TY - JOUR T1 - Autophagy-Mediated Insulin Receptor Down-Regulation Contributes to Endoplasmic Reticulum Stress-Induced Insulin Resistance JF - Molecular Pharmacology JO - Mol Pharmacol SP - 596 LP - 603 DO - 10.1124/mol.109.057067 VL - 76 IS - 3 AU - Lijun Zhou AU - Jingjing Zhang AU - Qichen Fang AU - Meilian Liu AU - Xianling Liu AU - Weiping Jia AU - Lily Q. Dong AU - Feng Liu Y1 - 2009/09/01 UR - http://molpharm.aspetjournals.org/content/76/3/596.abstract N2 - Endoplasmic reticulum (ER) stress is associated with obesity-induced insulin resistance, yet the underlying mechanisms remain to be fully elucidated. Here we show that ER stress-induced insulin receptor (IR) down-regulation may play a critical role in obesity-induced insulin resistance. The expression levels of IR are negatively associated with the ER stress marker C/EBP homologous protein (CHOP) in insulin target tissues of db/db mice and mice fed a high-fat diet. Significant IR down-regulation was also observed in fat tissue of obese human subjects and in 3T3-L1 adipocytes treated with ER stress inducers. ER stress had little effect on IR tyrosine phosphorylation per se but greatly reduced IR downstream signaling. The ER stress-induced reduction in IR cellular levels was greatly alleviated by the autophagy inhibitor 3-methyladenine but not by the proteasome inhibitor N-benzoyloxycarbonyl (Z)-Leu-Leu-leucinal (MG132). Inhibition of autophagy prevented IR degradation but did not rescue IR downstream signaling, consistent with an adaptive role of autophagy in response to ER stress-induced insulin resistance. Finally, chemical chaperone treatment protects cells from ER stress-induced IR degradation in vitro and obesity-induced down-regulation of IR and insulin action in vivo. Our results uncover a new mechanism underlying obesity-induced insulin resistance and shed light on potential targets for the prevention and treatment of obesity-induced insulin resistance and type 2 diabetes. ER -