What question did this study set out to answer?

This study aims to determine the impact of circadian misalignment on adipose tissue redox balance and metabolic dysfunction.

June 7, 2026

2513-P: Circadian Misalignment Disrupts Adipose Redox Homeostasis and Metabolism

Key Points

This study aims to determine the impact of circadian misalignment on adipose tissue redox balance and metabolic dysfunction.
Mice were exposed to optimal or mistimed eating schedules.
Redox dynamics profiling and isotope tracing were utilized to assess metabolism changes.
Group differences were analyzed using two-way ANOVA with post hoc multiple-comparison testing.
Mistimed eating impaired glucose homeostasis and decreased NAD+/NADH ratio in adipose tissue (p<0.01).
Restoring the NAD+/NADH ratio with LbNOX improved metabolic outcomes during high-fat diet feeding (p<0.05).
Metabolomic analyses revealed altered glucose oxidation and TCA cycle activity due to circadian misalignment.

Abstract

Introduction and Objective: Circadian misalignment from late-night eating or shift work is linked to obesity and type 2 diabetes, but the metabolic mechanisms are not well defined. Time-restricted eating improves metabolic health without reducing caloric intake, suggesting a role for temporal regulation of metabolism. The objective of this study was to determine whether disruption of adipose tissue redox balance contributes to metabolic dysfunction caused by circadian misalignment and whether restoring the NAD+/NADH ratio improves metabolic outcomes during diet-induced obesity. Methods: Mice were subjected to dark-restricted (optimal) or light-restricted (mistimed) eating schedules, with redox dynamics profiling and isotope tracing used to characterize metabolism changes. Adipose-specific redox state was manipulated by expressing LbNOX, a bacterial water-forming NADH oxidase, using Adiponectin-Cre (Adiponectin-Cre; LbNOXLSL ) to increase the NAH+/NADH ratio. Primary outcomes included glucose homeostasis and systemic metabolic parameters. Secondary outcomes included tissue-specific metabolic fluxes assessed by metabolomics and isotope tracing. Group differences were analyzed using two-way ANOVA with post hoc multiple-comparison testing. Results: Mistimed eating impaired glucose homeostasis and worsened metabolic outcomes compared with optimal eating, accompanied by a reduced NAD+/NADH ratio in adipose tissue. Metabolomic analyses showed altered nutrient flux, with prominent changes in glucose oxidation, TCA cycle activity, and pentose phosphate pathway flux. Restoring the adipose NAD+/NADH ratio with LbNOX improved metabolic measures during high-fat diet feeding and mitigated defects associated with circadian misalignment. Conclusion: Circadian misalignment induces adipose tissue redox imbalance that contributes to metabolic dysfunction in obesity. Correcting the NAD+/NADH ratio improves metabolic health in this setting, supporting a role for adipose redox homeostasis in mediating the metabolic effects of circadian rhythms. Disclosure Z. Zhu: None. C. Hepler: None. Funding American Diabetes Association (1-24-INI-01)

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