Metabolism: clinical and experimental最新文献

英文中文

Reconsidering KLK7's role in adipose inflammation: letter to the editor. 重新考虑KLK7在脂肪炎症中的作用：致编辑的信。

IF 10.8 1区医学 Q1 ENDOCRINOLOGY & METABOLISM

Metabolism: clinical and experimental

Pub Date : 2025-04-05 DOI: 10.1016/j.metabol.2025.156255

Yaohui Zhong, Jiaqi Wei, Rui Jiang

引用次数: 0

Propagation of senescent phenotypes by extracellular HMGB1 is dependent on its redox state 细胞外 HMGB1 对衰老表型的传播取决于其氧化还原状态。

IF 10.8 1区医学 Q1 ENDOCRINOLOGY & METABOLISM

Metabolism: clinical and experimental

Pub Date : 2025-04-04 DOI: 10.1016/j.metabol.2025.156259

Ji-Won Shin , Dong-Hyun Jang , So Young Kim , Je-Jung Lee , Tae-Hwan Gil , Eunha Shim , Ji Yeon Kim , Hyeon Soo Kim , Michael J. Conboy , Irina M. Conboy , Christopher D. Wiley , Jeon-Soo Shin , Ok Hee Jeon

Background & purpose

Cellular senescence spreads systemically through blood circulation, but its mechanisms remain unclear. High mobility group box 1 (HMGB1), a multifunctional senescence-associated secretory phenotype (SASP) factor, exists in various redox states. Here, we investigate the role of redox-sensitive HMGB1 (ReHMGB1) in driving paracrine and systemic senescence.

Methods

We applied the paracrine senescence cultured model to evaluate the effect of ReHMGB1 on cellular senescence. Each redox state of HMGB1 was treated extracellularly to assess systemic senescence both in vitro and in vivo. Senescence was determined by SA-β-gal & EdU staining, p16^INK4a and p21 expression, RT-qPCR, and Western blot methods. Bulk RNA sequencing was performed to investigate ReHMGB1-driven transcriptional changes and underlying pathways. Cytokine arrays characterized SASP profiles from ReHMGB1-treated cells. In vivo, young mice were administered ReHMGB1 systemically to induce senescence across multiple tissues. A muscle injury model in middle-aged mice was used to assess the therapeutic efficacy of HMGB1 blockade.

Results

Extracellular ReHMGB1, but not its oxidized form, robustly induced senescence-like phenotypes across multiple cell types and tissues. Transcriptomic analysis revealed activation of RAGE-mediated JAK/STAT and NF-κB pathways, driving SASP expression and cell cycle arrest. Cytokine profiling confirmed paracrine senescence features induced by ReHMGB1. ReHMGB1 administration elevated senescence markers in vivo, while HMGB1 inhibition reduced senescence, attenuated systemic inflammation, and enhanced muscle regeneration.

Conclusion

ReHMGB1 is a redox-dependent pro-geronic factor driving systemic senescence. Targeting extracellular HMGB1 may offer therapeutic potential for preventing aging-related pathologies.

背景与目的：细胞衰老通过血液循环系统传播，但其机制尚不清楚。高迁移率组框1 （HMGB1）是一种多功能衰老相关分泌表型（SASP）因子，存在于多种氧化还原状态。在这里，我们研究了氧化还原敏感的HMGB1 （ReHMGB1）在驱动旁分泌和全身衰老中的作用。方法：采用旁分泌衰老培养模型评价ReHMGB1对细胞衰老的影响。在细胞外处理HMGB1的每种氧化还原状态，以评估体外和体内的系统性衰老。采用SA-β-gal和EdU染色、p16INK4a和p21表达、RT-qPCR和Western blot方法检测衰老情况。进行大量RNA测序以研究rehmgb1驱动的转录变化及其潜在途径。细胞因子阵列表征了rehmgb1处理细胞的SASP谱。在体内，幼鼠全身注射ReHMGB1诱导多组织衰老。采用中年小鼠肌肉损伤模型评价HMGB1阻断剂的治疗效果。结果：细胞外ReHMGB1，而不是其氧化形式，在多种细胞类型和组织中强烈诱导类似衰老的表型。转录组学分析显示rage介导的JAK/STAT和NF-κB通路激活，驱动SASP表达和细胞周期阻滞。细胞因子分析证实了ReHMGB1诱导的旁分泌衰老特征。给药ReHMGB1提高了体内衰老标志物，而抑制HMGB1可减少衰老，减轻全身炎症，增强肌肉再生。结论：ReHMGB1是一种氧化还原依赖性的促衰老因子。靶向细胞外HMGB1可能为预防衰老相关病理提供治疗潜力。

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引用次数: 0

A complex multisystem disorder including hypopituitarism and hypoparathyroidism, associated with mutation in the gene encoding fatty acid synthase (FASN) 一种复杂的多系统疾病，包括垂体功能减退和甲状旁腺功能减退，与编码脂肪酸合成酶（FASN）的基因突变有关。

IF 10.8 1区医学 Q1 ENDOCRINOLOGY & METABOLISM

Metabolism: clinical and experimental

Pub Date : 2025-04-03 DOI: 10.1016/j.metabol.2025.156256

L.C. Gregory , S. Krywawych , S. Rahman , Carlos F. Lagos , S. Eaton , M.T. Dattani

Whole exome sequencing performed on a male patient with a complex phenotype including short stature associated with hypopituitarism, sensorineural deafness, hypoparathyroidism, retinal dystrophy, and developmental delay revealed a novel de novo variant in FASN (p.Ala2132Val), encoding fatty acid synthase. The patient failed to respond to growth-promoting treatment, only reaching a height of 128.3 cm (−6.98 SDS) at 24.7 years of age, and was prepubertal with a delayed bone age (13.6 years). Subsequent metabolic investigations demonstrated high triglyceride concentrations throughout an 18 h fast with a failure to increase 3-hydroxybutyrate, suggesting a defect in fatty acid oxidation or ketone body synthesis.

Human embryonic brain analysis revealed FASN expression in the diencephalon, hypothalamus and Rathke's pouch. Following the labelling of glucose with carbon-13 (C13) in cultured fibroblasts, mass spectrometry data revealed that more C13-glucose was incorporated into de novo synthesised palmitic acid in controls compared to patient cells, suggesting reduced fatty acid synthesis in the patient.

Our data suggest that the FASN p.Ala2132Val variant is associated with a complex phenotype including hypothalamo-pituitary dysfunction, consistent with previous studies showing that rodent neural/progenitor brain stem cells are governed by Fasn-dependent de novo lipogenesis (fatty acid synthesis) for proliferation.

对一名复杂表型的男性患者进行全外显子组测序，包括与垂体功能减退、感音神经性耳聋、甲状旁腺功能减退、视网膜营养不良和发育迟缓相关的身材矮小，结果显示FASN （p.a ala2132val）有一种新的从头变异，编码脂肪酸合成酶。该患者对促生长治疗无效，在24.7 岁时身高仅达到128.3 cm (-6.98 SDS)，且处于青春期前，骨龄延迟（13.6 岁）。随后的代谢研究表明，在18 h禁食期间，甘油三酯浓度较高，3-羟基丁酸盐未能增加，这表明脂肪酸氧化或酮体合成存在缺陷。人胚胎脑分析显示FASN在间脑、下丘脑和Rathke's pouch表达。在培养的成纤维细胞中用碳-13 （C13）标记葡萄糖后，质谱数据显示，与患者细胞相比，对照组中更多的C13-葡萄糖被纳入新合成的棕榈酸中，这表明患者的脂肪酸合成减少。我们的数据表明，FASN p.a ala2132val变异与包括下丘脑-垂体功能障碍在内的复杂表型相关，这与先前的研究一致，表明啮齿动物神经/祖脑干细胞由FASN依赖性的新生脂肪生成（脂肪酸合成）控制增殖。

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引用次数: 0

Revisiting gender differences in obesity and type 2 diabetes: Letter to the editor. 重新审视肥胖和2型糖尿病的性别差异：致编辑的信。

IF 10.8 1区医学 Q1 ENDOCRINOLOGY & METABOLISM

Metabolism: clinical and experimental

Pub Date : 2025-04-03 DOI: 10.1016/j.metabol.2025.156260

Yaohui Zhong, Jiaqi Wei, Rui Jiang

引用次数: 0

Prediction models for the implementation of precision medicine in the real world. Some critical issues. 在现实世界中实施精准医疗的预测模型。一些关键问题。

IF 10.8 1区医学 Q1 ENDOCRINOLOGY & METABOLISM

Metabolism: clinical and experimental

Pub Date : 2025-04-03 DOI: 10.1016/j.metabol.2025.156257

Claudia Menzaghi, Massimiliano Copetti, Christos S Mantzoros, Vincenzo Trischitta

引用次数: 0

Unraveling sphingolipid complexity in liver fibrosis: Perspectives for future research. 揭示肝纤维化中鞘磷脂的复杂性：未来研究的前景

IF 10.8 1区医学 Q1 ENDOCRINOLOGY & METABOLISM

Metabolism: clinical and experimental

Pub Date : 2025-04-02 DOI: 10.1016/j.metabol.2025.156254

Jiaqi Wei, Yaohui Zhong, Yaling Li, Jun Li

引用次数: 0

Hexosamine biosynthesis dysfunction-induced LIFR N-glycosylation deficiency exacerbates steatotic liver ischemia/reperfusion injury 己糖胺生物合成功能障碍诱导的LIFR n-糖基化缺乏加剧了脂肪变性肝缺血/再灌注损伤

IF 10.8 1区医学 Q1 ENDOCRINOLOGY & METABOLISM

Metabolism: clinical and experimental

Pub Date : 2025-04-02 DOI: 10.1016/j.metabol.2025.156258

Ran Liu , Gengqiao Wang , Yongbing Qian , Zhengting Jiang , Weimin Wang , Mao Cai , Shuhua Zhang , Guoliang Wang , Chuanzheng Wang , Tianhao Zou , Huan Cao , Di Zhang , Xueling Wang , Shenghe Deng , Tongxi Li , Jinyang Gu

Background

More and more steatotic livers undergo resection or transplantation but they exhibit higher susceptibility to ischemia-reperfusion injury (IRI), which results in increased perioperative complication morbidity and mortality. IRI is driven by various cytokines and receptors, both of which are extensively modified by N-glycosylation. We aim to elucidate susceptibility of steatotic livers to IRI from the perspective of N-glycosylation.

Methods

Differentially expressed genes and glycoproteins were identified with RNA-seq and N-glycoproteomics. Myeloid LIF or hepatocyte LIFR knockout mice were developed to examine the function of LIF and LIFR. Modalities including phosphoproteomics, ChIP-seq, single cell RNA-seq, metabolomics and immunoblotting were utilized to investigate underlying mechanisms.

Results

LIF transcription in myeloid cells and LIFR N-glycosylation in hepatocytes were substantially induced by IRI of normal livers. LIF and LIFR protected normal livers from IRI through activating STAT3 and promoting downstream TNFAIP3 expression, which was facilitated by LIFR N-glycosylation. Mechanistically, N-glycosylation at N238 stabilized LIFR protein by disrupting TRIM28-mediated K48 ubiquitination at LIFR K254. Furthermore, N-glycosylation at N358/N658/N675 of LIFR facilitated LIF/LIFR/gp130 complex formation and subsequent signal transduction. However, in steatotic livers, myeloid cell LIF transcription was partially inhibited due to hepatic microenvironment L-arginine insufficiency, while hepatocyte LIFR N-glycosylation was defective due to intracellular UDP-GlcNAc exhaustion. Importantly, combined L-arginine and GlcNAc treatment reversed LIF expression and LIFR N-glycosylation insufficiency, which represents potential therapeutic strategy to protect steatotic livers.

Conclusions

LIF expression and LIFR N-glycosylation insufficiency aggravates steatotic liver IRI, which can be reversed by combined L-arginine and GlcNAc treatment.

背景越来越多的脂肪肝手术切除或移植，但其易发生缺血再灌注损伤（IRI），导致围手术期并发症的发病率和死亡率增加。IRI是由多种细胞因子和受体驱动的，它们都被n -糖基化广泛修饰。我们旨在从n -糖基化的角度阐明脂肪变性肝脏对IRI的易感性。方法采用RNA-seq和n -糖蛋白组学方法对差异表达基因和糖蛋白进行鉴定。培养髓系LIF或肝细胞LIFR敲除小鼠，检测LIF和LIFR的功能。利用磷酸化蛋白质组学、ChIP-seq、单细胞RNA-seq、代谢组学和免疫印迹等方法研究其潜在机制。结果正常肝脏IRI可显著诱导髓细胞内LIFR转录和肝细胞内LIFR n -糖基化。liff和LIFR通过激活STAT3和促进下游TNFAIP3表达来保护正常肝脏免受IRI，这是由LIFR n -糖基化促进的。机制上，N238的n糖基化通过破坏trim28介导的LIFR K254的K48泛素化来稳定LIFR蛋白。此外，LIFR的N358/N658/N675位点的n糖基化促进了LIF/LIFR/gp130复合物的形成和随后的信号转导。然而，在脂肪变性肝中，由于肝微环境l -精氨酸不足，髓细胞LIF转录受到部分抑制，而由于细胞内UDP-GlcNAc耗竭，肝细胞LIFR n -糖基化缺陷。重要的是，l -精氨酸和GlcNAc联合治疗逆转了LIF表达和LIFR n -糖基化不足，这代表了保护脂肪变性肝的潜在治疗策略。结论slif表达和LIFR n -糖基化不足可加重脂肪变性肝IRI，而l -精氨酸联合GlcNAc可逆转这一过程。

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引用次数: 0

L-Kynurenine activates the AHR-PCSK9 pathway to mediate the lipid metabolic and ovarian dysfunction in polycystic ovary syndrome l -犬尿氨酸激活AHR-PCSK9通路介导多囊卵巢综合征的脂质代谢和卵巢功能障碍。

IF 10.8 1区医学 Q1 ENDOCRINOLOGY & METABOLISM

Metabolism: clinical and experimental

Pub Date : 2025-03-31 DOI: 10.1016/j.metabol.2025.156238

Yujiao Wang , Yifan Wu , Hongwei Jiang , Shang Li , Jingjing Li , Cong Wang , Lexin Yang , Xiying Zhou , Juanjuan Yu , Junyu Zhai , Zi-Jiang Chen , Yanzhi Du

Dysregulated amino acid metabolism is a key contributor to polycystic ovary syndrome (PCOS). This cross-sectional study revealed that serum levels of L-kynurenine (L-Kyn) were significantly elevated in women with PCOS, whereas pyridoxal 5′-phosphate (PLP) levels were markedly reduced. Moreover, human serum L-Kyn levels exhibited a positive correlated with low-density lipoprotein cholesterol (LDL-C) and a negative correlation with high-density lipoprotein cholesterol (HDL-C). Additionally, letrozole (LET) induced PCOS-like mice displayed increased hepatic L-Kyn levels. Mechanistically, both in vivo and in vitro experiments demonstrated that the upregulation of indoleamine 2,3-dioxygenase (IDO1) activates the aryl hydrocarbon receptor (AHR) - proprotein convertase subtilisin/kexin type 9 (PCSK9) pathway in the liver of PCOS-like mice, thereby contributing to dyslipidemia. Treatment with epacadostat, an inhibitor of the enzyme IDO1, or PLP, a cofactor for L-Kyn catabolism, effectively restored ovarian function, improved glucose tolerance, and ameliorated lipid profile abnormalities in PCOS-like mice.

氨基酸代谢失调是多囊卵巢综合征（PCOS）的一个关键因素。这项横断研究显示，多囊卵巢综合征（PCOS）患者血清l -犬尿氨酸（L-Kyn）水平显著升高，而吡哆醛5'-磷酸（PLP）水平显著降低。此外，人血清L-Kyn水平与低密度脂蛋白胆固醇（LDL-C）呈正相关，与高密度脂蛋白胆固醇（HDL-C）负相关。此外，来曲唑（LET）诱导的pcos样小鼠肝脏L-Kyn水平升高。在机制上，体内和体外实验均表明，吲哚胺2,3-双加氧酶（IDO1）上调可激活pcos样小鼠肝脏芳烃受体(AHR) -蛋白转化酶枯草素/酮素9型（PCSK9）通路，从而导致血脂异常。用epacadostat（一种IDO1酶抑制剂，或PLP， L-Kyn分解代谢的辅助因子）治疗pcos样小鼠，有效地恢复卵巢功能，改善糖耐量，改善脂质异常。

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引用次数: 0

Prevention of insulin-induced lipohypertrophy by coadministration of a low dose of high-affinity PI3K inhibitors 通过联合使用低剂量高亲和力PI3K抑制剂预防胰岛素诱导的脂肪肥大。

IF 10.8 1区医学 Q1 ENDOCRINOLOGY & METABOLISM

Metabolism: clinical and experimental

Pub Date : 2025-03-30 DOI: 10.1016/j.metabol.2025.156252

Barbara Becattini , Andrea Usseglio Gaudi , Per-Anders Jansson , Giovanni Solinas

Background

Insulin-induced lipohypertrophy (ILH) is the most frequent injection site side effect of insulin therapy. ILH consists of local adipose tissue overgrowth at the insulin injection site that eventually progresses to lipoma-like masses of a relatively large size, causing discomfort and disfiguration. Insulin injection into ILH areas delays insulin delivery, and the presence of ILH is associated with poor glycemic control and more frequent hypoglycemic events. Although, in principle, the development of ILH can be minimized by avoiding injecting insulin in the same spot, in practice, ILH remains highly prevalent. So far, no molecular mechanism for ILH has been proposed.

Methods

We screened a panel of PI3K inhibitors with different specificities for their capacity to reduce insulin signaling and growth of human primary adipocytes exposed to pharmacological doses of insulin. The two most effective inhibitors from the screening above were investigated in an in-vivo model of ILH.

Results

We identified PI3K inhibitors capable of reducing the hypertrophic (enlargement of lipid droplets) and hyperplastic (adipocyte differentiation) growth of primary human adipocytes exposed to pharmacological doses of insulin. Since preventing ILH development requires only a localized inhibition of PI3K activity, using a low dose of high-affinity PI3K inhibitors, we could prevent the development of ILH in a mouse model without inhibiting the systemic effects of insulin on blood glucose and without causing any apparent adverse reaction.

Conclusion

We now show evidence indicating that ILH is caused by pathological PI3K activation at insulin injection sites and that ILH can be prevented by local inhibition of PI3K activity at the injection site.

背景：胰岛素诱导的脂肪肥大（ILH）是胰岛素治疗中最常见的注射部位副作用。ILH由胰岛素注射部位的局部脂肪组织过度生长组成，最终发展为相对较大的脂肪瘤样肿块，引起不适和变形。胰岛素注射到ILH区域会延迟胰岛素的递送，ILH的存在与血糖控制不良和更频繁的低血糖事件有关。虽然原则上，避免在同一部位注射胰岛素可以将ILH的发展降到最低，但在实践中，ILH仍然非常普遍。到目前为止，还没有发现ILH的分子机制。方法：我们筛选了一组具有不同特异性的PI3K抑制剂，因为它们能够减少胰岛素信号传导和暴露于胰岛素药理学剂量的人原代脂肪细胞的生长。上述筛选的两种最有效的抑制剂在ILH体内模型中进行了研究。结果：我们发现PI3K抑制剂能够减少暴露于药理学剂量的胰岛素的原代人脂肪细胞的增生性（脂滴增大）和增生性（脂肪细胞分化）生长。由于预防ILH的发展只需要局部抑制PI3K活性，使用低剂量的高亲和力PI3K抑制剂，我们可以在不抑制胰岛素对血糖的全身作用的情况下阻止小鼠模型中ILH的发展，并且不会引起任何明显的不良反应。结论：我们现在有证据表明ILH是由胰岛素注射部位的病理性PI3K激活引起的，并且可以通过局部抑制注射部位的PI3K活性来预防ILH。

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引用次数: 0

Metabolic dysfunction-associated steatotic liver disease and malignancies: Unmasking a silent saboteur 代谢功能障碍相关的脂肪变性肝病和恶性肿瘤：揭露沉默的破坏者。

IF 10.8 1区医学 Q1 ENDOCRINOLOGY & METABOLISM

Metabolism: clinical and experimental

Pub Date : 2025-03-29 DOI: 10.1016/j.metabol.2025.156253

Stergios A. Polyzos , Christos S. Mantzoros

Not required for Editorials.

社论不需要。

引用次数: 0

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