Physical activity and exercise are understood to lead to beneficial effects on many aspects of health, including protection against acute and chronic disease. To identify the molecular mechanisms that regulate these adaptations, research has primarily focused on skeletal muscle and the cardiovascular system; however, the liver has recently become recognized as an important organ involved in almost all aspects of physical activity and exercise. Therefore, the focus of this thesis is to investigate how physical activity, exercise, and exercise-activated pathways, influence the response to acute metabolic perturbations of the liver. In study I, it was identified that prior physical activity via voluntary wheel running (VWR) attenuates lipopolysaccharide (LPS) induced liver inflammation, which was primarily evident when assessed after 6 hours as opposed to after 12 hours. To ascertain a molecular mechanism, a number of endpoints were measured, and it was observed that VWR increased the protein content of the molecular chaperone heat shock protein 70/72, suggesting it may mediate some of the protective effects. In study II, it was identified that the exercise-induced increase in liver mRNA expression of follistatin (FST) occurs after exhaustive but not moderate exercise. Using glucagon receptor knockout mice, and pre-treatment of propranolol to block the effects of epinephrine, it was observed that the exercise-induced increase in liver mRNA expression of FST is mediated by glucagon but not epinephrine. In study III, it was identified that interleukin-6 (IL-6), which is an exercise-inducible factor, improves indices of hepatic glucose homeostasis in vivo in both low fat diet and high fat diet fed mice. However, IL-6 had minimal effect on indices of hepatic glucose homeostasis when measured in vitro, using isolated primary hepatocytes, suggesting that the effects of IL-6 observed in vivo are secondary to a direct effect on the hepatocyte. In sum, the studies of this thesis provide evidence that physical activity, exercise, and exercise-activated pathways have pronounced effects on the liver, and moreover, these effects may protect against inflammation or improve aspects of metabolic health.