Chronic nutrient excess leads to metabolic disorders and insulin resistance. Activation of stress-responsive pathways via Nrf2 activation contributes to energy metabolism regulation. Here, inducible activation of Nrf2 in mice and transgenesis of the Nrf2 target, NQO1, conferred protection from diet-induced metabolic defects through preservation of glucose homeostasis, insulin sensitivity, and lipid handling with improved physiological outcomes. NQO1-RNA interaction mediated the association with and inhibition of the translational machinery in skeletal muscle of NQO1 transgenic mice. NQO1-Tg mice on high-fat diet had lower adipose tissue macrophages and enhanced expression of lipogenic enzymes coincident with reduction in circulating and hepatic lipids. Metabolomics data revealed a systemic metabolic signature of improved glucose handling, cellular redox, and NAD⁺ metabolism while label-free quantitative mass spectrometry in skeletal muscle uncovered a distinct diet- and genotype-dependent acetylation pattern of SIRT3 targets across the core of intermediary metabolism. Thus, under nutritional excess, NQO1 transgenesis preserves healthful benefits.

慢性营养过剩会导致代谢紊乱和胰岛素抵抗。通过 Nrf2 激活应激反应通​​路有助于能量代谢调节。在此，小鼠中 Nrf2 的诱导激活和 Nrf2 靶标 NQO1 的转基因通过维持葡萄糖稳态、胰岛素敏感性和脂质处理来保护免受饮食诱导的代谢缺陷，并改善生理结果。 NQO1-RNA 相互作用介导 NQO1 转基因小鼠骨骼肌翻译机制的关联和抑制。高脂肪饮食的 NQO1-Tg 小鼠脂肪组织巨噬细胞减少，脂肪生成酶表达增强，同时循环脂质和肝脏脂质减少。代谢组学数据揭示了改善葡萄糖处理、细胞氧化还原和 NAD ⁺代谢的系统代谢特征，而骨骼肌中的无标记定量质谱分析则揭示了跨中间代谢核心的 SIRT3 靶标的独特的饮食和基因型依赖性乙酰化模式。因此，在营养过剩的情况下，NQO1 转基因保留了健康益处。