294-OR: Hepatic Integrin ß1 Subunit Is Required for Liver Insulin Resistance but Not Fatty Liver in Diet-Induced Obese Mice

Obesity can lead to liver fibrosis and a selective insulin resistance whereby insulin-stimulated lipogenesis is maintained and liver triglycerides (TG) are elevated, while insulin suppression of liver glucose production (R_a) is impaired. The hypothesis that extracellular matrix (ECM) proteins of the fibrotic liver signal via integrin receptors contributing to hepatic insulin resistance was tested. Integrins consist of an α subunit that confers ligand specificity and a β subunit that interacts with adhesion proteins that transmit signals that lead to adaptations in cell function. The integrin β1 subunit is the primary isoform in the liver. Lean and diet-induced obese (DIO) C57Bl/6J mice with hepatocyte-specific deletion of the integrin β1 subunit (hitgβ1) knockout (KO) and wild type littermates (WT) were studied. Insulin clamps were performed in hitgβ1 KO and WT mice. R_a and glucose utilization (R_d) were measured before and during clamps. Metabolism in lean mice was unaffected by hitgβ1 KO. DIO WT mice were resistant to insulin suppression of R_a and had elevated liver TG. This insulin resistance to suppression of R_a was completely alleviated in DIO hitgβ1 KO mice. However, liver TG remained elevated. Alleviation of hepatic insulin resistance in DIO hitgβ1 KO mice was reflected by a greater activation of the insulin signaling pathway in hepatocytes. In contrast, impaired response of enzymes that participate in cytoskeletal organization and mitochondrial oxidation were observed in DIO hitgβ1 KO mice. It is postulated that impaired cytoskeletal organization decreases mitochondrial oxidation through effects on mitochondrial interactions. Impaired oxidation may contribute to the elevated TG that is present despite the improvement in insulin action. In conclusion, the hitgβ1 subunit contributes to selective hepatic insulin resistance in DIO mice. These data provide a mechanistic basis for an ECM - integrin receptor - insulin resistance axis in DIO mice.