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 with HHcy in vivo. The mechanism and the effect of G protein-coupled receptor 120 (GPR120) were also investigated. 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 proinflammatory 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 GPR120 reversed Hcy-induced JNK activation 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 a new mechanism of HHcy in the pathogenesis of insulin resistance.

• Authors: Yang Li, Heng Zhang, Changtao Jiang, Mingjiang Xu, Yanli Pang, Juan Feng, Xinxin Xiang, Wei Kong, Guoheng Xu, Yin Li, Xian Wang
• Journal: The Journal of biological chemistry (J Biol Chem) Vol. 288 Issue 14 Pg. 9583-9592 (Apr 05 2013) ISSN: 1083-351X [Electronic] United States
• PMID: 23417716 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Cytokines
• FFAR4 protein, mouse
• Insulin
• Receptors, G-Protein-Coupled
• Homocysteine
• MAP Kinase Kinase 4
• Glucose

Topics

• Adipocytes (cytology)
• Adipose Tissue (metabolism)
• Animals
• Cytokines (metabolism)
• Diabetes Mellitus, Type 2 (metabolism)
• Endoplasmic Reticulum (metabolism)
• Glucose (metabolism)
• Homocysteine (genetics)
• Hyperhomocysteinemia (metabolism)
• Immunohistochemistry (methods)
• Inflammation
• Insulin (metabolism)
• Insulin Resistance
• MAP Kinase Kinase 4 (metabolism)
• Macrophages (cytology, metabolism)
• Macrophages, Peritoneal (cytology)
• Male
• Mice
• Mice, Inbred C57BL
• Rats
• Rats, Sprague-Dawley
• Receptors, G-Protein-Coupled (metabolism)