Xinrui Li

Maternal obesity (MO) alters the intrauterine environment and increases the risk of a variety of developmental outcomes; however, the effects on placental cell population and development remain unclear. In this study, we investigated the impact of MO on placental cellular composition, development, and morphology in C57BL/6J mice fed a control or high-fat diet. Single-cell RNA sequencing of embryonic day (E) 13.5 placentas identified 16 transcriptionally distinct cell populations and revealed a reduction in the trophoblast progenitor cell population in MO placentas. MO suppressed trophoblast genes involved in placental development and mitochondrial oxidative phosphorylation, accompanied by decreased protein expression of peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PGC-1α), a key regulator of mitochondrial biogenesis. Furthermore, MO reduced the expression of Hand1 and Tfap2c, transcription factors involved in trophoblast differentiation and placental development, while increasing prolactin-family gene expression and STAT5 phosphorylation. At E17.5, MO caused female-specific reductions in placental weight and labyrinth zone area, along with increased Tnf expression and sustained suppression of Hand1 in female placentas. These findings suggest that MO disrupts trophoblast differentiation and placental metabolic function during midgestation, which may contribute to placental vulnerability later in pregnancy.

Maternal obesity (MO) is a growing global problem, which poses significant risks to fetal neurodevelopment and long‐term neurological functions of offspring, but the underlying molecular mechanisms remain to be established. To address this female mice were fed either a control diet or a high‐fat diet (HFD) for 2 months to induce obesity, and the same dietary treatments were maintained during pregnancy. Embryos were sampled at E11.5 and E13.5. Single‐cell RNA sequencing revealed reduced proportions of neurons and neural progenitors in embryos from obese mothers. The downregulation of neurogenesis, nervous system development and synaptic organization pathways were further confirmed by Gene Ontology analysis. Key neurogenic transcription factors, including Neurod1 , Neurog2 and Ascl1 , were suppressed in MO embryos, accompanied by increased expression of inflammatory markers, including tumour necrosis factor‐α (TNF‐α) and Cxcl2 , and inflammatory signalling mediators, Fos , Jun and Jund . Single‐cell ATAC sequencing revealed the activator protein 1 (AP‐1) binding sites in the promoter regions of Tnf and Cd68 , with MO‐enhancing AP‐1 transcription factor motif activity and increased chromatin accessibility in the loci of Tnfa and Cd68 genes. Furthermore, TNF‐α treatment of neurogenic cells suppressed Neurod1 and Neurog2 expression, suggesting a direct link between inflammatory signalling and impaired neurogenesis. Our findings suggest that MO creates a pro‐inflammatory environment that disrupts neurogenesis during early embryonic development, providing new insights into the neurodevelopmental disorders in offspring born to obese mothers. image Key points: Maternal obesity (MO) suppresses neurogenesis in the early embryos. Single‐cell RNA sequencing (scRNA‐seq) reveals decreased neurogenic cells and neurogenic factors in MO embryos. MO elevates activator protein 1 (AP‐1) transcription factor accessibility to the promoters of inflammatory genes. Inflammation induced by tumour necrosis factor‐α (TNF‐α) suppresses Neurod1 and Neurog2 expression and neurogenesis in vitro .

This study identifies mitochondrial proteostasis as an important molecular mechanism underlying the beneficial effects of aerobic exercise in improving polycystic ovary syndrome (PCOS). Exercise attenuated PCOS development and pathology through normalizing steroidogenic enzyme degradation via LONP1 upregulation, suppressing ovarian inflammation and fibrosis, and activating mitochondrial biogenesis pathways. Although the beneficial effects of exercise on PCOS have been well recognized, this study reveals the mitochondrial proteostasis pathway underlying these preventive effects.

Intralipid is a lipid emulsion used for preterm infants, but its biological effects on adipose development remain poorly examined. We investigated the effects of intravenous Intralipid on the adipose tissue development of midgestation fetal sheep. Intralipid20 infusion was started in fetuses at 88–90 days of gestation (dG) following clinical infant dosing guidance (0.5–1 g/kg/d estimated body weight, increasing daily by 0.5–1 g/kg/d to a maximum of 3 g/kg/d). Intralipid increased perirenal fat weight, adipocyte size, and lipid accumulation. Expression of key adipogenic genes was upregulated, including Pparg (Peroxisome Proliferator‐Activated Receptor Gamma), Fasn (Fatty Acid Synthase), Fabp4 (Adipocyte Fatty Acid Binding Protein 4), Acca (Acetyl‐CoA Carboxylase α), and Cebpa (CCAAT/Enhancer‐Binding Protein Alpha), while downregulating Pdgfra (Platelet‐Derived Growth Factor Receptor Alpha), Cidea (Cell death‐inducing DNA fragmentation factor α‐like effector A), Ppargc1a (Peroxisome Proliferator‐Activated Receptor Gamma Coactivator 1‐Alpha), and Ucp1 (Uncoupling Protein 1). Similar changes were confirmed in omental fat. Intralipid elicited mild inflammation in both perirenal and omental fat by increasing the expression of Tnfa (Tumor Necrosis Factor‐Alpha), with upregulation of Tlr4 (Toll‐Like Receptor‐4), and Tlr2 (Toll‐Like Receptor‐2) specifically in perirenal fat. Notably, this inflammatory response occurred without elevation of Il‐6 (Interleukin‐6) expression or NF‐κB activation. Moreover, Intralipid treatment suppressed the expression of fibrosis‐related genes, including Lh2b (lysyl oxidase‐like 2b) and P4ha (prolyl 4‐hydroxylase). These findings suggest that Intralipid administration at a developmental stage prior to normal term enhances ovine adipogenic differentiation and lipid accumulation which might be protective to premature infants, but it might slightly induce inflammation in the adipose tissues.

Background: The hypoxia-inducible factor 1α (HIF-1α) pathway plays a key role in promoting glycolysis and tumor progression under hypoxic conditions in cancer cells. Purple potato (PP) extract, which is a polyphenol-rich natural product, has previously been shown to enhance mitochondrial function and suppress tumor growth in several cancer models. We hypothesized that PP extract could counteract hypoxia-induced glycolysis by targeting the HIF-1α pathway. Methods: Human colonic epithelial Caco-2 cells were treated with PP extract under hypoxic conditions, and its effects on glycolysis, oxidative phosphorylation, and HIF-1α signaling were evaluated. Results: Under hypoxia PP extract suppressed glycolysis, as evidenced by reduced lactate production and lower phosphorylated pyruvate dehydrogenase levels. In parallel, genes associated with oxidative phosphorylation were upregulated by PP extract, suggesting a metabolic shift under hypoxia. Additionally, PP extract reduced the protein accumulation of HIF-1α and its transcriptional activator XBP1 induced by hypoxia. Correspondingly, the expression of several HIF-1α downstream target genes, including Vegfa, Pdk1, Ldha, Hk1, and Glut1, was markedly reduced. Functionally, PP extract inhibited cell proliferation, migration, and drug resistance under hypoxic stress, indicating a broader inhibitory effect on hypoxia-driven malignant phenotypes. Conclusion: These findings suggest that PP extract disrupts cancer cell adaptation to hypoxia and supports its potential as a dietary approach against hypoxia-driven colorectal cancer, through further preclinical studies are warranted.