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

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. 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. 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 wk. Glo1^+/- females exhibited impaired glycemic control and elevated triglycerides, along with perturbations in adipogenesis, peroxisome proliferator-activated receptor-γ (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 that altered glucose and lipid metabolism may be partially driven by the 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. Glo1 reduction disrupts metabolic health through sex- and age-dependent pathways largely independent of AGE accumulation, involving tissue-specific metabolic reprogramming and transcriptional regulation.NEW & NOTEWORTHY This study reveals that partial deficiency of glyoxalase 1 (Glo1) leads to age- and sex-specific metabolic dysfunction in mice through transcriptional and regulatory changes independent of advanced glycation end products (AGEs). Transcriptomic profiling and integrative genomics identified female-biased transcription factors and genome-wide association study (GWAS)-linked metabolic genes as key mediators. These findings uncover novel, AGE-independent regulatory pathways linking Glo1 to metabolic disease risk and emphasize the importance of sex-specific analysis in metabolic genomics research.