Endocrinology最新文献

During early pregnancy, human endometrial stromal cells differentiate into secretory decidual cells via a process regulated by ovarian steroid hormones. Decidual cells play a crucial role by secreting various factors that support essential events in forming a functional placenta, including uterine angiogenesis and the differentiation and development of trophoblasts. We previously reported that the conditional ablation of the transcription factor runt-related transcription factor 1 (RUNX1) in the mouse uterus leads to subfertility due to insufficient maternal angiogenesis and impaired trophoblast differentiation. In this study, we examined the role of RUNX1 in facilitating communication mechanisms among human decidual cells and other cell types present in the pregnant uterus. We demonstrate that RUNX1 regulates the conserved hypoxia-inducible factor 2 α-RAB27B pathway in primary human endometrial stromal cells (HESCs) during decidualization, which promotes the secretion of extracellular vesicles (EVs) by these cells. Consequently, the depletion of RUNX1 in HESC led to reduced EV secretion. Mass spectrometry identified several cargo proteins in decidual EVs, including angiopoietin-related protein 2 (ANGPTL2) and IGF2, which could regulate angiogenesis or trophoblast differentiation. We found that RUNX1 directly regulates their expression, resulting in partial changes to these cargoes when it is absent. We observed that delivering EVs lacking ANGPTL2 or IGF2 to human endothelial cells significantly decreased the formation of vascular networks compared to introducing control EVs carrying these factors. Furthermore, adding IGF2-depleted EVs to human trophoblast cells inhibited their differentiation into the extravillous trophoblast lineage. These findings collectively highlight the crucial role of decidual RUNX1 in promoting essential cell-cell interactions for angiogenesis and trophoblast differentiation during placenta formation.

We present a molecular mechanism underpinning how pulsatile patterns of glucocorticoid hormones maintain signal responsivity, evade hormone resistance, and promote homeostasis. Endogenous glucocorticoids are released in a pulsatile manner resulting in oscillating hormone signals with intermittent peaks of high glucocorticoids and troughs of low glucocorticoids. We show that ligand activation of glucocorticoid receptors rapidly triggers the post-translational modification SUMOylation, which is coupled to receptor degradation, whereby resistance to subsequent signal transduction is generated and ligand response attenuated. We find rapid, transient glucocorticoid receptor SUMOylation tracks ultradian (roughly hourly) pulse dynamics in cells, as well as circadian (daily) oscillatory rhythms in vivo, enabling cellular interpretation of fluctuating hormone patterns. Prolonged treatment with the long-acting synthetic glucocorticoid methylprednisolone disrupted glucocorticoid receptor SUMOylation levels in rat brain tissue. Pharmacological glucocorticoid therapy generates unremitting glucocorticoid signaling, which may substantially reduce the glucocorticoid receptor pool and contribute to the therapeutic problem of acquired glucocorticoid resistance. The physiological solution for maintaining signal responsivity over time is pulsatile hormone exposure, with pulsatile low glucocorticoid troughs which periodically limit receptor degradation and associated signal attenuation. We show low glucocorticoid periods allow time for depleted glucocorticoid receptor expression levels to recover and thereby maintain signal sensitivity. Our results reveal a molecular mechanism responsive to hormone pattern information, through which endogenous ultradian and circadian glucocorticoid fluctuations maintain glucocorticoid receptor expression and glucocorticoid sensitivity. Dynamic ligand-activated glucocorticoid receptor SUMOylation coupled to degradation is revealed as a component of glucocorticoid receptor protein regulation, whose expression is critical for metabolic, immunological, cognitive, and cardiovascular homeostasis.

Follicle-stimulating hormone (FSH) is an essential regulator of ovarian function. Inhibins are transforming growth factor β (TGFβ) family ligands produced in the gonads that suppress FSH synthesis by pituitary gonadotrope cells. Inhibins require a coreceptor, betaglycan or TGFBR3L, to mediate their actions. Female mice with a gonadotrope-specific knockout (KO) of betaglycan or global deletion of Tgfbr3l have increased FSH activity or levels and produce larger litters compared to controls. Females with both coreceptors knocked out (hereafter dKO) have dramatically increased circulating FSH, ovulate about 4 times as many eggs in natural cycles as controls but are infertile. Here, we show that dKO females show an increased number of implanted embryos at 7.5 days post coitum (dpc) but that their pregnancies fail around mid-gestation. Wild-type surrogates give birth to live young following transplantation of embryos from control or dKO females. Conversely, control but not dKO females can carry wild-type embryos to term, suggesting that the maternal environment in dKO mice cannot support full-term pregnancies. Elevated estradiol (E2) levels are deleterious to pregnancy in mice, and we detected increased E2 production in ovaries of pregnant dKOs. Treatment of these animals with aromatase inhibitors or a selective estrogen receptor degrader increased fetal survival. The results indicate that loss of inhibin action in murine gonadotropes results in excess E2 during pregnancy that precludes successful pregnancy.

The increase in the incidence of obesity has coincided with changes in lifestyle, diet, and environment. Comorbidities associated with obesity include cardiovascular disease, diabetes, musculoskeletal disorders, stroke, and thromboembolism, affecting public health. The effect of increased weight has recently become even more obvious, since obesity has been significantly associated with increased severity and higher mortality among COVID-19 patients. The need to decrease rates of obesity prompted a surge in the use of glucagon-like peptide-1 agonist medications. Twin studies, however, determined that increased weight has a large genetic component, estimating the heritability of obesity to be 45% to 70%. Surprisingly, obesity due to known single gene mutation comprises only 5% to 10% of individuals, who mostly exhibit early-onset severe obesity. Genome-wide linkage studies and association studies identified more than 250 genes associated with obesity, but each of these has a relatively small effect size. Further, several genetic syndromes, associated with neurodevelopmental disabilities and congenital malformations, encompass obesity in their constellation of symptoms. This review will summarize several known genetic causes of obesity, focusing specifically on how they relate to the brain circuitry that regulates food intake and energy homeostasis. The review will indicate a need for further studies to integrate the role of diet and environmental contribution with genetic components of this multifactorial condition. Given that genetics of obesity is unlikely to explain the recent dramatic temporal increase in the prevalence of obesity, our review will point to the need to understand interactions between genes and other contributing environmental or sex-dependent factors.

Serotonin (5-hydroxytryptamine; 5-HT) is transported into the human placenta through the serotonin transporter (SERT/SLC6A4) on the surface of the syncytiotrophoblast. During this transit, a significant amount of 5-HT becomes concentrated in the cytotrophoblast nucleus. We used immunochemistry, inhibitors of SERT and transglutaminase 2, and RNA sequencing to elucidate the mechanism and consequences of this nuclear localization. Exogenous 5-HT recapitulated the uptake of 5-HT into the trophoblasts and its preferential concentration in cytotrophoblast nuclei we observed in the intact placenta. Cystamine eliminated the staining of the nuclei in placental explants by exogenous 5-HT, suggesting that serotonylation mediated this phenomenon. This was confirmed by Western blots and immunoprecipitation that identified histone 3, and specifically the 5th glutamine residue in histone 3, as a site of serotonylation. Inhibiting SERT with escitalopram or transglutaminase 2 with cystamine blocked cytotrophoblast differentiation in vitro and led to marked changes in RNA expression. Of the 38 524 mRNAs identified in these trophoblasts, cystamine changed the expression of 1986 and escitalopram significantly altered 374. Both treatments altered the expression of 155 mRNAs either positively or negatively. The downregulated genes were involved with cell proliferation, morphogenesis, motility, and growth, whereas genes that were upregulated controlled cell survival and protection pathways. These findings suggest that maternal 5-HT promotes placental, embryonic/fetal, and organismal development through histone serotonylation and consequent alterations in gene expression. They raise the possibility that alterations in 5-HT flux in the placenta affect placental and fetal growth, as well as organismal somatic, neurologic developmental, and pathological trajectories.

Obesity is a major health problem, being a risk factor for many metabolic diseases. Obesity results from an imbalance in energy intake and energy expenditure. Animal models, particularly naturally occurring mouse models of obesity, have provided a framework of the basic mechanisms regulating energy homeostasis. However, there remain gaps in our understanding of the mechanisms underlying the pathophysiology of obesity. Mouse models of obesity remain an essential tool to further our knowledge, due to advanced tools for genetic manipulation and the possibility to study interaction with environmental factors, such as diet. While there are advantages to using mice as models of obesity, it should be recognized that there are limitations. In this mini-review we provide a brief overview of the monogenic mouse models of obesity that have led to the discovery of important physiological systems that regulate energy homeostasis, such as the leptin-melanocortin pathway, that translate well to humans. We also discuss confounding factors that, when taken into account, might improve translatability of these findings. Finally, we discuss potential strategies to determine functional consequences of non-coding genome-wide association study (GWAS) signals in mouse models.

Mitochondria are a major source of reactive oxygen species, such as superoxide anion (O2●─), contain the enzyme complexes of the electron transport chain and, in steroidogenic tissues, steroid hormone synthesizing P450 enzymes. Superoxide dismutase 2 (SOD2) is the main antioxidant enzyme localized in mitochondria for protection from oxidative insult by enzymatically converting O2●─ into H2O2, which is further degraded into H2O and O2. Although expressed at high levels in steroidogenic tissues and transcriptionally regulated by trophic hormones, SOD2's role in the regulation of steroid hormone production is not fully explored. To address its role in regulating steroidogenesis, we generated adrenal, ovary, and testis tissue specific SOD2-deficient mice. Adrenal/testis and adrenal/ovary SOD2-deficient mice exhibited a marked reduction in hormone stimulated corticosterone/testosterone and corticosterone/progesterone secretion in vivo, and hormone- or hormone + high-density lipoprotein-stimulated steroid production by steroidogenic tissues in vitro, respectively. RT-quantitative PCR measurements demonstrated dramatic reduction in mRNA levels of steroidogenic P450 enzymes and cholesterol transport protein, StAR. Small, but significant, declines in mRNA levels of certain hydroxysteroid dehydrogenases were also noted. Cellular levels of key biomarkers of oxidative stress revealed that mice with steroidogenic SOD2-deficiency exhibit high oxidative stress. Steroidogenic MLTC-1 cell lines stably overexpressing pairs of mitochondrial antioxidant enzymes, Sod2-catalase, Sod2-glutathione peroxidase-1, or Sod2-glutathione peroxidase-4, showed complete protection against oxidant-mediated suppression of steroidogenesis. These results led us to conclude that SOD2 plays an essential role in the regulation of steroidogenesis and that SOD2-deficiency-induced excessive oxidative stress adversely affects steroid production in mouse adrenal glands, ovary, and testis.

Breast cancer is the most frequently diagnosed cancer in women, with more than 316 000 new cases expected to be diagnosed in 2025. Nearly 80% of new breast cancer cases will be estrogen receptor-positive (ER+). While ER+ breast cancer has a high 5-year survival rate, patients are at risk of developing late recurrence and metastasis for 10 to 20 years after initial diagnosis. Late recurrence and metastasis are associated with therapy resistance and disease progression. Understanding the molecular mechanisms that drive therapy resistance and disease progression is essential for the development of therapies that will prevent and treat advanced ER+ breast cancer. This review will focus on mechanisms of therapy resistance associated with standard treatments for advanced ER+ breast cancer, including CDK4/6 inhibitors and PI3K/AKT/mTOR pathway inhibitors. Additionally, we will highlight how therapy resistance enriches for breast cancer stem-like populations and how targeting this population of cells may be advantageous for preventing breast cancer progression.

Mutations in the pituitary-specific transcription factor PROP1 are the most common known cause of hypopituitarism in humans. Prop1 is the first pituitary-specific gene in the hierarchy of transcription factors that regulate pituitary development. It is essential for regulating the transition of pituitary stem cells to hormone-producing cells in an epithelial to mesenchymal-like transition process. It is also critical for activation of the lineage specific transcription factor POU1F1 in early organogenesis. Prop1-deficient mice have pituitary dysmorphology and lack the cells that produce growth hormone (GH), thyroid-stimulating hormone (TSH), and prolactin (PRL). Prop1 is expressed in stem cells postnatally, but it is not known whether postnatal expression is necessary for completion of pituitary gland growth or organ maintenance. We tested whether PROP1 has a role in postnatal pituitary development by generating a conditional allele and deleting a crucial exon after birth. We determined that postnatal expression of Prop1 is important for appropriate expansion of the POU1F1 lineage and for robust expression of TSH, GH, and PRL in the early postnatal period. However, by 2 weeks of age, compensatory proliferation of committed POU1F1-expressing cells, but not SOX2-expressing stem cells, have normalized pituitary function. Thus, PROP1 appears to be dispensable after birth in mice.