The dose dependence of plasma nonesterified fatty acids (NEFA) and glycerol responses to epinephrine was determined in lactating cows treated with bovine somatotropin (bST). Also, the effects of insulin on lipolysis and glucose clearance were examined. Lactating cows (190 +/- 24 days postpartum) received daily subcutaneous injections of methionyl bST (40 mg) or excipient during two 12-day treatment periods. Epinephrine challenges (0.1, 0.2, 0.4, 0.8, 1.2, and 1.6 micrograms/kg body wt) were administered intravenously on days 6-11 and an insulin challenge (1 microgram/kg) on day 12. Milk energy secretion increased 55% without any change in voluntary feed intake during bST treatment. Circulating concentrations of NEFA were chronically elevated and reciprocally paralleled changes in net energy balance. Maximal response of plasma NEFA and glycerol to epinephrine was markedly increased during bST treatment, whereas the dose of signal-producing half-maximal response (ED50) was unchanged. Antilipolytic effects of insulin were also enhanced, whereas the effect of insulin on the fractional rate of glucose change was reduced. Thus bST alters tissue response to homeostatic signals to allow more nutrients to be partitioned for milk synthesis. Furthermore, the alterations in response to epinephrine and insulin appear to predominantly occur at a postreceptor level.