The role of inflammatory mediators in the development of insulin resistance and hepatocellular carcinoma

Over the last decade, obesity has been recognized as a chronic low inflammatory state that predisposes for the development of diseases, such as obesity-associated insulin resistance and cancer. The chronic low grade inflammation under obese conditions manifests not only as increase of inflammatory mediators, such as TNF-α and IL-6 in circulation, but also in elevated free fatty acids in the bloodstream. Though, this inflammatory condition has been shown to impair insulin action and to increase the incidence of cancer development. The liver specific contribution of IL-6 signaling as well as TLR signaling through the essential adaptor molecule MyD88 in these processes remains unclear. \nTo examine the role of hepatic IL-6 signaling in glucose homeostasis, we have conditionally inactivated the IL-6Rα in hepatocytes of mice (IL-6RαL-KO). While these animals showed no alterations in body weight gain and body fat content, IL-6RαL-KO mice developed systemic insulin resistance, manifested as attenuated insulin stimulated glucose transport in skeletal muscle and fat during hyperinsulinemic-euglycemic clamps. Insulin resistance in these mice developed in the presence of increased circulating levels of IL-6 and TNF-α that directly translated in enhanced activation of inflammatory signaling in liver and skeletal muscle, thereby impairing insulin action. Neutralization of TNF-α or ablation of Kupffer cells restored glucose tolerance in IL-6RαL-KO mice to normal, indicating that increased circulating TNF-α, derived from the Kupffer cells, impairs insulin action systemically. Thus, our results reveal an unexpected role for hepatic IL-6 signaling to limit hepatic inflammation and to protect from local and systemic insulin resistance. \nMoreover, TLR-mediated signaling was examined in the development of insulin resistance and HCC, using mice with hepatocyte-specific MyD88 deficiency (MyD88L-KO mice). While glucose homeostasis was largely unaltered, these mice exhibited decreased liver damage, reduced hepatic macrophage infiltration and a strong reduction in chemically induced hepatocellular carcinoma development. Interestingly, tumor livers of MyD88L-KO mice exhibit reduced JNK activation that could potentially account for the reduced liver tumorgenesis in these animals. \nTaken together, this study highlights the hepatic role of inflammatory IL-6 and TLR-induced signaling in the development of obesity-associated insulin resistance and hepatocellular carcinogenesis.