Molecular Metabolism最新文献_第6页

The transcription factor CUX1 exerts opposing roles in human and mouse adipocyte differentiation 转录因子CUX1在人和小鼠脂肪细胞分化中发挥相反的作用。

IF 6.6 2区医学 Q1 ENDOCRINOLOGY & METABOLISM

Molecular Metabolism

Pub Date : 2026-01-01 Epub Date: 2025-11-27 DOI: 10.1016/j.molmet.2025.102290

Yang Chen , Lin Liu , Ryan P. Calhoun , Lan Cheng , David Steger , Patrick Seale

Objective

Adipocyte differentiation is critical for the metabolically protective expansion of adipose tissue. Impaired differentiation drives lipodystrophy and pathologic tissue remodeling, major contributors to cardiometabolic diseases. The differentiation process is governed by master transcription factors, including the pioneer factor C/EBPβ, which initiates the adipogenic program. Here, we sought to identify novel C/EBPβ-associated factors that regulate human adipocyte differentiation.

Methods

We used chromatin immunoprecipitation followed by selective isolation of chromatin-associated proteins (ChIP-SICAP) to identify proteins that interact with C/EBPβ on chromatin during human adipocyte differentiation. Candidate factors were assessed for their effects on differentiation, through conducting a CRISPR/Cas9-based knockout screen in human adipocyte precursor cells (hAPCs). The transcription factor CUX1 emerged as a top candidate. We performed gain- and loss-of-function studies in primary human and mouse adipocyte differentiation models, coupled with RNA-seq and ChIP-seq, to define CUX1-regulated genes and pathways. In vivo relevance was tested using adipocyte precursor–selective Cux1 knockout and lineage reporter mice.

Results

Loss of CUX1 impaired, whereas its overexpression enhanced, adipocyte differentiation in hAPCs. RNA-seq and ChIP-seq analyses revealed that CUX1 promotes the expression of key adipogenic genes, including PPARG in hAPCs. By contrast, CUX1 exerted the opposite effect in mouse adipocyte differentiation. Cux1 deletion enhanced, while CUX1 overexpression suppressed, differentiation in mouse APCs (mAPCs). CUX1 exhibited distinct chromatin-binding patterns and motif enrichment profiles in mouse versus human cells. In vivo, Cux1 deletion in APCs of mice increased de novo adipocyte formation during early stages of obesity development.

Conclusions

The transcription factor CUX1 regulates adipocyte differentiation in opposite directions in humans and mice, emphasizing the need for species-specific models in metabolic disease research,

目的：脂肪细胞分化是脂肪组织代谢保护性扩张的关键。受损的分化驱动脂肪营养不良和病理组织重塑，主要贡献者心脏代谢疾病。分化过程由主转录因子控制，包括启动脂肪生成程序的先锋因子C/EBPβ。在这里，我们试图确定调节人类脂肪细胞分化的新的C/ ebp β相关因子。方法：采用染色质免疫沉淀-选择性分离染色质相关蛋白（ChIP-SICAP）技术鉴定在人脂肪细胞分化过程中与染色质上的C/EBPβ相互作用的蛋白。通过在人脂肪前体细胞（hAPCs）中进行基于CRISPR/ cas9的敲除筛选，评估候选因子对分化的影响。转录因子CUX1成为首选候选因子。我们在原代人和小鼠脂肪细胞分化模型中进行了功能增益和功能丧失研究，结合RNA-seq和ChIP-seq，以确定cux1调节的基因和途径。使用脂肪前体选择性Cux1敲除和谱系报告小鼠来测试体内相关性。结果：CUX1的缺失损害了hapc中脂肪细胞的分化，而其过表达则增强了脂肪细胞的分化。RNA-seq和ChIP-seq分析显示，CUX1促进hapc中关键脂肪形成基因的表达，包括PPARG。相比之下，CUX1在小鼠脂肪细胞分化中发挥相反的作用。Cux1缺失增强了小鼠APCs （mAPCs）的分化，而Cux1过表达抑制了APCs的分化。CUX1在小鼠和人类细胞中表现出不同的染色质结合模式和基序富集谱。在体内，小鼠apc中Cux1的缺失增加了肥胖发展早期脂肪细胞的新生形成。结论：转录因子CUX1调节人和小鼠脂肪细胞的分化方向相反，强调代谢疾病研究需要物种特异性模型。

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引用次数: 0

Multi-omics atlas of ovarian cellular and molecular responses to diabetes 卵巢细胞和分子对糖尿病反应的多组学图谱。

IF 6.6 2区医学 Q1 ENDOCRINOLOGY & METABOLISM

Molecular Metabolism

Pub Date : 2026-01-01 Epub Date: 2025-12-13 DOI: 10.1016/j.molmet.2025.102307

Zheng-Hui Zhao , Xue-Ying Chen , Cheng-Yan Zhuo, Xiang-Hong Ou, Qing-Yuan Sun

Diabetes is associated with compromised reproductive health; however, the cellular and molecular mechanisms underlying its impact on ovarian function remain largely unclear. In this study, we integrated single-cell RNA sequencing, DNA methylation profiling, and metabolomic analyses to comprehensively characterize the ovarian cellular landscape, epigenetic alterations, and metabolic reprogramming in diabetic female mice, with a focus on identifying diabetes-induced changes in ovarian cells. Our cell type-specific transcriptomic analysis revealed that dysregulated steroid hormone biosynthesis and impaired fatty acid metabolism are prominent features of diabetic ovarian dysfunction. Notably, key genes including Cyp11a1, Fshr, and Lhcgr exhibited reduced expression accompanied by increased DNA methylation levels in their gene regions within granulosa cells under diabetic conditions. Furthermore, disrupted granulosa cell differentiation was evident, leading to aberrant luteal cell formation and compromised luteal function. In parallel, metabolomic profiling revealed profound metabolic reprogramming in diabetic ovaries, with significant alterations in lipid metabolism pathways, including elevated unsaturated fatty acid and reduced glycerophospholipid metabolism. Taken together, these findings provide novel insights into the molecular pathways underlying ovarian dysfunction in the context of diabetes, thereby enhancing our understanding of folliculogenesis in metabolic disorders.

糖尿病与生殖健康受损有关；然而，其影响卵巢功能的细胞和分子机制仍不清楚。在这项研究中，我们整合了单细胞RNA测序、DNA甲基化分析和代谢组学分析，全面表征了糖尿病雌性小鼠的卵巢细胞景观、表观遗传改变和代谢重编程，重点是确定糖尿病诱导的卵巢细胞变化。我们的细胞类型特异性转录组学分析显示，类固醇激素生物合成失调和脂肪酸代谢受损是糖尿病卵巢功能障碍的突出特征。值得注意的是，在糖尿病条件下，颗粒细胞中关键基因Cyp11a1、Fshr和Lhcgr的表达减少，同时其基因区域的DNA甲基化水平升高。此外，颗粒细胞分化明显中断，导致黄体细胞形成异常，黄体功能受损。与此同时，代谢组学分析揭示了糖尿病卵巢中深刻的代谢重编程，脂质代谢途径显著改变，包括不饱和脂肪酸升高和甘油磷脂代谢降低。综上所述，这些发现为糖尿病背景下卵巢功能障碍的分子途径提供了新的见解，从而增强了我们对代谢性疾病中卵泡发生的理解。

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引用次数: 0

Effects of CT-388, a once-weekly signaling-biased dual GLP-1/GIP receptor agonist, on weight loss and glycemic control in preclinical models and participants with obesity CT-388是一种每周一次的信号偏倚双GLP-1/GIP受体激动剂，对临床前模型和肥胖参与者的体重减轻和血糖控制的影响

IF 6.6 2区医学 Q1 ENDOCRINOLOGY & METABOLISM

Molecular Metabolism

Pub Date : 2026-01-01 Epub Date: 2025-11-28 DOI: 10.1016/j.molmet.2025.102291

Manu V. Chakravarthy , Ruben Rodriguez , Anne Hergarden , Michael A. Elliott , Juan P. Frias , Federico A. Argüelles-Tello , Edgar Tenorio , Jonathan E. Rankin , Jingtao Wu , Shyam Krishnan , Daniel A. Erlanson , Raymond V. Fucini , Derek Bone , Jeffrey S. Iwig , Luis Acosta , Ashley Untereiner , Asmita Pant , Avalon Patton , Leyla L. Sanchez-Sanchez , Jian Luo , Stig K. Hansen

Biased agonism of the glucagon-like peptide-1/glucose-dependent insulinotropic polypeptide receptors (GLP-1R/GIPR) yields greater weight loss and better glycemic control than unbiased agonism in preclinical models. To evaluate whether biased agonism translates into improved efficacy for weight loss and glycemic control in clinical settings, we developed and characterized CT-388, a unimolecular peptide-based dual GLP-1R/GIPR agonist that is cAMP signal-biased at both receptors. In cell-based assays, CT-388 activated GLP-1R and GIPR with both having minimal receptor internalization vs their native ligands. CT-388 improved glycemic control in mice and monkeys, and reduced bodyweight, suppressed appetite, and improved metabolic dysfunction-associated steatohepatitis pathology in mice. In a phase 1, double-blind, randomized, placebo-controlled clinical study (NCT04838405) of CT-388 (subcutaneously administered single doses [0.5–7.5 mg] or 4 once-weekly doses [5–12 mg]) in otherwise healthy participants with overweight or obesity, CT-388 was generally well tolerated with a safety profile consistent with other incretin-based therapies; most treatment-emergent adverse events were mild or moderate. Glycemic parameters were improved during fasting conditions and an oral glucose tolerance test. The mean percent change in bodyweight from baseline to day 29 was −4.7% to −8.0% across CT-388 doses vs −0.5% with placebo. CT-388 pharmacokinetics supported once-weekly dosing. In conclusion, CT-388 demonstrated strong translatability from preclinical to clinical studies with consistent pharmacokinetics and pharmacodynamics across multiple species. In clinical settings, 4 weeks of CT-388 treatment produced clinically meaningful weight loss and improved glycemic control with favorable tolerability. These findings warrant further clinical evaluation of CT-388 for treating obesity and type 2 diabetes.

在临床前模型中，胰高血糖素样肽-1/葡萄糖依赖性胰岛素多肽受体（GLP-1R/GIPR）的偏激激动作用比非偏激激动作用产生更大的体重减轻和更好的血糖控制。为了评估偏倚激动剂是否在临床环境中转化为改善减肥和血糖控制的疗效，我们开发并表征了CT-388，一种基于单分子肽的双GLP-1R/GIPR激动剂，在两个受体上都有cAMP信号偏倚。在基于细胞的实验中，CT-388激活GLP-1R和GIPR，两者的受体内在化程度与它们的天然配体相比最低。CT-388改善了小鼠和猴子的血糖控制，减轻了体重，抑制了食欲，改善了小鼠代谢功能障碍相关的脂肪性肝炎病理。在一项1期、双盲、随机、安慰剂对照临床研究（NCT04838405）中，CT-388（单次皮下给药[0.5-7.5 mg]或4次每周一次[5-12 mg]）在超重或肥胖的健康参与者中具有良好的耐受性，其安全性与其他基于肠素的治疗一致；大多数治疗后出现的不良事件为轻度或中度。在空腹条件和口服葡萄糖耐量试验中，血糖参数得到改善。CT-388剂量组从基线到第29天的体重平均变化百分比为-4.7%至-8.0%，而安慰剂组为-0.5%。CT-388药代动力学支持每周一次给药。总之，CT-388在临床前和临床研究中表现出很强的可翻译性，在多个物种中具有一致的药代动力学和药效学。在临床环境中，4周的CT-388治疗产生了临床意义上的体重减轻和血糖控制改善，耐受性良好。这些发现为CT-388治疗肥胖和2型糖尿病的进一步临床评估提供了依据。

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引用次数: 0

Increased TGF-β/Activin-Smad2 signaling is associated with pancreatic β-cell dysfunction and glucose intolerance in gestational diabetes mellitus TGF-β/激活素- smad2信号的增加与妊娠期糖尿病胰腺β细胞功能障碍和葡萄糖耐受不良有关。

IF 6.6 2区医学 Q1 ENDOCRINOLOGY & METABOLISM

Molecular Metabolism

Pub Date : 2026-01-01 Epub Date: 2025-10-18 DOI: 10.1016/j.molmet.2025.102274

Talía Boronat-Belda , Hilda Ferrero , Sergi Soriano , Elena Ribes-García , Rubén Betoret-Gustems , Daniel Martínez-Bañón , Mónica Serrano-Selva , Juan Martínez-Pinna , Ángel Nadal , Iván Quesada , Paloma Alonso-Magdalena

Background

Gestational diabetes mellitus (GDM) is the most common metabolic disease during pregnancy and increases the prevalence of type 2 diabetes in both mothers and children. GDM management provides an opportunity to prevent and lower the global burden of diabetes across life. Molecular mechanisms underlying GDM are not completely understood. In this study, we explore the role of transforming growth factor beta (TGF-β) signaling in GDM, as this pathway reportedly affects pancreatic β-cell development, function, and proliferation.

Methods

We developed a GDM animal model. Serum circulating levels of TGF-β family ligands were measured in mice and human GDM. Pancreatic TGF-β signaling was investigated via gene and protein expression.

Results

Our GDM animal model recapitulates the main pathophysiological features of human GDM, including glucose intolerance, decreased insulin sensitivity and pancreatic β-cell malfunction. Islets from GDM mice showed impaired insulin secretion and content, altered ion channel activity, and decreased β-cell replication rate. This was accompanied by increased Smad2 signaling activation. Elevated serum activin-A and inhibin levels were found in mice and human GDM, suggesting their role as upstream signaling transducers of pancreatic Smad2 activation. Pharmacological inhibition of TGF-β/Activin-Smad2 signaling in mouse pancreatic islets resulted in improved pancreatic β-cell function and regeneration capacity.

Conclusions

Our data suggest that disruption of the pancreatic Smad2 pathway plays a critical role in the pathogenesis of GDM, contributing to abnormal glucose homeostasis and inadequate insulin secretion. Attenuation of this signaling pathway may represent a putative therapeutic target for GDM.

背景：妊娠期糖尿病（GDM）是妊娠期最常见的代谢性疾病，增加了母亲和儿童2型糖尿病的患病率。糖尿病管理为预防和降低终生糖尿病的全球负担提供了机会。GDM的分子机制尚不完全清楚。在本研究中，我们探讨了转化生长因子β (TGF-β)信号在GDM中的作用，因为据报道该途径影响胰腺β细胞的发育、功能和增殖。方法：建立GDM动物模型。测定小鼠和人GDM血清中TGF-β家族配体的循环水平。通过基因和蛋白表达研究胰腺TGF-β信号通路。结果：我们的GDM动物模型概括了人类GDM的主要病理生理特征，包括葡萄糖耐受不良、胰岛素敏感性降低和胰腺β细胞功能障碍。GDM小鼠胰岛胰岛素分泌和含量受损，离子通道活性改变，β细胞复制率降低。这伴随着Smad2信号激活的增加。在小鼠和人GDM中发现血清激活素- a和抑制素水平升高，表明它们是胰腺Smad2激活的上游信号转导。药理抑制小鼠胰岛TGF-β/激活素- smad2信号传导可改善胰腺β细胞功能和再生能力。结论：我们的数据表明，胰腺Smad2通路的破坏在GDM的发病机制中起着关键作用，导致葡萄糖稳态异常和胰岛素分泌不足。这种信号通路的衰减可能是GDM的一个假定的治疗靶点。

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引用次数: 0

Transient juvenile hypoglycemia in GH insensitive Laron syndrome pigs is associated with insulin hypersensitivity 生长激素不敏感Laron综合征猪的短暂幼年低血糖与胰岛素过敏有关。

IF 6.6 2区医学 Q1 ENDOCRINOLOGY & METABOLISM

Molecular Metabolism

Pub Date : 2026-01-01 Epub Date: 2025-10-20 DOI: 10.1016/j.molmet.2025.102273

Arne Hinrichs , Kalliopi Pafili , Gencer Sancar , Laeticia Laane , Silja Zettler , Malek Torgeman , Barbara Kessler , Judith Leonie Nono , Sonja Kunz , Birgit Rathkolb , Cristina Barosa , Cornelia Prehn , Alexander Cecil , Simone Renner , Elisabeth Kemter , Sabine Kahl , Julia Szendroedi , Martin Bidlingmaier , John Griffith Jones , Martin Hrabĕ de Angelis , Eckhard Wolf

Background and aims

Fasting hypoglycemia has clinical implications for children with growth hormone (GH)-insensitivity syndrome. This study investigates the pathophysiology of juvenile hypoglycemia in a large animal model for GH receptor (GHR) deficiency (the GHR-KO pig) and elucidates mechanisms underlying the transition to normoglycemia in adulthood.

Methods

Insulin sensitivity was assessed in juvenile and adult GHR-KO pigs and wild-type (WT) controls via hyperinsulinemic-euglycemic clamp (HEC) tests. Glucose turnover was measured using D-[6,6-²H₂] glucose and ²H₂O. Clinical chemical and targeted metabolomics parameters in blood serum were correlated with qPCR and western blot analyses of liver and adipose tissue.

Results

GHR-KO pigs showed increased insulin sensitivity (p = 0.0019), especially at young age (M-value +34% vs. WT), insignificantly reduced insulin levels, and reduced endogenous glucose production (p = 0.0007), leading to fasting hypoglycemia with depleted liver glycogen, elevated β-hydroxybutyrate, but no increase in NEFA levels. Low hormone-sensitive lipase phosphorylation in adipose tissue suggested impaired lipolysis in young GHR-KO pigs. Metabolomics indicated enhanced fatty acid beta-oxidation and use of glucogenic amino acids, likely serving as compensatory pathways to maintain energy homeostasis. In adulthood, insulin sensitivity remained elevated but less pronounced (M-value +20%), while insulin levels were significantly reduced, enabling normoglycemia and improved NEFA availability. Increased fat mass, but not sex hormones, appeared key to this metabolic transition, as early castration had no effect.

Conclusions

Juvenile hypoglycemia in GH insensitivity results from excessive insulin sensitivity, reduced glucose production, and impaired lipolysis. Normoglycemia in adulthood emerges through increased adiposity and moderated insulin sensitivity, independently of sex hormones. These findings elucidate the age-dependent metabolic adaptations in GH insensitivity.

背景和目的：空腹低血糖对生长激素（GH）不敏感综合征患儿具有临床意义。本研究在GH受体（GHR）缺乏症的大型动物模型（GHR - ko猪）中研究了青少年低血糖的病理生理学，并阐明了成年后向正常血糖过渡的机制。方法：通过高胰岛素-血糖钳夹（HEC）试验评估幼年、成年GHR-KO猪和野生型（WT）对照的胰岛素敏感性。葡萄糖转化率用D-[6,6- 2h2]葡萄糖和2H2O测定。血清中的临床化学和靶向代谢组学参数与肝脏和脂肪组织的qPCR和western blot分析相关。结果：GHR-KO猪表现出胰岛素敏感性增加（p=0.0019），特别是在年轻时（m值与WT相比+34%），胰岛素水平不显著降低，内源性葡萄糖生成减少（p=0.0007），导致空腹低血糖，肝糖原消耗，β-羟基丁酸升高，但NEFA水平未增加。脂肪组织中激素敏感的脂肪酶磷酸化水平低，表明年轻GHR-KO猪的脂肪分解受损。代谢组学表明，脂肪酸β -氧化和糖原氨基酸的使用增强，可能作为维持能量稳态的代偿途径。在成年期，胰岛素敏感性仍然升高，但不太明显（m值+20%），而胰岛素水平显着降低，使血糖正常并改善NEFA可用性。增加的脂肪量，而不是性激素，似乎是这种代谢转变的关键，因为早期阉割没有影响。结论：生长激素不敏感的青少年低血糖是由胰岛素过度敏感、葡萄糖生成减少和脂肪分解受损引起的。成年期的正常血糖是通过肥胖增加和胰岛素敏感性降低而出现的，独立于性激素。这些发现阐明了生长激素不敏感的年龄依赖性代谢适应。

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引用次数: 0

Corrigendum to “Insulin receptor-mediated signaling regulates pluripotency markers and lineage differentiation” [Mol Metab 18 (2018) 153–163] “胰岛素受体介导的信号传导调节多能性标志物和谱系分化”的更正[Mol Metab 18(2018) 153-163]。

IF 6.6 2区医学 Q1 ENDOCRINOLOGY & METABOLISM

Molecular Metabolism

Pub Date : 2026-01-01 Epub Date: 2025-11-28 DOI: 10.1016/j.molmet.2025.102285

Manoj K. Gupta , Dario F. De Jesus , Sevim Kahraman , Ivan A. Valdez , Farnaz Shamsi , Lian Yi , Adam C. Swensen , Yu-Hua Tseng , Wei-Jun Qian , Rohit N. Kulkarni

引用次数: 0

Loss of GLP-2R signaling in Glp2r−/− mice increases the long-term severity of graft versus host disease GLP-2R -/-小鼠中GLP-2R信号的缺失会增加移植物抗宿主病的长期严重程度。

IF 6.6 2区医学 Q1 ENDOCRINOLOGY & METABOLISM

Molecular Metabolism

Pub Date : 2026-01-01 Epub Date: 2025-12-17 DOI: 10.1016/j.molmet.2025.102311

Bernardo Yusta, Chi Kin Wong, Dianne Matthews, Jacqueline A. Koehler, Laurie L. Baggio, Daniel J. Drucker

Background

Glucagon-like peptide-2 (GLP-2) reduces systemic and gut inflammation while preserving mucosal integrity. Preclinical and clinical reports implicate GLP-2 receptor (GLP-2R) agonism as a potential therapy for graft vs. host disease (GvHD).

Methods

Here we assessed whether enhanced vs. loss of GLP-2R signaling modifies gut injury and inflammation in experimental murine acute GvHD (aGvHD). Allogeneic hematopoietic cell transplantation (HCT) was performed using bone marrow and splenocytes from BALB/cJ donor mice to induce aGvHD in C57BL/6J recipients. Chimerism was determined by flow cytometry of immune cell compartments. Inflammation was assessed by measuring circulating cytokines and histological scoring of gut mucosal damage. GLP-2 responsivity was assessed using histology and gene expression analyses. The gut microbiome was assessed by 16S rRNA sequencing.

Results

Allogeneic chimerism was >90% in peripheral blood and in the gut epithelial compartment. Gut GLP-2R signaling was preserved following allogeneic bone marrow transplantation. Surprisingly, GLP-2R agonism using teduglutide did not reduce circulating cytokines, gut injury, immune cell infiltration or the severity of aGvHD. In contrast, transplant recipient Glp2r^−/− mice exhibited reduced survival, associated with increased bacteremia. Shifts in microbial species abundance with gain or loss of GLP-2R signaling were not correlated with aGvHD clinical outcomes.

Conclusions

Activation of GLP-2R signaling did not reduce the severity of experimental aGvHD, failing to replicate a previous study using an identical aGvHD protocol. Nevertheless, loss of GLP-2R signaling in transplant recipients decreased survival and increased bacteremia, implicating an essential role for endogenous GLP-2R signaling in maintaining barrier function in the context of immune-mediated gut epithelial injury.

背景：胰高血糖素样肽-2 （GLP-2）在保持粘膜完整性的同时减少全身和肠道炎症。临床前和临床报告暗示GLP-2受体（GLP-2R）激动作用作为移植物抗宿主病（GvHD）的潜在治疗方法。方法：在这里，我们评估了GLP-2R信号的增强和丧失是否会改变实验性小鼠急性GvHD （aGvHD）的肠道损伤和炎症。采用BALB/cJ供体小鼠骨髓和脾细胞进行同种异体造血细胞移植（HCT）诱导C57BL/6J受体aGvHD。用流式细胞术检测免疫细胞室嵌合情况。通过测量循环细胞因子和肠黏膜损伤的组织学评分来评估炎症。通过组织学和基因表达分析评估GLP-2的反应性。通过16S rRNA测序评估肠道微生物组。结果：外周血和肠上皮腔异体嵌合率达90%。同种异体骨髓移植后，肠道GLP-2R信号得以保留。令人惊讶的是，使用teduglutide的GLP-2R激动作用并没有减少循环细胞因子、肠道损伤、免疫细胞浸润或aGvHD的严重程度。相比之下，移植受体Glp2r-/-小鼠的存活率降低，与菌血症增加有关。随着GLP-2R信号的增加或减少，微生物种类丰度的变化与aGvHD的临床结果无关。结论：GLP-2R信号的激活并没有降低实验性aGvHD的严重程度，未能复制先前使用相同aGvHD协议的研究。然而，移植受者GLP-2R信号的缺失降低了生存率并增加了菌血症，这意味着内源性GLP-2R信号在免疫介导的肠道上皮损伤中维持屏障功能方面发挥了重要作用。

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引用次数: 0

Protective role of soluble CD52 in obesity-associated steatotic liver disease and glucose dysregulation in mice 可溶性CD52在小鼠肥胖相关脂肪变性肝病和葡萄糖失调中的保护作用

IF 6.6 2区医学 Q1 ENDOCRINOLOGY & METABOLISM

Molecular Metabolism

Pub Date : 2026-01-01 Epub Date: 2025-11-04 DOI: 10.1016/j.molmet.2025.102279

Yuichiro Miyazawa , Tsutomu Wada , Yuichi Iwasa , Kento Fuse , Hisafumi Shioneri , Yasuhiro Onogi , Azusa Sameshima , Tomoyuki Yoshida , Ichiro Takasaki , Hisashi Mori , Keiichi Koizumi , Hiroshi Tsuneki , Shigeru Saito , Toshiyasu Sasaoka

Objectives

Soluble CD52 (sCD52) derived from activated CD4⁺ T cells regulates T cell immunity under autoimmune conditions; however, its role in obesity-associated chronic inflammation and glucose metabolism remains unclear. Therefore, we herein investigated the significance of CD52 in obesity.

Methods

CD52-knockout mice (KO) and their wild-type littermates were fed a high-fat diet (HFD) for 12 weeks and analyzed.

Results

sCD52 preferentially suppressed chronic liver inflammation and protected against impaired glucose tolerance and metabolic dysfunction-associated steatotic liver disease (MASLD) in obesity. No significant differences were observed in weight gain or energy metabolism in KO mice; however, glucose metabolism was impaired. A histological examination revealed more severe chronic inflammation and steatosis in KO mice, accompanied by changes in liver transcriptome profiles, but no significant differences in epididymal white adipose tissue (eWAT). In contrast, CD52 expression was significantly up-regulated in eWAT, with slightly higher levels in the liver and skeletal muscle in HFD-fed obese C57BL/6 mice than in chow-fed controls. sCD52 was released from the cultured eWAT of obese mice, but not lean mice, and circulating sCD52 levels were higher in obese mice. A re-analysis of a public single-nucleus RNA sequencing library revealed that increased CD52 in eWAT was linked to immune cells and adipocytes. T cell-derived purified sCD52 suppressed macrophage activation in vitro. In contrast, sCD52 was not secreted from 3T3-L1 adipocytes, although its protein levels increased with differentiation.

Conclusions

T cell-derived sCD52 mitigates the obesity-associated development of MASLD and glucose intolerance in mice.

目的：来自活化CD4+ T细胞的可溶性CD52 （sCD52）调节自身免疫条件下的T细胞免疫；然而，它在肥胖相关的慢性炎症和葡萄糖代谢中的作用尚不清楚。因此，我们在此研究CD52在肥胖中的意义。方法：对cd52基因敲除小鼠（KO）及其野生型仔鼠饲喂高脂饲料（HFD） 12周并进行分析。结果：sCD52优先抑制慢性肝脏炎症，防止肥胖患者糖耐量受损和代谢功能障碍相关的脂肪变性肝病（MASLD）。KO小鼠的体重增加和能量代谢无显著差异；然而，葡萄糖代谢受损。组织学检查显示KO小鼠更严重的慢性炎症和脂肪变性，伴随着肝脏转录组谱的变化，但附睾白色脂肪组织（eWAT）没有显著差异。相比之下，CD52在eWAT中的表达显著上调，hfd喂养的肥胖C57BL/6小鼠肝脏和骨骼肌中的表达水平略高于正常喂养的对照组。肥胖小鼠培养的eWAT中有sCD52释放，而瘦弱小鼠没有，肥胖小鼠的循环sCD52水平较高。对公共单核RNA测序文库的重新分析显示，eWAT中CD52的增加与免疫细胞和脂肪细胞有关。T细胞衍生的纯化sCD52体外抑制巨噬细胞活化。相比之下，3T3-L1脂肪细胞不分泌sCD52，尽管其蛋白水平随着分化而增加。结论：T细胞来源的sCD52减轻了小鼠肥胖相关的MASLD和葡萄糖耐受不良的发展。

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引用次数: 0

An atlas of mitochondrial ATP synthase activity across the lifespan 线粒体ATP合酶在整个生命周期中的活性图谱。

IF 6.6 2区医学 Q1 ENDOCRINOLOGY & METABOLISM

Molecular Metabolism

Pub Date : 2026-01-01 Epub Date: 2025-11-01 DOI: 10.1016/j.molmet.2025.102278

Muzna Saqib , Dylan C. Sarver , Christy M. Nguyen , Fangluo Chen , Marcus M. Seldin , G. William Wong

Mitochondrial dysfunction and declining energy production are hallmarks of aging, yet we lack a comprehensive systems-level view of ATP synthase (Complex V) activity across tissues, sex, and age. To overcome this, we leveraged a recently developed method to directly quantify complex V hydrolytic activity at scale in 32 tissues from young (10 weeks) and old (80 weeks) male and female mice. Our high-resolution atlas reveals several notable findings: 1) complex V activity differs markedly across tissues, with the highest levels seen in contractile organs such as the heart and striated muscles (quadriceps, hamstring, diaphragm, tongue); 2) sex influences complex V activity in a tissue-specific manner, with significant differences seen in the heart, liver, fat depots, pancreas, spleen, tongue, and cortex; 3) aging has a much larger impact than sex on complex V activity, with a greater number of age-dependent changes seen across tissues; 4) the directionality and magnitude of change in complex V activity across sex and age is variable and tissue dependent; 5) the expression of complex V related genes in human and mouse tissues across age shows only partial concordance with complex V activity, suggesting functional modulation by posttranscriptional mechanisms. This compendium of ATP synthase activity highlights organ-level variations in the mode and tempo of aging, affording an unprecedented view of the shared and divergent changes in ATP synthase function across sex and organ systems. Our data provide a valuable reference for comparative studies of mitochondrial adaptations across space and time, and in pathophysiological contexts.

线粒体功能障碍和能量产生下降是衰老的标志，但我们缺乏跨组织、性别和年龄的ATP合成酶（Complex V）活性的全面系统水平视图。为了克服这个问题，我们利用最近开发的一种方法，在32个来自幼龄（10周龄）和老年（80周龄）雄性和雌性小鼠的组织中，大规模地直接量化复合物V水解活性。我们的高分辨率图谱揭示了几个值得注意的发现：1)复杂的V活动在不同的组织中有明显的差异，在可收缩的器官中，如心脏和横纹肌（股四头肌、腘绳肌、横膈膜、舌肌），其水平最高；2)性别以组织特异性的方式影响复合物V的活性，在心脏、肝脏、脂肪库、胰腺、脾脏、舌头和皮层中存在显著差异；3)年龄对复杂V活性的影响远大于性别，各组织中随年龄变化的数量更多；复合物V活性变化的方向性和幅度在性别和年龄上是可变的和组织依赖性的；5)人类和小鼠组织中复合体V相关基因的表达与复合体V活性仅部分一致，提示复合体V的功能受转录后机制调控。这个ATP合酶活性的纲要强调了器官水平上衰老模式和速度的变化，为跨性别和器官系统的ATP合酶功能的共同和不同变化提供了前所未有的观点。我们的数据为线粒体适应跨时空和病理生理背景的比较研究提供了有价值的参考。

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引用次数: 0

Cross-species studies implicate the melanocortin 3 receptor more strongly in the control of pubertal development than energy balance 跨物种研究表明，与能量平衡相比，黑素皮质素3受体对青春期发育的控制更为强烈。

IF 6.6 2区医学 Q1 ENDOCRINOLOGY & METABOLISM

Molecular Metabolism

Pub Date : 2026-01-01 Epub Date: 2025-12-10 DOI: 10.1016/j.molmet.2025.102301

Katie Duckett , Alyce McClellan , Laura J. Corbin , Irene Cimino , Ahmed Elhakeem , Ana Goncalves Soares , Alice Williamson , Eloise Cross , Zammy Fairhurst-Hunter , Slavé Petrovski , Debra Rimmington , Jesús Alegre-Díaz , Jaime Berumen , Pablo Kuri-Morales , Roberto Tapia-Conyer , BELIEVE study,, Jacek Mokrosinski , I. Sadaf Farooqi , Asif Rasheed , Danish Saleheen , Stephen O’Rahilly

Hypothalamic neurons expressing either POMC or AGRP sense nutritional state directly and indirectly and transmit these neuropeptide signals to other brain centres through the melanocortin 3 and 4 receptors. MC4R is primarily concerned with the control of appetite and energy expenditure while MC3R is more closely related to the control of linear growth and the timing of puberty. The role of MC3R in the long-term control of energy balance and body composition is less clear, particularly in humans. We have undertaken studies in humans, domestic dogs and mice with the goal of clarifying the relative impact of MC3R deficiency on energy balance, growth and sexual development. By studying three large consanguineously enriched cohorts, totalling approximately 300K people, we identified nine individuals who are homozygous for functionally null MC3R variants. The body mass index (BMI) of the homozygous MC3R variant carriers was not significantly different from that of age, sex and demographically matched controls, with six of the nine homozygotes having a BMI <30 kg/m².

We detected a canine MC3R missense variant (p.M320I) which is common in labrador retrievers and showed that this significantly impairs receptor signalling. Dogs homozygous for p.M320I were lighter and showed delayed pubertal development but were not significantly more obese than wild-type or heterozygous dogs. We also established that the lack of Mc3r delayed pubertal development in both male and female mice.

Finally, we studied growth and pubertal trajectories of individuals carrying rare loss-of-function MC3R variants and found that male carriers had delayed peak weight velocity and genital development but had no evidence for excess body fat compared to non-carriers.

Our results support MC3R having a conserved role across mammals in controlling growth and pubertal timing. While MC3R deficiency may influence linear growth and body composition, complete loss of MC3R does not result in a penetrant human obesity syndrome.

表达POMC或AGRP的下丘脑神经元直接或间接地感知营养状态，并通过黑素皮质素3和4受体将这些神经肽信号传递到其他脑中枢。MC4R主要与食欲和能量消耗的控制有关，而MC3R与控制线性生长和青春期的时间更密切相关。MC3R在能量平衡和身体成分的长期控制中的作用尚不清楚，特别是在人类中。我们已经对人类、家养狗和老鼠进行了研究，目的是澄清MC3R缺乏对能量平衡、生长和性发育的相对影响。通过研究三个大的近亲富集队列，总共约30万人，我们确定了9个功能无效的MC3R变异纯合的个体。纯合子MC3R变异携带者的体重指数（BMI）与年龄、性别和人口统计学匹配的对照组没有显著差异，9个纯合子中有6个BMI < 30kg/m2。我们检测到犬MC3R错义变体（p.M320I），这在拉布拉多寻回犬中很常见，并表明这显著损害受体信号传导。p.M320I纯合子犬体重较轻，青春期发育较晚，但肥胖程度不明显高于野生型或杂合子犬。我们还证实，缺乏Mc3r会延迟雄性和雌性小鼠的青春期发育。最后，我们研究了携带罕见功能缺失MC3R变异的个体的生长和青春期轨迹，发现男性携带者的体重峰值速度和生殖器发育延迟，但与非携带者相比，没有证据表明存在多余的体脂。我们的研究结果支持MC3R在控制哺乳动物生长和青春期时间方面具有保守作用。虽然MC3R缺乏可能影响线性生长和身体组成，但MC3R的完全缺失不会导致渗透性人类肥胖综合征。

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引用次数: 0