In response to chronic (5 days) total parenteral nutrition (TPN) the liver adapts to become a major site of glucose disposal removing ~45% (4.5 mg/kg/min) of the exogenous glucose in the absence of marked hyperglycemia or hyperinsulinemia. Moreover ~70% of the glucose is not stored but is released as lactate. The aim of these studies was to determine the time course of the adaptation to TPN and the impact of glycogen depletion on the early time course of the hepatic adaptation. Three groups of studies were performed in chronically catheterized conscious dogs two weeks after surgery. Following an 18 h (n=5; 18h) fast TPN was infused into the inferior vena cava for 8 hours (n=5) or 24 hours (n=6). A third group of 42 h fasted animals (n=6; 42h) were infused with TPN for 8 hours. TPN was infused at a rate designed to match the dog's calculated basal energy and nitrogen requirements (glucose [9.5mg/kg/min] 75% of non-protein calories (NPC); Intralipid 25% NPC and Travasol). Hepatic metabolism was assessed using tracer and arterio-venous difference techniques. Net hepatic glucose uptake (-2.3±0.1 to 2.2±0.7 to 3.9±0.6 vs. -1.7±0.3 to 1.1±0.5 to 2.9±0.4 mg/kg/min; basal to 4 h to 8 h; 18 h vs. 42h) and net hepatic lactate release (0.7±0.3 to 0.6±0.1 to 1.4±0.2 vs. -0.6±0.1 to 0.1±0.1 to 0.8±0.1 mg/kg/min; basal to 4 h to 8 h) increased progressively. Both net hepatic glycogen repletion (45±13 vs. 37±6 mg/g liver) and tracer determined glycogen synthesis (1.7±0.3 vs. 1.7±0.3 mg/kg/min) were similar. After 24 h of TPN net hepatic glucose uptake (5.4±0.6 mg/kg/min) and net hepatic lactate release (2.6±0.4 mg/kg/min) increased even further, which is similar than that observed after 5 days of TPN. In summary: 1) the majority of the hepatic adaptation to TPN occurs within 24h after the initiation of TPN and 2) prior glycogen depletion does not augment the rate of hepatic adaptation.