Endocrinology最新文献

Evolution of the complex growth hormone gene cluster in macaques.

IF 3.8 3区医学

Endocrinology Pub Date : 2025-03-19 DOI: 10.1210/endocr/bqaf056

Michael Wallis

{"title":"Evolution of the complex growth hormone gene cluster in macaques.","authors":"Michael Wallis","doi":"10.1210/endocr/bqaf056","DOIUrl":"https://doi.org/10.1210/endocr/bqaf056","url":null,"abstract":"In higher primates, unlike other mammals, the growth hormone (GH) gene locus is complex, comprising several GH-like genes, resulting from gene duplication and divergent evolution, expressed in pituitary and placenta. There are 5 genes in this GH gene cluster in human and 5-7 in apes and most Old-World monkeys, but in macaques the cluster has expanded further. Here the nature and evolution of the GH locus in this important primate genus is explored. Analysis of genomic data for Macaca fascicularis (crab-eating macaque) revealed that the GH gene cluster in this species is variable, with at least 5 different haplotypes, comprising 11-14 GH-like genes. Gene-number heterozygosity was also detected in M. mulatta (rhesus macaque) with 9-13 genes. Analysis of genomic data for other macaque species revealed GH gene clusters containing 8-14 GH-like genes, but gene-number heterozygosity was not detected. Expression of GH-like genes in pituitary and placenta was examined for M. fascicularis. This analysis has established that complexity of the GH gene cluster increased during the evolution of macaques, by gene duplication and divergent evolution, and that these processes continue within at least two extant species. Analysis of rate of sequence change, and distribution of substitutions within the 3D structure, shows that for at least one GH-like gene (GH2) the changes reflect positive selection, implying adaptive biological change. Whether this involves changes in physiological (endocrine) function or response to viral or other pathogenic challenge is not yet clear.","PeriodicalId":11819,"journal":{"name":"Endocrinology","volume":" ","pages":""},"PeriodicalIF":3.8,"publicationDate":"2025-03-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143656542","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}

引用次数: 0

Target Discovery to Diabetes Therapy - TXNIP From Bench to Bedside with NIDDK.

IF 3.8 3区医学

Endocrinology Pub Date : 2025-03-19 DOI: 10.1210/endocr/bqaf055

Anath Shalev

{"title":"Target Discovery to Diabetes Therapy - TXNIP From Bench to Bedside with NIDDK.","authors":"Anath Shalev","doi":"10.1210/endocr/bqaf055","DOIUrl":"https://doi.org/10.1210/endocr/bqaf055","url":null,"abstract":"Diabetes is the most expensive chronic disease in the U.S. with over $400 billion in annual costs and it affects over 38 million Americans. While major advances in drug treatment have been made for type 2 diabetes (T2D) and the often-associated obesity, there are still no approved and effective medications targeting beta cell loss or islet dysfunction, which is one of the major underlying causes of both, type 1 diabetes (T1D) and T2D. In addition, there are no oral medications for T1D approved in the U.S. more than a hundred years after the discovery of insulin and attractive therapeutic targets are only starting to emerge. As we celebrate the 75th anniversary of the National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK), progress is finally being made in this area with NIDDK support. This mini-review follows the discovery of thioredoxin-interacting protein inhibitors as an example of a methodical approach to identify and develop an oral beta cell treatment for T1D. It further discusses how the initial molecular findings were translated into novel clinical treatment approaches that promote the patient's own islet health and beta cell function using drug repurposing as well as new drug discovery.","PeriodicalId":11819,"journal":{"name":"Endocrinology","volume":" ","pages":""},"PeriodicalIF":3.8,"publicationDate":"2025-03-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143656545","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}

引用次数: 0

IGF1 signaling regulates neuropeptide expression in hypothalamic neurons under physiological and pathological conditions.

IF 3.8 3区医学

Endocrinology Pub Date : 2025-03-19 DOI: 10.1210/endocr/bqaf051

Wenyuan He, Neruja Loganathan, Denise D Belsham

引用次数: 0

Manganese-induced precocious puberty alters mammary epithelial cell proliferation in female rats.

IF 3.8 3区医学

Endocrinology Pub Date : 2025-03-19 DOI: 10.1210/endocr/bqaf052

Alina M Hamilton, Vinod K Srivastava, Jill K Hiney, William L Dees, Robert K Dearth

{"title":"Manganese-induced precocious puberty alters mammary epithelial cell proliferation in female rats.","authors":"Alina M Hamilton, Vinod K Srivastava, Jill K Hiney, William L Dees, Robert K Dearth","doi":"10.1210/endocr/bqaf052","DOIUrl":"https://doi.org/10.1210/endocr/bqaf052","url":null,"abstract":"Precocious puberty (PP) is an established breast cancer risk factor. In the normal mammary gland, hormone receptor-positive (HR+) cells rarely proliferate. In breast cancer, proliferating epithelial cells are often HR+. It is not known if PP can modify this population of proliferating HR+ cells. Previously, we established a manganese-induced precocious puberty (MnPP) model to study the effects of PP on mammary gland development in female rats. Herein, we characterized the distribution of HR+ proliferating mammary epithelial cells in prepubertal and adult rodents, in association with precocious puberty. Female rats were exposed daily to 10mg/kg manganese chloride (MnCl2) or saline (control) from post-natal day (PND) 12 to PND 30 Mammary glands were collected on PNDs 30 and 120, processed for western blot analysis and double immunofluorescence staining for proliferating cell nuclear antigen (PCNA) and progesterone receptor (PR) or estrogen receptor (ER). MnPP increased the percentage of HR+ mammary epithelial cells co-expressing PCNA relative to normally developed controls at PND 30. This correlated with increased expression of ER regulated proteins in MnPP mammary glands relative to controls at PND 30, including FOXA1, AREG and c-Myc. Conversely, at PND 120 relative to PND 30, proliferating HR+ cells remained chronically elevated in MnPP mammary glands at PND 120, which coincided with decreased expression of cell cycle regulator, p27, and increased expression of PR-regulated markers, EREG and sp1. Collectively, these results suggest early puberty alters steroidal regulation of classic proliferative mechanisms in the prepubertal gland with increased prevalence of high-risk proliferating HR+ cells.","PeriodicalId":11819,"journal":{"name":"Endocrinology","volume":" ","pages":""},"PeriodicalIF":3.8,"publicationDate":"2025-03-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143656544","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}

引用次数: 0

FVB but Not B6 Mice Carrying the Thr92Ala-Dio2 Polymorphism Have Impaired Thyroid Hormonogenesis and Goiter.

IF 3.8 3区医学

Endocrinology Pub Date : 2025-03-14 DOI: 10.1210/endocr/bqaf046

Alice Batistuzzo, Xiaohan Zhang, Barbara M L C Bocco, Elizabeth A McAninch, Federico Salas-Lucia, Miriam O Ribeiro, Peter Arvan, Antonio C Bianco, Tatiana L Fonseca

{"title":"FVB but Not B6 Mice Carrying the Thr92Ala-Dio2 Polymorphism Have Impaired Thyroid Hormonogenesis and Goiter.","authors":"Alice Batistuzzo, Xiaohan Zhang, Barbara M L C Bocco, Elizabeth A McAninch, Federico Salas-Lucia, Miriam O Ribeiro, Peter Arvan, Antonio C Bianco, Tatiana L Fonseca","doi":"10.1210/endocr/bqaf046","DOIUrl":"https://doi.org/10.1210/endocr/bqaf046","url":null,"abstract":"The Thr92Ala-Dio2 polymorphism is prevalent worldwide, with about 50% of the population carrying at least one allele. The Ala92-Dio2 allele encodes a less active D2 enzyme and has been associated with neurodegenerative diseases, hypertension, and insulin resistance. To understand why its phenotypic effects are variable across different populations, in this study, we examined the impact of genetic background on the Thr92Ala-Dio2 polymorphism. We focused on the thyroid gland of two genetically distant mouse strains, the C57BL/6J (B6) and the FVB/N (FVB). While the B6-Ala92-Dio2 mice have no meaningful phenotype, the FVB-Ala92-Dio2 exhibit a goiter (about 2.3-fold heavier thyroid) with an about 1.7-fold enlarged thyroid follicular area and impaired hormonogenesis with reduced thyroglobulin content of T4 and T3, 35-50%-lower serum T4 and about 3-fold elevated serum TSH levels. Notably, the FVB-Ala92-Dio2 thyroid glands showed transcriptional evidence of endoplasmic reticulum (ER) stress, unfolded protein response (UPR), autophagy, and apoptosis. Female FVB-Ala92-Dio2 mice exhibited a more pronounced thyroid phenotype than males. These findings underscore the critical role of genetic background in modulating the phenotype outcomes of the Thr92Ala-Dio2 polymorphism and highlight its potential implications for understanding variable disease susceptibility in human populations.","PeriodicalId":11819,"journal":{"name":"Endocrinology","volume":" ","pages":""},"PeriodicalIF":3.8,"publicationDate":"2025-03-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143630071","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}

引用次数: 0

Type 2 deiodinase promotes fatty adipogenesis in muscle fibroadipogenic progenitors from adult male mice.

IF 3.8 3区医学

Endocrinology Pub Date : 2025-03-10 DOI: 10.1210/endocr/bqaf050

Cristina Luongo, Daniela Di Girolamo, Raffaele Ambrosio, Sara Di Cintio, Maria Angela De Stefano, Tommaso Porcelli, Domenico Salvatore

{"title":"Type 2 deiodinase promotes fatty adipogenesis in muscle fibroadipogenic progenitors from adult male mice.","authors":"Cristina Luongo, Daniela Di Girolamo, Raffaele Ambrosio, Sara Di Cintio, Maria Angela De Stefano, Tommaso Porcelli, Domenico Salvatore","doi":"10.1210/endocr/bqaf050","DOIUrl":"https://doi.org/10.1210/endocr/bqaf050","url":null,"abstract":"Fibro-adipogenic progenitor cells (FAPs) are a heterogeneous population of multipotent mesenchymal cells that give rise to fibroblasts and adipocytes. In response to muscle injury, FAPs are activated and cooperate with inflammatory and muscle stem cells to promote muscle regeneration. In pathological conditions, such as muscular dystrophies, this coordinated response is partially lost and an accumulation of FAPs is observed which is responsible for a maladaptive fibrosis, ectopic fat deposition and impaired muscle regeneration. The role of intracellular thyroid hormone (TH) signaling in this cellular context is largely unknown. Here we show that intracellular T3 concentration in FAPs is increased in vitro during adipogenic differentiation via the increase of the T3-producing type 2 deiodinase (D2). The adipogenic potential is reduced in FAPs cultured in the presence of rT3, a specific D2 inhibitor, while exogenous administration of THs is able to induce the expression of relevant adipogenic genes. Accordingly, upon genetic D2 depletion in vivo, adipogenesis was significantly reduced in D2KO compared to control mice. These data were confirmed using a FAP-inducible specific D2-KO mouse model, suggesting that a cell-specific D2-depletion in FAPs is sufficient to decrease fatty muscle infiltration and to improve muscle regeneration. Taken together, these data show that TH signaling is dynamically modulated in FAPs wherein D2-produced T3 is required to promote maturation of FAPs into adipocytes.","PeriodicalId":11819,"journal":{"name":"Endocrinology","volume":" ","pages":""},"PeriodicalIF":3.8,"publicationDate":"2025-03-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143585151","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}

引用次数: 0

Role of PROP1 in postnatal pituitary gland maturation.

IF 3.8 3区医学

Endocrinology Pub Date : 2025-03-06 DOI: 10.1210/endocr/bqaf047

Amanda Helen Winningham, Eve Camper Rhoads, Michelle Lynn Brinkmeier, Sebastian Alexis Vishnopolska, Jacob Otto Kitzman, Sally Ann Camper, María Inés Pérez Millán

{"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, María Inés Pérez Millán","doi":"10.1210/endocr/bqaf047","DOIUrl":"https://doi.org/10.1210/endocr/bqaf047","url":null,"abstract":"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.","PeriodicalId":11819,"journal":{"name":"Endocrinology","volume":" ","pages":""},"PeriodicalIF":3.8,"publicationDate":"2025-03-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","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":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Insl3-iCre mouse line: a novel effective tool for targeting Leydig cells to study their development and function.

IF 3.8 3区医学

Endocrinology Pub Date : 2025-03-06 DOI: 10.1210/endocr/bqaf048

Vassilios Papadopoulos

引用次数: 0

KNDy Neurons and the Control of the Gonadotropic Axis in the Midgestation Fetal Sheep.

IF 3.8 3区医学

Endocrinology Pub Date : 2025-03-06 DOI: 10.1210/endocr/bqaf049

Rebecka Amodei, Sonnet S Jonker, Evelyn Lazen, Casey C Nestor, Charles T Estill, Charles E Roselli

{"title":"KNDy Neurons and the Control of the Gonadotropic Axis in the Midgestation Fetal Sheep.","authors":"Rebecka Amodei, Sonnet S Jonker, Evelyn Lazen, Casey C Nestor, Charles T Estill, Charles E Roselli","doi":"10.1210/endocr/bqaf049","DOIUrl":"10.1210/endocr/bqaf049","url":null,"abstract":"KNDy neurons, located in the hypothalamic arcuate nucleus, co-express kisspeptin (Kiss), neurokinin B (NKB), and dynorphin (Dyn) and play a crucial role in regulating GnRH/LH secretion in midgestation sheep fetuses. We hypothesize that KNDy-GnRH signaling is established during midgestation, with negative feedback acting through KNDy neurons regulating testosterone levels needed for brain masculinization in male fetuses. We used immunofluorescence histochemistry to assess the effect of chemical castration with the GnRH antagonist degarelix on arcuate KNDy neurons in fetal sheep. Fluorescent in situ hybridization demonstrated the presence of steroid receptors in untreated midgestation fetal kisspeptin neurons. Additionally, unanesthetized cannulated midgestation fetal sheep were used to examine the effects of KNDy peptides on LH secretion and characterize receptor specificity. Treatment of male lamb fetuses with degarelix on day 62 of gestation resulted in significantly decreased plasma LH and testosterone concentrations (P < 0.05), accompanied by a significant increase in arcuate Kiss neurons (P < 0.05). In unanesthetized cannulated fetuses, bolus administration of KP-10 (a Kiss receptor agonist) and senktide (NK3 receptor agonist) elicited robust LH release within 15 minutes. Pretreatment with the NK3 receptor antagonist SB222200 blocked the LH response to senktide, whereas P271 (Kiss receptor antagonist) did not affect basal LH or block the LH response to KP-10. Blocking κ-opiate receptor (KOR) with PF4455242 significantly increased LH release. These results support the hypothesis that KNDy neurons regulate GnRH and gonadotropin secretion in midgestation sheep fetuses, acting as targets for negative feedback to maintain a stable androgen environment crucial for brain masculinization.","PeriodicalId":11819,"journal":{"name":"Endocrinology","volume":" ","pages":""},"PeriodicalIF":3.8,"publicationDate":"2025-03-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143572571","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}

引用次数: 0

Neurotensin Regulates Primate Ovulation Via Multiple Neurotensin Receptors.

IF 3.8 3区医学

Endocrinology Pub Date : 2025-03-04 DOI: 10.1210/endocr/bqaf041

Andrew C Pearson, Jessica S Miller, Hannah J Jensen, Ketan Shrestha, Thomas E Curry, Diane M Duffy

{"title":"Neurotensin Regulates Primate Ovulation Via Multiple Neurotensin Receptors.","authors":"Andrew C Pearson, Jessica S Miller, Hannah J Jensen, Ketan Shrestha, Thomas E Curry, Diane M Duffy","doi":"10.1210/endocr/bqaf041","DOIUrl":"https://doi.org/10.1210/endocr/bqaf041","url":null,"abstract":"Neurotensin (NTS), a small neuropeptide, was recently established as a key paracrine mediator of ovulation. NTS mRNA is highly expressed by granulosa cells in response to the luteinizing hormone (LH) surge, and multiple NTS receptors are expressed by cells of the ovulatory follicle. To identify the role of NTS receptors NTSR1 and SORT1 in ovulation in vivo, the dominant follicle of cynomolgus macaques (Macaca fascicularis) was injected with either vehicle control, the general NTS receptor antagonist SR142948, the NTSR1-selective antagonist SR48692, or the SORT1-selective antagonist AF38469. Human chorionic gonadotropin (hCG) was then administered to initiate ovulatory events. Ovulation was successful in all control-injected follicles. Rupture sites were smaller or absent after injection with NTS receptor antagonists. Histological analysis of follicles injected with SR142948, SR48692, or AF38469 revealed increased red blood cell extravasation and pooling in the follicle antrum when compared to controls. NTS receptor antagonist-injected follicles also showed dysregulated capillary formation and reduced luteinization of the granulosa cell layer. Prior in vitro studies showed that NTS significantly increased macaque ovarian microvascular endothelial cell (mOMEC) migration, while decreasing monolayer permeability. The NSTR1 antagonist SR48692 or siRNA knockdown of NTSR1 abrogated the ability of NTS to stimulate mOMEC migration and to decrease monolayer permeability. Similar experiments performed with the SORT1 antagonist AF38469 or siRNA knockdown of SORT1 also resulted in ablation of NTS-mediated changes in migration and permeability after SORT1 signaling was impaired. Together, these data implicate both NTSR1 and SORT1 as critical mediators of NTS-stimulated ovulation, luteinization, and angiogenesis of the ovulatory follicle.","PeriodicalId":11819,"journal":{"name":"Endocrinology","volume":" ","pages":""},"PeriodicalIF":3.8,"publicationDate":"2025-03-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143556244","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}

引用次数: 0