Central administration of REV-ERB agonist promotes opposite responses on energy balance in fasted and fed states

The REV-ERB alpha receptor has a recognised role in the regulation of the circadian rhythm system. However, recent evidence suggests that it also contributes to energy balance regulation. Both expression and function of REV-ERB alpha can be influenced by the energy status of the body. Considering the possibility of the involvement of REV-ERB alpha in the regulation of energy balance, which is critically regulated by the hypothalamus, and based on the impact of intermittent fasting, the present study evaluated the effects of central administration of REV-ERB alpha agonist on energy balance in rats exposed to 24 hours of fasting or ad lib. feeding conditions. Initially, 24-hour fasted rats received an acute i.c.v. administration of agonist at doses of 1, 5, 10 or 15 mu g per rat and feed efficiency was evaluated. Because 10 mu g was a sufficient dose to affect feed efficiency, subsequent experiments used this dose to assess effects of agonist on the following parameters: energy expenditure induced by physical activity and locomotor activity, time spent in physical activity over 24 hours, and glucose and insulin tolerance. In fasted rats, the agonist promoted increased food intake and feed efficiency, with a greater body weight gain associated with less time spent in locomotor activity, suggesting a reduction in energy expenditure induced by physical activity. Furthermore, a reduction in glucose tolerance was noted. By contrast, free-fed rats exhibited reduced food intake and feed efficiency with decreased body weight gain along with an increase in locomotor activity and physical activity-dependent energy expenditure. Thus, i.c.v. administration of REV-ERB alpha agonist regulates energy balance depending on the energy status of the organism; that is, it promotes a positive energy balance in the fasted state and a negative energy balance in the fed state. These results may be useful in understanding the underlying mechanisms of energy balance disorders and intermittent fasting for body weight control.