Misalignment of feeding rhythms with the light-dark cycle leads to disrupted peripheral circadian clocks and obesity. Conversely, restricting feeding to the active period mitigates metabolic syndrome through mechanisms that remain unknown. We found that genetic enhancement of adipocyte thermogenesis through ablation of the zinc finger protein 423 (ZFP423) attenuated obesity caused by consumption of a high-fat diet during the inactive (light) period by increasing futile creatine cycling in mice. Circadian control of adipocyte creatine metabolism underlies the timing of diet-induced thermogenesis, and enhancement of adipocyte circadian rhythms through overexpression of the clock activator brain and muscle Arnt-like protein-1 (BMAL1) ameliorated metabolic complications during diet-induced obesity. These findings uncover rhythmic creatine-mediated thermogenesis as an essential mechanism that drives metabolic benefits during time-restricted feeding.
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