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Insulin signaling in the heart is impaired by growth hormone: a direct and early event. 心脏中的胰岛素信号受到生长激素的损害:这是一个直接和早期的事件。
IF 3.5 4区 医学 Q2 ENDOCRINOLOGY & METABOLISM Pub Date : 2022-08-01 DOI: 10.1530/JME-21-0242
Marina C Muñoz, Verónica G Piazza, Valeria Burghi, Jorge F Giani, Carolina S Martinez, Nadia S Cicconi, Nadia V Muia, Yimin Fang, Sergio Lavandero, Ana I Sotelo, Andrzej Bartke, Patricia A Pennisi, Fernando P Dominici, Johanna G Miquet
Growth hormone (GH) exerts major actions in cardiac growth and metabolism. Considering the important role of insulin in the heart and the well-established anti-insulin effects of GH, cardiac insulin resistance may play a role in the cardiopathology observed in acromegalic patients. As conditions of prolonged exposure to GH are associated with a concomitant increase of circulating GH, IGF-1 and insulin levels, to dissect the direct effects of GH, in this study we evaluated the activation of insulin signaling in the heart using four different models: 1) transgenic mice overexpressing GH, with chronically elevated GH, IGF-1 and insulin circulating levels, 2) liver IGF-1-deficient mice, with chronically elevated GH and insulin but decreased IGF-1 circulating levels, 3) mice treated with GH for a short period of time, and 4) primary culture of rat cardiomyocytes incubated with GH. Despite the differences in the development of cardiomegaly and in the metabolic alterations among the three experimental mouse models analysed, exposure to GH was consistently associated with a decreased response to acute insulin stimulation in the heart at the receptor level and through the PI3K/Akt pathway. Moreover, a blunted response to insulin stimulation of this signaling pathway was also observed in cultured cardiomyocytes of neonatal rats incubated with GH. Therefore, the key novel finding of this work is that impairment of insulin signaling in the heart is a direct and early event observed as a consequence of exposure to GH, which may play a major role in the development of cardiac pathology.
生长激素(GH)在心脏生长和代谢中发挥重要作用。考虑到胰岛素在心脏中的重要作用以及生长激素的抗胰岛素作用,心脏胰岛素抵抗可能在肢端肥大症患者的心脏病理中起作用。由于长期暴露于生长激素的条件与伴随的循环生长激素、IGF1和胰岛素水平的增加有关,为了解剖生长激素的直接影响,在本研究中,我们使用四种不同的模型评估了心脏中胰岛素信号的激活:(i)转基因小鼠过度表达生长激素,长期升高生长激素、IGF1和胰岛素循环水平;(ii)肝脏IGF1缺陷小鼠,生长激素和胰岛素长期升高,但IGF1循环水平降低;(iii)短时间用生长激素治疗小鼠;(iv) GH孵育大鼠心肌细胞的原代培养。尽管所分析的三种实验小鼠模型在心脏肥大的发展和代谢改变方面存在差异,但生长激素暴露始终与心脏受体水平和PI3K/AKT通路对急性胰岛素刺激的反应降低有关。此外,在GH培养的新生大鼠心肌细胞中也观察到胰岛素刺激对该信号通路的迟钝反应。因此,这项工作的关键新发现是心脏中胰岛素信号的损伤是暴露于生长激素的直接和早期事件,这可能在心脏病理的发展中起主要作用。
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引用次数: 0
Temporal regulation of interferon signalling in human EndoC-βH1 cells. 人EndoC-βH1细胞干扰素信号传导的时间调控。
IF 3.5 4区 医学 Q2 ENDOCRINOLOGY & METABOLISM Pub Date : 2022-05-19 DOI: 10.1530/JME-21-0224
Shalinee Dhayal, Kaiyven Afi Leslie, Mohammad Baity, Pouria Akhbari, Sarah J Richardson, Mark A Russell, Noel G Morgan

During the development of type 1 diabetes, interferons (IFN) are elaborated from islet-infiltrating immune cells and/or from virally infected β-cells. They act via specific receptors to increase, acutely, the phosphorylation of the transcription factors STAT1 and 2. However, the longer-term impacts of chronic IFN stimulation are poorly understood and were investigated in the current study. Human EndoC-βH1 cells were treated with IFNα, IFNγ or IFNλ either acutely (<2 h) or chronically (≥24 h) and STAT phosphorylation, expression and activity were assessed by Western blotting and transcriptional reporter assays. Exposure of β-cells to IFNα or IFNλ induced a swift increase in the phosphorylation of both STAT1 and STAT2, whereas IFNγ increased only pSTAT1. Over more extended periods (≥24 h), STAT phosphorylation declined but STAT1 and STAT2 expression were enhanced in a sustained manner. All IFNs stimulated ISRE transcriptional activity (but with different time courses), whereas GAS activity was responsive only to IFNγ. The re-addition of a second bolus of IFNα, 24 h after an initial dose, failed to cause renewed STAT1/2 phosphorylation. By contrast, when IFNγ was added 24 h after exposure to IFNα, rapid STAT1 phosphorylation was re-initiated. Exposure of β-cells to IFNs leads to rapid, transient, STAT phosphorylation and to slower and more sustained increases in total STAT1/2 levels. The initial phosphorylation response is accompanied by marked desensitisation to the cognate agonist. Together, the results reveal that the response of β-cells to IFNs is regulated both temporally and quantitatively to achieve effective signal integration.

在1型糖尿病的发展过程中,干扰素(IFN)是从胰岛浸润免疫细胞和/或病毒感染的β细胞中产生的。它们通过特异性受体作用,急剧增加转录因子STAT1和2的磷酸化。然而,人们对慢性IFN刺激的长期影响知之甚少,并在当前的研究中进行了调查。用IFNα、IFNγ或IFNλ急性处理人EndoC-βH1细胞(
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引用次数: 3
Genetic bases of pheochromocytoma and paraganglioma. 嗜铬细胞瘤和副神经节瘤的遗传基础。
IF 3.5 4区 医学 Q2 ENDOCRINOLOGY & METABOLISM Pub Date : 2022-05-07 DOI: 10.1530/endoabs.81.s9.1
A. Cascón, Bruna Calsina, María Monteagudo, Sara Mellid, Alberto Díaz-Talavera, M. Currás-Freixes, M. Robledo
The genetics of pheochromocytoma and paraganglioma (PPGL) has become increasingly complex over the last two decades. The list of genes involved in the development of these tumors has grown steadily, and there are currently more than 20 driver genes implicated in either the hereditary or the sporadic nature of the disease. Although genetic diagnosis is achieved in about 75-80% of patients, the genetic aetiology remains unexplained in a significant percentage of cases. Patients lacking a genetic diagnosis include not only those with apparently sporadic PPGL, but also patients with a family history of the disease or with multiple tumors, that meet the criteria to be considered as candidates for carrying germline mutations in yet undiscovered genes. Mutations in known PPGL genes deregulate three main signaling pathways (hypoxia, kinase signaling and wnt-signaling pathways), which could be the starting point for the development of a personalised treatment for PPGL patients. Furthermore, the integration of results from several genomic high-throughput platforms enables the discovery of regulatory mechanisms that cannot be identified by analyzing each piece of information separately. These strategies are powerful tools for elucidating optimal therapeutic options based on molecular biomarkers in PPGL, and represent an important step towards the achievement of precision medicine for patients with metastatic PPGL.
嗜铬细胞瘤和副神经节瘤(PPGL)的遗传学在过去二十年中变得越来越复杂。参与这些肿瘤发展的基因列表稳步增长,目前有20多个驱动基因与该疾病的遗传性或散发性有关。尽管在大约75-80%的患者中实现了基因诊断,但在很大一部分病例中,遗传病因仍然无法解释。缺乏基因诊断的患者不仅包括那些明显散发性PPGL的患者,还包括有该疾病家族史或有多发肿瘤的患者,这些患者符合在尚未发现的基因中携带种系突变的候选标准。已知PPGL基因的突变解除了三种主要信号通路(缺氧、激酶信号通路和wnt信号通路)的调控,这可能是开发PPGL患者个性化治疗的起点。此外,整合来自几个基因组高通量平台的结果能够发现无法通过单独分析每条信息来识别的调控机制。这些策略是阐明基于PPGL分子生物标志物的最佳治疗方案的有力工具,也是实现转移性PPGL患者精准医疗的重要一步。
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引用次数: 3
The Chd4 subunit of the NuRD complex regulates Pdx1-controlled genes involved in β-cell function. NuRD复合体的Chd4亚基调节参与β细胞功能的pdx1控制基因。
IF 3.5 4区 医学 Q2 ENDOCRINOLOGY & METABOLISM Pub Date : 2022-05-01 DOI: 10.1530/JME-22-0011
Rebecca K Davidson, Staci A. Weaver, Nolan Casey, Sukrati Kanojia, Elise Hogarth, Rebecca Schneider Aguirre, E. Sims, C. Evans-Molina, Jason M Spaeth
Type 2 diabetes (T2D) is associated with loss of transcription factors (TFs) from a subset of failing β-cells. Among these TFs is Pdx1, which controls the expression of numerous genes involved in maintaining β-cell function and identity. Pdx1 activity is modulated by transcriptional coregulators and has recently been shown, through an unbiased screen, to interact with the Chd4 ATPase subunit of the Nucleosome Remodeling and Deacetylase complex. Chd4 contributes to the maintenance of cellular identity and functional status of numerous different cell types. Here, we demonstrate Pdx1 dynamically interacts with Chd4 under physiological and stimulatory conditions within islet β-cells. We establish a fundamental role for Chd4 in regulating insulin secretion and modulating numerous Pdx1 bound genes in vitro, including the MafA TF, where we discovered Chd4 is bound at the MafA Region 3 enhancer. Furthermore, we found that Pdx1:Chd4 interactions are significantly compromised in islet β-cells under metabolically-induced stress in vivo and in human donor tissues with T2D. Our findings establish a fundamental role for Chd4 in regulating insulin secretion and modulating Pdx1-bound genes in vitro, and disruption of Pdx1:Chd4 interactions coincides with β-cell dysfunction associated with T2D.
2型糖尿病(T2D)与β细胞亚群中转录因子(TFs)的缺失有关。在这些tf中有Pdx1,它控制许多参与维持β细胞功能和身份的基因的表达。Pdx1活性由转录共调节因子调节,最近通过无偏筛选显示,Pdx1活性与核小体重塑和去乙酰化酶复合物的Chd4 atp酶亚基相互作用。Chd4有助于维持许多不同细胞类型的细胞身份和功能状态。在这里,我们证明了Pdx1在生理和刺激条件下与Chd4在胰岛β细胞内动态相互作用。我们确定了Chd4在体外调节胰岛素分泌和调节许多Pdx1结合基因中的基本作用,包括MafA TF,其中我们发现Chd4结合在MafA区域3增强子上。此外,我们发现体内代谢诱导应激下胰岛β细胞中Pdx1:Chd4的相互作用在T2D患者供体组织中显著受损。我们的研究结果证实了Chd4在体外调节胰岛素分泌和调节Pdx1结合基因中的基本作用,并且Pdx1:Chd4相互作用的破坏与T2D相关的β细胞功能障碍相吻合。
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引用次数: 2
Liraglutide stimulates the β-catenin signaling cascade in mouse epididymal fat tissue. 利拉鲁肽刺激小鼠附睾脂肪组织中的β-连环蛋白信号级联反应。
IF 3.5 4区 医学 Q2 ENDOCRINOLOGY & METABOLISM Pub Date : 2022-05-01 DOI: 10.1530/JME-22-0026
J. Gu, W. Shao, Di Liu, Jiajun Feng, Juan Pang, T. Jin
Although canonical Wnt signaling pathway activation was shown to negatively regulate adipogenesis, recent investigations suggest that Wnt pathway effectors TCF7L2 and β-catenin (β-cat) in adipose tissues are also involved in energy homeostasis during adulthood. In assessing metabolic beneficial effect of GLP-1-based diabetes-drugs in high fat diet (HFD) challenged mice, we observed that liraglutide treatment affected expression of a battery of adipose tissue-specific genes, including that encode adiponectin and leptin, mainly in epididymal white adipose tissue (eWAT). Fourteen-week HFD challenge repressed TCF7L2 and β-cat S675 phosphorylation in eWAT while such repression was reversed by liraglutide treatment (150 µg/kg body weight daily) during week 10 to week 14. In Glp1r-/- mice, liraglutide failed in stimulating TCF7L2 or β-cat in eWAT. We detected Glp1r expression in mouse eWAT and its level is enriched in its "stromal vascular fraction" (SVF). Mouse eWAT-SVF showed reduced expression of Tcf7l2 and its Tcf7l2 level could not be stimulated by liraglutide treatment; while following adipogenic differentiation, rat eWAT-SVF showed elevated Tcf7l2 expression. Direct in vitro liraglutide treatment in eWAT-SVF stimulated CREB S133, β-cat S675 phosphorylation, and cellular cAMP level. Thus, cAMP/β-cat signaling cascade can be stimulated by liraglutide in eWAT via GLP-1R expressed in eWAT-SVF.
尽管典型的Wnt信号通路激活被证明对脂肪形成具有负调控作用,但最近的研究表明,脂肪组织中的Wnt通路效应物TCF7L2和β-catenin (β-cat)也参与成年期的能量稳态。在评估基于glp -1的糖尿病药物对高脂肪饮食(HFD)挑战小鼠的代谢有益作用时,我们观察到利拉鲁肽治疗影响了一系列脂肪组织特异性基因的表达,包括编码脂联素和瘦素的基因,主要在附睾白色脂肪组织(eWAT)中。第14周的HFD刺激抑制了eWAT中TCF7L2和β-cat S675的磷酸化,而在第10周至第14周,利拉鲁肽治疗(每天150µg/kg体重)逆转了这种抑制。在Glp1r-/-小鼠中,利拉鲁肽不能刺激eWAT中的TCF7L2或β-cat。我们在小鼠eWAT中检测到Glp1r的表达,其水平在其“基质血管部分”(SVF)中富集。小鼠eWAT-SVF Tcf7l2表达降低,利拉鲁肽不能刺激其Tcf7l2水平;而在成脂分化后,大鼠ewatt - svf显示Tcf7l2表达升高。体外利拉鲁肽直接治疗ewatt - svf刺激CREB S133、β-cat S675磷酸化和细胞cAMP水平。因此,利拉鲁肽可通过eat - svf中表达的GLP-1R刺激eat中cAMP/β-cat信号级联。
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引用次数: 3
Insights of the role of estrogen in obesity from two models of ERα deletion. 雌激素在两种ERα缺失模型中肥胖症中的作用
IF 3.5 4区 医学 Q2 ENDOCRINOLOGY & METABOLISM Pub Date : 2022-04-05 DOI: 10.1530/JME-21-0260
Rocío Del M Saavedra-Peña, Natalia Taylor, Matthew S Rodeheffer

Sex hormones play a pivotal role in physiology and disease. Estrogen, the female sex hormone, has been long implicated in having protective roles against obesity. However, the direct impact of estrogens in white adipose tissue (WAT) function and growth is not understood. Here, we show that the deletion of estrogen receptor alpha (ERα; Esr1) from adipocytes using Adipoq-credoes not affect adipose mass in male or female mice under normal or high-fat diet (HFD) conditions. However, loss of ERα in adipocyte precursor cells (APs) via Pdgfra-cre leads to exacerbated obesity upon HFD feeding in both male and female mice, with s.c. adipose (SWAT)-specific expansion in male mice. Further characterization of these mice revealed infertility and increased plasma levels of sex hormones, including estradiol in female mice and androgens in male mice. These findings compromise the study of estrogen signaling within the adipocyte lineage using the Pdgfra-crestrain. However, AP transplant studies demonstrate that the increased AP hyperplasia in male SWAT upon Pdgfra-cre-mediated ablation of ERα is not driven by AP-intrinsic mechanisms but is rather mediated by off-target effects. These data highlight the inherent difficulties in studying models that disrupt the intricate balance of sex hormones. Thus, better approaches are needed to study the cellular and molecular mechanisms of sex hormones in obesity and disease.

性激素在生理和疾病中起着关键作用。长期以来,人们一直认为雌性激素具有预防肥胖的作用。然而,雌激素对白色脂肪组织(WAT)功能和生长的直接影响尚不清楚。在这里,我们发现雌激素受体α (ERα;在正常或高脂饮食(HFD)条件下,使用adipoq -cred从脂肪细胞中提取Esr1并不影响雄性或雌性小鼠的脂肪量。然而,脂肪细胞前体细胞(APs)中的ERα通过pdgfr -cre丢失,导致雄性和雌性小鼠在高脂饲料喂养后肥胖加剧,雄性小鼠中s.c. adipose (SWAT)特异性扩增。对这些小鼠的进一步表征显示出不育和血浆性激素水平的增加,包括雌性小鼠的雌二醇和雄性小鼠的雄激素水平。这些发现损害了使用pdgfr -crestrain研究脂肪细胞系内雌激素信号的研究。然而,AP移植研究表明,pdgfra -cre介导的ERα消融后,男性SWAT中AP增生增加不是由AP内在机制驱动的,而是由脱靶效应介导的。这些数据凸显了研究破坏性激素复杂平衡的模型所固有的困难。因此,需要更好的方法来研究性激素在肥胖和疾病中的细胞和分子机制。
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引用次数: 1
The AR in bone marrow progenitor cells protects against short-term high caloric diet induced weight gain in male mice. 骨髓祖细胞中的AR对短期高热量饮食引起的雄性小鼠体重增加具有保护作用。
IF 3.5 4区 医学 Q2 ENDOCRINOLOGY & METABOLISM Pub Date : 2022-04-01 DOI: 10.1530/JME-22-0038
V. Venkatesh, P. K. Russell, Barbara Fam White, Michele V. Clarke, S. Golub, Salvatore Mangiofico, Christian Haralambous, J. Lokan, S. Andrikopoulos, J. Zajac, R. Davey
We previously identified a novel pathway of testosterone action via the androgen receptor (AR) in bone marrow mesenchymal precursor cells (BM-PCs) to negatively regulate fat mass and improve metabolic function in male mice. This was achieved using our PC-AR Gene Replacement mouse model in which the AR is only expressed in BM-PCs and deleted in all other tissues. We hypothesise that the markedly reduced fat mass and increased insulin sensitivity of PC-AR Gene Replacements will confer protection from diet-induced overweight and obesity. To test this, 6-week-old male PC-AR Gene Replacements and controls (wild-type (WT), Global-AR knockouts (KOs)) were fed a chow or high caloric diet (HCD) for 8 or 18 weeks. Following 8 weeks (short-term) of HCD, WT and Global-ARKOs had markedly increased subcutaneous white adipose tissue (WAT) and retroperitoneal visceral adipose tissue (VAT) mass compared to chow-fed controls. In contrast, PC-AR Gene Replacements were resistant to WAT and VAT accumulation following short-term HCD feeding accompanied by fewer large adipocytes and upregulation of expression of the metabolic genes Acaca and Pnlpa2. Following long-term HCD feeding for 18 weeks, the PC-AR Gene Replacements were no longer resistant to increased WAT and VAT adiposity; however, maintained their improved whole-body insulin sensitivity with an increased rate of glucose disappearance and increased glucose uptake into subcutaneous WAT. In conclusion, testosterone action via the AR in BM-PCs to negatively regulate fat mass and improve metabolism, confers resistance from short-term diet induced weight gain and partial protection from long-term diet induced obesity in male mice.
我们之前发现了一种新的睾酮作用途径,通过骨髓间充质前体细胞(BM-PCs)中的雄激素受体(AR)负调控雄性小鼠的脂肪量并改善代谢功能。这是使用我们的PC-AR基因置换小鼠模型实现的,其中AR仅在BM PC中表达,并在所有其他组织中缺失。我们假设PC-AR基因替代物显著减少的脂肪量和增加的胰岛素敏感性将提供对饮食诱导的超重和肥胖的保护。为了测试这一点,6周大的雄性PC-AR基因替代物和对照(野生型(WT)、全局AR敲除(KOs))被喂食食物或高热量饮食(HCD)8或18周。HCD治疗8周(短期)后,与食物喂养的对照组相比,WT和Global ARKOs的皮下白色脂肪组织(WAT)和腹膜后内脏脂肪组织(VAT)质量显著增加。相反,PC-AR基因替代物在短期HCD喂养后对WAT和VAT积累具有抗性,同时伴有较少的大脂肪细胞和代谢基因Acaca和Pnlpa2的表达上调。在HCD长期喂养18周后,PC-AR基因替代物对WAT和VAT肥胖增加不再具有抵抗力;然而通过增加葡萄糖消失率和增加皮下WAT的葡萄糖摄取来维持其改善的全身胰岛素敏感性。总之,在雄性小鼠中,睾酮通过BM PC中的AR负调节脂肪量和改善代谢的作用,对短期饮食诱导的体重增加具有抵抗力,并对长期饮食诱导的肥胖具有部分保护作用。
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引用次数: 0
Reviewing the physiological roles of the novel hormone-receptor pair INSL5-RXFP4: a protective energy sensor? 新型激素受体对INSL5-RXFP4的生理作用综述:保护性能量传感器?
IF 3.5 4区 医学 Q2 ENDOCRINOLOGY & METABOLISM Pub Date : 2022-04-01 DOI: 10.1530/JME-21-0241
D. Hechter, Brett Vahkal, Tiana Tiede, S. Good
There is no common consensus for the physiological role of insulin-like peptide 5 (INSL5) and its cognate receptor, relaxin family peptide receptor 4 (RXFP4). The experimental data for INSL5-RXFP4 expression and function point to a potential role of the peptide hormone and receptor pair in linking energy availability, homeostasis and inflammation. In this review, we summarize studies on the INSL5-RXFP4 system and propose that the current findings from diverse experimental settings point broadly to a role as a protective energy sensor (PES). Specifically, we review the evidence that (1) INSL5-RXFP4 could regulate immune response by decreasing the production of proinflammatory cytokines and may be involved in the stress response via the HPA axis; (2) INSL5-RXFP4 may signal through sensory neurons on the vagus nerve, transmitting signals to the central nervous system; and (3) INSL5-RXFP4 could have local autocrine/paracrine roles within the intestinal tract and immune cells. Further investigation and clarification of these proposed roles of INSL5-RXFP4 may prove a greater physiological relevance for the pair and add to existing evidence of INSL5-RXFP4 role as a PES.
胰岛素样肽5(INSL5)及其同源受体松弛素家族肽受体4(RXFP4)的生理作用尚未达成共识。INSL5-RXFP4表达和功能的实验数据表明,肽激素和受体对在连接能量可用性、稳态和炎症方面发挥着潜在作用。在这篇综述中,我们总结了对INSL5-RXFP4系统的研究,并提出目前来自不同实验环境的发现广泛指向保护性能量传感器(PES)的作用。具体而言,我们回顾了以下证据:(1)INSL5-RXFP4可以通过减少促炎细胞因子的产生来调节免疫反应,并可能通过HPA轴参与应激反应;(2) INSL5-RXFP4可能通过迷走神经上的感觉神经元发出信号,将信号传递给中枢神经系统;和(3)INSL5-RXFP4可能在肠道和免疫细胞内具有局部自分泌/旁分泌作用。对INSL5-RXFP4的这些拟议作用的进一步研究和澄清可能证明该对具有更大的生理相关性,并增加INSL5-RXFP4作为PES作用的现有证据。
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引用次数: 5
Endocrine and molecular factors of increased female reproductive performance in the Dummerstorf high-fertility mouse line FL1 Dummerstorf高生育率小鼠系FL1雌性繁殖性能提高的内分泌和分子因素
IF 3.5 4区 医学 Q2 ENDOCRINOLOGY & METABOLISM Pub Date : 2022-04-01 DOI: 10.1530/JME-22-0012
C. Ludwig, Simon Bohleber, A. Rebl, E. Wirth, M. T. Venuto, M. Langhammer, U. Schweizer, J. Weitzel, M. Michaelis
The Dummerstorf high-fertility mouse line FL1 is a worldwide unique selection experiment for increased female reproductive performance. After more than 190 generations of selection, these mice doubled the amount of offspring per litter compared to the unselected control line. FL1 females have a superior lifetime fecundity and the highest Silver fecundity index that has been described in mice, while their offspring show no signs of growth retardation. The reasons for the increased reproductive performance remained unclear. Thus, this study aims to characterize the Dummerstorf high-fertility mouse line FL1 on endocrine and molecular levels on the female side. We analyzed parameters of the hypothalamic pituitary gonadal axis on both hormonal and transcriptional levels. Gonadotropin-releasing hormone and follicle-stimulating hormone (FSH) concentrations were decreased in FL1 throughout the whole estrous cycle. Luteinizing hormone (LH) was increased in FL1 mice in estrus. Progesterone concentrations were decreased in estrus in FL1 mice and not affected in diestrus. We used a holistic gene expression approach in the ovary to obtain a global picture of how the high-fertility phenotype is achieved. We found several differentially expressed genes in the ovaries of FL1 mice that are associated with different female fertility traits. Our results indicate that ovulation rates in mice can be increased despite decreased FSH levels. Cycle-related alterations of progesterone and LH levels have the potential to improve follicular maturation, and interactions of endocrine and molecular factors lead to enhanced follicular survival, more successful folliculogenesis and therefore higher ovulation rates in female FL1 mice.
Dummerstorf高生育力小鼠FL1系是一项世界范围内独特的提高雌性生殖性能的选择实验。经过190多代的选择,这些老鼠每窝的后代数量是未选择的对照组的两倍。FL1雌性具有优越的终身繁殖力和最高的银繁殖力指数,而它们的后代没有生长迟缓的迹象。繁殖能力提高的原因尚不清楚。因此,本研究旨在从雌性内分泌和分子水平对Dummerstorf高生育小鼠系FL1进行表征。我们分析了下丘脑-垂体-性腺轴在激素和转录水平上的参数。促性腺激素释放激素和促卵泡激素(FSH)浓度在整个发情周期内均降低。FL1小鼠发情期黄体生成素(LH)升高。FL1小鼠发情时黄体酮浓度降低,发情时不受影响。我们在卵巢中使用整体基因表达方法来获得如何实现高生育表型的全局图片。我们在FL1小鼠的卵巢中发现了几个差异表达的基因,这些基因与不同的雌性生育特征相关。我们的研究结果表明,尽管卵泡刺激素水平降低,但小鼠的排卵率可以增加。周期相关的黄体酮和LH水平的改变有可能改善卵泡成熟,内分泌和分子因素的相互作用导致卵泡存活率提高,卵泡发生更成功,因此雌性FL1小鼠的排卵率更高。
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引用次数: 1
Evidence that nuclear receptors are related to terpene synthases. 核受体与萜烯合成酶有关的证据。
IF 3.5 4区 医学 Q2 ENDOCRINOLOGY & METABOLISM Pub Date : 2022-03-14 DOI: 10.1530/JME-21-0156
Douglas R Houston, Jane G Hanna, J Constance Lathe, Stephen G Hillier, Richard Lathe

Ligand-activated nuclear receptors (NRs) orchestrate development, growth, and reproduction across all animal lifeforms - the Metazoa - but how NRs evolved remains mysterious. Given the NR ligands including steroids and retinoids are predominantly terpenoids, we asked whether NRs might have evolved from enzymes that catalyze terpene synthesis and metabolism. We provide evidence suggesting that NRs may be related to the terpene synthase (TS) enzyme superfamily. Based on over 10,000 3D structural comparisons, we report that the NR ligand-binding domain and TS enzymes share a conserved core of seven α-helical segments. In addition, the 3D locations of the major ligand-contacting residues are also conserved between the two protein classes. Primary sequence comparisons reveal suggestive similarities specifically between NRs and the subfamily of cis-isoprene transferases, notably with dehydrodolichyl pyrophosphate synthase and its obligate partner, NUS1/NOGOB receptor. Pharmacological overlaps between NRs and TS enzymes add weight to the contention that they share a distant evolutionary origin, and the combined data raise the possibility that a ligand-gated receptor may have arisen from an enzyme antecedent. However, our findings do not formally exclude other interpretations such as convergent evolution, and further analysis will be necessary to confirm the inferred relationship between the two protein classes.

配体激活的核受体(nr)协调所有动物生命形式(后生动物)的发育、生长和繁殖,但nr是如何进化的仍然是个谜。考虑到NR配体包括类固醇和类维生素a主要是萜类,我们想知道NR是否可能是从催化萜类合成和代谢的酶进化而来的。我们提供的证据表明,NRs可能与萜烯合成酶(TS)酶超家族有关。基于超过10,000个三维结构比较,我们报告了NR配体结合域和TS酶具有7个α-螺旋段的保守核心。此外,两类蛋白之间的主要配体接触残基的三维位置也是保守的。一级序列比较揭示了NRs与顺式异戊二烯转移酶亚家族之间的相似性,特别是与脱氢多酚焦磷酸合成酶及其专性伙伴NUS1/NOGOB受体之间的相似性。NRs和TS酶之间的药理学重叠增加了它们具有遥远进化起源的争论的分量,并且综合数据提出了配体门控受体可能来自酶前体的可能性。然而,我们的研究结果并没有正式排除其他解释,如趋同进化,进一步的分析将需要证实两种蛋白质类别之间的推断关系。
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引用次数: 0
期刊
Journal of molecular endocrinology
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