Metabolism: clinical and experimental最新文献_第10页

Relationship of GDF15 with hepatic mitochondrial respiration is depending on the presence of fibrosis in obese individuals GDF15与肝脏线粒体呼吸的关系取决于肥胖个体中纤维化的存在。

IF 11.9 1区医学 Q1 ENDOCRINOLOGY & METABOLISM

Metabolism: clinical and experimental

Pub Date : 2025-09-13 DOI: 10.1016/j.metabol.2025.156391

Anna Giannakogeorgou , Sabine Kahl , Cesare Granata , Geronimo Heilmann , Lucia Mastrototaro , Bedair Dewidar , Pavel Bobrov , Irene Esposito , Aslihan Yavas , Sandra Trenkamp , Frank A. Granderath , Matthias Schlensak , Christos S. Mantzoros , Michael Roden , Patrick Schrauwen

Background and purpose

Preclinical studies reported elevated growth differentiation factor 15 (GDF15) when mitochondrial function is reduced. In humans, metabolic dysfunction-associated steatotic liver disease (MASLD) and steatohepatitis (MASH) exhibit different hepatic mitochondrial adaptation. We hypothesized that circulating GDF15 differently correlates with hepatic mitochondrial respiration in obesity and/or MASLD/MASH.

Methods

Humans without (n = 20) and with biopsy-confirmed MASLD (n = 20) or MASH (n = 20) underwent hyperinsulinemic-euglycemic clamps to assess whole-body (M-value) and adipose-tissue (insulin-induced NEFA suppression) insulin sensitivity. Fasting serum GDF15 and glucagon were quantified by ELISA. Mitochondrial respiration was measured in liver obtained during bariatric surgery by high-resolution respirometry. Associations were assessed with Spearman's nonparametric correlation.

Results

Serum GDF15 correlated negatively with M-value (r = −0.35, p = 0.017) and NEFA suppression (r = −0.29, p = 0.046), but not with hepatic mitochondrial respiration across the whole cohort. However, correlations were found upon stratification into groups based on the presence (n = 37, age: 41 ± 2y, BMI: 49 ± 1 kg/m²) or absence of hepatic fibrosis (n = 23, 44 ± 2 years, BMI: 49 ± 1 kg/m²). In persons without fibrosis, GDF15 correlated positively with fatty acid oxidation-linked (F_P; r = 0.35, p = 0.035) and maximal coupled (FNS_P; r = 0.42, p = 0.010) mitochondrial respiration. Conversely, GDF15 correlated negatively with hepatic FN_P in persons with fibrosis (r = −0.48, p = 0.022).

Conclusions

In humans with obesity, serum GDF15 correlates positively with hepatic mitochondrial respiration in persons without, but negatively in persons with hepatic fibrosis. Future studies are needed to investigate whether and how GDF15 affects hepatic mitochondrial respiration in a fibrosis-dependent manner and/or, conversely, how fibrosis might modulate hepatic GDF15 secretion through altered mitochondrial function.

背景和目的：临床前研究报道，当线粒体功能降低时，生长分化因子15 （GDF15）升高。在人类中，代谢功能障碍相关的脂肪性肝病（MASLD）和脂肪性肝炎（MASH）表现出不同的肝脏线粒体适应。我们假设在肥胖和/或MASLD/MASH中，循环GDF15与肝脏线粒体呼吸有不同的相关性。方法：没有（n = 20）和活检证实MASLD （n = 20）或MASH （n = 20）的人接受高胰岛素-正血糖钳夹，评估全身（m值）和脂肪组织（胰岛素诱导的NEFA抑制）胰岛素敏感性。ELISA法测定空腹血清GDF15和胰高血糖素含量。通过高分辨率呼吸计测量减肥手术中肝脏的线粒体呼吸。用Spearman非参数相关法评估相关性。结果：在整个队列中，血清GDF15与m值（r = -0.35,p = 0.017）和NEFA抑制（r = -0.29,p = 0.046）呈负相关，但与肝脏线粒体呼吸无关。然而,相关性被发现在分层分组基于存在(n = 37岁的年龄:41 ± 2 y, BMI: 49 ±1  kg / m2)或缺乏肝纤维化(n = 23日,44 ±2  年,BMI: 49 ±1  kg / m2)。在无纤维化的人群中，GDF15与脂肪酸氧化相关（FP; r = 0.35,p = 0.035）和最大耦合（FNSP; r = 0.42,p = 0.010）线粒体呼吸呈正相关。相反，在纤维化患者中，GDF15与肝脏FNP呈负相关（r = -0.48,p = 0.022）。结论：在肥胖人群中，血清GDF15与无肥胖人群的肝脏线粒体呼吸呈正相关，而与肝纤维化人群呈负相关。未来的研究需要调查GDF15是否以及如何以纤维化依赖的方式影响肝脏线粒体呼吸和/或相反，纤维化如何通过改变线粒体功能调节肝脏GDF15分泌。

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引用次数: 0

SerpinA3N in leptin-sensitive neurons is required for energy and glucose homeostasis and autonomic regulation 瘦素敏感神经元中的SerpinA3N是能量和葡萄糖稳态和自主调节所必需的。

IF 11.9 1区医学 Q1 ENDOCRINOLOGY & METABOLISM

Metabolism: clinical and experimental

Pub Date : 2025-09-09 DOI: 10.1016/j.metabol.2025.156387

Deng Fu Guo , Zili Luo , Alexis Olson , Donald A. Morgan , Elizabeth A. Newell , Kamal Rahmouni

Aims

SerpinA3N (Serpin peptidase inhibitor clade A member 3) is a serine protease inhibitor upregulated in the hypothalamus by leptin and obesity, yet its role in physiological regulation remains poorly understood. This study aims to elucidate the role of hypothalamic SerpinA3N in regulation of energy balance, glucose homeostasis, and autonomic and cardiovascular functions.

Methods and results

Immunostaining revealed that SerpinA3N is primarily expressed in neurons, including those expressing the leptin receptor (LepRb). Targeted deletion of SerpinA3N in LepRb neurons reduced body weight and adiposity and improved insulin sensitivity in female mice. SerpinA3N deficiency also enhanced leptin sensitivity, evidenced by amplified leptin-induced anorexia, weight loss, and LepRb signaling in the hypothalamic arcuate nucleus. Upon exposure to an obesogenic diet, mice lacking SerpinA3N in LepRb neurons exhibited attenuated weight gain, hepatic lipid accumulation and microgliosis. Notably, SerpinA3N deletion in LepRb neurons impaired baroreflex sensitivity and elevated renal sympathetic nerve activity, with dietary obesity further exacerbating sympathetic tone.

Conclusions

These findings identify neuronal SerpinA3N as a key regulator of energy balance, leptin and insulin sensitivity, and autonomic function.

目的：SerpinA3N（丝氨酸肽酶抑制剂分支A成员3）是一种丝氨酸蛋白酶抑制剂，在下丘脑中被瘦素和肥胖上调，但其在生理调节中的作用尚不清楚。本研究旨在阐明下丘脑SerpinA3N在调节能量平衡、葡萄糖稳态、自主神经和心血管功能中的作用。方法和结果：免疫染色显示，SerpinA3N主要表达在神经元中，包括表达瘦素受体（LepRb）的神经元。在LepRb神经元中靶向删除SerpinA3N可以降低雌性小鼠的体重和肥胖，并改善胰岛素敏感性。SerpinA3N缺乏也增强了瘦素敏感性，这可以通过瘦素引起的厌食症、体重减轻和下丘脑弓状核中的LepRb信号传导放大来证明。暴露于致肥性饮食后，LepRb神经元中缺乏SerpinA3N的小鼠表现出体重增加减轻、肝脏脂质积累和小胶质细胞增生。值得注意的是，LepRb神经元中SerpinA3N的缺失损害了压力反射敏感性和肾交感神经活动的升高，饮食肥胖进一步加剧了交感神经张力。结论：这些发现表明神经元SerpinA3N是能量平衡、瘦素和胰岛素敏感性以及自主神经功能的关键调节因子。

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引用次数: 0

Modulating metabolism to improve the therapeutic outcomes of CAR cell therapies: From bench to bedside 调节代谢以改善CAR细胞疗法的治疗效果：从实验到临床。

IF 11.9 1区医学 Q1 ENDOCRINOLOGY & METABOLISM

Metabolism: clinical and experimental

Pub Date : 2025-08-28 DOI: 10.1016/j.metabol.2025.156375

Dengxiong Li , Jie Wang , Ruicheng Wu , Qingxin Yu , Fanglin Shao , Dilinaer Wusiman , Zhipeng Wang , Zhouting Tuo , Luxia Ye , Yiqing Guo , Koo Han Yoo , Zhihong Liu , William C. Cho , Dechao Feng

Chimeric antigen receptor (CAR) cell therapies have emerged as a groundbreaking approach in cancer treatment, offering new hope for patients with refractory tumors. Despite their success, the therapeutic efficacy of CAR cell therapies is often undermined by metabolic factors within the tumor microenvironment (TME), which impede CAR cell function and lead to treatment resistance. Current literature has not fully explored how these metabolic processes contribute to CAR cell therapy failure, particularly in the context of solid tumors, where the TME presents unique challenges. Addressing this gap is crucial for enhancing the effectiveness of CAR cell therapies across a broader range of cancers. Here, we review the latest research on the metabolic mechanisms that influence CAR cell therapy outcomes, from preclinical studies to clinical applications. We conducted a comprehensive analysis of studies from PubMed and Web of Science, focusing on how various metabolic processes—such as hypoxia, immune cytokine signaling, glycolysis, adenine metabolism, cellular senescence, lactic acid increment, and cholesterol metabolism—affect CAR cell functions, including cytotoxicity, proliferation, stemness, and activation. Additionally, we examine how interactions between CAR cells and other components of the TME, such as tumor cells, stromal cells, and the extracellular matrix, contribute to an immune-suppressive environment that diminishes CAR cell efficacy. We also discuss potential strategies for overcoming these metabolic barriers, including the development of CAR cells with enhanced metabolic regulation, gene expression modulation, and the combination of CAR cell therapy with existing pharmacological treatments. Our findings underscore the critical role of metabolism in shaping the anti-tumor efficacy of CAR cell therapies in both hematologic and solid tumors. By targeting metabolic pathways within the TME, it is possible to enhance CAR cell infiltration, function, and persistence, thereby overcoming resistance and improving therapeutic outcomes. This approach not only addresses a key limitation in current CAR cell therapies but also paves the way for more effective cancer treatments in the future.

嵌合抗原受体（CAR）细胞疗法已经成为一种突破性的癌症治疗方法，为难治性肿瘤患者提供了新的希望。尽管取得了成功，但CAR细胞疗法的治疗效果经常受到肿瘤微环境（TME）内代谢因素的破坏，这些代谢因素阻碍了CAR细胞的功能并导致治疗耐药性。目前的文献并没有充分探讨这些代谢过程是如何导致CAR细胞治疗失败的，特别是在实体肿瘤的背景下，TME提出了独特的挑战。解决这一差距对于提高CAR细胞疗法在更广泛的癌症中的有效性至关重要。在这里，我们回顾了影响CAR细胞治疗结果的代谢机制的最新研究，从临床前研究到临床应用。我们对来自PubMed和Web of Science的研究进行了综合分析，重点关注各种代谢过程（如缺氧、免疫细胞因子信号传导、糖酵解、腺嘌呤代谢、细胞衰老、乳酸增加和胆固醇代谢）如何影响CAR细胞功能，包括细胞毒性、增殖、干细胞和活化。此外，我们还研究了CAR细胞与TME的其他成分（如肿瘤细胞、基质细胞和细胞外基质）之间的相互作用如何导致免疫抑制环境，从而降低CAR细胞的功效。我们还讨论了克服这些代谢障碍的潜在策略，包括开发具有增强代谢调节、基因表达调节的CAR细胞，以及将CAR细胞治疗与现有药物治疗相结合。我们的研究结果强调了代谢在血液和实体肿瘤中形成CAR细胞疗法抗肿瘤疗效的关键作用。通过靶向TME内的代谢途径，有可能增强CAR细胞的浸润、功能和持久性，从而克服耐药性并改善治疗结果。这种方法不仅解决了当前CAR细胞疗法的一个关键限制，而且为未来更有效的癌症治疗铺平了道路。

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引用次数: 0

Corrigendum to “Human subjects with impaired beta-cell function and glucose tolerance have higher levels of intra-islet intact GLP-1” [Metabolism, Volume 163 (2025), Article Number 156087] “β细胞功能受损和葡萄糖耐量受损的人类受试者具有更高水平的胰岛内完整GLP-1”的勘误表[Metabolism， Volume 163(2025)，文章号156087]

IF 11.9 1区医学 Q1 ENDOCRINOLOGY & METABOLISM

Metabolism: clinical and experimental

Pub Date : 2025-08-13 DOI: 10.1016/j.metabol.2025.156372

Teresa Mezza , Nicolai J. Wewer Albrechtsen , Gianfranco Di Giuseppe , Pietro Manuel Ferraro , Laura Soldovieri , Gea Ciccarelli , Michela Brunetti , Giuseppe Quero , Sergio Alfieri , Enrico Celestino Nista , Antonio Gasbarrini , Vincenzo Tondolo , Andrea Mari , Alfredo Pontecorvi , Andrea Giaccari , Jens J. Holst

引用次数: 0

Syndecan-1 regulates lipid metabolism and mitigates fibrosis during the transition from acute kidney injury to chronic kidney disease Syndecan-1调节脂质代谢，减轻急性肾损伤向慢性肾病转变过程中的纤维化。

IF 11.9 1区医学 Q1 ENDOCRINOLOGY & METABOLISM

Metabolism: clinical and experimental

Pub Date : 2025-08-07 DOI: 10.1016/j.metabol.2025.156374

Daoqi Shen , Liyu Lin , Yiqi Su , Ying Huang , Yaqiong Wang , Jiarui Xu , Wuhua Jiang , Zhen Zhang , Xiaoqiang Ding , Xialian Xu

Background

The transition from acute kidney injury (AKI) to chronic kidney disease (CKD) is characterized by persistent renal fibrosis, in which abnormal lipid metabolism plays a crucial role. Syndecan-1 (SDC-1) has been implicated in various tissue remodeling processes; however, its role in lipid metabolism and fibrosis during the progression from AKI to CKD is not well understood.

Methods

This study used a murine model of unilateral ischemia-reperfusion-induced AKI-to-CKD progression for in vivo analysis and employed transforming growth factor-beta (TGF-β)-induced fibrosis in Human Kidney-2 cells and primary mouse tubular epithelial cells for in vitro studies. The tubule-specific knockout and overexpression of SDC-1 mice were utilized to investigate kidney fibrosis and lipid metabolism.

Results

Following unilateral ischemia-reperfusion and TGF-β stimulation, SDC-1 expression was significantly reduced, exacerbating renal fibrosis. Notably, SDC-1 deficiency led to lipid accumulation in the kidneys, while its overexpression alleviated lipid overload and improved metabolic parameters. Furthermore, SDC-1 played a crucial role in regulating fatty acid-binding protein 7 (FABP7), and its absence resulted in increased FABP7 levels. Inhibition of FABP7 not only reduced fibrosis but also restored carnitine palmitoyltransferase 1α expression, which suggests that the SDC-1/FABP7 axis is critical for maintaining lipid homeostasis and mitigating fibrosis in the kidney.

Conclusion

These findings underscore the importance of SDC-1 in lipid metabolism and suggest that targeting lipid metabolic pathways may represent therapeutic strategies that can slow the progression of AKI to CKD.

背景：从急性肾损伤（AKI）到慢性肾脏疾病（CKD）的转变以持续的肾纤维化为特征，其中异常的脂质代谢起着至关重要的作用。Syndecan-1 （SDC-1）参与多种组织重塑过程；然而，在从AKI到CKD的过程中，其在脂质代谢和纤维化中的作用尚不清楚。方法：本研究采用小鼠单侧缺血再灌注诱导的aki向ckd进展模型进行体内分析，并采用转化生长因子β (TGF-β)诱导的人肾-2细胞和小鼠原代小管上皮细胞纤维化进行体外研究。利用小管特异性敲除和SDC-1小鼠的过表达来研究肾脏纤维化和脂质代谢。结果：单侧缺血再灌注和TGF-β刺激后，SDC-1表达明显降低，加重肾纤维化。值得注意的是，SDC-1缺乏导致肾脏脂质积累，而其过表达减轻了脂质过载并改善了代谢参数。此外，SDC-1在调节脂肪酸结合蛋白7 （FABP7）中起着至关重要的作用，其缺失导致FABP7水平升高。抑制FABP7不仅可以减少纤维化，还可以恢复肉碱棕榈酰基转移酶1α的表达，这表明SDC-1/FABP7轴对维持肾脏脂质稳态和减轻纤维化至关重要。结论：这些发现强调了SDC-1在脂质代谢中的重要性，并提示靶向脂质代谢途径可能是减缓AKI向CKD进展的治疗策略。

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引用次数: 0

Symphony of regulated cell death: Unveiling therapeutic horizons in sarcopenia 调控细胞死亡交响曲：揭示肌肉减少症的治疗前景

IF 11.9 1区医学 Q1 ENDOCRINOLOGY & METABOLISM

Metabolism: clinical and experimental

Pub Date : 2025-07-31 DOI: 10.1016/j.metabol.2025.156359

Jie Peng , Mi Zou , Qianmingyue Zhang , Dongcan Liu , Shuanghong Chen , Ruiying Fang , Yuan Gao , Xiaohua Yan , Liang Hao

Sarcopenia is a progressive musculoskeletal condition associated with aging, marked by a decline in muscle mass, strength, and performance. This condition not only compromises functional independence in older individuals but also contributes to escalating healthcare and economic burdens. Although the underlying mechanisms are complex and multifaceted, recent discoveries have emphasized the regulatory influence of multiple forms of programmed cell death—including apoptosis, ferroptosis, necroptosis, and pyroptosis—on skeletal muscle degeneration. These cell death pathways contribute to key pathological features such as muscle fiber loss, proteostasis imbalance, neuromuscular dysfunction, mitochondrial deficits, and persistent inflammation. This review synthesizes current understanding of the molecular underpinnings of regulated cell death (RCD) in sarcopenia and discusses emerging therapeutic interventions aimed at modulating these pathways. These include pharmacological agents (e.g., ferroptosis inhibitors, polyphenols), structured exercise programs (notably resistance), targeted nutritional support (e.g., amino acids, vitamin D), cell-based therapies, and gene-targeted strategies. Despite growing evidence supporting RCD as a viable therapeutic target, the interplay among different cell death modalities and the translation of mechanistic insights into clinical practice remain insufficiently understood. Advancing sarcopenia treatment will require integrated multi-omics analyses, identification of predictive biomarkers, and rigorously designed clinical studies to support personalized and effective therapeutic approaches.

肌肉减少症是一种与衰老相关的进行性肌肉骨骼疾病，其特征是肌肉质量、力量和表现的下降。这种情况不仅会损害老年人的功能独立性，而且还会增加医疗保健和经济负担。尽管潜在的机制是复杂和多方面的，但最近的发现强调了多种形式的程序性细胞死亡（包括细胞凋亡、铁下垂、坏死下垂和热死）对骨骼肌变性的调节作用。这些细胞死亡途径导致关键的病理特征，如肌纤维损失、蛋白质平衡失衡、神经肌肉功能障碍、线粒体缺陷和持续炎症。本文综述了目前对肌肉减少症中调节细胞死亡（RCD）的分子基础的理解，并讨论了旨在调节这些途径的新兴治疗干预措施。这些包括药理学药物（例如，铁衰落抑制剂，多酚），有组织的锻炼计划（特别是抵抗），靶向营养支持（例如氨基酸，维生素D），基于细胞的治疗和基因靶向策略。尽管越来越多的证据支持RCD作为一种可行的治疗靶点，但不同细胞死亡模式之间的相互作用以及将机制见解转化为临床实践的理解仍然不够充分。推进骨骼肌减少症的治疗将需要整合多组学分析，识别预测性生物标志物，以及严格设计的临床研究，以支持个性化和有效的治疗方法。

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引用次数: 0

The intersection of exercise, nitric oxide, and metabolism: Unraveling the role of eNOS in skeletal muscle and beyond 运动、一氧化氮和代谢的交叉：揭示eNOS在骨骼肌及其他部位的作用。

IF 11.9 1区医学 Q1 ENDOCRINOLOGY & METABOLISM

Metabolism: clinical and experimental

Pub Date : 2025-07-30 DOI: 10.1016/j.metabol.2025.156360

Pierre-Anne R. Laird , Rebecca M. Wall , Siobhan M. Craige

Exercise protects against several diseases including cardiometabolic disorders. However, the molecular mechanisms driving these adaptations remain incompletely defined. Endothelial nitric oxide synthase (eNOS), a key source of nitric oxide (NO), is implicated in regulating glucose uptake, fatty acid metabolism, and mitochondrial remodeling in response to exercise. eNOS is expressed in both endothelial and non-endothelial cells and its effects on metabolism are multifaceted. Notably, eNOS is highly expressed in endothelial cells which are ubiquitous throughout all organ systems allowing them to closely integrate with surrounding cell types. This unique feature of the endothelium enables eNOS to influence both local microenvironments and signaling across organ systems. This review summarizes current findings on the role of eNOS-derived NO in exercise metabolism. Evidence suggests eNOS contributes to improved metabolic flexibility, enhanced mitochondrial function, and tissue crosstalk. However, data across experimental models remain mixed, with both supportive and conflicting results. Collectively, the literature indicates that eNOS plays a central, though context-dependent, role in facilitating exercise-induced metabolic benefits. Identifying the specific mechanisms and tissue contributions of eNOS activity remains an important area for future investigation, with potential relevance to metabolic disease prevention and treatment.

运动可以预防多种疾病，包括心脏代谢紊乱。然而，驱动这些适应的分子机制仍然不完全确定。内皮型一氧化氮合酶（eNOS）是一氧化氮（NO）的重要来源，参与调节运动后的葡萄糖摄取、脂肪酸代谢和线粒体重塑。eNOS在内皮细胞和非内皮细胞中均有表达，其对代谢的影响是多方面的。值得注意的是，eNOS在内皮细胞中高度表达，内皮细胞普遍存在于所有器官系统中，使它们能够与周围的细胞类型紧密结合。内皮的这一独特特征使eNOS能够影响局部微环境和跨器官系统的系统信号。本文综述了enos衍生NO在运动代谢中的作用。有证据表明，eNOS有助于改善代谢灵活性，增强线粒体功能和组织串扰。然而，不同实验模型的数据仍然是混杂的，既有支持的结果，也有相互矛盾的结果。总的来说，文献表明eNOS在促进运动诱导的代谢益处方面发挥着核心作用，尽管这依赖于环境。确定eNOS活性的具体机制和组织贡献仍然是未来研究的重要领域，与代谢性疾病的预防和治疗具有潜在的相关性。

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引用次数: 0

Natural selection signatures of 65 syndromic and 8 monogenic obesity genes in 7 ethnic groups do not support the thrifty genotype hypothesis 7个民族65个综合征基因和8个单基因肥胖基因的自然选择特征不支持节俭基因型假说。

IF 11.9 1区医学 Q1 ENDOCRINOLOGY & METABOLISM

Metabolism: clinical and experimental

Pub Date : 2025-07-28 DOI: 10.1016/j.metabol.2025.156353

Sandra El Kouche , David Meyre

Background

The “thrifty genotype hypothesis” states that gene variants promoting efficient fat deposition may have been advantaged by natural selection to allow human survival during famine. Nowadays, such genes are rendered detrimental by progress as they promote fat deposition in preparation for a famine that never comes, resulting in widespread obesity. Obesity is genetically heterogeneous, with a continuum between very rare syndromic, rare monogenic, and common polygenic forms of obesity. The identification of natural selection signatures has been largely restricted to polygenic obesity-susceptibility variants, and this approach has failed to validate the thrifty genotype hypothesis. However, polygenic variants may not be as relevant as monogenic mutations, characterized by strong phenotypic effects on body mass index variation and obesity risk, in detecting significant signatures of natural selection.

Methods

We investigated the patterns of natural selection of 65 syndromic and 8 monogenic obesity genes in the gnomAD multiethnic population (N = 807,162).

Results

Our data suggest that most dominant syndromic obesity genes display negative signatures of natural selection (i.e., deleterious alleles are selectively purged from the population). In contrast, monogenic obesity genes exhibit neither negative nor positive patterns of natural selection. Our findings do not support the thrifty genotype hypothesis for syndromic and monogenic hyperphagic obesity in 7 ethnic groups.

Conclusion

Our work highlights the evolutionary mechanisms that have shaped the modern ethnic distribution of monogenic and syndromic obesity mutations, why some individuals are susceptible to obesity and have a profound impact on therapeutic strategies for managing chronic diseases.

背景：“节俭基因型假说”认为，促进脂肪高效沉积的基因变异可能是自然选择的优势，使人类能够在饥荒中生存。如今，这些基因由于进步而变得有害，因为它们促进脂肪沉积，为永远不会到来的饥荒做准备，从而导致普遍的肥胖。肥胖是遗传异质性的，在非常罕见的综合征型、罕见的单基因型和常见的多基因型肥胖之间存在连续性。自然选择特征的识别在很大程度上仅限于多基因肥胖易感性变异，这种方法未能验证节俭基因型假说。然而，在检测自然选择的显著特征方面，多基因变异可能不如单基因突变相关，单基因突变的特点是对体重指数变化和肥胖风险有很强的表型影响。方法：对gnomAD多民族人群（N = 807162） 65个综合征型肥胖基因和8个单基因肥胖基因的自然选择模式进行研究。结果：我们的数据表明，大多数显性综合征型肥胖基因表现出自然选择的负特征（即，有害等位基因被选择性地从人群中清除）。相比之下，单基因肥胖基因既没有表现出自然选择的消极模式，也没有表现出积极模式。我们的研究结果不支持节俭基因型假说在7个民族的综合征和单基因肥厚性肥胖。结论：我们的工作强调了形成单基因和综合征性肥胖突变的现代种族分布的进化机制，为什么一些个体易患肥胖，并对慢性疾病的治疗策略产生深远影响。

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引用次数: 0

Lactiplantibacillus plantarum strain 84-3-derived l-glutamine ameliorates glucose homeostasis via AMPK/PPARγ signaling pathway activation in type 2 diabetes 植物乳杆菌菌株84-3衍生的l-谷氨酰胺通过激活AMPK/PPARγ信号通路改善2型糖尿病患者的葡萄糖稳态

IF 11.9 1区医学 Q1 ENDOCRINOLOGY & METABOLISM

Metabolism: clinical and experimental

Pub Date : 2025-07-28 DOI: 10.1016/j.metabol.2025.156357

Tingting Liang , Tong Jiang , Zhuang Liang , Ya Chen , Tong Chen , Bo Dong , Xinqiang Xie , Bing Gu , Qingping Wu

Background

Gut microbiota and their metabolites play an essential role in type 2 diabetes (T2D). However, contributions of individual bacterial strains and their metabolites to T2D pathogenesis remain poorly understood. We investigated T2D regulation by Lactobacillus in various animal models to understand its therapeutic effects.

Methods and results

We performed a case-control study of Chinese adults using metabolome profiling and identified an inverse correlation between l-glutamine and T2D serum concentrations. The glnA and GLUL genes encoding glutamine synthetase (GS) in L. plantarum 84–3 were also identified. L. plantarum 84–3 treatment significantly decreased serum inflammation and improved metabolic phenotypes in streptozotocin- or tetraoxypyrimidine-induced T2D rats, including blood glucose, glucose tolerance, insulin resistance, and lipids. We confirmed elevated serum l-glutamine levels in the L. plantarum 84–3 group. RNA sequencing analysis demonstrated that L. plantarum 84–3-derived l-glutamine is a vital bioactive molecule, improving glucose homeostasis by activating the liver AMPK/PPAR signaling pathway and ameliorating T2D. We conducted co-culture fermentation experiments in vitro and in vivo, and metagenomic and metabolomic analyses revealed that resistance starch combined with L. plantarum 84–3 significantly enriched of Lactobacillus abundance and increased the l-glutamine level, affecting of alanine, aspartate, and glutamate metabolism pathways, which was confirmed in vivo in rats. The reduced L. plantarum and l-glutamine levels were validated in a human T2D cohort.

Conclusions

These findings revealed a novel therapeutic effect of L. plantarum in alleviating T2D-related glucose homeostasis by increasing circulating l-glutamine, which suggests viable preventive and therapeutic strategies for metabolic disorders.

背景：肠道菌群及其代谢产物在2型糖尿病（T2D）中起重要作用。然而，个别菌株及其代谢物对T2D发病机制的贡献仍然知之甚少。我们在各种动物模型中研究乳酸杆菌对T2D的调节，以了解其治疗作用。方法和结果：我们对中国成年人进行了一项病例对照研究，使用代谢组分析发现l-谷氨酰胺与T2D血清浓度呈负相关。同时还鉴定出了植物L. 84-3中编码谷氨酰胺合成酶（GS）的glnA和GLUL基因。L. plantarum 84-3治疗显著降低了链脲佐菌素或四氧嘧啶诱导的T2D大鼠的血清炎症，改善了代谢表型，包括血糖、葡萄糖耐量、胰岛素抵抗和血脂。我们证实84-3植物乳杆菌组血清l-谷氨酰胺水平升高。RNA测序分析表明，L. plantarum 84-3衍生的l-谷氨酰胺是一种重要的生物活性分子，通过激活肝脏AMPK/PPAR信号通路和改善T2D来改善葡萄糖稳态。我们进行了体外和体内共培养发酵实验，元基因组学和代谢组学分析显示，抗性淀粉与L. plantarum 84-3结合后显著增加了乳酸杆菌的丰度，提高了l-谷氨酰胺水平，影响了丙氨酸、天冬氨酸和谷氨酸的代谢途径，这在大鼠体内得到了证实。降低的植物乳杆菌和l-谷氨酰胺水平在人类T2D队列中得到验证。结论：这些发现揭示了植物乳草通过增加循环l-谷氨酰胺来缓解t2d相关葡萄糖稳态的新作用，为代谢紊乱的预防和治疗提供了可行的策略。

{"title":"Lactiplantibacillus plantarum strain 84-3-derived l-glutamine ameliorates glucose homeostasis via AMPK/PPARγ signaling pathway activation in type 2 diabetes","authors":"Tingting Liang , Tong Jiang , Zhuang Liang , Ya Chen , Tong Chen , Bo Dong , Xinqiang Xie , Bing Gu , Qingping Wu","doi":"10.1016/j.metabol.2025.156357","DOIUrl":"10.1016/j.metabol.2025.156357","url":null,"abstract":"<div><h3>Background</h3><div>Gut microbiota and their metabolites play an essential role in type 2 diabetes (T2D). However, contributions of individual bacterial strains and their metabolites to T2D pathogenesis remain poorly understood. We investigated T2D regulation by <em>Lactobacillus</em> in various animal models to understand its therapeutic effects.</div></div><div><h3>Methods and results</h3><div>We performed a case-control study of Chinese adults using metabolome profiling and identified an inverse correlation between <span>l</span>-glutamine and T2D serum concentrations. The <em>glnA</em> and <em>GLUL</em> genes encoding glutamine synthetase (GS) in <em>L. plantarum</em> 84–3 were also identified. <em>L. plantarum</em> 84–3 treatment significantly decreased serum inflammation and improved metabolic phenotypes in streptozotocin- or tetraoxypyrimidine-induced T2D rats, including blood glucose, glucose tolerance, insulin resistance, and lipids. We confirmed elevated serum <span>l</span>-glutamine levels in the <em>L. plantarum</em> 84–3 group. RNA sequencing analysis demonstrated that <em>L. plantarum</em> 84–3-derived <span>l</span>-glutamine is a vital bioactive molecule, improving glucose homeostasis by activating the liver AMPK/PPAR signaling pathway and ameliorating T2D. We conducted co-culture fermentation experiments <em>in vitro</em> and <em>in vivo</em>, and metagenomic and metabolomic analyses revealed that resistance starch combined with <em>L. plantarum</em> 84–3 significantly enriched of <em>Lactobacillus</em> abundance and increased the <span>l</span>-glutamine level, affecting of alanine, aspartate, and glutamate metabolism pathways, which was confirmed <em>in vivo</em> in rats. The reduced <em>L. plantarum</em> and <span>l</span>-glutamine levels were validated in a human T2D cohort.</div></div><div><h3>Conclusions</h3><div>These findings revealed a novel therapeutic effect of <em>L. plantarum</em> in alleviating T2D-related glucose homeostasis by increasing circulating <span>l</span>-glutamine, which suggests viable preventive and therapeutic strategies for metabolic disorders.</div></div>","PeriodicalId":18694,"journal":{"name":"Metabolism: clinical and experimental","volume":"172 ","pages":"Article 156357"},"PeriodicalIF":11.9,"publicationDate":"2025-07-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144753812","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Unraveling the roles of mitochondrial sirtuins in aging-related diseases: From mechanistic insights to therapeutic strategies 揭示线粒体sirtuins在衰老相关疾病中的作用：从机制见解到治疗策略。

IF 11.9 1区医学 Q1 ENDOCRINOLOGY & METABOLISM

Metabolism: clinical and experimental

Pub Date : 2025-07-24 DOI: 10.1016/j.metabol.2025.156356

Yanyan Cao , Yan Wang , Na Zhao , Ziyue Yuan , Lan Zhang , Peng Jin

Mitochondrial sirtuins, including SIRT3, SIRT4, and SIRT5, play pivotal roles in maintaining mitochondrial homeostasis by regulating oxidative phosphorylation, energy metabolism, and redox balance. Dysregulation of these enzymes is closely associated with the pathogenesis of aging-related diseases such as neurodegenerative diseases, metabolic diseases, and cardiovascular diseases. SIRT3 has been the most extensively studied, demonstrating protective effects against oxidative stress and metabolic dysregulation. In contrast, while SIRT4 and SIRT5 are less characterized, they are critical for the regulation of insulin sensitivity, nitrogen metabolism, and mitochondrial function. This review focuses on the involvement of mitochondrial sirtuins in modulating cellular metabolism, redox balance, and mitochondrial homeostasis, highlighting their roles in the development and progression of aging-related diseases. Furthermore, we provide an overview of small-molecule modulators targeting mitochondrial sirtuins, which aim to restore cellular function, attenuate aging processes, and offer novel therapeutic strategies for treating aging-related diseases.

线粒体sirtuins，包括SIRT3、SIRT4和SIRT5，通过调节氧化磷酸化、能量代谢和氧化还原平衡，在维持线粒体稳态中起关键作用。这些酶的失调与衰老相关疾病如神经退行性疾病、代谢性疾病和心血管疾病的发病密切相关。SIRT3已被广泛研究，显示出对氧化应激和代谢失调的保护作用。相比之下，虽然SIRT4和SIRT5的特征较少，但它们对胰岛素敏感性、氮代谢和线粒体功能的调节至关重要。本文综述了线粒体sirtuins在调节细胞代谢、氧化还原平衡和线粒体稳态中的作用，重点介绍了它们在衰老相关疾病的发生和进展中的作用。此外，我们提供了针对线粒体sirtuins的小分子调节剂的概述，旨在恢复细胞功能，减缓衰老过程，并为治疗衰老相关疾病提供新的治疗策略。

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引用次数: 0