Autophagy-mediated insulin receptor down-regulation contributes to endoplasmic reticulum stress-induced insulin resistance.
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.
Zhou
Lijun
L
Department of Biochemistry, University of Texas Health Science Center, 7703 Floyd Curl Dr., San Antonio, TX 78229, USA.
Zhang
Jingjing
J
Fang
Qichen
Q
Liu
Meilian
M
Liu
Xianling
X
Jia
Weiping
W
Dong
Lily Q
LQ
Liu
Feng
F
D041721:3T3-L1 Cells; D017667:Adipocytes / Q000378:metabolism; D000818:Animals; D001343:Autophagy; D004195:Disease Models, Animal; D015536:Down-Regulation; D004721:Endoplasmic Reticulum / Q000187:drug effects / Q000378:metabolism*; D006801:Humans; D007333:Insulin Resistance; D007976:Leupeptins / Q000494:pharmacology; D051379:Mice; D008815:Mice, Inbred Strains; D009765:Obesity / Q000150:complications / Q000378:metabolism*; D010766:Phosphorylation; D011972:Receptor, Insulin / Q000037:antagonists & inhibitors*; D013655:Taurochenodeoxycholic Acid / Q000494:pharmacology; D014443:Tyrosine / Q000378:metabolism
D007976:Leupeptins; D014443:Tyrosine; D013655:Taurochenodeoxycholic Acid; C031655:ursodoxicoltaurine; D011972:Receptor, Insulin; C072553:benzyloxycarbonylleucyl-leucyl-leucine aldehyde