High-fat diet (HFD)-induced obesity (DIO) is preceded by disruptions in endogenous circadian rhythmicity, including lengthening of its period (tau). We previously demonstrated that housing mice under a light-dark cycle (T-cycle) oscillating at their endogenous tau of 23.7 h prevents the DIO found under the 24-h T-cycle, suggesting that DIO is also secondary to disruptions caused by entrainment to non-tau-matching T-cycles. Here, we aimed to test this hypothesis by comparing energy homeostasis of low-fat diet (LFD) and HFD-fed female mice housed under four regimes: constant darkness (DD), a T-cycle oscillating at the tau of age-matched LFD-fed mice, a non-tau-matching 24-h T-cycle, or a T-cycle shorter than tau by the age-appropriate tau-24-h deviation (∆tau). In LFD-fed mice, energy homeostasis was unaffected by photic regime. In contrast, while HFD induced DIO across all regimes, onset occurred at similar times under DD and the 24-h T-cycle but was similarly delayed by 8 weeks under both the tau-like and ∆tau T-cycles. Notably, DIO onset under DD was preceded by the prevention of tau shortening, a characteristic of LFD-fed mice. Delayed DIO was not explained by reduced energy intake; instead, it was associated with a preserved locomotor activity level, suggesting higher energy expenditure, and was followed by a stronger (compared to 24-h T-cycle) tau-shortening aftereffect. In conclusion, these findings identify HFD-induced tau lengthening as a mechanism promoting early DIO under the conventional 24-h T-cycle. Importantly, they suggest that tau-shortening pharmacological or nutritional interventions may postpone DIO in susceptible individuals and settings, even during ad-libitum HFD feeding.
