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Functional interrogation of twenty type 2 diabetes-associated genes using isogenic human embryonic stem cell-derived β-like cells. 利用等基因人类胚胎干细胞衍生的β样细胞对20个2型糖尿病相关基因进行功能性询问。
Pub Date : 2023-11-07 Epub Date: 2023-10-18 DOI: 10.1016/j.cmet.2023.09.013
Dongxiang Xue, Narisu Narisu, D Leland Taylor, Meili Zhang, Caleb Grenko, Henry J Taylor, Tingfen Yan, Xuming Tang, Neelam Sinha, Jiajun Zhu, J Jeya Vandana, Angie Chi Nok Chong, Angela Lee, Erin C Mansell, Amy J Swift, Michael R Erdos, Aaron Zhong, Lori L Bonnycastle, Ting Zhou, Shuibing Chen, Francis S Collins

Genetic studies have identified numerous loci associated with type 2 diabetes (T2D), but the functional roles of many loci remain unexplored. Here, we engineered isogenic knockout human embryonic stem cell lines for 20 genes associated with T2D risk. We examined the impacts of each knockout on β cell differentiation, functions, and survival. We generated gene expression and chromatin accessibility profiles on β cells derived from each knockout line. Analyses of T2D-association signals overlapping HNF4A-dependent ATAC peaks identified a likely causal variant at the FAIM2 T2D-association signal. Additionally, the integrative association analyses identified four genes (CP, RNASE1, PCSK1N, and GSTA2) associated with insulin production, and two genes (TAGLN3 and DHRS2) associated with β cell sensitivity to lipotoxicity. Finally, we leveraged deep ATAC-seq read coverage to assess allele-specific imbalance at variants heterozygous in the parental line and identified a single likely functional variant at each of 23 T2D-association signals.

遗传学研究已经确定了许多与2型糖尿病(T2D)相关的基因座,但许多基因座的功能作用尚未探索。在这里,我们设计了20个与T2D风险相关的基因的等基因敲除人类胚胎干细胞系。我们研究了每种敲除对β细胞分化、功能和存活的影响。我们生成了来自每个敲除系的β细胞的基因表达和染色质可及性图谱。对与依赖HNF4A的ATAC峰重叠的T2D关联信号的分析确定了FAIM2 T2D关联信息的可能的因果变化。此外,综合关联分析确定了与胰岛素产生相关的四个基因(CP、RNASE1、PCSK1N和GSTA2),以及与β细胞对脂毒性敏感相关的两个基因(TAGLN3和DHRS2)。最后,我们利用深入的ATAC-seq读数覆盖率来评估亲本系中杂合变异体的等位基因特异性失衡,并在23个T2D关联信号中的每一个信号中确定了一个可能的功能变异体。
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引用次数: 0
Dietary restriction of isoleucine increases healthspan and lifespan of genetically heterogeneous mice. 异亮氨酸的饮食限制增加了遗传异质小鼠的健康寿命和寿命。
Pub Date : 2023-11-07 DOI: 10.1016/j.cmet.2023.10.005
Cara L Green, Michaela E Trautman, Krittisak Chaiyakul, Raghav Jain, Yasmine H Alam, Reji Babygirija, Heidi H Pak, Michelle M Sonsalla, Mariah F Calubag, Chung-Yang Yeh, Anneliese Bleicher, Grace Novak, Teresa T Liu, Sarah Newman, Will A Ricke, Kristina A Matkowskyj, Irene M Ong, Cholsoon Jang, Judith Simcox, Dudley W Lamming

Low-protein diets promote health and longevity in diverse species. Restriction of the branched-chain amino acids (BCAAs) leucine, isoleucine, and valine recapitulates many of these benefits in young C57BL/6J mice. Restriction of dietary isoleucine (IleR) is sufficient to promote metabolic health and is required for many benefits of a low-protein diet in C57BL/6J males. Here, we test the hypothesis that IleR will promote healthy aging in genetically heterogeneous adult UM-HET3 mice. We find that IleR improves metabolic health in young and old HET3 mice, promoting leanness and glycemic control in both sexes, and reprograms hepatic metabolism in a sex-specific manner. IleR reduces frailty and extends the lifespan of male and female mice, but to a greater degree in males. Our results demonstrate that IleR increases healthspan and longevity in genetically diverse mice and suggests that IleR, or pharmaceuticals that mimic this effect, may have potential as a geroprotective intervention.

低蛋白饮食可以促进不同物种的健康和长寿。支链氨基酸(BCAAs)亮氨酸、异亮氨酸和缬氨酸的限制在年轻C57BL/6J小鼠中概括了许多这些益处。限制饮食中的异亮氨酸(IleR)足以促进代谢健康,并且是C57BL/6J雄性低蛋白饮食的许多益处所必需的。在这里,我们检验了IleR将促进遗传异质性成年UM-HET3小鼠健康衰老的假设。我们发现IleR改善了年轻和老年HET3小鼠的代谢健康,促进了两性的瘦度和血糖控制,并以性别特异性的方式重新编程肝脏代谢。IleR可以减少雄性和雌性小鼠的虚弱,延长它们的寿命,但在雄性小鼠中的作用更大。我们的研究结果表明,IleR可以增加遗传多样性小鼠的健康寿命和寿命,并表明IleR或模拟这种效果的药物可能具有保护性干预的潜力。
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引用次数: 0
Microbiota-gut-brain axis drives overeating disorders. 微生物群-肠-脑轴导致饮食失调。
Pub Date : 2023-11-07 Epub Date: 2023-10-03 DOI: 10.1016/j.cmet.2023.09.005
Sijia Fan, Weiwei Guo, Dan Xiao, Mengyuan Guan, Tiepeng Liao, Sufang Peng, Airong Feng, Ziyi Wang, Hao Yin, Min Li, Jue Chen, Wei Xiong

Overeating disorders (ODs), usually stemming from dieting history and stress, remain a pervasive issue in contemporary society, with the pathological mechanisms largely unresolved. Here, we show that alterations in intestinal microbiota are responsible for the excessive intake of palatable foods in OD mice and patients with bulimia nervosa (BN). Stress combined with a history of dieting causes significant changes in the microbiota and the intestinal metabolism, which disinhibit the vagus nerve terminals in the gut and thereby lead to a subsequent hyperactivation of the gut-brain axis passing through the vagus, the solitary tract nucleus, and the paraventricular nucleus of the thalamus. The transplantation of a probiotic Faecalibacterium prausnitzii or dietary supplement of key metabolites restores the activity of the gut-to-brain pathway and thereby alleviates the OD symptoms. Thus, our study delineates how the microbiota-gut-brain axis mediates energy balance, unveils the underlying pathogenesis of the OD, and provides potential therapeutic strategies.

过度饮食障碍(ODs)通常源于节食史和压力,在当代社会仍然是一个普遍存在的问题,其病理机制在很大程度上尚未解决。在这里,我们发现肠道微生物群的改变是OD小鼠和神经性贪食症(BN)患者过量摄入适口食物的原因。压力与节食史相结合会导致微生物群和肠道代谢发生显著变化,从而解除对肠道迷走神经末梢的抑制,从而导致随后穿过迷走神经、孤束核和丘脑室旁核的肠脑轴过度激活。移植益生菌普氏Faecalibacterium prausnitzii或关键代谢产物的膳食补充剂可以恢复肠-脑通路的活性,从而缓解OD症状。因此,我们的研究描述了微生物群-肠-脑轴如何介导能量平衡,揭示了OD的潜在发病机制,并提供了潜在的治疗策略。
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引用次数: 0
Mitohormesis. 有丝分裂症。
Pub Date : 2023-11-07 DOI: 10.1016/j.cmet.2023.10.011
Yu-Wei Cheng, Jie Liu, Toren Finkel

Perturbation of mitochondrial function can trigger a host of cellular responses that seek to restore cellular metabolism, cytosolic proteostasis, and redox homeostasis. In some cases, these responses persist even after the stress is relieved, leaving the cell or tissue in a less vulnerable state. This process-termed mitohormesis-is increasingly viewed as an important aspect of normal physiology and a critical modulator of various disease processes. Here, we review aspects of mitochondrial stress signaling that, among other things, can rewire the cell's metabolism, activate the integrated stress response, and alter cytosolic quality-control pathways. We also discuss how these pathways are implicated in various disease states from pathogen challenge to chemotherapeutic resistance and how their therapeutic manipulation can lead to new strategies for a host of chronic conditions including aging itself.

线粒体功能的紊乱可以引发一系列细胞反应,寻求恢复细胞代谢、胞质蛋白稳定和氧化还原稳态。在某些情况下,这些反应甚至在压力缓解后仍然存在,使细胞或组织处于不那么脆弱的状态。这种被称为有丝分裂刺激的过程越来越被视为正常生理学的一个重要方面,也是各种疾病过程的关键调节剂。在这里,我们回顾了线粒体应激信号的各个方面,这些方面可以重新连接细胞的代谢,激活综合应激反应,并改变胞质质量控制途径。我们还讨论了这些途径如何与从病原体挑战到化疗耐药性的各种疾病状态有关,以及它们的治疗方法如何为包括衰老本身在内的一系列慢性疾病带来新的策略。
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引用次数: 0
Dynamic scRNA-seq of live human pancreatic slices reveals functional endocrine cell neogenesis through an intermediate ducto-acinar stage. 活的人类胰腺切片的动态scRNA-seq揭示了通过腺泡导管中期的功能性内分泌细胞新生。
Pub Date : 2023-11-07 Epub Date: 2023-10-27 DOI: 10.1016/j.cmet.2023.10.001
Mayur Doke, Silvia Álvarez-Cubela, Dagmar Klein, Isabella Altilio, Joseph Schulz, Luciana Mateus Gonçalves, Joana Almaça, Christopher A Fraker, Alberto Pugliese, Camillo Ricordi, Mirza M F Qadir, Ricardo L Pastori, Juan Domínguez-Bendala

Human pancreatic plasticity is implied from multiple single-cell RNA sequencing (scRNA-seq) studies. However, these have been invariably based on static datasets from which fate trajectories can only be inferred using pseudotemporal estimations. Furthermore, the analysis of isolated islets has resulted in a drastic underrepresentation of other cell types, hindering our ability to interrogate exocrine-endocrine interactions. The long-term culture of human pancreatic slices (HPSs) has presented the field with an opportunity to dynamically track tissue plasticity at the single-cell level. Combining datasets from same-donor HPSs at different time points, with or without a known regenerative stimulus (BMP signaling), led to integrated single-cell datasets storing true temporal or treatment-dependent information. This integration revealed population shifts consistent with ductal progenitor activation, blurring of ductal/acinar boundaries, formation of ducto-acinar-endocrine differentiation axes, and detection of transitional insulin-producing cells. This study provides the first longitudinal scRNA-seq analysis of whole human pancreatic tissue, confirming its plasticity in a dynamic fashion.

多个单细胞RNA测序(scRNA-seq)研究暗示了人类胰腺的可塑性。然而,这些都是基于静态数据集的,只能使用伪时间估计来推断命运轨迹。此外,对分离的胰岛的分析导致其他细胞类型的代表性严重不足,阻碍了我们询问外分泌-内分泌相互作用的能力。人类胰腺切片(HPSs)的长期培养为该领域提供了在单细胞水平上动态跟踪组织可塑性的机会。将来自不同时间点的相同供体HPS的数据集结合起来,无论是否有已知的再生刺激(BMP信号),都会产生存储真正的时间或治疗依赖性信息的集成单细胞数据集。这种整合揭示了与导管祖细胞激活、导管/腺泡边界模糊、导管-腺泡内分泌分化轴的形成以及过渡胰岛素产生细胞的检测一致的群体变化。这项研究首次对整个人类胰腺组织进行了纵向scRNA-seq分析,以动态方式证实了其可塑性。
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引用次数: 0
Death-seq and ye shall find: A novel screening strategy for dying cells. 死亡序列,你会发现:一种新的死亡细胞筛选策略。
Pub Date : 2023-10-03 DOI: 10.1016/j.cmet.2023.09.003
Ryan Wallis, Cleo L Bishop

Killing senescent cells to improve health-span holds great promise. However, screening for senescence-regulating genes and molecules is challenging because these cells do not proliferate. In this issue, Colville and Liu et al. develop Death-seq, a positive selection screening tool that overcomes this hurdle to offer broad genetic and pharmacological utility.

杀死衰老细胞以改善健康寿命是很有希望的。然而,筛选衰老调控基因和分子是具有挑战性的,因为这些细胞不会增殖。在本期中,Colville和Liu等人。开发Death-seq,这是一种阳性选择筛选工具,可以克服这一障碍,提供广泛的遗传和药理学用途。
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引用次数: 0
Neutrophils resist ferroptosis and promote breast cancer metastasis through aconitate decarboxylase 1. 中性粒细胞通过附子酸脱羧酶1抵抗脱铁,促进乳腺癌症转移。
Pub Date : 2023-10-03 DOI: 10.1016/j.cmet.2023.09.004
Yun Zhao, Zhongshun Liu, Guoqiang Liu, Yuting Zhang, Sheng Liu, Dailin Gan, Wennan Chang, Xiaoxia Peng, Eun Suh Sung, Keegan Gilbert, Yini Zhu, Xuechun Wang, Ziyu Zeng, Hope Baldwin, Guanzhu Ren, Jessica Weaver, Anna Huron, Toni Mayberry, Qingfei Wang, Yujue Wang, Maria Elena Diaz-Rubio, Xiaoyang Su, M Sharon Stack, Siyuan Zhang, Xuemin Lu, Ryan D Sheldon, Jun Li, Chi Zhang, Jun Wan, Xin Lu

Metastasis causes breast cancer-related mortality. Tumor-infiltrating neutrophils (TINs) inflict immunosuppression and promote metastasis. Therapeutic debilitation of TINs may enhance immunotherapy, yet it remains a challenge to identify therapeutic targets highly expressed and functionally essential in TINs but under-expressed in extra-tumoral neutrophils. Here, using single-cell RNA sequencing to compare TINs and circulating neutrophils in murine mammary tumor models, we identified aconitate decarboxylase 1 (Acod1) as the most upregulated metabolic enzyme in mouse TINs and validated high Acod1 expression in human TINs. Activated through the GM-CSF-JAK/STAT5-C/EBPβ pathway, Acod1 produces itaconate, which mediates Nrf2-dependent defense against ferroptosis and upholds the persistence of TINs. Acod1 ablation abates TIN infiltration, constrains metastasis (but not primary tumors), bolsters antitumor T cell immunity, and boosts the efficacy of immune checkpoint blockade. Our findings reveal how TINs escape from ferroptosis through the Acod1-dependent immunometabolism switch and establish Acod1 as a target to offset immunosuppression and improve immunotherapy against metastasis.

转移导致乳腺癌相关死亡率。肿瘤浸润性中性粒细胞(TINs)引起免疫抑制并促进转移。TINs的治疗性衰弱可能会增强免疫治疗,但识别TINs中高表达和功能必需但在肿瘤外中性粒细胞中表达不足的治疗靶点仍然是一个挑战。在这里,使用单细胞RNA测序来比较小鼠乳腺肿瘤模型中的TINs和循环中性粒细胞,我们确定乌头酸脱羧酶1(Acod1)是小鼠TINs中最上调的代谢酶,并验证了Acod1在人类TINs中的高表达。Acod1通过GM-CSF-JAK/STAT5-C/EBPβ途径激活,产生衣康酸,介导Nrf2依赖性防御铁蛋白脱失,并维持TIN的持久性。Acod1消融可减少TIN浸润,抑制转移(但不是原发性肿瘤),增强抗肿瘤T细胞免疫力,并提高免疫检查点阻断的疗效。我们的研究结果揭示了TIN如何通过Acod1依赖性免疫代谢转换从脱铁性贫血中逃逸,并将Acod1确立为抵消免疫抑制和改善免疫治疗以对抗转移的靶点。
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引用次数: 0
Restricting mealtime ameliorates neurodegeneration. 限制用餐时间可以改善神经退行性变。
Pub Date : 2023-10-03 DOI: 10.1016/j.cmet.2023.09.006
Xiao Tian, David A Sinclair

Alzheimer's disease is often accompanied by disruptions in circadian rhythms, which may exacerbate the disease's progression. In this issue, Whittaker and colleagues demonstrate that the modulation of circadian rhythms by time-restricted feeding can alter the disease trajectory in Alzheimer's mouse models.

阿尔茨海默病通常伴随着昼夜节律的紊乱,这可能会加剧疾病的进展。在这个问题上,Whittaker和他的同事证明,通过限时喂食来调节昼夜节律可以改变阿尔茨海默氏症小鼠模型的疾病轨迹。
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引用次数: 0
Regulatory T cells require IL6 receptor alpha signaling to control skeletal muscle function and regeneration. 调节性T细胞需要IL6受体α信号来控制骨骼肌功能和再生。
Pub Date : 2023-10-03 Epub Date: 2023-09-20 DOI: 10.1016/j.cmet.2023.08.010
Maike Becker, Sini S Joseph, Francisco Garcia-Carrizo, Robby Z Tom, Daria Opaleva, Isabelle Serr, Matthias H Tschöp, Tim J Schulz, Susanna M Hofmann, Carolin Daniel

Muscle-residing regulatory T cells (Tregs) control local tissue integrity and function. However, the molecular interface connecting Treg-based regulation with muscle function and regeneration remains largely unexplored. Here, we show that exercise fosters a stable induction of highly functional muscle-residing Tregs with increased expression of amphiregulin (Areg), EGFR, and ST2. Mechanistically, we find that mice lacking IL6Rα on T cells (TKO) harbor significant reductions in muscle Treg functionality and satellite and fibro-adipogenic progenitor cells, which are required for muscle regeneration. Using exercise and sarcopenia models, IL6Rα TKO mice demonstrate deficits in Tregs, their functional maturation, and a more pronounced decline in muscle mass. Muscle injury models indicate that IL6Rα TKO mice have significant disabilities in muscle regeneration. Treg gain of function restores impaired muscle repair in IL6Rα TKO mice. Of note, pharmacological IL6R blockade in WT mice phenocopies deficits in muscle function identified in IL6Rα TKO mice, thereby highlighting the clinical implications of the findings.

肌肉驻留调节性T细胞(Tregs)控制局部组织的完整性和功能。然而,将基于Treg的调节与肌肉功能和再生联系起来的分子界面在很大程度上仍未被探索。在这里,我们发现运动促进了高功能肌肉驻留Tregs的稳定诱导,同时增加了两调节蛋白(Areg)、EGFR和ST2的表达。从机制上讲,我们发现T细胞(TKO)缺乏IL6Rα的小鼠的肌肉Treg功能以及肌肉再生所需的卫星和纤维成脂祖细胞显著减少。使用运动和少肌症模型,IL6RαTKO小鼠表现出Tregs缺陷、功能成熟和肌肉质量更明显的下降。肌肉损伤模型表明,IL6RαTKO鼠在肌肉再生方面有显著障碍。Treg功能增强可恢复IL6RαTKO小鼠受损的肌肉修复。值得注意的是,野生型小鼠的药理学IL6R阻断在IL6RαTKO小鼠中发现了肌肉功能的表型缺陷,从而突出了该发现的临床意义。
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引用次数: 0
Ketogenesis promotes tolerance to Pseudomonas aeruginosa pulmonary infection. 酮体生成促进对铜绿假单胞菌肺部感染的耐受性。
Pub Date : 2023-10-03 DOI: 10.1016/j.cmet.2023.09.001
Kira L Tomlinson, Ying-Tsun Chen, Alex Junker, AndreaCarola Urso, Tania Wong Fok Lung, Danielle Ahn, Casey E Hofstaedter, Swikrity U Baskota, Robert K Ernst, Alice Prince, Sebastián A Riquelme

Pseudomonas aeruginosa is a common cause of pulmonary infection. As a Gram-negative pathogen, it can initiate a brisk and highly destructive inflammatory response; however, most hosts become tolerant to the bacterial burden, developing chronic infection. Using a murine model of pneumonia, we demonstrate that this shift from inflammation to disease tolerance is promoted by ketogenesis. In response to pulmonary infection, ketone bodies are generated in the liver and circulate to the lungs where they impose selection for P. aeruginosa strains unable to display surface lipopolysaccharide (LPS). Such keto-adapted LPS strains fail to activate glycolysis and tissue-damaging cytokines and, instead, facilitate mitochondrial catabolism of fats and oxidative phosphorylation (OXPHOS), which maintains airway homeostasis. Within the lung, P. aeruginosa exploits the host immunometabolite itaconate to further stimulate ketogenesis. This environment enables host-P. aeruginosa coexistence, supporting both pathoadaptive changes in the bacteria and the maintenance of respiratory integrity via OXPHOS.

铜绿假单胞菌是肺部感染的常见原因。作为革兰氏阴性病原体,它可以引发活跃且极具破坏性的炎症反应;然而,大多数宿主对细菌负荷具有耐受性,发展为慢性感染。使用小鼠肺炎模型,我们证明了生酮促进了从炎症到疾病耐受的转变。作为对肺部感染的反应,酮体在肝脏中产生并循环到肺部,在那里它们对不能显示表面脂多糖(LPS)的铜绿假单胞菌菌株进行选择。这种酮适应的LPS菌株不能激活糖酵解和破坏组织的细胞因子,反而促进脂肪的线粒体分解代谢和氧化磷酸化(OXPHOS),从而维持气道稳态。在肺部,铜绿假单胞菌利用宿主免疫代谢产物衣康酸盐进一步刺激生酮。此环境启用host-P。铜绿假单胞菌共存,支持细菌的病理适应性变化和通过OXPHOS维持呼吸完整性。
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引用次数: 0
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Cell metabolism
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