Endocrinology最新文献

The progesterone receptor (PR) is a critical regulator of hormone signaling in breast tissue, with its 2 primary isoforms, PR-A and PR-B, exhibiting distinct and sometimes opposing functions. These isoforms arise from alternative promoter usage within the PGR gene, resulting in structural differences that influence their transcriptional activity, regulatory interactions, and post-translational modifications. This review explores the historical discovery of PR isoforms, their structural and functional differences, and the molecular mechanisms governing their transcriptional regulation. We also discuss their physiological roles in normal mammary gland development and how their dysregulation contributes to breast cancer progression, endocrine resistance, and cancer stem cell expansion. Understanding the distinct roles of PR isoforms in breast cancer biology holds significant implications for developing targeted therapeutic strategies aimed at modulating isoform-specific PR activity in hormone-driven cancers.

γ-Aminobutyric acid (GABA) and kisspeptin play essential roles in reproduction and metabolism, being expressed in the central nervous system and peripheral organs (ovaries, testes, pancreas, liver, and white adipose tissue [WAT]). While previous research has shed light on their functions, the interaction between GABA and kisspeptin in regulating these processes remains poorly explored. In a recent study, in which we evaluated the action of GABA through GABAB receptors (GABABRs) in Kiss1-expressing cells, we focused on male mice lacking GABABR specifically in Kiss1 cells (Kiss1-GABAB1KO), revealing normal reproductive functions but impaired glucose homeostasis that worsened with age. Here, we explored reproduction and metabolism in Kiss1-GABAB1KO females. Kiss1-GABAB1KO females had increased Kiss1/Tac2 expression in the arcuate nucleus (ARC), while displaying normal estrous cycles and fertility. Metabolically, they showed increased expression of key ARC metabolic genes (Npy/Agrp, Pomc, Lepr), increased WAT weight and leptin secretion, and body weight (BW) gain, not linked to food intake (FI) changes. They exhibited normal glucose levels but heightened insulin secretion and peripheral insulin resistance, potentially due to increased WAT mass. Kisspeptin was specifically increased in KO WAT. Interestingly, BW in older KO females was not different from WTs, yet maintained elevated WAT kisspeptin content, similar to younger females. Our results highlight the effect of GABA, through GABABRs, in the regulation of the WAT kisspeptin system and ARC gene expression in female mice, underscoring that the effect of deletion of GABABRs in Kiss1 cells found in this and our previous study is sex, age, and tissue specific.

Prenatal androgen excess (PNA), an etiologic factor for polycystic ovary syndrome (PCOS), is implicated in programming long-term reproductive deficits in females such as anovulation, subfertility, and hyperandrogenism. Impaired steroid hormone feedback is a key neuroendocrine feature suspected to underpin the development of reproductive dysfunction in both clinical PCOS and in PNA mice exposed to dihydrotestosterone during late gestation. PNA is suspected to act in the brain to program the impaired sensitivity of the GnRH neuronal network to progesterone negative feedback, centrally dysregulating the hypothalamic-pituitary-ovarian axis controlling reproduction. To test the hypothesis that androgen-sensitive neurons mediate PNA programming, we generated PNA female mice with a neuron-specific deletion of androgen receptors (AR) (NeurARKO) using Cre-lox transgenics. Following confirmation of embryonic AR deletion, PNA NeurARKO females were reproductively phenotyped and assessed for changes in progesterone receptor expression in the brain. PNA-induced reproductive traits including delayed pubertal onset, acyclicity, altered ovarian morphology, and subfertility were not different between NeurARKO and wild-type mice. In contrast, downregulation of progesterone receptor expression in PNA wild-type mice was protected against in PNA NeurARKO mice. Together, these findings suggest that although neuronal AR may contribute to PCOS-like impaired sensitivity to progesterone feedback, their deletion alone is insufficient to rescue reproductive dysfunction associated with PCOS.

As a common endocrinopathy of reproductive-aged women, polycystic ovary syndrome (PCOS) is characterized by ovarian hyperandrogenism, insulin resistance, and preferential abdominal fat accumulation. These characteristics in normal-weight women with PCOS are accompanied by subcutaneous abdominal adipose stem cells that intrinsically exaggerate lipid accumulation during adipocyte development in vitro in combination with an increased amount of highly lipolytic visceral fat. PCOS-related adipose characteristics are intimately linked with hyperandrogenism through genetic inheritance and epigenetic events programmed during prenatal and postnatal life. Accordingly, evolutionary theory submits that such events in PCOS may have ancestral origins, providing survival advantages in 3 contexts: (1) food scarcity with risk of starvation; (2) infectious disease risks, alleviated by visceral and omental fat; and (3) benefits from increased muscularity. But such adaptations also involve costs, given that PCOS-related traits also tend to reduce reproduction, due to oligo-anovulation. This review examines the evolutionary origins of PCOS risk as a syndrome potentiated by environmental mismatches (especially contemporary obesity and low physical activity), combined with adaptive physiological systems governed by trade-offs between survival and reproduction. This hypothesis is supported by a plethora of recent studies on physiological and behavioral differences between subsistence-level and modern Westernized populations, and by analyses of survival-reproduction trade-offs in nonhuman mammals. Studies of PCOS models using prenatally testosterone-treated and naturally hyperandrogenic animal models provide crucial insights for understanding how today's illnesses likely emerged from ancient developmental-metabolic strategies, and how knowledge about the evolutionary past can help guide current research and the development of more effective therapies.

Glucagon-like peptide-1 (GLP-1) is produced within the central nervous system (CNS) by preproglucagon (PPG) neurons. This brain-derived GLP-1, rather than that released from the gut, is the physiological agonist for brain GLP-1 receptors (GLP-1Rs). With brain GLP-1Rs being a major target for eating suppression, understanding the physiology and the translational potential of PPG neurons is of pivotal importance, particularly since PPG neuron activation is also strongly associated with stress. This review critically summarizes the current knowledge of PPG neuron anatomy, physiology, and molecular makeup together with insight into the relevant research tools, and consideration of the different PPG neuron populations within the CNS, to provide an appraisal of the potential of these neurons as drug targets and the associated risks and benefits.

Anaplastic thyroid cancer (ATC) is one of the most lethal endocrine cancers with no enduring therapies. Thyroid hormone receptor β (TRβ), a recognized tumor suppressor, modulates the transcriptome altering gene expression in numerous intracellular signaling pathways. Our recent studies revealed that TRβ agonism inhibits glycogen metabolism in ATC cells. Our goal in the present study was to delineate the molecular mechanisms by which TRβ regulates glycogen synthesis and breakdown. In ATC cells, activation of TRβ induced changes in expression of genes and proteins in glycogen signaling concordant with downregulation of cancer metabolism. The impact on the cancer cell metabolic phenotype was determined by glycogen levels, cell viability, and reactive oxygen species characterization. Our results revealed that TRβ activation differentially regulates glycogen signaling pathways reflective of the genetic landscape of the cells. This suggests TRβ can suppress tumor growth and progression through multiple steps in glycogen metabolism, giving it a unique and distinct role in fine-tuning the microenvironment of the cell as an internal sensor of the general environment of the cell. These studies reveal the potential of a synergistic effect of TRβ agonism and inhibition of glycogen metabolism in the treatment of aggressive dedifferentiated thyroid cancers.

Context: Women with polycystic ovary syndrome (PCOS) and PCOS animal models have diminished brown adipose tissue (BAT) activity, potentially contributing to metabolic dysfunction. Besides classical androgens, adrenal 11-oxygenated androgens are elevated in women with PCOS. However, it remains unknown whether these 11-oxygenated androgens affect BAT metabolism.

Objective: To study the effects of 11-ketotestosterone (KT) and 11-ketodihydrotestosterone (KDHT) on BAT metabolism.

Methods: The female mouse brown adipocyte cell line T37i was treated with increasing concentrations (0.1-10 µM) of testosterone (T), dihydrotestosterone (DHT), KT, or KDHT during or after differentiation. In addition, female mice received a daily injection of vehicle, DHT, KT, or KDHT (100 µg) for 1 day or 1 week. Adipose depots were collected for RNA sequencing (RNAseq) analysis and Gene Set Enrichment Analysis (GSEA).

Results: During differentiation, T, KT, DHT, and KDHT treatment of T37i cells dose-dependently reduced lipid droplet accumulation, and downregulated mRNA expression of adipogenic markers by up to 50%, with KDHT having the weakest effect. In mature T37i cells, only the high concentrations of these androgens exhibited inhibitory effects. RNAseq analysis revealed that DHT exposure induced the most differentially regulated genes in BAT, followed by KT and KDHT treatment. GSEA indicated that 1-day treatment with DHT and KT, but not KDHT, resulted in the downregulation of metabolic pathways in BAT.

Conclusion: 11-Oxygenated androgens at high concentrations directly inhibit brown adipocyte differentiation in vitro and KT acutely downregulates BAT metabolic transcriptome in vivo, a result not observed with KDHT. These findings suggest that elevated 11-oxygenated androgens may impair BAT function, contributing to metabolic complications associated with hyperandrogenic conditions, including PCOS.

Pericytes are mural cells distributed in the basement membrane of precapillary arterioles, capillaries, and postcapillary venules and are indispensable parts of the vascular microenvironment. To date, pericytes have been found to play a crucial role in vascular homeostasis in several organs. The pituitary gland has a complex network of blood vessels that support endocrine function; thus, pericytes also have irreplaceable functions in the pituitary vascular microenvironment, including angiogenesis, vascular regulation, neuroendocrine, extracellular matrix regulation, and mesenchymal-like differentiation potential. Notably, emerging evidence suggests potential functional heterogeneity between anterior and posterior pituitary pericytes, which may underlie their specialized roles in regulating lobe-specific vascular and neuroendocrine activities. Additionally, the underlying impact of pericytes on pituitary lesions, such as tumors, apoplexy, and fibrosis, has been revealed in the past decade. In this review, we introduce the fundamental characteristics of pituitary pericytes on the basis of their morphological characteristics, molecular markers, and origin; emphasize their multiple functions under physiological conditions; and explore their latent role in pituitary diseases. This review is the first to provide a comprehensive overview of the physiological functions and pathological mechanisms of pituitary pericytes, in an attempt to develop new ideas for future research.

Endometriosis is a pathological condition characterized by the ectopic growth of endometrial cells, leading to chronic pelvic pain and infertility. Epidemiological studies have associated exposure to dioxin-like polychlorinated biphenyls, particularly PCB126, with an increased risk of endometriosis. However, the underlying mechanisms of this association remain poorly understood. We utilized a surgically induced endometriosis mouse model and human endometrial cell lines to assess the impact of PCB126 on endometriosis progression. Mice were exposed to environmentally relevant doses of PCB126. Endometriotic lesion growth, estrogen receptor signaling, receptor tyrosine kinase activity, and gene expression changes induced by PCB126-mediated elevation of DNA methyltransferase 3A (DNMT3A) were evaluated using histology, bioluminescent imaging, immunoblotting, and RNA sequencing. Functional validation was conducted using a pharmacologic AXL inhibitor and tissue-specific Dnmt3a knockout mice. PCB126 significantly promoted the growth of ectopic lesions and humanized models of endometriosis. Mechanistically, PCB126 enhanced estrogen receptor β (ESR2) activity by upregulating AXL and its ligand, growth arrest-specific 6, and elevating DNMT3A expression. The inhibition of AXL signaling suppressed the growth of endometriotic lesions. ESR2 directly regulated Dnmt3a expression, and loss of Dnmt3a reduced lesion growth and inflammatory cytokine production, thereby reversing immune dysregulation. These findings establish a mechanistic link between PCB126 exposure and epigenetic and immune reprogramming in endometriotic lesions. Our findings establish a mechanistic connection between environmental PCB126 exposure and endometriosis progression via the AXL/ESR2/DNMT3A axis. This study provides new insight into how endocrine-disrupting chemicals promote hormone-sensitive diseases through epigenetic and immunological pathways, offering potential targets for therapeutic intervention.