Bond Jacob M, Dzubanova Martina, Addington Adele K, Najt Charles P, Gilbert Elizabeth R, Tencerova Michaela, Craige Siobhan M
Translational Biology, Medicine, and Health, Fralin Biomedical Research Institute, Virginia Tech, Roanoke, VA, USA.
Laboratory of Molecular Physiology of Bone, Institute of Physiology of the Czech Academy of Sciences, Prague 4, Czech Republic; Faculty of Sciences, Charles University, Prague, Czech Republic.
Redox Biol. 2025 Sep;85:103698. doi: 10.1016/j.redox.2025.103698. Epub 2025 Jun 6.
Reactive oxygen species (ROS) are critical mediators of cellular signaling that regulate metabolic homeostasis, including lipid uptake, synthesis, and storage. NADPH oxidase 4 (NOX4), a significant enzymatic source of ROS, has been identified as a redox-sensitive regulator of glucose and lipid metabolism. However, its contribution to sex-specific metabolic regulation remains poorly defined. This study compared how NOX4 knock-out (NOX4 KO) shifted systemic and tissue-specific metabolic phenotypes between male and female mice fed with a high-fat diet (HFD) for 20-weeks. We observed that male NOX4 mice on HFD exhibited reduced adiposity, diminished liver lipid accumulation, and improved glucose and insulin tolerance compared to male WT mice on HFD. In contrast, female NOX4 KO mice developed increased adiposity and lipid accumulation in peripheral adipose depots, accompanied by impaired glucose tolerance. Gene expression profiling in skeletal muscle and liver revealed distinct, sex-specific patterns of changes in genes related to lipid uptake, synthesis, and storage, possibly implicating differential activation of PPAR signaling pathways supportive of in vivo data. These findings identify NOX4 as a central regulator of sexually dimorphic lipid metabolism, acting through redox-sensitive transcriptional networks to shape divergent metabolic responses to HFD.
活性氧（ROS）是细胞信号传导的关键介质，可调节代谢稳态，包括脂质摄取、合成和储存。NADPH氧化酶4（NOX4）是ROS的重要酶源，已被确定为葡萄糖和脂质代谢的氧化还原敏感调节剂。然而，其对性别特异性代谢调节的贡献仍不清楚。本研究比较了20周高脂饮食（HFD）喂养的雄性和雌性小鼠中，NOX4基因敲除（NOX4 KO）如何改变全身和组织特异性代谢表型。我们观察到，与HFD喂养的雄性野生型（WT）小鼠相比，HFD喂养的雄性NOX4小鼠脂肪量减少，肝脏脂质积累减少，葡萄糖和胰岛素耐受性改善。相反，雌性NOX4 KO小鼠外周脂肪库中的脂肪量增加和脂质积累增加，同时伴有葡萄糖耐受性受损。骨骼肌和肝脏中的基因表达谱揭示了与脂质摄取、合成和储存相关的基因变化的独特性别特异性模式，这可能暗示了支持体内数据的PPAR信号通路的差异激活。这些发现确定NOX4是性别二态性脂质代谢的核心调节因子，通过氧化还原敏感的转录网络发挥作用，以塑造对HFD的不同代谢反应。
