenous inhibitor TRB3. Resistin treatment also decreased plasma adiponectin levels and reduced both hypothalamic and peripheral expression of adiponectin receptors. Additionally, we reported that ICV resistin increased plasma FGF21 levels and down-regulated its receptor components in the hypothalamus and peripheral tissues promoting FGF21 resistance. Interestingly we also showed that resistin effects were abolished in TLR4 knock out mice and in neuronal cells expressing TLR4 siRNAs. Our study reveals a novel mechanism of insulin resistance onset orchestrated by central resistin/TLR4 pathway that impairs adiponectin signaling and promotes FGF21 resistance.