Hyperhomocysteinemia promotes insulin resistance by inducing endoplasmic reticulum stress in adipose tissue

Abstract

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. In the present study, the direct effect of Hcy on adipose ER stress was investigated by the use of primary rat adipocytes in vitro and mice withHHcyin vivo. The mechanism and the effect ofGprotein-coupled receptor 120 (GPR120) were also investigated.We found that phosphorylation or expression of variantERstress markers was elevated in adipose tissue ofHHcymice. HHcy activated c-Jun N-terminal kinase (JNK), the downstream signal ofERstress 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 proinflammatory cytokines. Both in vivo and in vitro assays revealed that Hcy-promoted macrophage infiltration aggravated ERstress in adipose tissue. Chemical chaperonesPBAandTUDCA could reverse Hcy-induced inflammation and restore insulin-stimulated glucose uptake and Akt activation. Activation of GPR120 reversed Hcy-inducedJNKactivation and prevented inflammation but not ER stress. Therefore, HHcy inhibited insulin sensitivity in adipose tissue by inducing ER stress, activating JNK to promote proinflammatory cytokine production and facilitating macrophage infiltration. These findings reveal anewmechanismofHHcy in the pathogenesis of insulin resistance. © 2013 by The American Society for Biochemistry and Molecular Biology, Inc.