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Increased secretion of proinflammatory cytokines, such as tumor necrosis factor-alpha (TNFα), is often associated with adipose tissue dysregulation, which often accompanies obesity. High levels of TNFα have been linked to the development of insulin resistance in several tissues and organs, including skeletal muscle and the liver. In this study, we examined the complex regulatory roles of TNFα in murine hepatocytes utilizing a combination of global proteomic and phosphoproteomic analyses. Our results show that TNFα promotes extensive changes not only of protein levels, but also the dynamics of their downstream phosphorylation signaling. We provide evidence that TNFα induces DNA replication and promotes G1/S transition through activation of the MAPK pathway. Our data also highlight several other novel proteins, many of which are regulated by phosphorylation and play a role in the progression and development of insulin resistance in hepatocytes.