Molecular and Cellular Endocrinology最新文献_第2页

Rapid downregulation of DICER is a hallmark of adipose tissue upon high-fat diet feeding DICER的快速下调是脂肪组织在摄入高脂肪饮食后的一个特征。

IF 3.8 3区医学 Q2 CELL BIOLOGY

Molecular and Cellular Endocrinology

Pub Date : 2024-11-12 DOI: 10.1016/j.mce.2024.112413

Søren Madsen , A. Augusto Peluso , Caio Y. Yonamine , Lars R. Ingerslev , Morten Dall , Patricia S.S. Petersen , Kaja Plucinska , Marta Pradas-Juni , Roger Moreno-Justicia , Alba Gonzalez-Franquesa , Kurt Højlund , Jan-Wilhelm Kornfeld , Brice Emanuelli , Sara G. Vienberg , Jonas T. Treebak

Adipose tissue regulates whole-body energy balance and is crucial for metabolic health. With energy surplus, adipose tissue expands, which may lead to local areas of hypoxia and inflammation, and consequently impair whole-body insulin sensitivity. We report that DICER, a key enzyme for miRNA maturation, is significantly lower in abdominal subcutaneous white adipose tissue of men with obesity compared with men with a lean phenotype. Furthermore, DICER is profoundly downregulated in mouse adipose tissue and liver within the first week on a high-fat diet (HFD), and remains low after prolonged HFD feeding. Downregulation of DICER in mice occurs in both mature adipocytes and stromal vascular cells. Mechanistically, chemically induced hypoxia in vitro shows DICER degradation via interaction with hypoxia-inducible factor 1-α (HIF1α). Moreover, DICER and HIF1α interact in brown adipose tissue post-HFD which may signal for DICER degradation. Finally, RNA sequencing reveals a striking time-dependent downregulation of total miRNA content in mouse subcutaneous adipose tissue after HFD feeding. Collectively, HFD in mice reduces adipose tissue DICER, likely due to hypoxia-induced interaction with HIF1α during tissue expansion, and this significantly impacts miRNA content.

脂肪组织调节全身能量平衡，对新陈代谢健康至关重要。能量过剩时，脂肪组织会膨胀，这可能会导致局部区域缺氧和炎症，从而损害全身胰岛素敏感性。我们报告说，与瘦型男性相比，肥胖男性腹部皮下白色脂肪组织中的 DICER（一种 miRNA 成熟的关键酶）含量明显较低。此外，在小鼠摄入高脂饮食（HFD）的第一周内，DICER在小鼠脂肪组织和肝脏中就会被严重下调，并且在长期摄入HFD后仍保持较低水平。小鼠成熟脂肪细胞和基质血管细胞中的 DICER 均出现下调。从机理上讲，体外化学诱导缺氧显示 DICER 通过与缺氧诱导因子 1-α （HIF1α）相互作用而降解。此外，DICER 和 HIF1α 在高血脂后的棕色脂肪组织中相互作用，这可能是 DICER 降解的信号。最后，RNA 测序显示，小鼠皮下脂肪组织中的 miRNA 总含量在摄入 HFD 后出现了显著的时间依赖性下调。总之，小鼠摄入高氟日粮后，脂肪组织中的DICER减少，这可能是由于组织扩张过程中缺氧诱导的与HIF1α的相互作用，并显著影响了miRNA的含量。

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引用次数: 0

Transforming growth factor β-2 is rhythmically expressed in both WT and BMAL1-deficient hypothalamic neurons and regulates neuropeptide Y: Disruption by palmitate 转化生长因子β-2在WT和BMAL1缺陷的下丘脑神经元中均有节律地表达，并调节神经肽Y：棕榈酸酯的干扰。

IF 3.8 3区医学 Q2 CELL BIOLOGY

Molecular and Cellular Endocrinology

Pub Date : 2024-11-08 DOI: 10.1016/j.mce.2024.112411

Aws F. Mustafa , Wenyuan He , Denise D. Belsham

The hypothalamus contains neuropeptide Y (NPY)-expressing neurons that control food intake and regulate energy homeostasis. During the development of obesity, neuroinflammation occurs in the hypothalamus before peripheral tissues, but the cytokines involved have not been thoroughly studied. Among them is the transforming growth factor beta (TGF-β) family of cytokines. Herein, we demonstrate that Tgfb 1–3, as well as its receptors Tgfbr1 and Tgfbr2, exhibit high levels of expression in the whole hypothalamus, primary hypothalamic culture, and immortalized hypothalamic neurons. Of interest, only Tgfb2 mRNA displays circadian expression in the immortalized hypothalamic neurons and maintains this rhythmicity in BMAL1-KO-derived hypothalamic neurons that are deficient of inherent clock gene rhythmicity. Although BMAL2 may serve as an alternative rhythm generation mechanism in the absence of BMAL1, its knockdown did not affect Tgfb2 expression. Treatment of immortalized NPY-expressing neurons with TGF-β2 upregulates the core circadian oscillators Bmal1 and Nr1d1, and importantly, also Npy mRNA expression. With obesity, the hypothalamus is exposed to elevated levels of palmitate, a saturated fatty acid that promotes neuroinflammation by upregulating pro-inflammatory cytokines. Palmitate treatment disrupts the expression of TGF-β signaling components, increases BMAL1 binding to the Tgfb2 5’ regulatory region, and upregulates Npy mRNA, whereas antagonizing TGFBRI attenuates the upregulation of Npy. These results suggest that hypothalamic neuronal TGF-β2 lies at the intersection of circadian rhythms, feeding neuropeptide control, and neuroinflammation. A better understanding of the underlying mechanisms that link nutrient excess to hypothalamic dysfunction is critical for the development of effective prevention and treatment strategies.

下丘脑中含有表达神经肽 Y（NPY）的神经元，它们能控制食物摄入量并调节能量平衡。在肥胖症的发展过程中，下丘脑的神经炎症先于外周组织发生，但对其中涉及的细胞因子尚未进行深入研究。其中包括转化生长因子β（TGF-β）家族细胞因子。在这里，我们证明了 Tgfb 1-3 及其受体 Tgfbr1 和 Tgfbr2 在整个下丘脑、原代下丘脑培养物和永生化的下丘脑神经元中的高水平表达。有趣的是，只有 Tgfb2 mRNA 在永生化的下丘脑神经元中显示出昼夜节律性表达，并在 BMAL1-KO 衍生的下丘脑神经元中保持这种节律性，而这些神经元缺乏固有的时钟基因节律性。虽然 BMAL2 可能是 BMAL1 缺失时的另一种节律生成机制，但其敲除并不影响 Tgfb2 的表达。用 TGF-β2 处理永生化的 NPY 表达神经元可上调核心昼夜节律振荡器 Bmal1 和 Nr1d1，重要的是还能上调 Npy mRNA 的表达。随着肥胖症的发生，下丘脑暴露于棕榈酸酯水平的升高，棕榈酸酯是一种饱和脂肪酸，它通过上调促炎细胞因子来促进神经炎症。棕榈酸酯处理会破坏 TGF-β 信号元件的表达，增加 BMAL1 与 Tgfb2 5' 调控区的结合，并上调 Npy mRNA，而拮抗 TGFBRI 可减轻 Npy 的上调。这些结果表明，下丘脑神经元 TGF-β2 位于昼夜节律、进食神经肽控制和神经炎症的交叉点。更好地了解将营养过剩与下丘脑功能障碍联系起来的潜在机制对于制定有效的预防和治疗策略至关重要。

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引用次数: 0

Puerarin reduces diabetic nephropathy-induced podocyte pyroptosis by modulating the SIRT1/NLRP3/caspase-1 pathway 葛根素通过调节SIRT1/NLRP3/caspase-1途径减少糖尿病肾病诱导的荚膜细胞脓毒症

IF 3.8 3区医学 Q2 CELL BIOLOGY

Molecular and Cellular Endocrinology

Pub Date : 2024-11-06 DOI: 10.1016/j.mce.2024.112409

Lu Wang , Xiaohai Xie , Qiuyan Chen , Yulin Chen , Xiaohui Xu , Tao Liang

Background

Chronic kidney inflammation and podocyte injury are key pathological features of Diabetic Nephropathy (DN). Puerarin has been shown to inhibit podocyte pyroptosis and provide renal protection, although its molecular mechanism remains unclear.

Methods

The effects and mechanisms of puerarin on podocyte pyroptosis were investigated in a DN mouse model. In vivo, a DN model was established using streptozotocin (STZ) and treated with puerarin, a SIRT1 agonist, or a SIRT1 inhibitor. In vitro, a podocyte pyroptosis model was induced under high glucose (HG) conditions, and lentivirus transfection was used to either silence or overexpress SIRT1. Techniques including ELISA, transmission electron microscopy, flow cytometry, PCR, and Western blotting were employed to explore the molecular mechanisms by which puerarin inhibits podocyte pyroptosis.

Results

The study showed that SIRT1 expression was significantly downregulated in STZ-induced DN mice and HG-induced MPC-5 cell pyroptosis models. Overexpression of SIRT1 decreased the secretion of inflammatory factors, reduced reactive oxygen species (ROS) release, improved podocyte injury, restored podocyte function, and inhibited the expression of the NLRP3 inflammasome and its downstream factors. Furthermore, puerarin increased SIRT1 expression in DN mice and HG-treated MPC-5 cells, inhibited the activation of the NLRP3/Caspase-1 pathway, reduced podocyte pyroptosis, and alleviated renal inflammatory damage.

Conclusion

These findings suggest that puerarin may inhibit podocyte pyroptosis, reduce podocyte injury, and mitigate renal inflammatory damage by modulating the SIRT1/NLRP3/Caspase-1 pathway.

背景：慢性肾脏炎症和荚膜细胞损伤是糖尿病肾病（DN）的主要病理特征。葛根素已被证明可抑制荚膜细胞脓毒症并提供肾脏保护，但其分子机制仍不清楚：方法：在 DN 小鼠模型中研究葛根素对荚膜细胞脓毒症的影响和机制。在体内，使用链脲佐菌素（STZ）建立 DN 模型，并用葛根素、SIRT1 激动剂或 SIRT1 抑制剂治疗。在体外，在高糖（HG）条件下诱导荚膜细胞热解模型，并使用慢病毒转染来沉默或过表达 SIRT1。采用酶联免疫吸附、透射电子显微镜、流式细胞术、PCR和Western印迹等技术探讨葛根素抑制荚膜细胞脓毒症的分子机制：结果：研究表明，SIRT1在STZ诱导的DN小鼠和HG诱导的MPC-5细胞脓毒症模型中表达明显下调。过表达 SIRT1 可减少炎症因子的分泌，降低活性氧（ROS）的释放，改善荚膜细胞损伤，恢复荚膜细胞功能，抑制 NLRP3 炎性体及其下游因子的表达。此外，葛根素还能增加 DN 小鼠和经 HG 处理的 MPC-5 细胞中 SIRT1 的表达，抑制 NLRP3/Caspase-1 通路的激活，减少荚膜细胞的脓毒症，减轻肾脏炎症损伤：这些研究结果表明，葛根素可通过调节SIRT1/NLRP3/Caspase-1通路，抑制荚膜细胞脓毒症，减少荚膜细胞损伤，减轻肾脏炎症损伤。

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引用次数: 0

Female C57BL/6 mice exhibit protection against nonalcoholic fatty liver disease and diabesity accompanied by differential regulation of hepatic lipocalin prostaglandin D2 synthase 雌性 C57BL/6 小鼠对非酒精性脂肪肝和肥胖症的保护作用伴随着肝脏脂联素前列腺素 D2 合成酶的不同调节。

IF 3.8 3区医学 Q2 CELL BIOLOGY

Molecular and Cellular Endocrinology

Pub Date : 2024-11-04 DOI: 10.1016/j.mce.2024.112404

Md Asrarul Islam , Rhema Khairnar , Joshua Fleishman , Sandra E. Reznik , Louis Ragolia , Shruthi Gobbooru , Sunil Kumar

引用次数: 0

PRDM16 in thermogenic adipocytes mediates an inter-organ protective signaling against alcohol-associated liver disease 发热脂肪细胞中的 PRDM16 介导器官间保护信号，防止酒精相关性肝病。

IF 3.8 3区医学 Q2 CELL BIOLOGY

Molecular and Cellular Endocrinology

Pub Date : 2024-11-04 DOI: 10.1016/j.mce.2024.112407

Shanshan Liu , Kezhou Zhu , Yunying Huang , Weilai Ye , Jun Wu

Alcohol-associated liver disease (ALD) is one of the major chronic liver diseases and despite the dire clinical needs and extensive research efforts, no effective therapies are available for late-stages of ALD except for liver transplantation. Adipose tissue dysfunction has been implicated in the progression of ALD. Furthermore, it has been previously suggested that thermogenic fat can be activated after alcohol consumption. In this study, increased thermogenic gene expression was detected in both classical brown adipose tissue and beige adipocytes in mice that were given alcohol challenges even when housed at thermoneutrality. In particular, higher expression level of Prdm16, the key transcriptional co-component for beige fat function, was observed in the subcutaneous fat of mice after alcohol challenges. The objective of the present study is to explore the functional significance of adipocyte PRDM16 in the context of ALD. Even though Prdm16 adipocyte-specific-deleted mice (Prdm16-adKO) did not show liver defects at the basal level, following two different alcohol challenge regimens, exacerbated ALD phenotypes were observed in Prdm16-adKO mice compared to that of the control Prdm16 ^fl/fl mice. Mechanistic investigation suggests that adipose dysfunction after alcohol abuse, including alcohol-induced changes in adipose lipolytic activity, fatty acid oxidation and adipokine levels, may render the worsened ALD phenotype in Prdm16-adKO mice. These results indicate PRDM16-mediated signaling in fat plays a protective role against liver injury caused by alcohol abuse, suggesting it may represent a potential therapeutic target against ALD.

酒精相关性肝病（ALD）是主要的慢性肝病之一，尽管临床需求迫切，研究工作也十分广泛，但除了肝脏移植外，目前还没有针对ALD晚期的有效疗法。脂肪组织功能障碍与 ALD 的进展有关。此外，有研究表明，饮酒后可激活生热脂肪。在本研究中，即使小鼠在恒温饲养条件下接受酒精挑战，也能在其经典棕色脂肪组织和米色脂肪细胞中检测到生热基因表达的增加。特别是，在酒精挑战后的小鼠皮下脂肪中，观察到米色脂肪功能的关键转录辅成分 Prdm16 表达水平较高。本研究旨在探讨脂肪细胞 PRDM16 在 ALD 中的功能意义。尽管Prdm16脂肪细胞特异性缺失小鼠（Prdm16-adKO）在基础水平上没有表现出肝脏缺陷，但在两种不同的酒精挑战方案后，与对照组Prdm16fl/fl小鼠相比，Prdm16-adKO小鼠的ALD表型加剧了。机理研究表明，酒精滥用后的脂肪功能障碍，包括酒精诱导的脂肪分解活性、脂肪酸氧化和脂肪因子水平的变化，可能导致 Prdm16-adKO 小鼠的 ALD 表型恶化。这些结果表明，PRDM16介导的脂肪信号传导对酗酒引起的肝损伤具有保护作用，表明它可能是ALD的潜在治疗靶点。

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引用次数: 0

NLRP3 inhibitor alleviates glycemic variability-induced cognitive impairment in aged rats with type 2 diabetes mellitus NLRP3抑制剂可缓解血糖变化诱发的2型糖尿病老年大鼠认知功能障碍

IF 3.8 3区医学 Q2 CELL BIOLOGY

Molecular and Cellular Endocrinology

Pub Date : 2024-11-01 DOI: 10.1016/j.mce.2024.112406

Wei Yang, Si-Cong Si, Jing Li, Yi-Xin Ma, Huan Zhao, Jia Liu

Glycemic variability (GV) markedly exacerbates cognitive impairment in elderly patients with type 2 diabetes mellitus (T2DM), in part through chronic inflammation. This study investigated the therapeutic efficacy of the NLRP3 inflammasome inhibitor MCC950 in mitigating GV-induced cognitive impairment in an aged rat model of T2DM. Aged Sprague-Dawley rats with induced T2DM were subjected to GV conditions, and the effects of MCC950 were evaluated through measurement of body weight, blood glucose, lipid profiles, insulin level, inflammatory markers, and cognitive function. Transcriptomic analysis was performed on the hippocampus and prefrontal cortex. Treatment with MCC950 significantly alleviated weight loss and hyperglycemia in the GV group compared with the control group. MCC950 also reduced the levels of cholesterol, triglycerides, and pro-inflammatory markers (interleukin-1β (IL-1β) and interleukin-18 (IL-18)). Most notably, MCC950 improved spatial learning and memory retention in the GV group. Immunohistochemical analysis indicated a reduction in inflammasome activation and an increase in the expression level of the neuronal marker NeuN in the hippocampus. Transcriptomic analysis revealed that MCC950 altered neuroactive ligand-receptor interaction pathways in the hippocampus and influenced receptor binding and cell adhesion processes in the prefrontal cortex. These findings validated the efficacy of NLRP3 inhibitor in mitigating GV-induced cognitive impairment in elderly rats with T2DM and provided the basis for subsequent clinical studies exploring the broader potential of NLRP3-targeted interventions in addressing diabetes-associated cognitive impairment.

血糖变异（GV）会明显加剧老年 2 型糖尿病（T2DM）患者的认知障碍，部分原因是慢性炎症。本研究调查了 NLRP3 炎性体抑制剂 MCC950 在老年 T2DM 大鼠模型中减轻 GV 引起的认知障碍的疗效。将诱导 T2DM 的老年 Sprague-Dawley 大鼠置于龙胆紫条件下，通过测量体重、血糖、血脂、胰岛素水平、炎症标志物和认知功能来评估 MCC950 的效果。对海马和前额叶皮层进行了转录组分析。与对照组相比，MCC950能明显减轻龙胆紫组的体重减轻和高血糖症状。MCC950还降低了胆固醇、甘油三酯和促炎标志物（白细胞介素-1β（IL-1β）和白细胞介素-18（IL-18））的水平。最值得注意的是，MCC950能改善龙胆紫组的空间学习能力和记忆保持能力。免疫组化分析表明，炎性体激活减少，海马中神经元标志物 NeuN 的表达水平升高。转录组分析表明，MCC950改变了海马中神经活性配体与受体的相互作用途径，并影响了前额叶皮质中受体结合和细胞粘附过程。这些发现验证了 NLRP3 抑制剂在减轻 GV 诱导的 T2DM 老年大鼠认知功能损害方面的功效，并为后续临床研究提供了基础，以探索 NLRP3 靶向干预在解决糖尿病相关认知功能损害方面的更广泛潜力。

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引用次数: 0

Status of sperm mitochondrial functions and DNA methylation in infertile men with clinical varicocele before and after treatment 临床精索静脉曲张不育男性精子线粒体功能和 DNA 甲基化治疗前后的状况。

IF 3.8 3区医学 Q2 CELL BIOLOGY

Molecular and Cellular Endocrinology

Pub Date : 2024-10-30 DOI: 10.1016/j.mce.2024.112393

Deepshikha Arya , Prakash Pawar , Rahul Gajbhiye , Deepti Tandon , Priyank Kothari , Reshma Goankar , Dipty Singh

Varicocele has been associated with reduced male fertility potential. Treatment modalities for varicocele improve semen parameters, yet more than 50% of cases remain infertile. Varicocele-induced heat and hypoxia stress may affect sperm mitochondrial functions, possibly leading to aberrant epigenetic modifications. This study includes 30 fertile men and 40 infertile men with clinical varicocele. The effect of varicocele treatment (antioxidant supplementation and or varicocelectomy) was evaluated after 3 months of treatment. Mitochondrial membrane potential (MMP) and intracellular reactive oxygen species (iROS) were measured by flow cytometry using JC-1 and DCFDA, respectively. mtDNA copy number and deletions were determined by PCR. DNA methylation was analysed by pyrosequencing. Present investigations suggest that infertile men with varicocele have abnormal semen parameters; significantly low MMP, high iROS, and high mtDNA copy number. Semen parameters were improved in a subset of men of both the treatment modalities; however, it was noted that varicocelectomy helped better in improving sperm parameters compared to antioxidant treatment. Both treatment modalities helped in reducing iROS and mtDNA copy number significantly; however, they were noneffective in improving MMP. Altered DNA methylation at mitochondria D loop and mitochondrial structure and function genes UQCRC2, MIC60, TOM22, and LETM1 (promoter region) were observed in varicocele group. The DNA methylation levels were restored after varicocele treatment; however, the restoration was not consistent at all CpG sites. Both the treatment modalities helped in restoring the altered DNA methylation levels of mitochondrial genes but the restoration is nonhomogeneous across the studied CpG sites.

精索静脉曲张与男性生育能力下降有关。精索静脉曲张的治疗方法可改善精液参数，但仍有 50%以上的病例无法生育。精索静脉曲张诱发的热和缺氧应激可能会影响精子线粒体的功能，从而可能导致异常的表观遗传修饰。这项研究包括 30 名可育男性和 40 名患有临床精索静脉曲张的不育男性。治疗 3 个月后，对精索静脉曲张治疗（补充抗氧化剂和或进行精索静脉曲张切除术）的效果进行了评估。线粒体膜电位（MMP）和细胞内活性氧（iROS）分别通过使用 JC-1 和 DCFDA 的流式细胞术进行测量。DNA甲基化采用热测序法进行分析。目前的研究表明，患有精索静脉曲张的不育男性精液参数异常；MMP明显偏低，iROS偏高，mtDNA拷贝数偏高。两种治疗方法都能改善部分男性的精液参数；但与抗氧化剂治疗相比，精索静脉曲张切除术更有助于改善精子参数。两种治疗方法都有助于显著降低iROS和mtDNA拷贝数，但对改善MMP无效。在精索静脉曲张组中，线粒体 D 环和线粒体结构与功能基因 UQCRC2、MIC60、TOM22 和 LETM1（启动子区域）的 DNA 甲基化发生了改变。精索静脉曲张治疗后，DNA 甲基化水平得到了恢复，但并非所有 CpG 位点的甲基化水平都得到了恢复。两种治疗方式都有助于恢复线粒体基因已改变的 DNA 甲基化水平，但在所研究的 CpG 位点上，恢复情况并不一致。

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引用次数: 0

An optimized fractionation method reveals insulin-induced membrane surface localization of GLUT1 to increase glycolysis in LβT2 cells 优化的分馏方法揭示了胰岛素诱导的 GLUT1 膜表面定位增加 LβT2 细胞中的糖酵解。

IF 3.8 3区医学 Q2 CELL BIOLOGY

Molecular and Cellular Endocrinology

Pub Date : 2024-10-29 DOI: 10.1016/j.mce.2024.112405

Olivia Molinar-Inglis , Kiara Wiggins , Anjali Varma , Zena Del Mundo , Jose M. Adame , Alyssa Cozzo , Oscar Muñoz , Uyen-Vy Le , Davina Trinh , Alexis C. Garcia , Metztli Cisneros-Aguirre , Monica L. Gonzalez Ramirez , Jeremiah Keyes , Jin Zhang , Mark A. Lawson , JoAnn Trejo , Dequina A. Nicholas

Insulin is an important regulator of whole-body glucose homeostasis. In insulin sensitive tissues such as muscle and adipose, insulin induces the translocation of glucose transporter 4 (GLUT4) to the cell membrane, thereby increasing glucose uptake. However, insulin also signals in tissues that are not generally associated with glucose homeostasis. In the human reproductive endocrine axis, hyperinsulinemia suppresses the secretion of gonadotropins from gonadotrope cells of the anterior pituitary, thereby linking insulin dysregulation to suboptimal reproductive health. In the mouse, gonadotropes express the insulin receptor which has the canonical signaling response of IRS, AKT, and mTOR activation. However, the functional outcomes of insulin action on gonadotropes are unclear. Here, we demonstrate through use of an optimized cell fractionation protocol that insulin stimulation of the LβT2 gonadotropic cell line results in the unexpected translocation of GLUT1 to the plasma membrane. Using our high purity fractionation protocol, we further demonstrate that though Akt signaling in response to insulin is intact, insulin-induced translocation of GLUT1 occurs independently of Akt activation in LβT2 cells.

胰岛素是全身葡萄糖平衡的重要调节剂。在肌肉和脂肪等对胰岛素敏感的组织中，胰岛素会诱导葡萄糖转运体 4（GLUT4）转运到细胞膜上，从而增加葡萄糖的摄取。然而，胰岛素也会在通常与葡萄糖平衡无关的组织中发出信号。在人类生殖内分泌轴中，高胰岛素血症会抑制垂体前叶促性腺激素细胞分泌促性腺激素，从而将胰岛素失调与生殖健康不良联系起来。在小鼠体内，促性腺激素表达胰岛素受体，而胰岛素受体具有激活 IRS、AKT 和 mTOR 的典型信号反应。然而，胰岛素作用于促性腺激素的功能结果尚不清楚。在这里，我们通过使用优化的细胞分馏方案证明，胰岛素刺激 LβT2 促性腺激素细胞系会导致 GLUT1 意外地转位到质膜上。利用我们的高纯度分馏方案，我们进一步证明，尽管对胰岛素做出反应的 Akt 信号是完整的，但胰岛素诱导的 GLUT1 转位在 LβT2 细胞中的发生与 Akt 激活无关。

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引用次数: 0

FSH increases lipid droplet content by regulating the expression of genes related to lipid storage in Rat Sertoli cells FSH 通过调节大鼠 Sertoli 细胞中脂质储存相关基因的表达增加脂滴含量

IF 3.8 3区医学 Q2 CELL BIOLOGY

Molecular and Cellular Endocrinology

Pub Date : 2024-10-28 DOI: 10.1016/j.mce.2024.112403

Marina Ercilia Dasso, Cecilia Lucia Centola, Maria Noel Galardo, Maria Fernanda Riera, Silvina Beatriz Meroni

Sertoli cells (SCs) are essential for appropriate spermatogenesis. From a metabolic standpoint, they catabolize glucose and provide germ cells with lactate, which is their main energy source. SCs also oxidize fatty acids (FAs), which are stored as triacylglycerides (TAGs) within lipid droplets (LDs), to fulfill their own energy requirements. On the other hand, it has been demonstrated that FSH regulates some of SCs functions, but little is known about its effect on lipid metabolism. In the present study, we aimed to analyze FSH-mediated regulation of (1) lipid storage in LDs and (2) the expression of genes involved in FAs activation and TAG synthesis and storage in SCs. SCs obtained from 20-day-old rats were cultured for different incubation periods with FSH (100 ng/ml). It was observed that FSH increased LD content and TAG levels in SCs. There were also increments in the expression of Plin1, Fabp5, Acsl1, Acsl4, Gpat3, and Dgat1, which suggests that these proteins may mediate the increase in TAGs and LDs elicited by FSH. Regarding the signaling involved in FSH actions, it was observed that dbcAMP increased LD, and H89, a PKA inhibitor, inhibited FSH stimulus. Also, dbcAMP increased Plin2, Fabp5, Acsl1, Acsl4, and Dgat1 mRNA levels, confirming a role of the cAMP/PKA pathway in the regulation of lipid storage in SCs. Altogether, these results suggest that FSH, via the cAMP/PKA pathway, regulates lipid storage in SCs ensuring the availability of substrates to satisfy their energy requirements.

正常的精子发生离不开肥大细胞（SC）。从新陈代谢的角度来看，它们分解葡萄糖并为生殖细胞提供乳酸，这是它们的主要能量来源。生精细胞还会氧化脂肪酸（FA），以三酰甘油（TAG）的形式储存在脂滴（LD）中，以满足自身的能量需求。另一方面，已有研究表明 FSH 可调节 SCs 的某些功能，但对其对脂质代谢的影响却知之甚少。在本研究中，我们旨在分析 FSH 介导的（1）LDs 脂质储存和（2）SCs 中参与 FAs 激活和 TAG 合成及储存的基因表达的调控。用 FSH（100 毫微克/毫升）培养 20 天龄大鼠的 SCs 不同孵育期。结果发现，FSH 增加了 SCs 中的 LD 含量和 TAG 水平。Plin1、Fabp5、Acsl1、Acsl4、Gpat3和Dgat1的表达也有所增加，这表明这些蛋白可能介导了FSH引起的TAG和LD的增加。关于参与 FSH 作用的信号传导，观察到 dbcAMP 增加了 LD，而 PKA 抑制剂 H89 抑制了 FSH 的刺激。此外，dbcAMP 还增加了 Plin2、Fabp5、Acsl1、Acsl4 和 Dgat1 的 mRNA 水平，证实了 cAMP/PKA 通路在调节 SCs 脂质储存中的作用。总之，这些结果表明，FSH通过cAMP/PKA途径调节SCs的脂质储存，确保底物的可用性以满足其能量需求。

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引用次数: 0

Selenoprotein M protects cardiac endothelial cell integrity against high-glucose stress via enhancing Parkin-mediated mitophagy 硒蛋白M通过增强Parkin介导的有丝分裂来保护心脏内皮细胞的完整性，使其免受高葡萄糖应激的影响。

IF 3.8 3区医学 Q2 CELL BIOLOGY

Molecular and Cellular Endocrinology

Pub Date : 2024-10-23 DOI: 10.1016/j.mce.2024.112392

Bin Zhao , Wen-Liang Tan , Bing-Bo Yu , Jun Fan , Chang Liu , Jian Liu , Zhen Liu

Selenoprotein M (SELENOM) has emerged as a crucial factor in maintaining cellular redox homeostasis and mitigating oxidative damage. This study aims to investigate its protective role in cardiac endothelial cells under hyperglycemic stress, a condition commonly associated with diabetes mellitus and its cardiovascular complications. Diabetic mice model and human umbilical vein endothelial cells (HUVECs) were applied for in vivo and in vitro studies. Results reveal that hyperglycemia significantly downregulates SELENOM expression in both diabetic mouse hearts and primary cultured cardiac endothelial cells. Overexpression of SELENOM in HUVECs mitigated high-glucose-induced FITC-Dextran diffusion and the loss of transendothelial electrical resistance. Additionally, SELENOM overexpression decreased reactive oxygen species (ROS) levels, preserved tight junction protein expression, and maintained cellular structural integrity under hyperglycemic conditions. Furthermore, SELENOM overexpression attenuated high-glucose-induced mitochondrial apoptosis. High-glucose conditions decreased Parkin and increased p62 and Beclin1 expressions. SELENOM overexpression restored Parkin levels and promoted co-localization of LAMP1 and TOMM20. Knockdown of Parkin significantly attenuated these protective effects, suggesting the importance of Parkin in Selenoprotein M-mediated mitophagy. Collectively, these findings suggest that Selenoprotein M enhances Parkin-mediated mitophagy to protect endothelial cells from hyperglycemic stress, offering potential therapeutic insights for diabetic cardiovascular complications.

硒蛋白M（SELENOM）已成为维持细胞氧化还原平衡和减轻氧化损伤的关键因素。本研究旨在探讨硒蛋白 M 在高血糖应激状态下对心脏内皮细胞的保护作用，高血糖应激状态通常与糖尿病及其心血管并发症有关。研究采用糖尿病小鼠模型和人脐静脉内皮细胞（HUVECs）进行体内和体外研究。结果发现，高血糖会显著下调糖尿病小鼠心脏和原代培养的心脏内皮细胞中SELENOM的表达。SELENOM在HUVECs中的过表达减轻了高血糖诱导的FITC-二聚体扩散和跨内皮电阻的损失。此外，SELENOM的过表达降低了活性氧（ROS）水平，保护了紧密连接蛋白的表达，并在高血糖条件下保持了细胞结构的完整性。此外，SELENOM的过表达还减轻了高血糖诱导的线粒体凋亡。高血糖条件减少了Parkin的表达，增加了p62和Beclin1的表达。SELENOM的过表达恢复了Parkin的水平，并促进了LAMP1和TOMM20的共定位。敲除Parkin能明显减弱这些保护作用，表明Parkin在硒蛋白M介导的有丝分裂中的重要性。总之，这些研究结果表明，硒蛋白M能增强Parkin介导的有丝分裂，保护内皮细胞免受高血糖应激，为糖尿病心血管并发症提供了潜在的治疗思路。

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