Circadian Rhythms Group, Max Planck Institute for Biophysical Chemistry, Göttingen, Germany.
Chronophysiology Group, Medical Department 1, University of Lübeck, Lübeck, Germany.
Mol Metab. 2017 Mar 29;6(6):512-523. doi: 10.1016/j.molmet.2017.03.008. eCollection 2017 Jun.
Circadian gene mutant mice show dampened 24-h feeding rhythms and an increased sensitivity to high-fat diet (HFD) feeding. Restricting HFD access to the dark phase counteracts its obesogenic effect in wild-type mice. The extent to which altered feeding rhythms are causative for the obesogenic phenotype of mutant mice, however, remains unknown.
Metabolic parameters of wild-type (WT) and mutant mice (MT) were investigated under and nighttime restricted HFD feeding. Liver circadian clock function was partially rescued by hydrodynamic tail vein delivery of WT- DNA vectors in mutant mice and transcriptional, metabolic, endocrine and behavioral rhythms studied.
Nighttime-restricted feeding restored food intake, but not body weight regulation in MT mice under HFD, suggesting -dependent metabolic dysregulation downstream of circadian appetite control. Liver-directed gene therapy partially restored liver circadian oscillator function and transcriptome regulation without affecting centrally controlled circadian behaviors. Under HFD, MT mice with partially restored liver clock function (MT-LR) showed normalized body weight gain, rescued 24-h food intake rhythms, and WT-like energy expenditure. This was associated with decreased nighttime leptin and daytime ghrelin levels, reduced hepatic lipid accumulation, and improved glucose tolerance. Transcriptome analysis revealed that hepatic rescue in MT mice affected a range of metabolic pathways.
Liver gene therapy improves resistance against HFD-induced metabolic impairments in mice with circadian clock disruption. Restoring or stabilizing liver clock function might be a promising target for therapeutic interventions in obesity and metabolic disorders.
昼夜节律基因突变小鼠表现出 24 小时摄食节律减弱和对高脂肪饮食（HFD）喂养的敏感性增加。限制 HFD 在暗期的摄入可抵消其在野生型小鼠中的致肥胖作用。然而，改变的摄食节律在多大程度上导致突变小鼠的肥胖表型仍然未知。
在 和夜间限制 HFD 喂养下，研究了野生型（WT）和 突变型（MT）小鼠的代谢参数。通过在突变小鼠的尾静脉进行 WT-DNA 载体的水力传递，部分挽救了肝脏昼夜节律钟功能，并研究了转录、代谢、内分泌和行为节律。
夜间限制喂养恢复了 MT 小鼠在 HFD 下的食物摄入量，但不能调节体重，表明昼夜节律食欲控制的下游存在依赖的代谢失调。肝定向 基因治疗部分恢复了肝脏昼夜节律振荡器功能和转录组调节，而不影响中枢控制的昼夜节律行为。在 HFD 下，部分恢复肝脏时钟功能的 MT 小鼠（MT-LR）表现出正常的体重增加、恢复的 24 小时摄食节律和 WT 样的能量消耗。这与夜间瘦素和日间胃饥饿素水平降低、肝脂质积累减少以及葡萄糖耐量改善有关。转录组分析显示，MT 小鼠中肝脏的 挽救影响了一系列代谢途径。
肝脏 基因治疗可改善昼夜节律钟中断的小鼠对 HFD 诱导的代谢损伤的抵抗力。恢复或稳定肝脏时钟功能可能是肥胖和代谢紊乱治疗干预的一个有前途的靶点。
