Endocrinology最新文献

{"title":"Neuroendocrinology and Genetics of Obesity.","authors":"Rebecca E Ruggiero-Ruff, Djurdjica Coss","doi":"10.1210/endocr/bqaf121","DOIUrl":"https://doi.org/10.1210/endocr/bqaf121","url":null,"abstract":"<p><p>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 impact 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 (GLP-1) agonist medications. Twin studies, however, determined that increased weight has a large genetic component, estimating the heritability of obesity to be 45%-70%. Surprisingly, obesity due to known single gene mutation comprises only 5-10% of individuals, who mostly exhibit early onset severe obesity. Genome-wide linkage studies and association studies identified over 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 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.</p>","PeriodicalId":11819,"journal":{"name":"Endocrinology","volume":" ","pages":""},"PeriodicalIF":3.8,"publicationDate":"2025-07-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144674200","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":"Ablation of steroidogenic superoxide dismutase 2 increases oxidative stress and diminishes steroid hormone production.","authors":"Wen-Jun Shen, Ting-Ting Huang, Yuan Cortez, Syed Kashif Zaidi, Sara Arshad, Fredric B Kraemer, Salman Azhar","doi":"10.1210/endocr/bqaf120","DOIUrl":"https://doi.org/10.1210/endocr/bqaf120","url":null,"abstract":"<p><p>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-qPCR 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.</p>","PeriodicalId":11819,"journal":{"name":"Endocrinology","volume":" ","pages":""},"PeriodicalIF":3.8,"publicationDate":"2025-07-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144636505","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":"Emerging Insights into Brown Adipose Tissue Crosstalk with Pancreatic β-Cells in Metabolic Regulation.","authors":"Chenxu Yan, George Burley, Hanyu Gao, Yan-Chuan Shi","doi":"10.1210/endocr/bqaf118","DOIUrl":"https://doi.org/10.1210/endocr/bqaf118","url":null,"abstract":"<p><p>Brown adipose tissue (BAT), traditionally recognized for its role in thermogenesis, has emerged as an active endocrine organ that coordinates systemic energy expenditure with glucose homeostasis. This review explores the emerging concept of bidirectional crosstalk between BAT and pancreatic β-cells, focusing on potential mechanisms through which BAT may regulate insulin secretion and β-cell survival. In addition to its thermogenic function, BAT serves as a metabolic sink and secretes various hormones (batokines), metabolites, and exosomes that can influence β-cell function directly or indirectly. Key batokines such as FGF21, IL-6, EPDR1, Nrg4 and PLTP have shown potential in preservation β-cell health, although their clinical relevance requires further investigation. Emerging evidence also points to BAT-derived exosomes and microRNAs, including miR-26a, as novel regulators of insulin secretion. Neural mechanisms may contribute to this inter-organ communication via sympathetic and sensory innervation, and BAT-derived neurotrophic factors may modulate autonomic inputs to peripheral tissues, including the pancreas. Conversely, β-cells influence BAT activation via hormonal (e.g., insulin, glucagon), exosomal, and central pathways, forming a proposed BAT-brain-islet axis. This bidirectional communication appears disrupted in obesity and diabetes, where BAT dysfunction and β-cell stress exacerbate metabolic decline. Despite growing interest, mechanistic insights into BAT-islet crosstalk remain incomplete. Future research using omics technologies, co-culture systems and in vivo manipulation models will be critical to identify novel mediators and clarify their roles in metabolic regulation. Understanding this inter-organ communication may offer new therapeutic avenues for obesity and diabetes.</p>","PeriodicalId":11819,"journal":{"name":"Endocrinology","volume":" ","pages":""},"PeriodicalIF":3.8,"publicationDate":"2025-07-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144636506","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":"Epigenomic Modulators and Thyroid Hormone Receptor Beta Agonists: A New Paradigm for Tumor Suppression in Thyroid Cancer.","authors":"John L Rustad, Noelle E Gillis, James Lignos, Kathleen A Bright, Seth Frietze, Frances E Carr","doi":"10.1210/endocr/bqaf116","DOIUrl":"https://doi.org/10.1210/endocr/bqaf116","url":null,"abstract":"<p><p>The transcription factor thyroid hormone receptor beta (TRβ), a recognized tumor suppressor, interacts with chromatin modifying protein complexes to modulate the transcriptome and induce a tumor suppression gene regulatory network. Recent studies have linked poorly differentiated and anaplastic thyroid cancers to aberrant epigenomic signaling, chromatin accessibility, and gene expression. As no enduring treatments are available for these aggressive thyroid cancers and treatment resistant disease, unveiling the epigenomic co-regulatory proteins mediating TRβ signaling will advance the understanding of the molecular mechanisms of TRβ action to block tumor progression and reveal potential novel therapeutic targets. In this review, we summarize novel findings on the epigenomic landscape in the context of TRβ in thyroid malignancy, including the identification of previously unrecognized TRβ interactors and the mapping of nine distinct functional protein communities that constitute the TRβ interactome in thyroid cells. We also explore how targeting TRβ interactors using existing epigenetic enzyme inhibitors-such as HDAC, LSD1, and BET inhibitors-in combination with TRβ agonists, may work synergistically to reprogram tumor epigenetics and suppress oncogenic transcriptional programs.</p>","PeriodicalId":11819,"journal":{"name":"Endocrinology","volume":" ","pages":""},"PeriodicalIF":3.8,"publicationDate":"2025-07-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144636507","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":"Pituitary-targeted knockout of glucocorticoid receptors disrupts growth hormone expression during embryonic development.","authors":"Scott Thomas Klug, Laura E Ellestad, Tom E Porter","doi":"10.1210/endocr/bqaf119","DOIUrl":"https://doi.org/10.1210/endocr/bqaf119","url":null,"abstract":"<p><p>Numerous studies have implicated glucocorticoids in the regulation of somatotroph differentiation. However, few studies have investigated a requirement for glucocorticoid receptors (GR) in this process. We hypothesized that GR is essential for the normal ontogeny of pituitary growth hormone (GH) during mouse embryonic development. Anterior pituitary cells were isolated from e12.5-e13.5 mice and e11 chickens and cultured with or without corticosterone (CORT) in the absence or presence of ZK98299, a GR-specific antagonist. CORT induced GH mRNA expression in pituitary cells from both species, and this response was blocked by inclusion of the GR antagonist. Mouse embryos with pituitary-targeted knockout of GR were generated utilizing the cre-LoxP Recombinase system under control of the pituitary-specific alpha-glycoprotein subunit (αGSU) promoter. All cre-positive GR(-/-) embryos died at birth. Therefore, anterior pituitary, brain, heart, liver, and muscle tissues, were collected on embryonic days 17.5/18.5 for RNA isolation and RT-qPCR analysis. Cre mRNA expression was only found in the pituitary, and GR mRNA levels were significantly decreased in the pituitaries of GR(-/-) embryos. GH mRNA was significantly decreased in pituitary-targeted GR(-/-) knockout embryos in comparison to wild-type GR(+/+) embryos. Significant differences in expression of other pituitary hormones in GR(-/-) embryos were not observed, indicating that the effect of pituitary-targeted knockout of GR was restricted to disruption of GH gene expression. To our knowledge, this is the first report that homozygous GR knockout in the anterior pituitary gland in mice suppresses embryonic GH expression, confirming an essential role for GR signaling in the normal ontogeny of somatotrophs.</p>","PeriodicalId":11819,"journal":{"name":"Endocrinology","volume":" ","pages":""},"PeriodicalIF":3.8,"publicationDate":"2025-07-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144636508","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":"Prolactin Regulates Seasonal Changes in Renal Rheostasis in Djungarian Hamsters.","authors":"Sayantan Sur, Zoe Adam, Timothy A Liddle, Calum Stewart, Irem Denizli, Broderick M B Parks, Leslie S Phillmore, Tyler J Stevenson","doi":"10.1210/endocr/bqaf117","DOIUrl":"https://doi.org/10.1210/endocr/bqaf117","url":null,"abstract":"<p><p>Seasonal changes in photoperiod regulate multiple physiological systems in vertebrates, including metabolism, reproduction, and immune function. Kidney mass and renal physiology are known to vary annually, but the endocrine and molecular mechanisms underlying these changes are poorly defined. Prolactin (PRL), a photosensitive hormone is implicated in seasonal energy rheostasis, yet its role in programmed regulation of renal physiology is unknown. Using Djungarian hamsters (Phodopus sungorus), we investigated how photoperiod and PRL regulate seasonal changes in kidney mass, morphology, and transcriptome. Ingestive behaviour, kidney histology, and transcriptomic profiles were assessed. We found that long photoperiods and PRL treatment induced renal hypertrophy and convoluted tubule (CT) expansion, whereas exposure to short photoperiods resulted in a reduction in all measurements. Transcriptomic analysis revealed photoperiod- and PRL-responsive gene modules related to mitochondrial metabolism, solute transport, and epithelial remodeling. Among these, Cdh2, encoding N-cadherin, was downregulated by long photoperiods and PRL, and negatively correlated with CT diameter, suggesting a role in epithelial adhesion during tubular expansion. These findings place prolactin as a key hormonal effector for programmed seasonal kidney function and identify Cdh2 as a target to drive renal physiology.</p>","PeriodicalId":11819,"journal":{"name":"Endocrinology","volume":" ","pages":""},"PeriodicalIF":3.8,"publicationDate":"2025-07-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144599678","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":"Correction to: \"Developmental Switch from Prolonged Insulin Action to Increased Insulin Sensitivity in Protein Tyrosine Phosphatase 1B-Deficient Hepatocytes\".","authors":"","doi":"10.1210/endocr/bqaf113","DOIUrl":"https://doi.org/10.1210/endocr/bqaf113","url":null,"abstract":"","PeriodicalId":11819,"journal":{"name":"Endocrinology","volume":"166 9","pages":""},"PeriodicalIF":3.8,"publicationDate":"2025-07-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144642141","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":"Role of PROP1 in Postnatal Pituitary Gland Maturation.","authors":"Amanda Helen Winningham, Eve Camper Rhoads, Michelle Lynn Brinkmeier, Sebastian Alexis Vishnopolska, Jacob Otto Kitzman, Sally Ann Camper, Maria Ines Perez-Millan","doi":"10.1210/endocr/bqaf047","DOIUrl":"10.1210/endocr/bqaf047","url":null,"abstract":"<p><p>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.</p>","PeriodicalId":11819,"journal":{"name":"Endocrinology","volume":" ","pages":""},"PeriodicalIF":3.8,"publicationDate":"2025-07-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12235079/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143572574","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":"The Impact of Neuregulin 4 on Metabolic Dysregulation in Lipodystrophy.","authors":"Leonie Wagner, Juliane Estrada-Kunz, Lisa Roth, Juliane Weiner, Susan Kralisch, Annett Hoffmann, Michael Stumvoll, Mathias Fasshauer, Thomas Ebert, Kerstin Krause, Konstanze Miehle, Anke Tönjes","doi":"10.1210/endocr/bqaf112","DOIUrl":"10.1210/endocr/bqaf112","url":null,"abstract":"<p><p>Lipodystrophies (LDs) are rare disorders characterized by the partial or complete loss of subcutaneous adipose tissue, leading to severe metabolic complications. Although metreleptin therapy has shown beneficial effects, its therapeutic efficacy is limited, particularly in patients with partial LD. Neuregulin 4 (NRG4), a batokine secreted by brown adipose tissue, regulates lipid metabolism and hepatic function, but its relevance in LD has not been investigated. In this study, we observed significantly reduced serum NRG4 levels in patients with LD compared to matched healthy controls. NRG4 levels declined further during metreleptin therapy, potentially reflecting fat mass reduction or limited treatment response. To explore functional relevance, we treated a transgenic LD mouse model with recombinant NRG4. While NRG4 enhanced thermogenic gene expression in brown and inguinal white adipose tissue, it did not improve systemic metabolic parameters or hepatic steatosis. In vitro, NRG4 failed to rescue impaired adipogenesis and thermogenesis in brown adipocytes from LD mice but increased insulin-stimulated fatty acid uptake in white adipocytes, indicating a preserved functional response despite differentiation defects. NRG4 also activated hepatic AMPK signaling without improving lipid accumulation. These findings suggest that NRG4 promotes adipose tissue remodeling but is insufficient to restore systemic metabolic homeostasis in LD. Together, our data indicate that NRG4's beneficial effects may depend on the presence of functional adipose tissue, which is profoundly impaired in LD. Consequently, while NRG4 may support local plasticity in adipose tissue, it is insufficient as a therapy for metabolic restoration in LD.</p>","PeriodicalId":11819,"journal":{"name":"Endocrinology","volume":" ","pages":""},"PeriodicalIF":3.8,"publicationDate":"2025-07-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12236340/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144526983","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":"Canine Adrenomedullary and Pheochromocytoma Organoids: A Novel In Vitro Model.","authors":"Marit F van den Berg, Elpetra P M Timmermans-Sprang, Fleur C Viets, Lucas van den Berg, Fatima Danawar, Monique E van Wolferen, Hans S Kooistra, Guy C M Grinwis, Wilhelmina H A de Jong, Martijn van Faassen, Sara Galac","doi":"10.1210/endocr/bqaf114","DOIUrl":"10.1210/endocr/bqaf114","url":null,"abstract":"<p><strong>Context: </strong>Given the lack of effective medical treatment for pheochromocytomas (PCCs), a reliable in vitro model is needed to explore new therapies. Organoids are three-dimensional (3D) self-renewing structures that exhibit key features of their tissue of origin, providing valuable platforms for disease modeling and drug screening.</p><p><strong>Objective: </strong>This study aimed to establish and characterize organoid cultures of canine normal adrenal medullas and PCCs.</p><p><strong>Methods: </strong>Normal adrenal medullas from healthy dogs and tumor tissue from client-owned dogs with PCC were used to develop organoids. Primary cell suspensions were cultured in a 3D matrix, and organoids were established under optimized conditions. Organoids were characterized using histology, immunohistochemistry, immunofluorescence, qPCR, and metanephrine analysis by LC-MS/MS.</p><p><strong>Results: </strong>Five adrenomedullary organoid lines were successfully established, demonstrating sustained growth. Organoid cultures were also derived from 9 PCCs, although expansion was limited after passages 1 to 2. Both adrenomedullary and PCC organoids expressed differentiation markers (chromogranin A, synaptophysin, phenylethanolamine N-methyltransferase) and stem/progenitor markers (nestin, SOX10). Organoids retained key functional traits, as indicated by metanephrine levels in culture supernatants, which initially mirrored primary tumor patterns. A decline in both differentiation marker expression and metanephrine levels was observed over time, possibly due to organoid dedifferentiation or selective loss of differentiated chromaffin cells.</p><p><strong>Conclusion: </strong>This study demonstrates the establishment of the first adrenomedullary and PCC organoid lines. While further optimization is needed, these organoids offer valuable potential as an in vitro model to investigate PCC pathophysiology and explore novel treatment strategies for this therapeutically challenging tumor.</p>","PeriodicalId":11819,"journal":{"name":"Endocrinology","volume":" ","pages":""},"PeriodicalIF":3.8,"publicationDate":"2025-07-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12264429/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144505212","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}