We have recently reported that inhibition of TGF- in the brain reduced fat-related energy substrates concentrations in response to exercise. We investigated the relevance between the mobilization of fat-related energy substrates (non-esterified fatty acid, NEFA and ketone bodies) during exercise and the effects of TGF- in the brain. Low-intensity exercise was simulated by contraction of the hindlimbs, induced by electric stimulation at 2 Hz in anesthetized rats (Sim-Ex). As with actual exercise, it was confirmed that mobilization of carbohydrate-related energy substrates (glucose and lactic acid) occurred immediately after the onset of Sim-Ex and mobilization of fat-related energy substrates followed thereafter. The timing of mobilization of fat-related substrates corresponded to that of the increase in TGF- in CSF in Sim-Ex. The level of TGF- in CSF significantly increased after 10 min of Sim-Ex and remained elevated until 30 min of Sim-Ex. Intracisternal administration of TGF- caused rapid mobilization of fat-related energy substrates. Meanwhile, there were no effects on the changes in carbohydrate-related substrates. The levels of catecholamines were slightly elevated after TGF- administration, and although not significantly in statistical terms, we consider that at least a part of TGF- signal was transducted via sympathetic nervous system because of these increase. These data indicate that TGF- in the brain is closely related to the mobilization of fat-related energy substrates during low-intensity exercise. We hypothesized that central nervous system plays a role in the regulation of energy metabolism during low-intensity exercise and this may be mediated by TGF-.