Hepatic insulin resistance (IR) plays a central role in the pathophysiology of impaired glucose tolerance, type 2 diabetes and nonalcoholic fatty liver disease (NAFLD) and steatohepatitis (NASH), which is emerging as a major cause of liver failure and hepatocellular carcinoma. Impaired autophagy may also contribute to hepatic insulin resistance, but the interactions between insulin sensitivity and autophagy are incompletely understood. The Unc-51 Like Autophagy Activating Kinase 1 (ULK1) is an early stage autophagosome formation related kinase that is activated in selective autophagy and may be independent of nutrient or energy status. We observed that in addition to its role in autophagy regulation, ULK1 may also directly regulate insulin signaling by modulating AKT dephosphorylation. Specifically, silencing ULK1 significantly impairs insulin-stimulated activation of AKT and GSK3β in hepatocytes in the absence of significant changes in autophagy. To understand the role of ULK1 in hepatic insulin action ULK1 liver specific knock-out mice were generated. Body weight increased in L-ULK1KO relative to wild type mice on normal chow diet or 60% high fat diet. L-ULK1 KO mice exhibited impaired glucose tolerance and insulin resistance. Serum concentrations of insulin, triglyceride, cholesterol, AST and ALT were increased. Phosphorylation levels of FOXO1 and FOXO3a were decreased in concert with increased expression levels of PEPCK and G6pase and increased hepatic glucose production. In contrast, L-ULK2 KO mice were phenotypically normal. Thus, ULK1 independently and directly regulates hepatic insulin sensitivity and glucose homeostasis.
Y. Koo: None. M.P. Garneau: None. Q. Zhang: None. E. Abel: None.