Studies have reported that GLP-1 does not lead to an increase in ?-oxidation in mice pancreatic cells . Our data alone cannot implicate that GLP-1 directly increases ?-oxidation. It is tempting to speculate, however, that oxidation may be a result of decreased stress and fat load via autophagy, which is enhanced at the transcriptional level by exendin-4 and is further maintained by an increase in GRP78; hence additional experiments will be required to gain insight into the exact mechanisms of autophagic regulation by GLP-1 analogs. Down-regulation of the CPI-613 insulin receptor protein levels in insulin-target tissues such as liver, skeletal muscle, and adipose tissue has been shown to correlate with insulin resistance . Zhou et al. have identified an interesting link between ER stress, autophagy, and insulin resistance. They have demonstrated that obesity induces insulin resistance by ER stress-dependent down-regulation of the IR; and, ER stressstimulated IR degradation is mediated by the autophagydependent process. They also demonstrated that the expression levels of IR were negatively associated with CHOP in insulin target tissues of db/db mice and mice fed a high-fat diet. In the work presented here we provide a plausible series of mechanisms associated with GLP-1 analog treatment that result in a beneficial relationship between autophagy and ER stress in hepatic steatosis. Arguably, GLP-1 in our work reduced ER stress and promoted autophagy, which, in turn, lead to reduction in both fat load and unfolded proteins. The results of our studies both in vitro and in vivo reveal restoration of normal metabolism in hepatocytes and consequently improve their chances for survival. Taken together, we have demonstrated that GLP-1 agonists can rescue hepatocytes from toxic fatty acids in vitro, or steatosis in vivo, by promoting autophagy and mitigating ER-stress mediated apoptosis.