1400-P: Endothelial Cell Autophagy Contributes to HFD-Induced Obesity and Insulin Resistance in Mice

Autophagy is a catabolic process and plays crucial roles in cellular physiology, including energy homeostasis, cell survival, and inflammation. Autophagy-related gene 7 (ATG7) is an essential regulator of autophagosome formation. Although endothelial cell ATG7 (EC-ATG7) plays a critical role in atherosclerosis, thrombosis, and injuries from ischemia/reperfusion, the role of EC-ATG7 in obesity and insulin resistance is not known. Because endothelial function contributes to insulin resistance by regulating blood flow and delivery of nutrients and hormones to metabolic tissues, EC autophagy may affect metabolism and insulin resistance. Thus, we hypothesize that EC-ATG7 contributes to high-fat diet (HFD) -induced obesity and insulin resistance. To examine the role of EC-ATG7 in obesity and insulin resistance, we generated an EC-specific ATG7 knockout mouse (ATG7^ΔEC) by breeding Cdh5-CRE mouse with ATG7^flox/flox mouse. ATG7^ΔEC mice were fed a normal chow diet (NCD) or HFD for twelve weeks. HFD-fed ATG7^ΔEC mice gained less body weight compared with HFD-fed wild-type (WT) mice, while body weight was not different when the mice were fed NCD. HFD-fed ATG7^ΔEC mice demonstrated lower food intake. Interestingly, intraperitoneal injection of low dose 2-arachidonoyl glycerol (2AG) , a cannabinoid receptor agonist, restored the food intake in ATG7^ΔEC mice but not in WT mice. This indicates that the EC-ATG7 affects food intake by stimulating endogenous cannabinoid receptor (s) in the brain. Furthermore, HFD-fed ATG7^ΔEC mice were more insulin sensitive than HFD-fed WT mice.

In conclusion, our findings demonstrate a novel function of EC-ATG7 in regulating food intake and insulin resistance.