In order to determine whether insulin receptors in the brain or in the periphery are more important for the control of food intake, four doses of insulin (0.1, 0.5, 1.0 and 2.0 U/day) were each infused continuously over 24 h into rats with chronic catheters in the common carotid artery (C) or the superior vena cava (VC). Daily food intake was unchanged from baseline levels by insulin doses of 0.1 to 1.0U. However, intake increased by 8.1 +/- 1.3 kcal for the C rats and by 10.2 +/- 1.8 kcal for the VC rats during the 2.0U infusion and was also increased on the subsequent day, by 10.9 +/- 1.9 kcal and 15.4 +/- 3.0 kcal for C and VC groups respectively. Rats were fed half an hour after insulin infusions began and measures of short-term intake made over the next 30 min were unaffected by any of the insulin doses. When injected into C catheters prior to sacrifice greater than 90% of 57Co labelled microspheres were recovered in arterioles of the brain, skull and facial regions. As brain blood flow is 1.8% of cardiac output, insulin levels in the brain blood supply would have been substantially greater for C rats. The similar increases in food intake for C and VC rats clearly show that insulin fails to produce greater effects when infused directly into the brain. Instead, these findings suggest that the effect of insulin on daily food intake is predominantly a function of insulin receptor activation in the periphery.