Metabolism: clinical and experimental最新文献_第9页

SRSF1 is essential for pancreatic β-cell proliferation and the maintenance of glucose homeostasis in mice SRSF1对小鼠胰腺β细胞增殖和葡萄糖稳态维持至关重要。

IF 11.9 1区医学 Q1 ENDOCRINOLOGY & METABOLISM

Metabolism: clinical and experimental

Pub Date : 2026-01-01 Epub Date: 2025-10-24 DOI: 10.1016/j.metabol.2025.156421

Xue You , Qian Peng , Wenju Qian , Zhiqin Xie , Yijun Lin , Yikuo Gai , Jingran Ye , Ying Feng

Background

β-Cell proliferation is vital for adapting to metabolic stress. Failure to expand β-cell mass during insulin resistance and aging contributes to dysfunction and diabetes. Understanding the mechanisms behind β-cell proliferation issues and dysfunction is crucial. SRSF1 is a central regulator of cell proliferation and survival, but its influence on β-cell proliferation and glucose control remains unclear. This study aims to investigate the role of SRSF1 in β-cell proliferation and its impact on glucose regulation. By examining the consequences of SRSF1 deficiency in pancreatic β-cells, we seek to elucidate the mechanisms linking SRSF1 to β-cell maintenance and function.

Methods

Mice with pancreatic β-cell-specific deletion of SRSF1 and a Rosa26-tdT lineage reporter were generated. Pancreatic sections were analyzed using immunostaining for insulin, glucagon, somatostatin, Ki67, tdT, proinsulin, TUNEL, and ER stress markers, as well as HE staining. Glucose tolerance tests, glucose and insulin measurements were performed in knockout and control mice. RNA-seq analyzed gene expression changes in 4-month-old islets, while scRNA-seq assessed cellular heterogeneity and gene expression profiles in 10-month-old mice islets. Knockdown assays and puromycin labeling experiments measured new protein synthesis.

Results

SRSF1 deficiency resulted in glucose intolerance and impaired insulin secretion, worsening with age. At early stages, knockout islets exhibited reduced β-cell proliferation accompanied by compensatory α-cell expansion. By 4 months, RNA-seq analysis showed downregulation of ribosome biogenesis and cell cycle genes, along with upregulation of α-cell determinants and progenitor-associated factors. Histological examination further revealed a decreased β-cell fraction, an increased α-cell fraction, and a small subset of α-cells co-expressing somatostatin, indicative of transient, stress-associated phenotypic plasticity. scRNA-seq identified ER stress and altered β-cell fate in knockout β-cells from 10-month-old mice. Notably, these changes were absent in 4-month-old knockout islets, indicating ER stress as a secondary response to proliferative defects from SRSF1 deficiency. Mechanistically, SRSF1 employs mechanisms similar to MYC to promote β-cell proliferation, with its effects on β-cells through the regulation of MYC expression.

Conclusions

SRSF1 is essential for β-cell proliferation and function through MYC-mediated pathways. Its deficiency disrupts β-cell homeostasis and contributes to metabolic dysfunction in mice, underscoring its importance in preserving functional β-cells and maintaining glucose balance.

背景：β-细胞增殖对适应代谢应激至关重要。在胰岛素抵抗和衰老过程中，β细胞质量扩大失败会导致功能障碍和糖尿病。了解β细胞增殖问题和功能障碍背后的机制至关重要。SRSF1是细胞增殖和存活的中心调节因子，但其对β-细胞增殖和葡萄糖控制的影响尚不清楚。本研究旨在探讨SRSF1在β-细胞增殖中的作用及其对葡萄糖调节的影响。通过研究胰腺β细胞中SRSF1缺乏的后果，我们试图阐明SRSF1与β细胞维持和功能之间的联系机制。方法：生成胰腺β细胞特异性缺失SRSF1和Rosa26-tdT谱系报告基因的小鼠。胰腺切片采用胰岛素、胰高血糖素、生长抑素、Ki67、tdT、胰岛素原、TUNEL和内质网应激标志物的免疫染色和HE染色进行分析。在敲除小鼠和对照小鼠中进行葡萄糖耐量试验、葡萄糖和胰岛素测量。RNA-seq分析了4月龄小鼠胰岛的基因表达变化，而scRNA-seq评估了10月龄小鼠胰岛的细胞异质性和基因表达谱。敲低实验和嘌呤霉素标记实验测量了新蛋白的合成。结果：SRSF1缺乏导致葡萄糖耐受不良，胰岛素分泌受损，并随着年龄的增长而加重。在早期阶段，敲除胰岛表现出β-细胞增殖减少并伴有代偿性α-细胞扩增。4 个月时，RNA-seq分析显示核糖体生物发生和细胞周期基因下调，α-细胞决定因子和祖细胞相关因子上调。组织学检查进一步显示，β-细胞比例下降，α-细胞比例增加，α-细胞共表达生长抑素的一小部分α-细胞，表明短暂的，与应激相关的表型可塑性。scRNA-seq鉴定了10月龄小鼠的ER应激和敲除β细胞改变的β细胞命运。值得注意的是，这些变化在4个月大的敲除胰岛中不存在，这表明内质网应激是SRSF1缺乏引起的增生性缺陷的继发性反应。在机制上，SRSF1通过类似于MYC的机制促进β-细胞增殖，通过调控MYC的表达对β-细胞产生作用。结论：SRSF1通过myc介导的途径对β细胞增殖和功能至关重要。它的缺乏破坏了β细胞的稳态，导致小鼠代谢功能障碍，强调了它在保护功能β细胞和维持葡萄糖平衡中的重要性。

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引用次数: 0

Glucoprivation-induced nutrient preference relies on distinct NPY neurons that project to the paraventricular nucleus of the hypothalamus 葡萄糖活化诱导的营养偏好依赖于投射到下丘脑室旁核的不同NPY神经元。

IF 11.9 1区医学 Q1 ENDOCRINOLOGY & METABOLISM

Metabolism: clinical and experimental

Pub Date : 2026-01-01 Epub Date: 2025-10-10 DOI: 10.1016/j.metabol.2025.156415

Nawarat Rattanajearakul , Kunio Kondoh , Ou Fu , Shiki Okamoto , Kenta Kobayashi , Ken-ichiro Nakajima , Yasuhiko Minokoshi

Background

Neural pathways related to total calorie intake have been extensively studied. However, it remains unclear how these mechanisms control food selection.

Methods

Male mice were subjected to glucoprivation through the intraperitoneal (i.p.) administration of 2-deoxy-d-glucose (2DG) and were examined for food selection between a high-carbohydrate diet (HCD) and a high-fat diet (HFD) in a diet choice paradigm. This involved the chemogenetic or optogenetic modulation of the neural activity of AMP-activated protein kinase (AMPK)-regulated corticotropin-releasing hormone (CRH) neurons, melanocortin-4 receptor (MC4R) neurons in the paraventricular nucleus of the hypothalamus (PVH), and neuropeptide Y (NPY) neurons projecting to the PVH.

Results

Glucoprivation induced by 2DG administration in mice influenced two distinct neural pathways in the PVH that separately promote the intake of an HCD or an HFD. Injection of 2DG activated PVH-projecting NPY neurons in the nucleus of the solitary tract (NTS) and ventrolateral medulla (VLM), resulting in a rapid increase in HCD intake through stimulation of PVH AMPK–regulated CRH neurons and recovery from glucoprivation. In contrast, PVH-projecting NPY neurons in the NTS, VLM, and arcuate nucleus of the hypothalamus (ARC) promoted HFD intake by inhibiting MC4R neurons in the PVH, reflecting the strong innate preference for an HFD in mice. The ARC NPY neurons specifically promoted HFD selection.

Conclusion

Our findings reveal a previously unrecognized mechanism for food selection between HCD and HFD during glucoprivation.

背景：与总热量摄入相关的神经通路已被广泛研究。然而，尚不清楚这些机制如何控制食物选择。方法：通过腹腔注射2-脱氧-d-葡萄糖（2DG）对雄性小鼠进行葡萄糖剥夺，并在饮食选择范式中检查高碳水化合物饮食（HCD）和高脂肪饮食（HFD）之间的食物选择。这涉及到amp激活的蛋白激酶（AMPK）调节的促肾上腺皮质激素释放激素（CRH）神经元、下丘脑室旁核（PVH）的黑素皮质素-4受体（MC4R）神经元以及投射到PVH的神经肽Y （NPY）神经元的神经活性的化学发生或光遗传调节。结果：2DG诱导的小鼠葡萄糖活化影响PVH中两条不同的神经通路，分别促进HCD或HFD的摄入。注射2DG激活孤立束核（NTS）和髓腹外侧核（VLM）中PVH-投射的NPY神经元，通过刺激PVH- ampk调节的CRH神经元，导致HCD摄入量迅速增加，并从葡萄糖活化中恢复。相反，下丘脑NTS、VLM和弓形核（ARC）中PVH投射的NPY神经元通过抑制PVH中的MC4R神经元来促进HFD摄入，反映了小鼠对HFD的强烈先天偏好。ARC NPY神经元特别促进了HFD的选择。结论：我们的研究结果揭示了一种以前未被认识到的HCD和HFD在葡萄糖活化过程中的食物选择机制。

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引用次数: 0

Sepsis-induced lipid droplet accumulation enhances antibacterial innate immunity through mechanisms dependent on DGAT-1 and interferon-beta 脓毒症诱导的脂滴积累通过依赖于DGAT-1和干扰素- β的机制增强抗菌先天免疫。

IF 11.9 1区医学 Q1 ENDOCRINOLOGY & METABOLISM

Metabolism: clinical and experimental

Pub Date : 2026-01-01 Epub Date: 2025-09-17 DOI: 10.1016/j.metabol.2025.156389

Filipe S. Pereira-Dutra , Julia Cunha Santos , Ellen Kiarely Souza , Rodrigo Vieira Savi , Tamyris S. Souza , Helen Gil , Hugo Espinheira-Silva , Felipe Ferraro-Moreira , Guilherme Iack , Tamires Cunha-Fernandes , Tathiany Igreja-Silva , Lohanna Palhinha , Mariana Macedo Campos , Ester Fernanda Terra Souza , Amanda França Cordeiro , Pablo Andrade-dos-Santos , Douglas Mathias Oliveira , Vinicius Soares Cardoso , Matheus A. Rajão , Livia Teixeira , Patrícia T. Bozza

Lipid droplets (LDs) are lipid-rich organelles recognized as central players in lipid homeostasis, signaling, and inflammation. While their functions in inflammation are well-documented, the mechanisms of LDs in antibacterial immunity and infection resistance remain less understood. Our results show that E. coli-infection trigger immunometabolic reprogramming and LD accumulation in murine macrophages (BMDM). Moreover, purified LDs from LPS-stimulated and E. coli-infected macrophages exhibited direct E. coli anti-bacterial activity. Pharmacological inhibition or genetic knockdown of DGAT1, a key enzyme in triglyceride synthesis, reduced LD formation, bacterial clearance, and pro-inflammatory responses (nitric oxide, PGE₂, CCL2, IL-6). Notably, DGAT1 inhibition impaired the expression of IFN-β and interferon-stimulated genes (ISGs), including viperin, iNOS, cathelicidin and IGTP, in E. coli-infected macrophages. In a cecal-ligation and puncture model of sepsis in C57BL/6 mice, DGAT1 inhibition reduced sepsis-induced LD accumulation in peritoneal cells and decreased levels of IFN-β, CCL2, nitric oxide, and lipid mediators (PGE₂, LTB₄, and RvD1) in the peritoneum. Furthermore, DGAT1 inhibition accelerated sepsis-related mortality, coinciding with elevated bacterial loads in the peritoneum and bloodstream at 6- and 24-h post-sepsis. Our results demonstrate that LDs are critical regulators of innate immunity infection resistance, contributing to both bacterial clearance and the coordination of a protective proinflammatory response during sepsis through mechanisms dependent on DGAT-1 and Type I IFN.

脂滴（ld）是一种富含脂质的细胞器，被认为是脂质稳态、信号传导和炎症的中心角色。虽然它们在炎症中的功能已被充分证明，但lld在抗菌免疫和感染抵抗中的机制仍不太清楚。我们的研究结果表明，大肠杆菌感染引发巨噬细胞的免疫代谢重编程和LD积累。此外，从lps刺激和大肠杆菌感染的巨噬细胞中纯化的ld显示出直接的大肠杆菌抗菌活性。DGAT1是甘油三酯合成、减少LD形成、细菌清除和促炎反应（一氧化氮、PGE2、CCL2、IL-6）的关键酶，其药理抑制或基因敲低。值得注意的是，DGAT1抑制抑制了大肠杆菌感染巨噬细胞中IFN-β和几种干扰素刺激基因（ISGs）的表达，包括viperin、iNOS、cathelicidin和IGTP。在C57BL/6小鼠脓毒症的盲肠结扎和穿刺模型中，DGAT1抑制降低了脓毒症诱导的腹膜细胞LD积累，降低了IFN-β、CCL2、一氧化氮和脂质介质（PGE2、LTB4和RvD1）的水平。此外，DGAT1抑制加速败血症相关死亡率，与败血症后6和24小时腹膜和血液中细菌负荷升高相一致。我们的研究结果表明，ld是先天免疫感染抵抗的关键调节因子，通过依赖于DGAT-1和I型IFN的机制，在败血症期间促进细菌清除和保护性促炎反应的协调。

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引用次数: 0

BMAL2 controls adipose tissue inflammation and metabolic adaptation during obesity BMAL2在肥胖过程中控制脂肪组织炎症和代谢适应。

IF 11.9 1区医学 Q1 ENDOCRINOLOGY & METABOLISM

Metabolism: clinical and experimental

Pub Date : 2026-01-01 Epub Date: 2025-09-20 DOI: 10.1016/j.metabol.2025.156396

Morgane A. Philippe , Blandine Fruchet , Lucie Cagninacci , Lucie Beaudoin , Alexis Gadault , Bastien Aznar , Nicolas Venteclef , Etienne Challet , Agnès Lehuen , Ute C. Rogner , Amine Toubal

Contemporary lifestyle modifications such as changes in nutritional and sleep/wake rhythms increase the risk of metabolic and inflammatory complications linked to obesity, including type 2 diabetes (T2D) and metabolic dysfunction-associated steatohepatitis (MASH). BMAL2 (Brain and Muscle ARNT Like Protein 2) is a transcription factor belonging to the circadian clock transcriptional feedback loop which synchronizes internal biological rhythms to environment. In humans, reduced expression in white adipose tissue (WAT) and specific polymorphisms of BMAL2 are associated with obesity and T2D. In this study we report that Bmal2 deletion in mice leads to increased body weight gain during diet-induced obesity. Loss of BMAL2 triggers the inflammatory response by increasing Tnfα expression and modifying adipocyte progenitor fate. This results in reduced lipid storage capacity within the WAT and increased ectopic storage in the liver. These functional and structural alterations culminate in the onset of hepatic steatosis and insulin resistance in liver and WAT. Overall, our investigations underscore the role of BMAL2 in the development and function of adipocytes, as well as in their inflammatory potential within the WAT. Our findings contribute to the understanding of the role of circadian clock genes in obesity and interconnected metabolic complications.

当代生活方式的改变，如营养和睡眠/觉醒节律的改变，增加了与肥胖相关的代谢和炎症并发症的风险，包括2型糖尿病（T2D）和代谢功能障碍相关的脂肪性肝炎（MASH）。BMAL2 （Brain and Muscle ARNT Like Protein 2）是一种属于生物钟转录反馈回路的转录因子，它将内部生物节律与环境同步。在人类中，白色脂肪组织（WAT）的表达减少和BMAL2的特定多态性与肥胖和T2D有关。在这项研究中，我们报告了Bmal2缺失导致小鼠在饮食引起的肥胖期间体重增加。BMAL2的缺失通过增加Tnfα表达和改变脂肪细胞祖细胞命运触发炎症反应。这导致WAT内的脂质储存能力降低，并增加肝脏的异位储存。这些功能和结构的改变最终导致肝脂肪变性和胰岛素抵抗的发生。总的来说，我们的研究强调了BMAL2在脂肪细胞的发育和功能中的作用，以及它们在WAT内的炎症潜能。我们的发现有助于理解生物钟基因在肥胖和相互关联的代谢并发症中的作用。

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引用次数: 0

Hepatic steatosis associates with leukopoietic activity and atherosclerotic inflammation: mechanistic insights into cardiovascular risk 肝脂肪变性与白细胞生成活性和动脉粥样硬化炎症相关：心血管风险的机制见解。

IF 11.9 1区医学 Q1 ENDOCRINOLOGY & METABOLISM

Metabolism: clinical and experimental

Pub Date : 2026-01-01 Epub Date: 2025-11-03 DOI: 10.1016/j.metabol.2025.156427

Shady Abohashem , Wesam Aldosoky , Taimur Abbasi , Tawseef Dar , Robert Rollings , Brian Tung , Basma Hammad , Fatima Saeed , Abdelrahman Ali , Richard A.P. Takx , Brian B. Ghoshhajra , Ahmed Tawakol , Michael T. Osborne

<div><h3>Background</h3><div>Hepatic steatosis (HS) is associated with an increased risk of major adverse cardiovascular events (MACE). However, the underlying mechanisms linking HS to MACE remain incompletely understood. This study aimed to investigate the role of the leukopoietic-arterial axis in mediating the relationship between imaging markers of HS and MACE.</div></div><div><h3>Methods and materials</h3><div>This longitudinal retrospective cohort study included 445 individuals without active cancer, liver disease or alcohol abuse, or baseline cardiovascular disease who underwent clinical <sup>18</sup>F-FDG-PET/CT imaging. Hepatic glucose uptake (HGU), uptake in the bone marrow (BM) and spleen (as a marker of leukopoiesis), and activity in the aorta (as a measure of arterial inflammation, ArtI) were evaluated. Hepatic and splenic attenuations were analyzed to assess hepatic attenuation index (HAI) and determine nonalcoholic fatty liver disease (NAFLD) status. Metabolic Dysfunction Associated Steatotic Liver disease (MASLD) was defined based on NAFLD status and other metabolic criteria. MACE was adjudicated.</div></div><div><h3>Results</h3><div>In fully adjusted models, HGU associated with heightened BM (standardized β [95 % confidence interval]: 0.353 [0.276, 0.430], <em>p</em> < 0.001) and spleen activities (0.548 [0.475, 0.621], <em>p</em> < 0.001) as well as ArtI (0.529 [0.453, 0.605], <em>p</em> < 0.001). Similar associations were observed for HAI and MASLD or NAFLD status. Notably, these associations remained significant after adjusting for other confounders and among individuals without MASLD/NAFLD. A total of 28 individuals developed MACE over 4 years median follow-up. Furthermore, the leukopoietic-arterial activity mediated the link between imaging markers of HS (i.e., HGU, HAI, MASLD) and MACE, (<em>p</em> < 0.05).</div></div><div><h3>Conclusion</h3><div>Our study suggests an important role for the leukopoietic-arterial axis in HS and MACE. These findings may inform therapeutic avenues for reducing the cardiovascular risk associated with HS.</div></div><div><h3>Structured abstract</h3><div>This study examines the connection between hepatic steatosis (HS) and major adverse cardiovascular events (MACE) through the leukopoietic-arterial axis. Among 445 patients without history of liver disease or alcohol abuse, imaging markers of hepatic steatosis (i.e., hepatic glucose uptake (HGU)), and metabolic dysfunction associated steatotic liver disease (MASLD), associated with increased activity in bone marrow and spleen, and atherosclerotic plaques. These associations persisted irrespective of MASLD status and after adjusting for relevant confounders. Heightened uptake in leukopoietic tissues and the arteries mediated the relationship between HS markers (i.e., HGU, MASLD) and MACE development. These findings shed light on novel mechanistic pathways and potential targets for interventions to reduce the burden of HS-related CVD.</di

背景：肝脂肪变性（HS）与主要不良心血管事件（MACE）的风险增加有关。然而，将HS与MACE联系起来的潜在机制仍然不完全清楚。本研究旨在探讨白细胞-动脉轴在介导HS与MACE影像标志物之间关系中的作用。方法和材料：这项纵向回顾性队列研究纳入了445名无活动性癌症、肝脏疾病、酒精滥用或基线心血管疾病的患者，他们接受了临床18F-FDG-PET/CT成像。测量肝脏葡萄糖摄取（HGU）、骨髓和脾脏葡萄糖摄取（作为白细胞生成的标志）以及主动脉活性（作为动脉炎症的衡量指标，ArtI）。分析肝脏和脾脏的衰减以评估肝衰减指数（HAI）并确定非酒精性脂肪性肝病（NAFLD）状态。代谢功能障碍相关脂肪变性肝病（MASLD）是根据NAFLD状态和其他代谢标准来定义的。梅斯被判有罪。结果：在完全调整的模型中，HGU与BM升高相关（标准化β[95 %置信区间]:0.353 [0.276,0.430],p ）。结论：我们的研究表明白细胞-动脉轴在HS和MACE中起重要作用。这些发现可能为降低HS相关心血管风险的治疗途径提供信息。结构摘要：本研究通过白细胞-动脉轴探讨肝脂肪变性（HS）与主要不良心血管事件（MACE）之间的联系。在445名无肝脏疾病或酒精滥用史的患者中，肝脂肪变性的影像学标志物（即肝糖摄取（HGU））和代谢功能障碍相关的脂肪变性肝病（MASLD）与骨髓和脾活性以及动脉粥样硬化斑块活性增加有关。无论MASLD状态如何，在调整了相关混杂因素后，这些关联仍然存在。白细胞生成组织和动脉摄取的增加介导了HS标志物（即HGU， MASLD）与MACE发展之间的关系。这些发现揭示了减轻hs相关CVD负担的机制途径和潜在干预目标。

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引用次数: 0

Enhancing cardiac serine biosynthesis mitigates the progression of dilated cardiomyopathy in mice 增强心脏丝氨酸生物合成可减轻扩张型心肌病的进展。

IF 11.9 1区医学 Q1 ENDOCRINOLOGY & METABOLISM

Metabolism: clinical and experimental

Pub Date : 2026-01-01 Epub Date: 2025-09-18 DOI: 10.1016/j.metabol.2025.156395

Maryam Kay , Anne-Maj Samuelsson , Nike Bharucha , Xueyi Li , Rohin Ramchandani , Rachel E. Baum , Diego Ruiz Arvizo , Aurélie Laguerre , Sherin Lajevardi , Shrikaar Kambhampati , Christian M. Metallo , Michael S. Kapiloff , Ioannis Karakikes

Genetic dilated cardiomyopathy (DCM) is a leading cause of heart failure. However, disease-modifying therapies remain limited. Metabolic dysfunction has emerged as a key driver of DCM pathogenesis, and impaired serine biosynthesis, catalyzed by the rate-limiting enzyme phosphoglycerate dehydrogenase (PHGDH), has recently been identified as a potential therapeutic target. Here, we evaluated the therapeutic potential of increasing serine biosynthesis through AAV9-mediated PHGDH gene augmentation in a transgenic TM54 mouse model of DCM with established pathology. Longitudinal echocardiography showed preserved systolic function and prevented ventricular dilatation in TM54 mice treated with AAV9-PHGDH compared to AAV9-GFP controls. Histological analysis revealed reduced myocardial fibrosis and cardiomyocyte hypertrophy in AAV9-PHGDH-treated TM54 hearts, indicating a reversal of pathological remodeling. Metabolic profiling, including targeted metabolomics and in vivo ¹³C-glucose tracing analysis, revealed that serine levels increased in hearts treated with AAV9-PHGDH, accompanied by decreases in glucose-derived pyruvate and lactate. At the same time, mitochondrial oxidative metabolism remained intact, indicating a shift of glycolytic carbon towards serine biosynthesis. Collectively, these findings show that enhancing cardiac serine synthesis through PHGDH gene augmentation therapy preserves contractile function and mitigates disease progression in vivo, suggesting a novel metabolic therapeutic strategy for DCM.

遗传性扩张型心肌病（DCM）是心力衰竭的主要原因。然而，疾病改善疗法仍然有限。代谢功能障碍已成为DCM发病机制的关键驱动因素，而由限速酶磷酸甘油脱氢酶（PHGDH）催化的丝氨酸生物合成受损，最近已被确定为潜在的治疗靶点。在此，我们通过aav9介导的PHGDH基因增强，在具有既定病理的转基因TM54小鼠DCM模型中评估了增加丝氨酸生物合成的治疗潜力。纵向超声心动图显示，与AAV9-GFP对照组相比，AAV9-PHGDH治疗TM54小鼠的收缩功能得到保留，心室扩张得到抑制。组织学分析显示，aav9 - phgdh处理的TM54心脏心肌纤维化和心肌细胞肥大减少，表明病理性重构逆转。代谢分析，包括靶向代谢组学和体内13c -葡萄糖示踪分析，显示AAV9-PHGDH处理心脏的丝氨酸水平升高，同时葡萄糖衍生的丙酮酸和乳酸降低。同时，线粒体氧化代谢保持完整，表明糖酵解碳向丝氨酸生物合成转移。总之，这些研究结果表明，通过PHGDH基因增强治疗增强心脏丝氨酸合成可以保持收缩功能并减轻体内疾病进展，这为DCM提供了一种新的代谢治疗策略。

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引用次数: 0

NSD2 exacerbates metabolic dysfunction-associated steatotic liver disease progression by suppressing TFEB-mediated autophagy-lysosomal pathway NSD2通过抑制tfeb介导的自噬-溶酶体途径加剧代谢功能障碍相关的脂肪变性肝病进展。

IF 11.9 1区医学 Q1 ENDOCRINOLOGY & METABOLISM

Metabolism: clinical and experimental

Pub Date : 2026-01-01 Epub Date: 2025-10-10 DOI: 10.1016/j.metabol.2025.156416

Yuan Qiao , Yijia Zhang , Cuiting Sun , Qi Jin , Peng Qu , Zecheng Li , Yang Qiu , Hua Meng , Dantao Peng , Liang Peng

Objectives

Impaired autophagy is increasingly recognized as a key contributor to the pathogenesis of metabolic dysfunction-associated steatotic liver disease (MASLD). However, its underlying molecular mechanisms remain largely undefined. Emerging evidence implicates epigenetic regulators in modulating autophagic pathways in metabolic diseases. Therefore, this study aimed to elucidate the role of a histone methyltransferase, nuclear receptor binding SET domain protein 2 (NSD2), in regulating autophagy and its contribution to MASLD progression.

Methods

NSD2 expression levels were evaluated in liver tissues from patients with MASLD and mouse models. Functional studies were conducted using hepatocyte-specific Nsd2 knockout and overexpression mouse models, along with cleavage under targets and tagmentation analysis in hepatocyte cell lines. Additionally, the effects of pharmacological NSD2 inhibition using NSC663284 were evaluated in human liver organoids. Autophagy, hepatic steatosis, and related epigenetic changes were assessed through molecular and histological techniques.

Results

NSD2 expression was markedly elevated in both patient livers and murine models, correlating positively with disease severity. Hepatic NSD2 deficiency alleviated diet-induced autophagy impairment and steatosis, while NSD2 overexpression exacerbated these pathologies. Mechanistically, NSD2 epigenetically suppressed TFEB transcription by promoting trimethylation of histone H4 at lysine 20, impairing autophagy. Pharmacological inhibition of NSD2 with NSC663284 similarly alleviated hepatic steatosis in human liver organoids.

Conclusion

NSD2 acts as a key epigenetic suppressor of TFEB-mediated autophagy in the liver, promoting lipid accumulation and MASLD progression. Targeting NSD2 represents a promising therapeutic strategy for MASLD.

目的：受损的自噬越来越被认为是代谢功能障碍相关脂肪变性肝病（MASLD）发病机制的关键因素。然而，其潜在的分子机制在很大程度上仍未明确。新出现的证据暗示表观遗传调节剂在代谢疾病中调节自噬途径。因此，本研究旨在阐明组蛋白甲基转移酶核受体结合SET结构域蛋白2 （NSD2）在调节自噬及其对MASLD进展的贡献中的作用。方法：检测MASLD患者肝组织及小鼠模型中NSD2的表达水平。使用肝细胞特异性Nsd2敲除和过表达小鼠模型进行功能研究，并在肝细胞细胞系中进行靶向切割和标记分析。此外，我们还评估了NSC663284对人肝类器官NSD2的药理抑制作用。通过分子和组织学技术评估自噬、肝脂肪变性和相关的表观遗传改变。结果：NSD2在患者肝脏和小鼠模型中的表达均显著升高，且与疾病严重程度呈正相关。肝脏NSD2缺乏可减轻饮食诱导的自噬损伤和脂肪变性，而NSD2过表达则加重了这些病理。机制上，NSD2通过促进赖氨酸20位点组蛋白H4的三甲基化来抑制TFEB转录，从而损害自噬。NSC663284对NSD2的药理抑制同样减轻了人肝类器官的肝脂肪变性。结论：NSD2是tfeb介导的肝脏自噬的关键表观遗传抑制因子，促进脂质积累和MASLD进展。靶向NSD2是治疗MASLD的一种有前景的治疗策略。

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引用次数: 0

Phenome-wide associations of coffee intake in the human phenotype project 人类表型项目中咖啡摄入的全现象关联。

IF 11.9 1区医学 Q1 ENDOCRINOLOGY & METABOLISM

Metabolism: clinical and experimental

Pub Date : 2026-01-01 Epub Date: 2025-10-03 DOI: 10.1016/j.metabol.2025.156412

Jin Dai , Wen Dai , Yoriko Heianza , Lu Qi

Objective

Coffee is one of the most widely consumed beverages globally and has been linked to favorable health outcomes. However, its system-wide relationships with human biology and the underlying mechanisms remain poorly characterized. This study aimed to investigate the relationship between coffee consumption and continuous glucose monitoring (CGM) metrics and other biological systems in healthy adults.

Research design and methods

In the Human Phenotype Project, 8666 generally healthy Israeli adults provided two weeks of real-time dietary logs, from which coffee intake was estimated. Participants wore CGM devices throughout this period, and multimodal data spanning 11 additional systems (e.g., gut microbiome, serum lipidomics, and body composition) were collected. We employed machine learning approaches to quantify the extent to which each system reflected coffee intake. We performed linear regression to identify individual traits associated with coffee intake, with false discovery rates < 0.05 considered significant.

Results

This cross-sectional study identified continuously-monitored glucose regulation and gut microbial composition as the most reflective systems of coffee intake, with further analyses revealing favorable glycemic profiles spanning diverse aspects of glucose regulation with increasing coffee intake, and Clostridium phoceensis (i.e., Lawsonibacter asaccharolyticus) as the most significant species positively associated with coffee intake. Additionally, coffee intake was favorably associated with traits across body composition, serum lipidomics, and hepatic, hematopoietic, and renal systems.

Conclusions

This study found that habitual coffee intake was linked to multifaceted favorable glucose control captured by CGM and favorable profiles across multiple biological systems, providing mechanistic insights that may guide precision nutrition strategies for diabetes prevention.

目的：咖啡是全球消费最广泛的饮料之一，与良好的健康结果有关。然而，其与人类生物学的全系统关系及其潜在机制仍然缺乏特征。本研究旨在探讨健康成年人饮用咖啡与连续血糖监测（CGM）指标和其他生物系统之间的关系。研究设计和方法：在人类表型项目中，8666名一般健康的以色列成年人提供了两周的实时饮食日志，从中估计咖啡摄入量。在此期间，参与者佩戴了CGM装置，并收集了跨越11个额外系统的多模式数据（例如，肠道微生物组、血清脂质组学和身体成分）。我们使用机器学习方法来量化每个系统反映咖啡摄入量的程度。我们进行了线性回归，以确定与咖啡摄入量相关的个体特征，错误发现率 这项横断面研究确定了连续监测的葡萄糖调节和肠道微生物组成是咖啡摄入量最能反映的系统，进一步的分析显示，随着咖啡摄入量的增加，葡萄糖调节的各个方面都出现了有利的血糖分布，而phoce梭菌（即Lawsonibacter asaccharolyticus）是与咖啡摄入量呈正相关的最显著的物种。此外，咖啡摄入量与身体组成、血清脂质组学、肝脏、造血和肾脏系统的特征呈正相关。结论：本研究发现，习惯性咖啡摄入与CGM捕获的多方面有利的葡萄糖控制和多种生物系统的有利特征有关，为糖尿病预防的精确营养策略提供了机制见解。

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引用次数: 0

Semaglutide, the first approved GLP-1 receptor agonist for the management of metabolic dysfunction-associated steatohepatitis Semaglutide，首个被批准用于治疗代谢功能障碍相关脂肪性肝炎的GLP-1受体激动剂。

IF 11.9 1区医学 Q1 ENDOCRINOLOGY & METABOLISM

Metabolism: clinical and experimental

Pub Date : 2026-01-01 Epub Date: 2025-10-03 DOI: 10.1016/j.metabol.2025.156397

Chrysoula Boutari , Michael A. Hill , Christos S. Mantzoros

引用次数: 0

Administration of the KCa channel activator SKA-31 improves long-term endothelial function, blood pressure regulation and cardiac performance in rats with type 2 diabetes KCa通道激活剂SKA-31可改善2型糖尿病大鼠的长期内皮功能、血压调节和心脏功能。

IF 11.9 1区医学 Q1 ENDOCRINOLOGY & METABOLISM

Metabolism: clinical and experimental

Pub Date : 2026-01-01 Epub Date: 2025-10-01 DOI: 10.1016/j.metabol.2025.156410

Ramesh C. Mishra , Rayan Khaddaj Mallat , Cini M. John , Darrell D. Belke , Liam Hamm , Latika Singh , Taeyoeb Kim , Grace George , Yong-Xiang Chen , Heike Wulff , Andrew P. Braun

Objective

Our goal in the present study was to examine whether long-term administration of the selective K_Ca channel activator SKA-31 would mitigate the development/severity of type 2 diabetes (T2D)-associated cardiovascular (CV) complications in adult male Goto-Kakizaki (GK) rats with spontaneous T2D.

Methods

Adult male T2D GK rats instrumented with radio-telemeters were administered either vehicle or the K_Ca channel activator SKA-31 (10 mg/kg) at ~14 weeks of age by daily intraperitoneal injection for 12 consecutive weeks. In vivo and ex vivo analyses of CV function, immune system status, vascular signaling and metabolic hormones were performed following treatment.

Results

Vehicle-treated T2D GK rats exhibited gradual increases in systolic and diastolic blood pressure, whereas SKA-31 administration led to lower mean arterial pressure, along with improvements in cardiac function (i.e., ejection fraction, fractional shortening) and structure (i.e., end systolic and diastolic volumes), as determined by echocardiography. SKA-31 treatment in vivo further improved vascular endothelial function in small mesenteric arteries, as determined by arterial pressure myography, and increased the protein expression of vasodilatory signaling molecules in the vascular wall. Prolonged SKA-31 treatment did not impair vasodilatory responsiveness in skeletal muscle and coronary arteries, elicit a pro-inflammatory profile in T2D GK rats or produce any adverse histological effects in brain, kidney or liver.

Conclusions

The results of our study demonstrate that low-dose administration of the K_Ca channel activator SKA-31 improved CV function in an established rat model of spontaneous T2D and reveal a potential novel strategy to oppose CV-related morbidity in T2D.

目的：本研究的目的是研究长期服用选择性KCa通道激活剂SKA-31是否会减轻自发性T2D成年雄性Goto-Kakizaki （GK）大鼠2型糖尿病（T2D）相关心血管（CV）并发症的发展/严重性。方法：使用无线电遥测仪的成年雄性T2D GK大鼠，于~14 周龄每日腹腔注射载药或KCa通道激活剂SKA-31(10 mg/kg)，连续12周。在体内和离体分析治疗后的心血管功能、免疫系统状态、血管信号和代谢激素。结果：经超声心动图检测，经药物处理的T2D GK大鼠的收缩压和舒张压逐渐升高，而SKA-31可降低平均动脉压，并改善心功能（即射血分数、分数缩短）和结构（即收缩期和舒张末期容积）。通过动脉压肌图检测，SKA-31在体内治疗进一步改善了肠系膜小动脉的血管内皮功能，并增加了血管壁血管舒张信号分子的蛋白表达。长期ka -31治疗不会损害骨骼肌和冠状动脉的血管舒张反应性，也不会引起T2D GK大鼠的促炎反应，也不会对脑、肾或肝产生任何不良组织学影响。结论：我们的研究结果表明，在建立的自发性T2D大鼠模型中，低剂量的KCa通道激活剂SKA-31改善了CV功能，并揭示了一种潜在的对抗T2D中CV相关发病率的新策略。

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引用次数: 0