63-LB: Transthyretin Contributes to Insulin Resistance and Its Role in Exercise-Induced Improvement of Insulin Sensitivity in Obese Mice

A major cause of type 2 diabetes is impaired insulin sensitivity. Our aim is to investigate the role of transthyretin (TTR), a molecule implicated in exercise-induced anorexia, in obesity-related insulin resistance and exercise-induced insulin sensitivity improvement. We found that serum TTR levels were elevated in obese C57BL/6 mice (DIO) induced by high-fat diet and 14 people with metabolic syndrome. Serum TTR levels in normal or DIO mice were decreased or normalized by treadmill training as a result of the decreased TTR-mRNA expression in the liver. Injection of recombinant TTR- adenovirus by tail-vein in normal mice caused TTR overexpression in the liver and increased TTR secretion to circulation, resulting in insulin resistance and glucose intolerance. Although the increased TTR levels in serum did not further impair glucose intolerance, it counteracted the exercise-induced improvement of insulin sensitivity in DIO mice. As expected, AMPK activity in muscle was induced by treadmill training in both normal and DIO mice, whereas it was inhibited by TTR overexpression. Although we did not find TTR-mRNA expression in the muscle, we detected TTR protein in muscle by western blotting and immunohistochemistry. Markedly, the change of TTR levels in muscle was in consistent with that in serum of both normal and DIO mice with exercise or not. Further in C2C12 skeletal muscle cells, we demonstrated that TTR protein could be internalized in a time-dependent manner, and exogenous TTR pure protein or adenovirus-mediated high expression of TTR protein inhibited the AMPK pathway activity in a dose-dependent manner. Our results suggest that TTR contributes to insulin resistance, and exercise may improve insulin resistance by reducing TTR expression in the liver, TTR secretion to circulation, and TTR uptake in skeletal muscle, thus increasing AMPK activity.