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Aims: Type 2 diabetes is a chronic inflammatory metabolic disease, the key point being insulin resistance.Endoplasmic reticulum (ER) stress plays a critical role in the pathogenesis of type 2 diabetes.Previously, we found that hyperhomocysteinemia (HHcy) induced insulin resistance in adipose tissue.Here, we hypothesized that HHcy induces ER stress, which in turn promotes insulin resistance.Methods: The direct effect of Hcy on adipose ER stress was investigated by use of primary rat adipocytes in vitro and mice with HHcy in vivo.The mechanism and the effect of G protein-coupled receptor 120 (GPR 120) were also investigated.Results:We found that phosphorylation or expression of variant ER stress markers was elevated in adipose tissue of HHcy mice.HHcy activated c-Jun N-terminal kinase (JNK), the downstream signal of ER stress in adipose tissue, and activated JNK participated in insulin resistance by inhibiting Akt activation.Furthermore, JNK activated c-Jun and p65, which in turn triggered the transcription of pro-inflammatory cytokines.Both in vivo and in vitro assays revealed that Hcy-promoted macrophage infiltration aggravated ER stress in adipose tissue.Chemical chaperones PBA and TUDCA could reverse Hcy-induced inflammation and restore insulin-stimulated glucose uptake and Akt activation.Activation of GPR 120 reversed Hcy-induced JNK activation and prevented inflammation but not ER stress.Conclusion: HHcy inhibited insulin sensitivity in adipose tissue by inducing ER stress, activating JNK to promote pro-inflammatory cytokine production and facilitating macrophage infiltration.These findings reveal a new mechanism of HHcy in the pathogenesis of insulin resistance.