Protein O-GlcNAcylation in reproductive biology and the impact of metabolic disease

BACKGROUND Protein O-GlcNAcylation is a reversible post-translational modification which regulates the function of thousands of proteins to control generic and cell type-specific actions. O-GlcNAc addition and removal downstream of the hexosamine biosynthetic pathway (HBP) is mediated by only two enzymes: O-GlcNAc transferase (OGT) and O-GlcNAcase (OGA), respectively. Crucially, O-GlcNAcylation provides a regulatory layer to protein function that is responsive to metabolic status and thus metabolic disease impinges on this system. Animal and ex vivo models show that O-GlcNAcylation is important for peri-conceptual and pregnancy processes. OBJECTIVE AND RATIONALE Fundamental knowledge about O-GlcNAcylation of proteins involved in reproductive processes is lacking. Here, we give relevant, and mechanistically well understood, examples of how protein O-GlcNAcylation can affect cellular processes and examine available data on germ cells, embryonic development, endometrial receptivity, and placentation. OGT and OGA regulation are placed within the wider context of reproductive biology. We also highlight gaps in knowledge and suggest avenues for next-phase research. SEARCH METHODS PubMed and Google Scholar (2013–2024) were interrogated, including only publications in English. Search terms included: GlcNAc AND Oocyte, GlcNAc AND Sperm, GlcNAc AND Embryo, GlcNAc AND Cell Differentiation, GlcNAc AND Endometrium, GlcNAc AND Endometrial Receptivity, GlcNAc AND Placenta, GlcNAc AND diabetes, and GlcNAc AND obesity. OUTCOMES Some evidence for the global impact of O-GlcNAcylation in maturation of oocytes and sperm, pre-implantation development, implantation, and placentation has been gathered by pharmacological inhibition and/or targeted mutagenesis of OGT and OGA. Blocking or inactivating OGT gives an embryonic lethal phenotype in most species. Mouse embryos can tolerate inactivation of OGA, but the offspring are growth-restricted and die postnatally. In general, HBP utilization in pre-implantation differs between species. This is likely to be the case in post-implantation development too, but it is already clear from stem cell biology that O-GlcNAcylation is important in the differentiation of most embryonic cell lineages including neurones, osteoclasts, enterocytes, and adipocytes. The identification of the progesterone receptor as an OGT target suggests important and widespread involvement of O-GlcNAcylation in reproductive processes. In the adult endometrium, protein O-GlcNAcylation decreases during decidualization, however, there is some evidence to suggest that O-GlcNAcylation of specific proteins promotes receptivity to the implanting embryo. In placenta, key aspects of development (e.g. angiogenesis) and function (e.g. transport, hormone production) are influenced by O-GlcNAcylation. Hyperglycaemia-induced changes in protein O-GlcNAcylation have negative impacts throughout reproductive systems and while there is less information on the consequences of lipid-mediated alterations to this post-translational modification, available evidence points to skewed protein O-GlcNAcylation contributing to impaired reproductive function in individuals living with obesity. WIDER IMPLICATIONS This review highlights protein O-GlcNAcylation as a regulator of reproductive processes and identifies large knowledge gaps which must be filled to improve fundamental understanding. Targeting O-GlcNAcylation regulatory networks, including acceptor site mutagenesis, in defined cell populations of reproductive tissues will advance knowledge. The interface of O-GlcNAcylation with metabolic disease needs disentangling to determine how interventions to alleviate disease impact reproductive outcomes. REGISTRATION NUMBER N/A.