To examine the effect of different hepatic portal glucose concentrations on food intake and metabolism, rats were given hepatic portal or jugular infusions (83 microliters/min for 2 h) of 0.3, 0.6, and 1.2 M glucose, equiosmotic NaCl, or a mock control infusion. Food intake was decreased to the same extent by the three concentrations of glucose infused into the hepatic portal vein and unaffected by any concentration of glucose infused into the jugular vein. Parallel to the changes in food intake, hepatic glycogen content was increased by glucose infused into the hepatic portal vein but not jugular vein. Conversely, systemic plasma glucose levels were increased by glucose infused into the jugular vein but not hepatic portal vein. Plasma insulin levels increased to the same extent irrespective of the route of infusion. Food intake was unaffected by the osmolarity of glucose infused into the hepatic portal vein, but was decreased by hyperosmotic NaCl control infusions. Hyperosmotic NaCl infusions also elevated levels of circulating fat fuels, indicating a stress response. The results show that the critical metabolic event in the liver that influences food intake is only indirectly coupled to the concentration of glucose in the hepatic portal vein.