Abstract 127: Heme Oxygenase-1 Ameliorates High Fat-induced Insulin Resistance Through Inhibition Of Nuclear Factor kB andTumor Necrosis Factor-alpha Pathway In Skeletal Muscle
Because an inverse linear relationship between the glucose utilization and expression of TNF-alpha in skeletal muscle has been reported, this association may conform a critical key in the development of insulin resistance where elevated plasma free fatty acids plays a key role. Heme oxygenase is a microsomal enzyme that catalyzes the degradation of heme into biliverdin, which is subsequently reduced to bilirubin, free iron and carbon monoxide. Induction of heme oxygenase-1 (HO-1) has been potentially associated with cellular protection, especially against oxidative insults and inflammation. In the current study, we investigated the role of HO-1 in skeletal muscle on insulin resistance induced by high fat diet. Exposure of C2C12 skeletal muscle cells to palmitate led to enhanced TNF-alpha expression, which was inversely correlated with a fall in insulin-stimulated Akt phosphorylation as well as GLUT4 translocation. Immunoblotting analysis revealed that palmitate enhances phosphorylation of IkBalpha of C2C12 cells suggesting NF-kB activation is involved. To investigate cytoprotective effect of HO-1, we performed adenovirus-mediated HO-1 gene transfer to C2C12 cells. HO-1-transduced C2C12 (HO-1-C2C12) cells with increased accumulation of bilirubin and HO activity did not exhibit any palmitate-elicited changes which were observed in Lac-Z-transduced C2C12 cells. We, then, treated mouse with CoPP to induce HO-1 (HO-1 mouse), and perform hyperinsulinemic-euglycemic glucose clamp to investigate insulin resistance in vivo. After 3-month-high fat diet, both control and HO-1 mouse gained body weight almost identically, however, insulin sensitivity was significantly impaired in control mouse as compared with HO-1 mouse. Skeletal muscle of control mouse displayed enhanced TNF-alpha expression with NF-kB activation which caused impaired Akt phosphorylation as well as GLUT 4 translocation as compared with those of HO-1 mouse. Taken together, these observations suggest that HO-1 in skeletal muscle may be a new therapeutic target against insulin resistance through inhibition of NF-kB/TNF-alpha pathway.