Sleep Deprivation Exacerbates High‐Fat Diet‐Induced Obesity and MAFLD Through Melatonin Reduction Mediated NF‐κB Activation

The rising prevalence of unhealthy lifestyles characterized by chronic sleep deprivation (SD) combined with a high-fat diet (HFD), represents a significant health concern. However, the synergistic effects of these factors on metabolic disorders remain poorly understood. To address this, we developed a model of 'Unhealthy Lifestyles Zebrafish' (UHL) to investigate the interaction between chronic SD and HFD. We demonstrated that SD synergistically exacerbated HFD-induced obesity, lipid accumulation, and the progression of Metabolic Dysfunction-Associated Fatty Liver Disease (MAFLD). Compared to zebrafish exposed to HFD alone, the UHL zebrafish exhibited more severe metabolic dysregulation, including elevated cholesterol levels, metabolic inflammation, and bile acid imbalance. Mechanistically, this synergy was driven by melatonin deficiency resulting from SD, which triggered NF-κB activation. This activation led to the upregulation of pro-inflammatory cytokines (TNF-α, IL-6, IL-1β). Crucially, exogenous melatonin supplementation reversed these detrimental effects by inhibiting NF-κB activation and restoring metabolic homeostasis. Conversely, pharmacological activation of NF-κB antagonized melatonin's protective effects. This study confirms the critical role of the melatonin/NF-κB axis in mediating the synergistic impact of sleep deprivation and a high-fat diet on obesity and MAFLD. These findings advocate for integrated lifestyle interventions targeting both sleep quality and dietary habits in metabolic health management.