UCLA

Glyoxalase 1 (Glo1) is a critical enzyme responsible for the clearance of toxic dicarbonyls, which are precursors for advanced glycation end products (AGEs). Glo1 has been implicated in the progression of cardiometabolic disorders such as obesity, insulin resistance, and coronary artery disease; however, the underlying mechanisms have yet to be elucidated. We characterized female and male Glo1 heterozygous knockdown (Glo1+/-) mice by evaluating metabolic phenotypes such as body weight, adiposity, glycemic control and plasma lipid profiles. We also evaluated atherosclerotic burden, levels of AGEs, and gene expression profiles across cardiometabolic tissues (liver, adipose, muscle and aorta) to identify pathway perturbations and potential regulatory genes. Partial loss of Glo1 resulted in obesity, hyperglycemia, dyslipidemia and reorganization of lipid metabolism in metabolic tissues in an age and sex-dependent manner. Glo1+/- females displayed altered glycemic control and increased plasma triglycerides, which aligned with significant perturbations in genes involved in adipogenesis, PPARg and insulin signaling, and fatty acid metabolism pathways in liver and adipose tissues. Conversely, Glo1+/- males developed increased skeletal muscle mass and visceral adipose depots along with changes in lipid metabolism pathways. For both cohorts, most phenotypes were manifested after 14 weeks of age indicating an age-dependent effect. Evaluation of methylglyoxal-derived AGEs demonstrated changes in only male skeletal muscle but not in female tissues, thus unlikely explaining the broad phenotypic and multitissue gene expression alterations in both sexes. Network analysis of the tissue-specific gene expression data identified transcription factors involved in cardiometabolic diseases such as Pparg (adipose), Hnf4a (liver), and Tcf21 (aorta) whose targets are altered in response to Glo1 deficiency. Our results indicate that Glo1 deficit perturbs metabolic health and metabolic pathways in a sex- and age-dependent manner without concordant changes in AGEs across metabolic tissues.