To acquire smooth performance in endurance exercise, the function of whole body organs, such as skeletal muscle, liver, adipose tissue, etc. should be fully coordinated. These integrated coordination seem to be achieved by the function of central nervous system. The hypothalamus is known to play an important role in whole body energy metabolism, however, its involvement to physical exercise was not fully understood. In this study, its contribution to fat metabolism during endurance exercise was investigated. Experiments Under the isoflurane anesthesia, cannulae for microinjection or a guide cannula for microdialysis was implanted into the ventromedial hypothalamus (VMH) of a rat. After at least 7 days of recovery period, rats were subjected to treadmill running at exercise intensity corresponding to 55% of maximum oxygen consumption (15 m/min, 10° incline). During treadmill running, the changes in respiratory exchange ratio (RER) and oxygen consumption (respiratory gas analysis) and the extracellular concentration of noradrenaline in VMH (microdialysis analysis) was determined. 10 ~ 15 min before onset of running, lidocaine (10 μg in 0.5 μl), phentolamine (4.2 μg in 1.0 μl), timolol (4.2 μg in 1.0 μl) and propranolol (8.0 μg in 1.0 μl) was injected bilaterally into VMH. 6-hydroxydopamine treatment and microdialysis analysis were done according to Fujikawa et al (2007). Respiratory gas analysis was executed according to Ishikawa et al. (2006). Results and discussion Bilateral microinjection of lidocaine into VMH caused suppression of the decrease in the RER during treadmill running when compared to those administered artificial cerebrospinal fluid (aCSF). This means that the attenuation of VMH function inhibits enhancement of fatty acid oxidation during exercise. The increase in the extracellular concentration of noradrenaline in VMH was observed during running by microdialysis analysis. This demonstrates the activation of noradrenergic neurons projecting to VMH during exercise. The destruction of noradrenergic neurons in VMH by prior administration of 6-OHDA showed similar suppression of fatty acid oxidation as the lidocaine treatment during running. This suggests the involvement of noradrenergic neurons which are projecting to VMH and activated during running play an important role in enhancement of fatty acid oxidation during exercise. Furthermore, among microinjection of adrenoceptor antagonists into VMH, only beta-blockers (timolol and propranolol) caused suppression of fatty acid oxidation during running. These treatments had no effect on RER and oxygen consumption in sedentary state. These results indicate the importance of noradrenergic neurons projecting to and the pivotal role of beta-adrenoceptor in VMH on the regulation of energy metabolism during endurance exercise.