Mistimed eating disrupts the circadian rhythm of hepatic metabolism, thereby increasing the risk of fatty liver disease. Responding to nutrient status and light cues respectively, insulin and melatonin coordinately regulate hepatic lipid homeostasis and circadian clock oscillation. However, whether non-active phase eating-induced hepatic lipid accumulation involves altered rhythmic interactions between insulin and melatonin remains unclear. This study employed a porcine model to investigate the effects of eating time on hepatic lipid metabolism through a 3-month comparative trial of daytime-restricted feeding (DRF) versus nighttime-restricted feeding (NRF). Compared to DRF, NRF promoted hepatic lipogenesis and reversed the circadian rhythm of circulating insulin, synchronizing it with melatonin. To determine whether the temporal coordination of insulin and melatonin regulates hepatic lipid metabolism, we administered these hormones to immortalized porcine hepatocytes either synchronously (SYN) or alternately (ALT) at 12-h intervals for 72 h. The results showed that SYN increased intracellular triglyceride (TG) accumulation in hepatocytes, enhanced mitochondrial fission, reduced mitochondrial membrane potential and ATP production during circadian time 0-12 phase, while upregulating the core clock gene BMAL1 levels in this stage. Overall, this study demonstrated that nighttime eating in diurnal animals induces an imbalance in BMAL1-mediated hepatic mitochondrial fission and fusion by synchronizing the circadian rhythms of insulin and melatonin, promoting triglyceride accumulation through impaired metabolic efficiency. Our findings establish a mechanistic link between mistimed eating and hepatic steatosis from the perspective of hormone rhythms regulated by food and light, offering new insights for chrononutrition-based interventions in metabolic diseases.
Circadian Biology