Endocrinology最新文献

{"title":"A Dynamic Shift in Estrogen Receptor Expression During Granulosa Cell Differentiation in the Ovary.","authors":"Chan Jin Park, Ji-Eun Oh, PoChing Lin, Sherry Zhou, Mary Bunnell, Emmanuel Bikorimana, Michael J Spinella, Hyunjung Jade Lim, CheMyong J Ko","doi":"10.1210/endocr/bqaf006","DOIUrl":"10.1210/endocr/bqaf006","url":null,"abstract":"<p><p>This study uncovers a dynamic shift in estrogen receptor expression during granulosa cell (GC) differentiation in the ovary, highlighting a transition from estrogen receptor alpha (ESR1) to estrogen receptor beta (ESR2). Using a transgenic mouse model with Esr1-iCre-mediated Esr2 deletion, we demonstrate that ESR2 expression is absent in GCs derived from ESR1-expressing ovarian surface epithelium (OSE) cells. Single-cell analysis of the OSE-GC lineage reveals a developmental trajectory from Esr1-expressing OSE cells to Foxl2-expressing pre-GCs, culminating in GCs exclusively expressing Esr2. Transcriptome analyses identified vasculature-derived TGFβ1 ligands as key regulators of this transition. Supporting this, TGFβ1 treatment of cultured embryonic ovaries reduced Esr1 expression while promoting Esr2 expression. This study underscores the capability of GCs to switch from ESR1 to ESR2 expression as a fundamental aspect of normal differentiation.</p>","PeriodicalId":11819,"journal":{"name":"Endocrinology","volume":" ","pages":""},"PeriodicalIF":3.8,"publicationDate":"2025-01-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143002195","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Critical Insights Into LEAP2 Biology and Physiological Functions: Potential Roles Beyond Ghrelin Antagonism.","authors":"Mario Perelló","doi":"10.1210/endocr/bqaf011","DOIUrl":"10.1210/endocr/bqaf011","url":null,"abstract":"<p><p>Liver-expressed antimicrobial peptide 2 (LEAP2) has recently emerged as a novel hormone that reduces food intake and glycemia by acting through the growth hormone secretagogue receptor (GHSR), also known as the ghrelin receptor. This discovery has led to a fundamental reconceptualization of GHSR's functional dynamics, now understood to be under a dual and opposing regulation. LEAP2 exhibits several distinctive features. LEAP2 is released by hepatocytes and enterocytes, 2 cell types that lack classical regulatory secretory mechanisms and may respond differently to nutrient signals. LEAP2 is also found in higher concentrations in plasma than ghrelin, even under energy deficit conditions, and modulates GHSR by inhibiting both ghrelin-dependent and ghrelin-independent activities. Given these characteristics, LEAP2 appears to play a major role in regulating GHSR activity in vivo, extending beyond simple ghrelin antagonism and being crucial for the long-term regulation of energy balance. A deeper understanding of how LEAP2 functions may clarify the functional implications of GHSR in different physiological contexts and unlock new therapeutic strategies for treating obesity, diabetes, and other metabolic disorders.</p>","PeriodicalId":11819,"journal":{"name":"Endocrinology","volume":" ","pages":""},"PeriodicalIF":3.8,"publicationDate":"2025-01-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143002169","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Transcriptional Cofactors for Thyroid Hormone Receptors.","authors":"Megan J Ritter, Izuki Amano, Anthony N Hollenberg","doi":"10.1210/endocr/bqae164","DOIUrl":"10.1210/endocr/bqae164","url":null,"abstract":"<p><p>Thyroid hormone (TH) is essential throughout life. Its actions are mediated primarily by the thyroid hormone receptor (THR), which is a nuclear receptor. Classically, the THRs act as inducible transcription factors. In the absence of TH, a corepressor complex is recruited to the THR to limit TH-related gene expression. In the presence of TH, the corepressor complex is dismissed and a coactivator complex is recruited to facilitate TH-related gene expression. These coregulators can interact with multiple nuclear receptors and are also key in maintaining normal physiologic function. The nuclear receptor corepressor 1 (NCOR1) and the nuclear receptor corepressor 2 (NCOR2) have been the most extensively studied corepressors of the THR involved in histone deacetylation. The steroid receptor coactivator/p160 (SRC) family and in particular, SRC-1, plays a key role in histone acetylation associated with the THR. The Mediator Complex is also required for pretranscription machinery assembly. This mini-review focuses on how these transcriptional cofactors influence TH-action and signaling, primarily via histone modifications.</p>","PeriodicalId":11819,"journal":{"name":"Endocrinology","volume":" ","pages":""},"PeriodicalIF":3.8,"publicationDate":"2025-01-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11702866/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142827745","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"GLP-1 and the Neurobiology of Eating Control: Recent Advances.","authors":"Lauren A Jones, Daniel I Brierley","doi":"10.1210/endocr/bqae167","DOIUrl":"10.1210/endocr/bqae167","url":null,"abstract":"<p><p>Obesity is now considered a chronic relapsing progressive disease, associated with increased all-cause mortality that scales with body weight, affecting more than 1 billion people worldwide. Excess body fat is strongly associated with excess energy intake, and most successful anti-obesity medications (AOMs) counter this positive energy balance through the suppression of eating to drive weight loss. Historically, AOMs have been characterized by modest weight loss and side effects which are compliance-limiting, and in some cases life-threatening. However, the field of obesity pharmacotherapy has now entered a new era of AOMs based on analogues of the gut hormone and neuropeptide glucagon-like peptide-1 (GLP-1). The latest versions of these drugs elicit unprecedented levels of weight loss in clinical trials, which are now starting to be substantiated in real-world usage. Notably, these drugs reduce weight primarily by reducing energy intake, via activation of the GLP-1 receptor on multiple sites of action primarily in the central nervous system, although the most relevant sites of action, and the neural circuits recruited remain contentious. Here we provide a targeted synthesis of recent developments in the field of GLP-1 neurobiology, highlighting studies which have advanced our understanding of how GLP-1 signaling modulates eating, and identify open questions and future challenges we believe still need to be addressed to aid the prevention and/or treatment of obesity.</p>","PeriodicalId":11819,"journal":{"name":"Endocrinology","volume":"166 2","pages":""},"PeriodicalIF":3.8,"publicationDate":"2025-01-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11745901/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143002359","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"GLP-1 and Its Analogs: Does Sex Matter?","authors":"Stina Börchers, Karolina P Skibicka","doi":"10.1210/endocr/bqae165","DOIUrl":"10.1210/endocr/bqae165","url":null,"abstract":"<p><p>While obesity and diabetes are prevalent in both men and women, some aspects of these diseases differ by sex. A new blockbuster class of therapeutics, glucagon-like peptide 1 (GLP-1) analogs (eg, semaglutide), shows promise at curbing both diseases. This review addresses the topic of sex differences in the endogenous and therapeutic actions of GLP-1 and its analogs. Work on sex differences in human studies and animal research is reviewed. Preclinical data on the mechanisms of potential sex differences in the endogenous GLP-1 system as well as the therapeutic effect of GLP-1 analogs, focusing on the effects of the drugs on the brain and behavior relating to appetite and metabolism, are highlighted. Moreover, recent clinical evidence of sex differences in the therapeutic effects of GLP-1 analogs in obesity, diabetes, and cardiovascular disease are discussed. Lastly, we review evidence for the role of GLP-1 analogs in mood and reproductive function, with particular attention to sex differences. Overall, while we did not find evidence for many qualitative sex differences in the therapeutic effect of clinically approved GLP-1 analogs, a growing body of literature highlights quantitative sex differences in the response to GLP-1 and its analogs as well as an interaction of these therapeutics with estrogens. What also clearly emerges is the paucity of data in female animal models or women in very basic aspects of the science of GLP-1-gaps that should be urgently mended, given the growing popularity of these medications, especially in women.</p>","PeriodicalId":11819,"journal":{"name":"Endocrinology","volume":" ","pages":""},"PeriodicalIF":3.8,"publicationDate":"2025-01-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11733500/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142881508","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Mechanisms of Low Temperature-induced GH Resistance via TRPA1 Channel Activation in Male Nile Tilapia.","authors":"Zhikai Cao, Nan Wang, Xinrui Liu, Wenjun Deng, Rui Dong, Quan Jiang","doi":"10.1210/endocr/bqaf013","DOIUrl":"10.1210/endocr/bqaf013","url":null,"abstract":"<p><p>Low temperatures significantly impact growth in ectothermic vertebrates, though the underlying mechanisms remain poorly understood. This study investigates the role of transient receptor potential ankyrin 1 (TRPA1) channels in mediating low-temperature effects on growth performance and GH resistance in Nile tilapia (Oreochromis niloticus). Prolonged exposure to low temperature (16 °C for 35 days) impaired growth performance and induced GH resistance, characterized by elevated serum GH levels and decreased IGF-1 levels. Molecular analysis revealed tissue-specific upregulation of TRPA1 expression in the pituitary and liver under low-temperature conditions, concurrent with alterations in GH/IGF-1 axis-related gene expression. Pharmacological modulation of TRPA1 using an agonist mimicked low-temperature effects on the GH/IGF-1 axis, while an antagonist reversed cold-induced hormonal changes. In vitro experiments with tilapia hepatocytes demonstrated that TRPA1 activation decreased IGF-1 expression through calcium ion/calmodulin-dependent pathways and disrupted GH-induced JAK2/STAT5 signaling. Additionally, TRPA1 activation induced GH receptor degradation primarily through lysosomal pathways, with partial involvement of proteasomal mechanisms. This study is the first to reveal that TRPA1 channels play a crucial role in mediating the effects of low temperature on GH resistance in fish, providing new insights into temperature regulation of endocrine function. The evolutionary conservation of TRPA1 and the GH/IGF-1 axis suggests potential relevance to stress-induced endocrine dysfunction in other vertebrates, including mammals.</p>","PeriodicalId":11819,"journal":{"name":"Endocrinology","volume":" ","pages":""},"PeriodicalIF":3.8,"publicationDate":"2025-01-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143045956","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"A New Leydig Cell-Exclusive Cre Line Allows Lineage Tracing of Fetal and Adult Leydig Cell Populations in the Mouse.","authors":"Nicholas M Robert, Shirley Ferrier-Tarin, Jacques J Tremblay","doi":"10.1210/endocr/bqaf012","DOIUrl":"10.1210/endocr/bqaf012","url":null,"abstract":"<p><p>Leydig cells produce hormones that are required for male development, fertility, and health. Two Leydig cell populations produce these hormones but at different times during development: fetal Leydig cells, which are active during fetal life, and adult Leydig cells, which are functional postnatally. Historically, our ability to understand the origin and function of Leydig cells has been made difficult by the lack of genetic models to exclusively target these cells. Taking advantage of the Leydig cell-exclusive expression pattern of the Insl3 gene, we used a CRISPR/Cas9 gene-editing strategy to knock-in iCre recombinase into the mouse Insl3 locus. To demonstrate the Leydig cell-exclusive nature of our iCre line, lineage-tracing experiments were performed by crossing Insl3iCre mice with a Rosa26LoxSTOPLox-TdTomato reporter. iCre activity was restricted to male offspring. TdTomato fluorescence was detected both in fetal and adult Leydig cells and colocalized with CYP17A1, a classic Leydig cell marker. Prior to birth, fluorescence was observed in fetal Leydig cells beginning at embryonic day 13.0. Fluorescence was also detected in adult Leydig cells starting at postnatal day 5 and continuing to the mature testis. Fluorescence was not detected in any other fetal or adult tissue examined, except for the unexpected finding that the adrenal cortex contains some Insl3-expressing Leydig-like cells. Our Leydig cell-exclusive iCre line therefore constitutes an invaluable new tool to study not only the origin of Leydig cells but also to target genes that have been long-proposed to be important for the development and functioning of these critical endocrine cells.</p>","PeriodicalId":11819,"journal":{"name":"Endocrinology","volume":" ","pages":""},"PeriodicalIF":3.8,"publicationDate":"2025-01-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11772553/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143002198","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Glutamatergic Input From Arcuate Nucleus Kiss1 Neurons to Preoptic Kiss1 Neurons Is Required for LH Surge in Female Mice.","authors":"Jian Qiu, Rajae Talbi, Martha A Bosch, Elizabeth Medve, Larry S Zweifel, Oline K Rønnekleiv, Víctor M Navarro, Martin J Kelly","doi":"10.1210/endocr/bqaf015","DOIUrl":"10.1210/endocr/bqaf015","url":null,"abstract":"<p><p>Hypothalamic kisspeptin (Kiss1) neurons are vital for maintaining fertility in the mammal. In the female rodent, Kiss1 neurons populate the anteroventral periventricular/periventricular nuclei (Kiss1AVPV/PeN) and the arcuate nucleus (Kiss1ARH). Kiss1ARH neurons (also known as KNDy neurons since they coexpress neurokinin B and dynorphin) are considered the \"pulse-generator\" neurons that presynaptically excite gonadotropin-releasing hormone (GnRH) axons in the median eminence, whereas the Kiss1AVPV/PeN neurons are the \"surge-generator\" neurons that depolarize preoptic GnRH neurons directly to drive ovulation. Traditionally, it is believed that Kiss1ARH neurons are relatively quiet during the late follicular, preovulatory stage of the reproductive cycle due to the 17β-estradiol (E2)-mediated downregulation of the expression of the KNDy peptides. However, based on our single-cell, quantitative polymerase chain reaction and whole-cell electrophysiological recordings, we found that the messenger RNA (mRNA) expression of vesicular glutamate transporter 2 (Vglut2) mRNA and excitatory cation channels in Kiss1ARH neurons were significantly upregulated by E2, which increased the excitability and glutamate release from these \"pulse-generator\" neurons. Presently, we demonstrate that optogenetic stimulation of Kiss1ARH neurons releases glutamate to excite Kiss1AVPV/PeN neurons via activation of both ionotropic and metabotropic glutamate receptors. CRISPR mutagenesis of Vglut2 in Kiss1ARH neurons abolished glutamatergic neurotransmission, which significantly reduced the overall glutamatergic input to Kiss1AVPV/PeN neurons. The mutagenesis of Vglut2 in Kiss1ARH neurons abrogated the E2-induced luteinizing hormone surge and reduced the formation of corpus lutea, indicative of a reduced ovulatory drive in these Vglut2-mutated Kiss1ARH mice. Therefore, Kiss1ARH neurons appear to play a critical role in augmenting the GnRH surge through glutamatergic neurotransmission to Kiss1AVPV/PeN neurons.</p>","PeriodicalId":11819,"journal":{"name":"Endocrinology","volume":" ","pages":""},"PeriodicalIF":3.8,"publicationDate":"2025-01-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11788511/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143046022","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Decreasing miR-433-3p Activity in the Osteoblast Lineage Blunts Glucocorticoid-mediated Bone Loss.","authors":"Prachi Thakore, Sangita Karki, Henry C Hrdlicka, John Garcia-Munoz, Renata C Pereira, Anne M Delany","doi":"10.1210/endocr/bqaf008","DOIUrl":"10.1210/endocr/bqaf008","url":null,"abstract":"<p><p>Glucocorticoid excess causes bone loss due to decreased bone formation and increased bone resorption; miR-433-3p is a microRNA (miRNA) that negatively regulates bone formation in male mice by targeting Runx2 as well as RNAs involved in Wnt, protein kinase A, and endogenous glucocorticoid signaling. To examine the impact of miR-433-3p on glucocorticoid-mediated bone loss, transgenic mice expressing a miR-433-3p tough decoy inhibitor in the osteoblast lineage were administered prednisolone via slow-release pellets. Bone loss was greater in control mice treated with prednisolone compared with miR-433-3p tough decoy mice due to higher osteoclast activity in the controls. In whole femurs, Rankl was significantly higher in prednisolone-treated controls compared with miR-433-3p tough decoy mice. Surprisingly, negative regulators of Wnt signaling Sost and Dkk1 were higher in miR-433-3p tough decoy mice and were unaffected by prednisolone. Luciferase- 3'-untranslated region reporter assays demonstrated that Sost is a novel miR-433-3p target, whereas Dkk1 is a previously validated miR-433-3p target. miR-433-3p levels are lower in matrix-synthesizing osteoblasts than in more osteocytic cells; thus the impact of miR-433-3p on the osteoblast lineage may be dependent on cell context: it is a negative regulator in matrix-depositing osteoblasts by targeting RNAs important for differentiation and function but a positive regulator in osteocytes, due to its ability to target prominently expressed negative regulators of Wnt signaling, Sost and Dkk1. The mechanisms by which miR-433-3p indirectly regulates glucocorticoid-mediated osteoclastogenesis remain unknown. However, we speculate that this regulation may be mediated by miR-433-3p activity in osteocytes, which play an important role in controlling osteoclastogenesis.</p>","PeriodicalId":11819,"journal":{"name":"Endocrinology","volume":" ","pages":""},"PeriodicalIF":3.8,"publicationDate":"2025-01-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11791524/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143002222","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Modeling Clinical Radioiodine Uptake By Using Organoids Derived From Differentiated Thyroid Cancer.","authors":"Xinyue Zhang, Jiaye Liu, Yinyun Ni, Ying Yang, Tian Tian, Xiaofeng Zheng, Zhihui Li, Rui Huang","doi":"10.1210/endocr/bqae162","DOIUrl":"10.1210/endocr/bqae162","url":null,"abstract":"<p><p>Radioiodine-refractory differentiated thyroid cancer (RAI-R DTC) accounts for the vast majority of thyroid-related mortality and, until recently, there were limited preclinical models for iodine uptake prediction. In the current study, we aim to establish a primary tumor-derived organoid model of DTC and predict radioiodine (RAI) uptake of tumor residue. The genotypic and phenotypic features between organoid and parental tissue were compared. The RAI uptake assay was used to evaluate the organoid's RAI uptake capacity, and related patients' RAI whole-body scans were used to verify the assay's predictive sensitivity. A total of 20 patient-derived DTC organoids have been established. Whole-exome sequencing and immunofluorescence analysis demonstrated that organoids faithfully recapitulated main features of the original tumor tissue. RAI-avid organoids (n = 11) presented significantly higher RAI uptake than the RAI-refractory (RAI-R) group (n = 9; 384.4 ± 102.7 vs 54.2 ± 13.2 cpm/105 cells, P < .0001). A threshold value in organoids of less than 250 cpm/105 cell was found to have a predictive sensitivity of 95.0% for distinguishing RAI-R from RAI-avid patients when paired to clinical information. Notably, we found that several tyrosine kinase inhibitors moderately re-sensitize iodine uptake by using organoids derived from 3 patients with different genetic mutation backgrounds. In conclusion, patient-derived DTC organoids recapitulated the main characteristics of their parental tissues and preserved ability to uptake radioiodine, showing potential in the development of novel drugs to boost iodine avidity.</p>","PeriodicalId":11819,"journal":{"name":"Endocrinology","volume":" ","pages":""},"PeriodicalIF":3.8,"publicationDate":"2024-11-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142806708","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}