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Maternal nutrition exerts profound and lasting effects on infant development, with implications extending beyond somatic growth to long-term brain function and metabolic health. For example, newborns from mothers with obesity or diabetes exhibit increased susceptibility to metabolic disorders, including insulin resistance (IR) and type 2 diabetes (T2D), often emerging in childhood or adolescence. While genetic inheritance contributes to this intergenerational risk, early-life nutritional exposures are increasingly recognized as primary drivers of persistent metabolic programming. Among key classes of nutrients, branched-chain amino acids (BCAAs)—leucine, isoleucine, and valine—have emerged as potent modulators of metabolic health in human adults. Elevated circulating BCAAs are among the most accurate predictors of future insulin resistance (IR) and T2D, with a two-fold increase in serum levels conferring a 2.5-fold risk of diabetes onset within 6–10 years. This elevation can directly cause organ toxicity, exacerbating metabolic deficits in a feed-forward loop. However, the extent to which maternal BCAA overnutrition during gestation and lactation impacts offspring metabolic programming and predisposes to dysfunction remains unclear.

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Current Issue

Multi-omics after O-GlcNAc alteration identified cellular processes promoting aneuploidy after loss of O-GlcNAc transferase

Samuel S. Boyd, Dakota R. Robarts, Khue Nguyen, Maite Villar, ... Chad Slawson

Multi-omics after O-GlcNAc alteration identified cellular processes promoting aneuploidy after loss of O-GlcNAc transferase

 

Objective

Pharmacologic or genetic manipulation of O-GlcNAcylation, an intracellular, single sugar post-translational modification, are difficult to interpret due to the pleotropic nature of O-GlcNAc and the vast signaling pathways it regulates.

Method

To address the pleotropic nature of O-GlcNAc, we employed either OGT (O-GlcNAc transferase), OGA (O-GlcNAcase) liver knockouts, or pharmacological inhibition of OGA coupled with multi-Omics analysis and bioinformatics.

Results

We identified numerous genes, proteins, phospho-proteins, or metabolites that were either inversely or equivalently changed between conditions. Moreover, we identified pathways in OGT knockout samples associated with increased aneuploidy. To test and validate these pathways, we induced liver growth in OGT knockouts by partial hepatectomy. OGT knockout livers showed a robust aneuploidy phenotype with disruptions in mitosis, nutrient sensing, protein metabolism/amino acid metabolism, stress response, and HIPPO signaling demonstrating how OGT is essential in controlling aneuploidy pathways.

Conclusion

These data show how a multi-Omics platform can disentangle the pleotropic nature of O-GlcNAc to discern how OGT fine-tunes multiple cellular pathways involved in aneuploidy.

 

 

Articles in Press

Multi-omics after O-GlcNAc alteration identified cellular processes promoting aneuploidy after loss of O-GlcNAc transferase

Samuel S. Boyd, Dakota R. Robarts, Khue Nguyen, Maite Villar, ... Chad Slawson

Multi-omics after O-GlcNAc alteration identified cellular processes promoting aneuploidy after loss of O-GlcNAc transferase

 

Objective

Pharmacologic or genetic manipulation of O-GlcNAcylation, an intracellular, single sugar post-translational modification, are difficult to interpret due to the pleotropic nature of O-GlcNAc and the vast signaling pathways it regulates.

Method

To address the pleotropic nature of O-GlcNAc, we employed either OGT (O-GlcNAc transferase), OGA (O-GlcNAcase) liver knockouts, or pharmacological inhibition of OGA coupled with multi-Omics analysis and bioinformatics.

Results

We identified numerous genes, proteins, phospho-proteins, or metabolites that were either inversely or equivalently changed between conditions. Moreover, we identified pathways in OGT knockout samples associated with increased aneuploidy. To test and validate these pathways, we induced liver growth in OGT knockouts by partial hepatectomy. OGT knockout livers showed a robust aneuploidy phenotype with disruptions in mitosis, nutrient sensing, protein metabolism/amino acid metabolism, stress response, and HIPPO signaling demonstrating how OGT is essential in controlling aneuploidy pathways.

Conclusion

These data show how a multi-Omics platform can disentangle the pleotropic nature of O-GlcNAc to discern how OGT fine-tunes multiple cellular pathways involved in aneuploidy.

 

 

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