Time-restricted feeding corrects aggravation of glucose intolerance and circadian disruption induced by weight cycling in obese young mice

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Abstract Weight cycling (WC), defined as weight gain, loss, and regain, is common in obesity, but its metabolic consequences remain unclear. We tested whether WC-aggravated glucose intolerance in obesity is age-dependent and linked to circadian disruption. Young (7w) and mid-aged (12m) mice underwent a 15-week dietary intervention: Lean and Obese mice fed normal chow (NC) and high-fat diet (HFD) throughout, respectively. WC mice undergone HFD-induced weight gain, NC-induced weight loss, and a second HFD-induced weight regain. Late-onset obese (LO) mice ate HFD only paralleling weight regain of WC. In young, but not mid-aged mice, prior obesity accelerated weight regain upon HFD re-exposure, and aggravated glucose intolerance beyond that observed in Obese mice. This occurred without a worse adipose inflammatory profile. Rather, WC young mice exhibited blunting of light/dark-phase oscillation of feeding and energy metabolism, adipose and hepatic core clock gene oscillation, and increased hepatic expression of clock and gluconeogenic genes during the inactive phase. Restricting food availability to the active phase did not alter final weight regain, but improved glucose tolerance selectively in WC mice, normalized hepatic gluconeogenic and clock-genes’ expression in both liver and adipose tissue. These findings identify circadian disruption as a modifiable mediator of the adverse metabolic impact of WC in young-adulthood obesity. Highlights Weight cycling is common in obesity, but whether it worsens metabolic dysfunction beyond persistent obesity remains unclear. We asked whether weight cycling aggravates glucose intolerance in an age-dependent manner and whether circadian disruption contributes to this effect. In young, but not mid-aged mice, weight cycling accelerated weight regain and worsened glucose intolerance, accompanied by blunted diurnal oscillation of behavioral parameters and core clock gene expression, without exaggerated adipose inflammation. Active-phase time-restricted feeding improved WC-induced aggravated glucose tolerance and circadian oscillation, identifying circadian disruption as a modifiable mechanism linking weight cycling adverse metabolic outcomes in young-adulthood obesity.

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