Dynamic metabolism is exhibited by early mammalian embryos to support changing cell fates during development. It is widely acknowledged that metabolic pathways not only satisfy cellular energetic demands, but also play pivotal roles in the process of cell signalling, gene regulation, cell proliferation and differentiation. Recently, various new technological advances have been made in metabolomics and computational analysis, deepening our understanding of the crucial role of dynamic metabolism during early mammalian embryogenesis. In this Review, we summarize recent studies on oocyte and embryo metabolism and its regulation, with a particular focus on its association with key developmental events such as fertilization, zygote genome activation and cell fate determination. In addition, we discuss the mechanisms of certain metabolites that, in addition to serving as energy sources, contribute to epigenetic modifications.

While proliferating cells optimize their metabolism to produce biomass, the metabolic objectives of cells that perform non-proliferative tasks are unclear. The opposing requirements for optimizing each objective result in a trade-off that forces single cells to prioritize their metabolic needs and optimally allocate limited resources. Here, we present single-cell optimization objective and trade-off inference (SCOOTI), which infers metabolic objectives and trade-offs in biological systems by integrating bulk and single-cell omics data, using metabolic modeling and machine learning. We validated SCOOTI by identifying essential genes from CRISPR-Cas9 screens in embryonic stem cells, and by inferring the metabolic objectives of quiescent cells, during different cell-cycle phases. Applying this to embryonic cell states, we observed a decrease in metabolic entropy upon development. We further uncovered a trade-off between glutathione and biosynthetic precursors in one-cell zygote, two-cell embryo, and blastocyst cells, potentially representing a trade-off between pluripotency and proliferation. A record of this paper's transparent peer review process is included in the supplemental information.

Thyroid eye disease (TED) is the most common orbital disease in adults. Targeting expanded orbital adipose tissue (OAT) removed by surgery has therapeutic potential. However, drugs targeting OAT are unavailable because of the lack of deciphering features of OAT. Here, we aimed to investigate the mechanism underlying OAT expansion and identify a drug targeting OAT in TED. We found an increasing number of adipocytes with smaller size in TED-derived OATs as compared with controls, indicating that hyperplasia rather than hypertrophy contributed to OAT enlargement in TED. Typically smaller-sized adipocytes in TED patient-derived OATs were noted to localize surrounding vessels. RNA sequencing revealed enriched vascular endothelial growth factor receptor (VEGFR) genes in adipocytes differentiated from preadipocytes of TED-derived stromal vascular fraction (SVF). Similarly, OATs in patients with TED also expressed a higher level of VEGFR-1 and -2. We induced adipogenesis in TED-derived SVF with or without Lenvatinib, an FDA-approved small-molecule VEGFR inhibitor. Lenvatinib significantly suppressed lipid accumulation in a dose-dependent manner. In conclusion, our study revealed the potential anti-adipogenic effect of Lenvatinib on the OAT of TED-affected patients. In addition to proposing a drug for TED treatment, this study shows the therapeutic potential of anti-adipogenesis drugs targeting the VEGF pathway.

Thyroid-associated ophthalmopathy (TAO) is an autoimmune orbital disease influenced by multiple factors, including genetic and immune factors. The enlargement of orbital fat tissues are mainly due to abnormal activation of adipocyte differentiation. Epigenetic modifications provide mechanistic insight for regulating gene expression and cellular differentiation. Lysine specific demethylase 1 (LSD1) is reported in regulation of adipogenesis. Therefore, it is critical to investigate the relationship between epigenetic modifier LSD1 and histone modification level during TAO process. In this study, combined with the clinic study and highthrough sequencing approach, our results revealed that the volume of orbital fat tissue was lower in TAO patients compared to non-TAO patients, whereas the number of adipocytes was higher in TAO patients compared to non-TAO patients, the expression level of adipocyte differentiation markers were higher in TAO samples. Consistently, at the cellular system, the expression level of adipogenic markers were higher in the TAO derived cells compared with the non-TAO cells. And we found LSD1 was highly expressed in TAO-derived cells. However, knocking down LSD1 decreased the expression of adipocyte markers. Mechanistically, LSD1 promoted adipocyte gene activation by demethylating H3K9me2 at the promoter regions. Finally, treatment with pargyline, an LSD1 inhibitor, inhibited adipogenesis in a dose-dependent manner, and the same inhibition of adipogenesis results were obtained with treatment with teprotumumab alone or combined with pargyline. Overall, our study indicates that epigenetic modifications were dysregulated in TAO process, and these data elucidated a novel mechanism of adipocyte differentiation during TAO progression and positioned LSD1 as a potential anti-adipogenesis target in TAO. Further understanding of the interaction betwen transcription factors and epigeneic modifiers or other histone modifications in TAO is essential for providing new perspectives in TAO mechanistic study and clinical intervention.

Whether metabolites enriched at early developmental stages affect cellular and organismal aging remains unclear. In this study, we comprehensively profiled the metabolic landscape of mouse oocytes in comparison to cleavage-stage embryos. Our analysis revealed that oocytes display accumulation of reductive metabolites that diminish following fertilization. Notably, we identified serotonin (5-hydroxytryptamine, 5-HT) as an oocyte-enriched metabolite with protective roles in aging. The underlying mechanisms operate through dual pathways: (i) in a canonical pathway serotonin acts via its receptor 5HTR1B to modulate mitochondrial function, and (ii) in a non-canonical pathway serotonin promotes serotonylation of HSP90β, which effectively reduces endoplasmic reticulum stress. Overall, our study demonstrates that oocyte-enriched metabolites including serotonin can alleviate aging-related cellular and systemic phenotypes, suggesting new avenues for anti-aging strategies.