Akhtar Farheen, Malik Dania, Sengupta Arjun, Haynes Paula, Klok Jaco, Sehgal Amita, Weljie Aalim M
Department of Systems Pharmacology and Translational Therapeutics.
Circadian and Sleep Institute.
bioRxiv. 2025 Jul 25:2025.07.22.665580. doi: 10.1101/2025.07.22.665580.
Precise temporal regulation of metabolism by sleep and circadian rhythms is essential for dynamic energy homeostasis, yet the link between systemic metabolism and respiratory demands remains poorly defined. We combined high-resolution respirometry with LC-MS-based metabolomics to characterize respiratory dynamics and metabolic states in to uncover genotype-specific impacts of sleep and circadian disruption. Wild-type flies under light-dark cycles (WT-LD) showed rhythmic respiratory patterns reflective of anticipatory coordination of mitochondrial energy metabolism, amino acid turnover, and redox cycling. In contrast, short-sleep mutants (, ) exhibited elevated metabolic rates and reactive shifts of fuel preferences toward lipid and amino acid catabolism and displayed signs of mitochondrial stress. Circadian-clock disrupted flies ( , WT-DD) showed reactive and widespread metabolic dysregulation and impaired redox homeostasis. These findings demonstrate that both sleep and circadian systems are essential for aligning metabolic substrate selection with energy demands, offering mechanistic insights into how disruptions in behavioral states compromise metabolic health.
通过睡眠和昼夜节律对新陈代谢进行精确的时间调节对于动态能量平衡至关重要，然而全身代谢与呼吸需求之间的联系仍不清楚。我们将高分辨率呼吸测定法与基于液相色谱-质谱联用的代谢组学相结合，以表征呼吸动力学和代谢状态，从而揭示睡眠和昼夜节律紊乱对特定基因型的影响。在明暗循环条件下的野生型果蝇（WT-LD）表现出有节律的呼吸模式，反映了线粒体能量代谢、氨基酸周转和氧化还原循环的预期协调。相比之下，短睡眠突变体（，）表现出代谢率升高，燃料偏好向脂质和氨基酸分解代谢的反应性转变，并显示出线粒体应激的迹象。昼夜节律紊乱的果蝇（，WT-DD）表现出反应性和广泛的代谢失调以及氧化还原稳态受损。这些发现表明，睡眠和昼夜节律系统对于使代谢底物选择与能量需求相匹配都是必不可少的，为行为状态的破坏如何损害代谢健康提供了机制性见解。
