PMID- 23417716 OWN - NLM STAT- MEDLINE DCOM- 20130531 LR - 20220331 IS - 1083-351X (Electronic) IS - 0021-9258 (Print) IS - 0021-9258 (Linking) VI - 288 IP - 14 DP - 2013 Apr 5 TI - Hyperhomocysteinemia promotes insulin resistance by inducing endoplasmic reticulum stress in adipose tissue. PG - 9583-9592 LID - S0021-9258(20)67323-9 [pii] LID - 10.1074/jbc.M112.431627 [doi] AB - 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. FAU - Li, Yang AU - Li Y AD - Department of Physiology and Pathophysiology, School of Basic Medical Sciences, Peking University, Beijing 10091, China and the Key Laboratory of Molecular Cardiovascular Science, Ministry of Education, Beijing 100191, China. FAU - Zhang, Heng AU - Zhang H AD - Department of Physiology and Pathophysiology, School of Basic Medical Sciences, Peking University, Beijing 10091, China and the Key Laboratory of Molecular Cardiovascular Science, Ministry of Education, Beijing 100191, China. FAU - Jiang, Changtao AU - Jiang C AD - Department of Physiology and Pathophysiology, School of Basic Medical Sciences, Peking University, Beijing 10091, China and the Key Laboratory of Molecular Cardiovascular Science, Ministry of Education, Beijing 100191, China. FAU - Xu, Mingjiang AU - Xu M AD - Department of Physiology and Pathophysiology, School of Basic Medical Sciences, Peking University, Beijing 10091, China and the Key Laboratory of Molecular Cardiovascular Science, Ministry of Education, Beijing 100191, China. FAU - Pang, Yanli AU - Pang Y AD - Department of Physiology and Pathophysiology, School of Basic Medical Sciences, Peking University, Beijing 10091, China and the Key Laboratory of Molecular Cardiovascular Science, Ministry of Education, Beijing 100191, China. FAU - Feng, Juan AU - Feng J AD - Department of Physiology and Pathophysiology, School of Basic Medical Sciences, Peking University, Beijing 10091, China and the Key Laboratory of Molecular Cardiovascular Science, Ministry of Education, Beijing 100191, China. FAU - Xiang, Xinxin AU - Xiang X AD - Department of Physiology and Pathophysiology, School of Basic Medical Sciences, Peking University, Beijing 10091, China and the Key Laboratory of Molecular Cardiovascular Science, Ministry of Education, Beijing 100191, China. FAU - Kong, Wei AU - Kong W AD - Department of Physiology and Pathophysiology, School of Basic Medical Sciences, Peking University, Beijing 10091, China and the Key Laboratory of Molecular Cardiovascular Science, Ministry of Education, Beijing 100191, China. FAU - Xu, Guoheng AU - Xu G AD - Department of Physiology and Pathophysiology, School of Basic Medical Sciences, Peking University, Beijing 10091, China and the Key Laboratory of Molecular Cardiovascular Science, Ministry of Education, Beijing 100191, China. FAU - Li, Yin AU - Li Y AD - Department of Physiology and Pathophysiology, School of Basic Medical Sciences, Peking University, Beijing 10091, China and the Key Laboratory of Molecular Cardiovascular Science, Ministry of Education, Beijing 100191, China. Electronic address: yinli@bjmu.edu.cn. FAU - Wang, Xian AU - Wang X AD - Department of Physiology and Pathophysiology, School of Basic Medical Sciences, Peking University, Beijing 10091, China and the Key Laboratory of Molecular Cardiovascular Science, Ministry of Education, Beijing 100191, China. Electronic address: xwang@bjmu.edu.cn. LA - eng PT - Journal Article PT - Research Support, Non-U.S. Gov't DEP - 20130217 PL - United States TA - J Biol Chem JT - The Journal of biological chemistry JID - 2985121R RN - 0 (Cytokines) RN - 0 (FFAR4 protein, mouse) RN - 0 (Insulin) RN - 0 (Receptors, G-Protein-Coupled) RN - 0LVT1QZ0BA (Homocysteine) RN - EC 2.7.12.2 (MAP Kinase Kinase 4) RN - IY9XDZ35W2 (Glucose) SB - IM MH - Adipocytes/cytology MH - Adipose Tissue/*metabolism MH - Animals MH - Cytokines/metabolism MH - Diabetes Mellitus, Type 2/*metabolism MH - Endoplasmic Reticulum/*metabolism MH - Glucose/metabolism MH - Homocysteine/genetics MH - Hyperhomocysteinemia/*metabolism MH - Immunohistochemistry/methods MH - Inflammation MH - Insulin/metabolism MH - *Insulin Resistance MH - MAP Kinase Kinase 4/metabolism MH - Macrophages/cytology/metabolism MH - Macrophages, Peritoneal/cytology MH - Male MH - Mice MH - Mice, Inbred C57BL MH - Rats MH - Rats, Sprague-Dawley MH - Receptors, G-Protein-Coupled/metabolism PMC - PMC3617262 EDAT- 2013/02/19 06:00 MHDA- 2013/06/01 06:00 PMCR- 2014/04/05 CRDT- 2013/02/19 06:00 PHST- 2013/02/19 06:00 [entrez] PHST- 2013/02/19 06:00 [pubmed] PHST- 2013/06/01 06:00 [medline] PHST- 2014/04/05 00:00 [pmc-release] AID - S0021-9258(20)67323-9 [pii] AID - M112.431627 [pii] AID - 10.1074/jbc.M112.431627 [doi] PST - ppublish SO - J Biol Chem. 2013 Apr 5;288(14):9583-9592. doi: 10.1074/jbc.M112.431627. Epub 2013 Feb 17.