Intercellular endotrophin contributes to ER stress-linked adipocyte dysfunction in obesity

Abstract

Endotrophin (ETP), a cleavage product of collagen VI (Col6) a3, causes systemic insulin resistance (IR) by increasing adipose tissue inflammation and fibrosis. Here we report that extracellular ETP was internalized partly through the caveolin-1 linked endocytosis, and trafficked to the endosome and endoplasmic reticulum (ER). High levels of intercellular ETP directly interact with SEC13, a component of the COPII coat vesicles known as key mediators of ER-Golgi trafficking, and these ETP-SEC13 complex interferes the cellular trafficking in the conditions of ER stress, leading to ER stress-related apoptosis, inflammation, and IR in adipocytes. Col6a3 knockout in 3T3-L1 adipocytes protected against these effects and preserved insulin sensitivity under ER stress condition; this was abrogated by in vitro ETP reconstitution. Adipocyte-specific ETP transgenic mice on a high-fat diet treated with the ER stress inhibitor tauroursodeoxycholic acid showed improved systemic IR and inflammation caused by overexpression of ETP. Thus, ETP promotes ER stress-linked apoptosis and inflammation specifically in adipocytes that resulting in systemic IR in obesity, and which is partly through the inhibition of COPII vesicles trafficking in adipocytes.