Increased RTN3 Leads to Obesity and Hypertriglyceridemia by Interacting with HSPA5

Background —Reticulon 3 (RTN3) is an endoplasmic reticulum protein that has been previously shown to play a role in neurodegenerative diseases, but little is known about its role in lipid metabolism. Methods —Obesity patients (149), hypertriglyceridemia patients (343), and healthy controls (84) were enrolled to assess their levels of RTN3. To explore pathophysiological roles of RTN3 in the control of lipid metabolism, we utilized Tg-RTN3 and RTN3-null transgenic mouse models and multiple C. elegans strains for molecular characterization. The underlying mechanisms were studied using 3T3L1 cell cultures in vitro . Results —We report that overexpressed RTN3 in mice induces obesity and higher accumulation of triglycerides (TGs). Remarkably, increased RTN3 expression is also found in patients with obesity and hypertriglyceridemia. We reveal that RTN3 plays critical roles in regulating the biosynthesis and storage of TGs and in controlling lipid droplet expansion. Mechanistically, RTN3 regulates these events through its interactions with HSPA5, and this enhanced interaction increases SREBP-1c and AMPK activity. Conclusions —This study provides evidence for a role of RTN3 in inducing obesity and TG accumulation, and suggests that inhibiting the expression of RTN3 in fat tissue may be a novel therapeutic approach to treat obesity and hypertriglyceridemia.