Mice held at an environmental photic cycle oscillating at their -like period length do not show the high-fat diet-induced obesity that develops under the 24-hour photic cycle.

Circadian disruptions precede high-fat diet (HFD)-induced obesity (DIO). Deviation of the endogenous circadian rhythm period length () from 24 hours correlates with mice inter-strain DIO under the 24-hour light-dark cycle (T-cycle). Additionally, entrainment to a -resembling T-cycle attenuates DIO, to some extent, in muted mice. These phenomena suggest that entrainment to a 24-hour T-cycle promotes DIO beyond that expected from the HFD-induced metabolic disruptions. However, the hypothesis that entrainment to a -resembling T-cycle attenuates DIO has not been tested in wild-type mice. Therefore, we examined, in newborn female FVB/N mice, whether DIO found under their 'regular' 24-hour T-cycle is attenuated under a T-cycle oscillating at their -resembling period of 23.7 h, which is diverted from 24 hours by only 0.3 h. Compared to mice fed a low-fat diet, those fed an HFD under the 24-hour T-cycle showed a disrupted pattern of circadian locomotor activity prior to DIO onset. Both these phenomena were absent under the -like T-cycle. DIO developed under the 24-hour T-cycle despite similar caloric intake, and was associated with the lower locomotor activity of HFD-fed mice compared to the other mouse groups. These results demonstrated that DIO is secondary to HFD-induced circadian disruptions that are not harmonized by the strongest Zeitgeber (light-dark cycle) when oscillating at a period that diverts by as little as ca. 0.3-h from . More importantly, imposing a light-dark cycle oscillating at a -like period length, which enhances entrainment and presumably reinforces endogenous circadian rhythms, prevented HFD-induced circadian disruptions and enabled tighter control of energy homeostasis, as manifested by the absence of DIO, even under HFD feeding. These results support the identification of related biomarkers, which may be considered as risk-factors for DIO. Moreover, these findings may promote the development of clock-related pharmaceutical interventions that will reduce the gap between and 24 hours, and increase the robustness of the endogenous and entrained circadian rhythms. This will enable reducing DIO, even without caloric restriction or time-restricted feeding.