Metabolism: clinical and experimental最新文献_第8页

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 : 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 : 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

Emerging roles of TRIM in metabolic regulation TRIM在代谢调节中的新作用

IF 11.9 1区医学 Q1 ENDOCRINOLOGY & METABOLISM

Metabolism: clinical and experimental

Pub Date : 2025-09-21 DOI: 10.1016/j.metabol.2025.156394

Jiaxing Wang , Qiangzhou Wang , Xinrui Li , Qingqing Cai , Yulin Bi , Chenyang Xu , Hao Bai , Lihong Gu , Guobin Chang , Shihao Chen

Recent findings have broadened our understanding of the tripartite motif (TRIM) protein family, positioning these proteins as pivotal regulators of cellular metabolism and cell fate. Primarily functioning as versatile E3 ubiquitin ligases, TRIM proteins orchestrate key metabolic pathways—including glucose, lipid, and amino acid metabolism—through both ubiquitination-dependent and -independent mechanisms such as oligomerization and epigenetic modification. For example, TRIM38, TRIM11, and TRIM24 have been reported to modulate glycolytic flux and insulin signaling by targeting key glucose transporters and glycolytic enzymes, with effects on cancer metabolism and insulin responses in model systems. Similarly, TRIM21 and TRIM56 have been implicated in fatty acid synthesis, oxidation, and cholesterol balance, with potential relevance to fatty-liver conditions and atherosclerosis. Moreover, TRIM-mediated regulation of amino acid metabolism-particularly through pathways involving glutamine and branched-chain amino acids-plays a central role in tumor metabolic reprogramming and survival. Beyond enzymatic regulation, TRIM proteins exert non-canonical functions through epigenetic modulation and interactions with signaling networks. This review synthesizes current insights into the multifaceted roles of TRIM proteins in metabolic control and cell death, suggesting that ferroptosis may link TRIM proteins to lipid and amino acid metabolism, and highlights the connection between TRIM proteins and metabolic stress as a key area for future research.

最近的发现扩大了我们对TRIM蛋白家族的理解，将这些蛋白定位为细胞代谢和细胞命运的关键调节因子。TRIM蛋白主要作为多功能E3泛素连接酶，通过泛素化依赖和非泛素化机制（如寡聚化和表观遗传修饰）协调关键的代谢途径，包括葡萄糖、脂质和氨基酸代谢。例如，据报道，TRIM38、TRIM11和TRIM24通过靶向关键的葡萄糖转运体和糖酵解酶来调节糖酵解通量和胰岛素信号传导，从而影响模型系统中的癌症代谢和胰岛素反应。同样，TRIM21和TRIM56与脂肪酸合成、氧化和胆固醇平衡有关，可能与脂肪肝和动脉粥样硬化有关。此外，trimm介导的氨基酸代谢调节-特别是通过谷氨酰胺和支链氨基酸的途径-在肿瘤代谢重编程和生存中起着核心作用。除了酶的调节，TRIM蛋白通过表观遗传调节和与信号网络的相互作用发挥非规范功能。这篇综述综合了目前对TRIM蛋白在代谢控制和细胞死亡中的多方面作用的认识，表明铁死亡可能将TRIM蛋白与脂质和氨基酸代谢联系起来，并强调了TRIM蛋白与代谢应激之间的联系是未来研究的一个关键领域。

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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 : 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

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 : 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

Emerging role of E4BP4/NFIL3 in metabolic homeostasis E4BP4/NFIL3在代谢稳态中的新作用。

IF 11.9 1区医学 Q1 ENDOCRINOLOGY & METABOLISM

Metabolism: clinical and experimental

Pub Date : 2025-09-16 DOI: 10.1016/j.metabol.2025.156390

Shuman Ran , Siqi Wang , Qi Jin , Genzheng Liu , Xiaobin Xue , Peng Qu , Liang Peng , Hua Meng

E4BP4/NFIL3 (E4 promoter-binding protein 4 or nuclear factor interleukin-3-regulated protein), is well-established for its association with circadian rhythm regulation and immune function. Recent advances in research have revealed its emerging and indispensable role in metabolic homeostasis, positioning it at the crossroads of circadian biology, immune responses, and metabolic balance. This review summarizes three decades of research on E4BP4/NFIL3 and explores its structural basis and regulatory functions. We synthesized current insights into the regulatory pathways that govern E4BP4/NFIL3 and discuss its central role in various metabolic scenarios, emphasizing its emerging significance as a pivotal metabolic regulator. Finally, we identify critical, unresolved questions and propose future research directions to enhance our understanding of E4BP4/NFIL3's broader implications in metabolic health.

E4BP4/NFIL3 （E4启动子结合蛋白4或核因子白介素-3调节蛋白）因其与昼夜节律调节和免疫功能相关而被证实。最近的研究进展表明，它在代谢稳态中发挥着不可或缺的作用，处于昼夜节律生物学、免疫反应和代谢平衡的十字路口。本文综述了近30年来有关E4BP4/NFIL3的研究，并对其结构基础和调控功能进行了探讨。我们综合了目前对E4BP4/NFIL3调控途径的见解，并讨论了其在各种代谢情景中的核心作用，强调了其作为关键代谢调节剂的新意义。最后，我们确定了关键的、未解决的问题，并提出了未来的研究方向，以增强我们对E4BP4/NFIL3在代谢健康中的更广泛影响的理解。

引用次数: 0

Disruption of mitochondria-associated membranes contributes to the dysregulation of insulin secretion in undernutrition, obesity, and double burden of malnutrition 线粒体相关膜的破坏有助于营养不良、肥胖和营养不良双重负担中胰岛素分泌的失调。

IF 11.9 1区医学 Q1 ENDOCRINOLOGY & METABOLISM

Metabolism: clinical and experimental

Pub Date : 2025-09-15 DOI: 10.1016/j.metabol.2025.156393

Thiago dos Reis Araujo , Joel Alves da Silva Junior , Bruna Lourençoni Alves , Dimitrius Santiago Passos Simões Fróes Guimarães , Lohanna Monali Barreto , Mariana Roberta Rodrigues Muniz , Jennifer Rieusset , Everardo Magalhães Carneiro

Aims/hypothesis

Nutritional disorders directly affect the endocrine pancreas, increasing the susceptibility to type 2 diabetes mellitus. However, the molecular mechanisms underlying these alterations remain unknown. This study aims to characterize the role of endoplasmic reticulum (ER)-mitochondria contact sites, known as mitochondrial-associated membranes (MAMs), in insulin secretion dysfunctions associated with undernutrition, obesity, and the double burden of malnutrition (DBM).

Methods

Rat pancreatic INS-1E β-cells were cultured in a medium without amino acids supplemented with 1 × (control) or 0.25 × (amino acid restriction) of an amino acid solution for 48 h, and then cells were exposed to a fatty acid mix for 48 h. Male C57BL/6 mice were fed a normoprotein diet (14 % protein) or protein-restricted diet (6 % protein) for 6 weeks and subsequently a high-fat diet (35 % kcal) for 12 weeks. ER-mitochondria interactions were evaluated by in situ proximity ligation assay and transmission electronic microscopy.

Results

Our findings indicate that protein restriction reduces ER-mitochondria contacts in pancreatic beta-cells, leading to decreased mitochondrial metabolism and glucose-stimulated insulin secretion (GSIS). In contrast, obesity increases ER-mitochondria contact points, mitochondrial metabolism, and GSIS in pancreatic beta-cells, without alterations in viability. DBM results in a significant increase in ER-mitochondria contacts, elevated mitochondrial calcium levels, increased production of reactive oxygen species, and cell death, collectively contributing to impaired GSIS response in the context of obesity.

Conclusions/interpretation

These data indicates that MAMs play a crucial role in GSIS during nutritional disorders such as undernutrition, obesity, and DBM. Importantly, changes in MAMs precede GSIS impairment, therefore targeting these interactions might prevent further disruption in beta-cell function.

目的/假设：营养失调直接影响胰腺内分泌，增加2型糖尿病的易感性。然而，这些变化背后的分子机制尚不清楚。本研究旨在描述内质网(ER)-线粒体接触部位（称为线粒体相关膜（MAMs））在与营养不良、肥胖和营养不良双重负担（DBM）相关的胰岛素分泌功能障碍中的作用。方法：将大鼠胰腺INS-1E β细胞在不含氨基酸的培养基中，添加1 × （对照）或0.25 × （氨基酸限制）的氨基酸溶液培养48 h，然后将细胞暴露于脂肪酸混合物中48 h。雄性C57BL/6小鼠喂食正常蛋白饮食（14 %蛋白质）或蛋白质限制饮食（6 %蛋白质）6 周，随后喂食高脂肪饮食（35 % kcal） 12 周。通过原位接近结扎试验和透射电镜评估er -线粒体相互作用。结果：我们的研究结果表明，蛋白质限制减少了胰腺β细胞中er -线粒体的接触，导致线粒体代谢和葡萄糖刺激胰岛素分泌（GSIS）下降。相比之下，肥胖增加了胰β细胞的er -线粒体接触点、线粒体代谢和GSIS，而不改变生存能力。DBM导致er -线粒体接触显著增加，线粒体钙水平升高，活性氧产生增加，细胞死亡，共同导致肥胖背景下GSIS反应受损。结论/解释：这些数据表明MAMs在营养失调（如营养不良、肥胖和DBM）期间的GSIS中起着至关重要的作用。重要的是，MAMs的变化先于GSIS损伤，因此靶向这些相互作用可能会防止β细胞功能的进一步破坏。

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引用次数: 0

27-Hydroxycholesterol exacerbates hepatic insulin resistance via plasma membrane cholesterol remodeling 羟基胆固醇通过质膜胆固醇重塑加剧肝脏胰岛素抵抗。

IF 11.9 1区医学 Q1 ENDOCRINOLOGY & METABOLISM

Metabolism: clinical and experimental

Pub Date : 2025-09-15 DOI: 10.1016/j.metabol.2025.156392

Jinni Yang , Xue Yang , Yuan Zheng , Anhui Wang , Ziwen Kong , Qinwen Xiao , Yuan Tian , Haijuan Dong , Zunjian Zhang , Min Wang , Rui Song

Background and aims

Insulin resistance is a key driver of metabolic disorders, yet its molecular mechanisms remain elusive. This study identifies 27-hydroxycholesterol (27HC), a cholesterol-derived metabolite, and investigates its role in insulin resistance.

Methods

Targeted metabolomics quantified absolute and relative levels of 27HC (27HC/cholesterol ratio) in patients, mice, and hepatocytes. Insulin resistant mouse models were established to characterize spatiotemporal dynamics of 27HC and related enzymes. Functional analyses assessed 27HC's effect on insulin signaling across multiple hepatocyte types. Transcriptomic analysis identified key effector pathways. Plasma membrane cholesterol accessibility was evaluated using biosensors and validated by cholesterol rescue. Membrane protein extraction, immunofluorescence, and flow cytometry were employed to assess the impact of 27HC on insulin receptor (IR) distribution and binding capacity.

Results

Elevated 27HC levels were observed in patients with metabolic dysfunction-associated steatotic liver disease (MASLD), obese and type 2 diabetic mice (T2DM), and PA-treated HepG2 and primary hepatocytes, correlating with impaired insulin sensitivity. CYP27A1 was identified as the key enzyme regulating liver 27HC levels. In vitro studies demonstrated that 27HC disrupts insulin signaling in HepG2, AML12, and primary hepatocytes, whereas CYP27A1 knockdown restored IR responsiveness. 27HC suppresses SREBP2-dependent cholesterol biosynthesis, depleting accessible cholesterol in the plasma membrane, triggering IR mislocalization and signal attenuation. Liver-specific CYP27A1 silencing in mice fed a high-fat diet improved systemic insulin sensitivity and restored metabolic homeostasis.

Conclusion

Our findings establish 27HC as a key effector linking cholesterol metabolism to insulin resistance and propose CYP27A1 inhibition as a potential therapeutic strategy for insulin resistance.

背景和目的：胰岛素抵抗是代谢紊乱的关键驱动因素，但其分子机制尚不明确。本研究确定了27-羟基胆固醇（27HC），一种胆固醇衍生的代谢物，并研究了其在胰岛素抵抗中的作用。方法：靶向代谢组学量化患者、小鼠和肝细胞中27HC （27HC/胆固醇比值）的绝对和相对水平。建立胰岛素抵抗小鼠模型，表征27HC及相关酶的时空动态。功能分析评估了27HC对多种肝细胞类型胰岛素信号传导的影响。转录组学分析确定了关键的效应通路。用生物传感器评估质膜胆固醇可及性，并通过胆固醇抢救进行验证。采用膜蛋白提取、免疫荧光和流式细胞术评估27HC对胰岛素受体（IR）分布和结合能力的影响。结果：在代谢功能障碍相关脂肪变性肝病（MASLD）、肥胖和2型糖尿病小鼠（T2DM）以及pa处理的HepG2和原代肝细胞中观察到27HC水平升高，与胰岛素敏感性受损相关。CYP27A1被认为是调节肝脏27HC水平的关键酶。体外研究表明，27HC破坏HepG2、AML12和原代肝细胞中的胰岛素信号传导，而CYP27A1敲低可恢复IR反应性。27HC抑制srebp2依赖性胆固醇的生物合成，耗尽质膜内可接近的胆固醇，引发IR错定位和信号衰减。高脂饮食小鼠肝脏特异性CYP27A1沉默可改善全身胰岛素敏感性并恢复代谢稳态。结论：我们的研究结果表明，27HC是连接胆固醇代谢和胰岛素抵抗的关键效应因子，并提出CYP27A1抑制是胰岛素抵抗的潜在治疗策略。

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引用次数: 0

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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