Sex and photoperiod shape hepatic redox homeostasis in diet-induced obesity in association with a melatonin-NRF2-circadian regulatory axis

Feb 28, 2026Free radical biology & medicine

Sex and day length influence liver balance of oxidation in diet-induced obesity linked to melatonin, antioxidant response, and body clock regulation

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Abstract

Obesity is associated with sex- and photoperiod-dependent differences in hepatic oxidative status and metabolism.

Males on a long photoperiod (18 hours of light) showed increased liver fat accumulation compared to females.
Females exhibited more oxidative damage in the liver despite having lower levels of fat.
Activation of the NRF2/HO-1 antioxidant pathway was greater in females, along with higher levels of circulating melatonin.
Males demonstrated a higher total antioxidant capacity, indicating different strategies for managing oxidative stress.
Changes in clock gene expression and BMAL1 protein levels suggest a link between circadian regulation and antioxidant responses.
These findings highlight a melatonin-NRF2-circadian regulatory axis that influences redox balance in obesity.

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Obesity is associated with hepatic oxidative stress, metabolic dysregulation, and altered circadian regulation. Although both sex and photoperiod influence redox homeostasis, their combined impact in obesity remains insufficiently understood. Here, we examined the effects of sex and day length on hepatic oxidative status, antioxidant responses and circadian regulation in cafeteria diet-induced obese rats exposed for eight weeks to either a short (6-h light; L6) or long (18-h light; L18) photoperiod. Sex- and photoperiod-dependent differences were observed in systemic metabolism and hepatic lipid accumulation, with males showing enhanced steatosis under L18, whereas females exhibited greater oxidative damage despite lower hepatic lipid content. Females displayed increased activation of the NRF2/HO-1 antioxidant pathway and higher circulating melatonin concentrations, whereas males relied on greater inducible total antioxidant capacity (ORAC). These redox signatures were accompanied by coordinated changes in clock gene expression and BMAL1 protein abundance, indicating that hepatic clock components are linked to differential antioxidant adaptation. Together, these findings demonstrate that sex and photoperiod shape hepatic redox homeostasis in obesity, supporting a melatonin-NRF2-circadian regulatory axis that connects environmental timing cues with sexually dimorphic redox responses.

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Sex and photoperiod shape hepatic redox homeostasis in diet-induced obesity in association with a melatonin-NRF2-circadian regulatory axis

Abstract

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