Metabolic effects of a selective hepatic vagotomy (HV) were investigated in nonfasted (N) and 24-h fasted (F) rats, at rest and immediately after a 50-min exercise period (26 m/min, 0% grade). In nonfasted rats, no significant differences between HV and sham-operated (SHM) groups were found in blood substrates [free fatty acids (FFA) or glucose], insulin, and muscle glycogen levels, either at rest or after exercise. In F rats, liver glycogen was almost completely depleted at rest. This depletion was associated with a significantly (P less than 0.05) lower plasma FFA concentration at rest in HV compared with SHM rats (mean +/- SE, 0.57 +/- 0.04 vs. 0.83 +/- 0.1 mmol/l). No differences in FFA levels were observed between the same two groups after the exercise period. Exercise, however, resulted in a 2.5 times greater glycogen breakdown in the soleus muscle of HV compared with SHM rats. Hepatic vagotomy in the F condition was also associated with lower resting and exercising insulin concentrations. It is concluded that HV, when followed by a 24-h fast, may influence metabolic substrate regulation at rest and to a certain extent during exercise. These data support the concept of the existence of hepatic glucoreceptors responsive to a decrease in liver glycogen content.