Supplementary data from: Systems genomics reveals age- and sex-dependent metabolic dysregulation from Glo1 reduction in mice

Objectives: Glyoxalase 1 (Glo1) detoxifies reactive dicarbonyl compounds
such as methylglyoxal, a precursor of advanced glycation end products
(AGEs), which contribute to metabolic disorders. However, the contribution
of AGE-independent mechanisms to Glo1-related metabolic dysfunction
remains unclear. Methods: We conducted a longitudinal study in male and
female Glo1 heterozygous knockdown (Glo1⁺/⁻) mice (~50% Glo1 expression).
Metabolic phenotypes, including body weight, adiposity, glycemic control,
and plasma lipid levels, were assessed over time. Atherosclerotic burden,
AGE levels, and gene expression profiles in liver, adipose, muscle,
kidney, and aorta were examined to identify pathway alterations and
regulatory genes affected by Glo1 reduction. Results: Partial Glo1 loss
resulted in obesity, hyperglycemia, dyslipidemia, and altered lipid
metabolism in an age- and sex-dependent manner, with most phenotypes
emerging after ~14 weeks. Glo1⁺/⁻ females exhibited impaired glycemic
control and elevated triglycerides, along with perturbations in
adipogenesis, PPARγ signaling, insulin signaling, and fatty acid
metabolism in liver and adipose tissue. Glo1⁺/⁻ males displayed increased
skeletal muscle mass and visceral adiposity with changes in lipid
metabolic pathways. Methylglyoxal-derived AGE accumulation was altered
only in male skeletal muscle and did not explain broader phenotypes.
Transcriptomic analyses suggest altered glucose and lipid metabolism may
be partially driven by alternative detoxification of methylglyoxal to
metabolites such as pyruvate. Transcription factor analysis identified
Hnf4a (across tissues) and Arntl (in aorta, liver, and kidney) as
female-biased regulators altered by Glo1 deficiency. Conclusions: Glo1
reduction disrupts metabolic health through sex- and age-dependent
pathways largely independent of AGE accumulation, involving
tissue-specific metabolic reprogramming and transcriptional regulation.

研究目的：乙二醛酶1（Glyoxalase 1, Glo1）可降解活性二羰基化合物，例如甲基乙二醛——晚期糖基化终末产物（advanced glycation end products, AGEs）的前体物质，而AGEs可诱发代谢紊乱。然而，不依赖AGEs的机制在Glo1相关代谢功能异常中的作用仍不明确。

研究方法：本研究针对雄性与雌性Glo1杂合敲低（Glo1 heterozygous knockdown, Glo1⁺/⁻）小鼠（Glo1表达量约为正常水平的50%）开展了一项纵向研究。研究人员定期评估小鼠的代谢表型，包括体重、体脂、血糖控制情况及血浆脂质水平。同时检测肝脏、脂肪组织、肌肉、肾脏及主动脉的动脉粥样硬化负荷、AGEs水平与基因表达谱，以明确Glo1表达降低所影响的信号通路与调控基因。

研究结果：部分Glo1缺失会以年龄与性别依赖的方式引发肥胖、高血糖、血脂异常及脂质代谢紊乱，多数表型在小鼠约14周龄后显现。Glo1⁺/⁻雌性小鼠出现血糖控制受损与甘油三酯水平升高，同时肝脏与脂肪组织内的脂肪生成、过氧化物酶体增殖物激活受体γ（PPARγ）信号通路、胰岛素信号通路及脂肪酸代谢均发生紊乱。Glo1⁺/⁻雄性小鼠则表现为骨骼肌质量增加与内脏体脂升高，且脂质代谢通路发生改变。仅在雄性小鼠的骨骼肌中，甲基乙二醛衍生的AGEs积累水平发生改变，但这无法解释整体的代谢表型变化。转录组学分析显示，葡萄糖与脂质代谢的改变可能部分通过甲基乙二醛的替代解毒途径实现，即其被代谢为丙酮酸等物质。转录因子分析显示，肝细胞核因子4α（Hnf4a）（在各组织中）与芳香烃受体核转位蛋白样（Arntl）（存在于主动脉、肝脏及肾脏中）是受Glo1缺失影响的雌性偏向性调控因子。

研究结论：Glo1表达降低通过性别与年龄依赖的通路破坏代谢健康，该过程在很大程度上不依赖AGEs积累，涉及组织特异性代谢重编程与转录调控。