Molecular Metabolism最新文献_第3页

Single cell transcriptomics of human weight loss links adipocyte NPY1R to control of lipolysis. 人类减肥的单细胞转录组学将脂肪细胞NPY1R与脂肪分解控制联系起来。

IF 6.6 2区医学 Q1 ENDOCRINOLOGY & METABOLISM

Molecular Metabolism

Pub Date : 2025-12-16 DOI: 10.1016/j.molmet.2025.102305

Julius E R Grothen, Jaime M Martinez, Nikos Sidiropoulos, Lucas Massier, Danae Zareifi, Jiawei Zhong, Ida Davidsen, Jette W Platou, Jette Mandelbaum, Pia Rothe, Henning Hvid, Mads Grønborg, Christian Toft Madsen, Jens M Bruun, Mikael Rydén, Niklas Mejhert, Jørn W Helge, Zachary Gerhart-Hines, Thomas Å Pedersen

Background: Combination of increased physical exercise and hypocaloric diet has long been recognized to improve cardiometabolic health and adipose tissue function, including lipid turnover. How such lifestyle interventions mediate benefits at the cellular level remains unknown. Given the critical role of subcutaneous white adipose tissue (scWAT) to systemic metabolic homeostasis, we set out to interrogate how exercise and diet lifestyle intervention impacted scWAT in individuals living with obesity, with a particular focus on lipolytic capacity and cell-specific gene profiling.

Methods: Single nuclei RNA sequencing (snRNAseq) was performed on cryopreserved scWAT biopsies originally collected before and after lifestyle intervention, involving regular exercise and hypocaloric diet in obese individuals. Findings on regulation of lipolysis in adipocytes were followed up with meta-analysis of clinical studies and pharmacological experiments in mature human adipocytes.

Results: snRNAseq analysis revealed intervention-induced changes in all scWAT cell-types. In adipocytes genes linked to protein and organelle turnover, branch chain amino acid catabolism, and lipolytic control were most significantly regulated. We identified a cell autonomous brake on adipocyte lipolysis via the neuropeptide Y receptor 1 (NPY1R). Expression of adipocyte NPY1R was reduced after weight loss and correlated positively with body fat percentage and body mass index. Findings were confirmed in meta-analysis across 23 studies. Finally, we found a negative correlation between NPY1R and beta-adrenergic-induced lipolysis and that NPY dose-dependently attenuated lipolysis and cAMP-signaling in primary human subcutaneous adipocytes.

Conclusions: Our work suggests that decreases in adipocyte NPY1R during weight loss boost lipolytic capacity and contribute to improved systemic cardiometabolic health.

背景：长期以来，人们一直认为增加体育锻炼和低热量饮食相结合可以改善心脏代谢健康和脂肪组织功能，包括脂质转化。这种生活方式干预如何在细胞水平上介导益处尚不清楚。鉴于皮下白色脂肪组织（scWAT）在全身代谢稳态中的关键作用，我们着手研究运动和饮食生活方式干预如何影响肥胖个体的scWAT，特别关注脂肪分解能力和细胞特异性基因谱。方法：对生活方式干预前后收集的冷冻保存的scWAT活检进行单核RNA测序（snRNAseq），包括肥胖个体的定期运动和低热量饮食。通过对成熟人脂肪细胞的临床研究和药理学实验进行meta分析，进一步研究了脂肪细胞对脂肪分解的调节作用。结果：snRNAseq分析显示干预诱导的所有scWAT细胞类型的变化。在脂肪细胞中，与蛋白质和细胞器转换、支链氨基酸分解代谢和脂溶控制相关的基因受到最显著的调节。我们通过神经肽Y受体1 （NPY1R）确定了脂肪细胞脂解的细胞自主制动。减肥后脂肪细胞NPY1R表达降低，与体脂率和体重指数呈正相关。研究结果在23项研究的荟萃分析中得到证实。最后，我们发现NPY1R与β -肾上腺素能诱导的脂肪分解呈负相关，并且NPY剂量依赖性地减弱了原代人皮下脂肪细胞的脂肪分解和camp信号。结论：我们的研究表明，减肥过程中脂肪细胞NPY1R的降低提高了脂肪分解能力，并有助于改善全身心脏代谢健康。

{"title":"Single cell transcriptomics of human weight loss links adipocyte NPY1R to control of lipolysis.","authors":"Julius E R Grothen, Jaime M Martinez, Nikos Sidiropoulos, Lucas Massier, Danae Zareifi, Jiawei Zhong, Ida Davidsen, Jette W Platou, Jette Mandelbaum, Pia Rothe, Henning Hvid, Mads Grønborg, Christian Toft Madsen, Jens M Bruun, Mikael Rydén, Niklas Mejhert, Jørn W Helge, Zachary Gerhart-Hines, Thomas Å Pedersen","doi":"10.1016/j.molmet.2025.102305","DOIUrl":"10.1016/j.molmet.2025.102305","url":null,"abstract":"<p><strong>Background: </strong>Combination of increased physical exercise and hypocaloric diet has long been recognized to improve cardiometabolic health and adipose tissue function, including lipid turnover. How such lifestyle interventions mediate benefits at the cellular level remains unknown. Given the critical role of subcutaneous white adipose tissue (scWAT) to systemic metabolic homeostasis, we set out to interrogate how exercise and diet lifestyle intervention impacted scWAT in individuals living with obesity, with a particular focus on lipolytic capacity and cell-specific gene profiling.</p><p><strong>Methods: </strong>Single nuclei RNA sequencing (snRNAseq) was performed on cryopreserved scWAT biopsies originally collected before and after lifestyle intervention, involving regular exercise and hypocaloric diet in obese individuals. Findings on regulation of lipolysis in adipocytes were followed up with meta-analysis of clinical studies and pharmacological experiments in mature human adipocytes.</p><p><strong>Results: </strong>snRNAseq analysis revealed intervention-induced changes in all scWAT cell-types. In adipocytes genes linked to protein and organelle turnover, branch chain amino acid catabolism, and lipolytic control were most significantly regulated. We identified a cell autonomous brake on adipocyte lipolysis via the neuropeptide Y receptor 1 (NPY1R). Expression of adipocyte NPY1R was reduced after weight loss and correlated positively with body fat percentage and body mass index. Findings were confirmed in meta-analysis across 23 studies. Finally, we found a negative correlation between NPY1R and beta-adrenergic-induced lipolysis and that NPY dose-dependently attenuated lipolysis and cAMP-signaling in primary human subcutaneous adipocytes.</p><p><strong>Conclusions: </strong>Our work suggests that decreases in adipocyte NPY1R during weight loss boost lipolytic capacity and contribute to improved systemic cardiometabolic health.</p>","PeriodicalId":18765,"journal":{"name":"Molecular Metabolism","volume":" ","pages":"102305"},"PeriodicalIF":6.6,"publicationDate":"2025-12-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145781569","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"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

Branched chain amino acids prime metabolic inflammation 支链氨基酸引发代谢性炎症。

IF 6.6 2区医学 Q1 ENDOCRINOLOGY & METABOLISM

Molecular Metabolism

Pub Date : 2025-12-15 DOI: 10.1016/j.molmet.2025.102308

Nandini K. Doshi , Tristan Pesaresi , Trishya Pagadala , William Dion , Yang Zhang , Natalie L. David , Tânia Amorim , Wenjia Wang , G.V. Naveen Kumar , Bokai Zhu , Silvia Liu , Parth Patwari , Pouneh K. Fazeli , Matthew L. Steinhauser

Sterile inflammation is associated with a broad range of metabolic stressors including both dietary excess and prolonged fasting. In a 10-day human fasting study, we previously identified a surge in the circulating inflammatory biomarker, C-reactive protein (CRP), which we leveraged in the current study to identify novel metabolic inflammatory correlates. With a variety of longitudinal metabolic variables as input, including metabolomics, we identified branched chain amino acids (BCAA) as the top candidate inflammatory correlate. We then used in vitro myeloid/macrophage culture and in vivo murine models to test BCAA as a determinant of inflammatory signaling. Short-term exposure to BCAA alone had modest effects on a variety of immune readouts; however, when coupled with a second stimulus, such as exposure to endotoxin or when administered to diet-induced obese mice, members of the JAK/STAT/cytokine signaling pathways were augmented on the transcriptional level by concurrent BCAA administration in multiple tissues, including visceral adipose and liver. The modifying effect of BCAA on inflammatory stressors translated into increased levels of circulating inflammatory cytokines. Collectively, these data position BCAA as an immune priming factor, a potential mechanism underlying the well-established association between circulating BCAA and diverse diseases of aging.

无菌性炎症与多种代谢应激源有关，包括饮食过量和长时间禁食。在一项为期10天的人体禁食研究中，我们之前发现了循环炎症生物标志物c反应蛋白（CRP）的激增，我们在当前的研究中利用它来确定新的代谢性炎症相关因素。通过多种纵向代谢变量作为输入，包括代谢组学，我们确定支链氨基酸（BCAA）是炎症相关的首选候选。然后，我们使用体外骨髓/巨噬细胞培养和体内小鼠模型来测试BCAA作为炎症信号传导的决定因素。短期单独暴露于BCAA对各种免疫读数的影响不大；然而，当与第二种刺激相结合时，如暴露于内毒素或给药于饮食诱导的肥胖小鼠时，在包括内脏脂肪和肝脏在内的多个组织中，同时给药BCAA会在转录水平上增加JAK/STAT/细胞因子信号通路成员。BCAA对炎症应激源的调节作用转化为循环炎症细胞因子水平的增加。总的来说，这些数据表明BCAA是一种免疫启动因子，是循环BCAA与多种衰老疾病之间建立良好关联的潜在机制。

{"title":"Branched chain amino acids prime metabolic inflammation","authors":"Nandini K. Doshi , Tristan Pesaresi , Trishya Pagadala , William Dion , Yang Zhang , Natalie L. David , Tânia Amorim , Wenjia Wang , G.V. Naveen Kumar , Bokai Zhu , Silvia Liu , Parth Patwari , Pouneh K. Fazeli , Matthew L. Steinhauser","doi":"10.1016/j.molmet.2025.102308","DOIUrl":"10.1016/j.molmet.2025.102308","url":null,"abstract":"<div><div>Sterile inflammation is associated with a broad range of metabolic stressors including both dietary excess and prolonged fasting. In a 10-day human fasting study, we previously identified a surge in the circulating inflammatory biomarker, C-reactive protein (CRP), which we leveraged in the current study to identify novel metabolic inflammatory correlates. With a variety of longitudinal metabolic variables as input, including metabolomics, we identified branched chain amino acids (BCAA) as the top candidate inflammatory correlate. We then used <em>in vitro</em> myeloid/macrophage culture and <em>in vivo</em> murine models to test BCAA as a determinant of inflammatory signaling. Short-term exposure to BCAA alone had modest effects on a variety of immune readouts; however, when coupled with a second stimulus, such as exposure to endotoxin or when administered to diet-induced obese mice, members of the JAK/STAT/cytokine signaling pathways were augmented on the transcriptional level by concurrent BCAA administration in multiple tissues, including visceral adipose and liver. The modifying effect of BCAA on inflammatory stressors translated into increased levels of circulating inflammatory cytokines. Collectively, these data position BCAA as an immune priming factor, a potential mechanism underlying the well-established association between circulating BCAA and diverse diseases of aging.</div></div>","PeriodicalId":18765,"journal":{"name":"Molecular Metabolism","volume":"104 ","pages":"Article 102308"},"PeriodicalIF":6.6,"publicationDate":"2025-12-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145775023","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"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

The innate thermogenic capacity of brown adipose tissue develops independently of sympathetic signaling 褐色脂肪组织的先天产热能力的发展独立于交感信号。

IF 6.6 2区医学 Q1 ENDOCRINOLOGY & METABOLISM

Molecular Metabolism

Pub Date : 2025-12-09 DOI: 10.1016/j.molmet.2025.102299

Ethan C. Fein , Sarmistha Mukherjee , Joseph A. Baur , Patrick Seale

Brown adipose tissue (BAT) dissipates energy as heat in response to β-adrenergic signaling induced by the sympathetic nervous system (SNS). While this pathway is essential for the cold-induced remodeling and metabolic activity of BAT, its role in developmental programming is unclear. Here, we show that brown adipocytes acquire thermogenic identity during embryogenesis independently of sympathetic innervation and β-adrenergic signaling. Genetic sympathectomy or disrupted β-adrenergic signaling had minimal effects on thermogenic gene expression or tissue morphology during either embryonic or postnatal BAT development in the absence of cold stress. Functional analyses revealed that the SNS is likely required for circulatory support of BAT activity during β-adrenergic stimulation but not for the development of the thermogenic capacity of BAT itself. These findings demonstrate that developmental and cold-responsive BAT remodeling are mechanistically distinct processes. Defining the molecular programs that drive BAT development may reveal new strategies to enhance BAT formation and function without relying on β-adrenergic stimulation.

棕色脂肪组织（BAT）响应交感神经系统（SNS）诱导的β-肾上腺素能信号，以热量的形式耗散能量。虽然这一途径对BAT的冷诱导重塑和代谢活性至关重要，但其在发育编程中的作用尚不清楚。在这里，我们发现棕色脂肪细胞在胚胎发生过程中独立于交感神经支配和β-肾上腺素能信号获得产热特性。在没有冷应激的胚胎或出生后BAT发育过程中，遗传交感神经切除或β-肾上腺素能信号中断对产热基因表达或组织形态的影响微乎其微。功能分析显示，在β-肾上腺素能刺激期间，SNS可能是支持BAT活性循环的必要条件，而不是支持BAT本身产热能力的发展。这些发现表明发育性和冷响应性BAT重塑在机制上是不同的过程。确定驱动BAT发育的分子程序可能会揭示新的策略来增强BAT的形成和功能，而不依赖于β-肾上腺素能刺激。

{"title":"The innate thermogenic capacity of brown adipose tissue develops independently of sympathetic signaling","authors":"Ethan C. Fein , Sarmistha Mukherjee , Joseph A. Baur , Patrick Seale","doi":"10.1016/j.molmet.2025.102299","DOIUrl":"10.1016/j.molmet.2025.102299","url":null,"abstract":"<div><div>Brown adipose tissue (BAT) dissipates energy as heat in response to β-adrenergic signaling induced by the sympathetic nervous system (SNS). While this pathway is essential for the cold-induced remodeling and metabolic activity of BAT, its role in developmental programming is unclear. Here, we show that brown adipocytes acquire thermogenic identity during embryogenesis independently of sympathetic innervation and β-adrenergic signaling. Genetic sympathectomy or disrupted β-adrenergic signaling had minimal effects on thermogenic gene expression or tissue morphology during either embryonic or postnatal BAT development in the absence of cold stress. Functional analyses revealed that the SNS is likely required for circulatory support of BAT activity during β-adrenergic stimulation but not for the development of the thermogenic capacity of BAT itself. These findings demonstrate that developmental and cold-responsive BAT remodeling are mechanistically distinct processes. Defining the molecular programs that drive BAT development may reveal new strategies to enhance BAT formation and function without relying on β-adrenergic stimulation.</div></div>","PeriodicalId":18765,"journal":{"name":"Molecular Metabolism","volume":"103 ","pages":"Article 102299"},"PeriodicalIF":6.6,"publicationDate":"2025-12-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145743408","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"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

Glycolytic activation of β-cell Na+/K+-ATPases containing β1-subunits accelerates Na+ extrusion, prolonging the duration of Ca2+ oscillations but decreasing insulin secretion 含有β1亚基的β细胞Na+/K+- atp酶的糖酵解激活加速了Na+的挤压，延长了Ca2+振荡的持续时间，但减少了胰岛素的分泌。

IF 6.6 2区医学 Q1 ENDOCRINOLOGY & METABOLISM

Molecular Metabolism

Pub Date : 2025-12-04 DOI: 10.1016/j.molmet.2025.102296

Matthew T. Dickerson , Prasanna K. Dadi , Reagan P. McDevitt , Jordyn R. Dobson , Soma Behera , Spencer J. Peachee , Shannon E. Gibson , Tenzin Wangmo , David A. Jacobson

Electrogenic Na⁺/K⁺ ATPases (NKAs) control β-cell Ca²⁺ influx and insulin secretion by integrating the signal strength of stimulatory G protein (G_s)-coupled ligands (e.g., GLP-1, glucagon) and inhibitory G protein (G_i)-coupled ligands (e.g., somatostatin, epinephrine). However, there is a significant gap in our understanding of how specific NKA subunits contribute to β-cell function. Here, we demonstrate that the NKA β1-subunit (NKAβ1) is highly expressed and functional at the plasma membrane of mouse and human β-cells. β-cell-specific NKAβ1 knockout improves glucose tolerance and hepatic insulin sensitivity, coinciding with enhanced first- and second-phase glucose-stimulated insulin secretion (GSIS). Electrophysiological studies reveal that β-cell NKAβ1 enhances somatostatin-induced NKA currents, increases action potential afterhyperpolarization amplitude, and accelerates action potential frequency. Loss of NKAβ1 delays glucose-stimulated Ca²⁺ entry by impairing glycolysis-dependent NKA activation and reduces Na⁺ clearance efficiency during Ca²⁺ oscillations, resulting in prolonged silent phases. Thus, glycolytic stimulation of Na⁺ influx dictates silent phase duration via the kinetics of Na⁺ clearance by NKA, which is diminished in β-cells without NKAβ1. Furthermore, NKAβ1 differentially modulates β-cell G protein-coupled receptor (GPCR) signaling by attenuating G_i-GPCR effects and augmenting G_s-coupled GLP-1 receptor-mediated cAMP production and Ca²⁺ entry. β-cell NKAβ1 knockdown in human pseudoislets led to tonically elevated intracellular Ca²⁺ and increased insulin secretion. These findings establish NKAβ1-containing NKA complexes as critical regulators of β-cell electrical activity, Ca²⁺ oscillations, and secretory patterns, with direct consequences for systemic glucose homeostasis.

电致Na+/K+ atp酶（NKAs）通过整合刺激G蛋白（Gs）偶联配体（如GLP-1、胰高血糖素）和抑制G蛋白（Gi）偶联配体（如生长抑素、肾上腺素）的信号强度来控制β细胞Ca2+内流和胰岛素分泌。然而，在我们对特定NKA亚基如何促进β细胞功能的理解上存在重大差距。在这里，我们证明了NKAβ1亚基（NKAβ1）在小鼠和人β细胞的质膜上高度表达和发挥功能。β细胞特异性NKAβ1敲除可改善葡萄糖耐量和肝脏胰岛素敏感性，与第一和第二阶段葡萄糖刺激胰岛素分泌（GSIS）增强相一致。电生理研究表明，β-细胞NKAβ1增强生长抑素诱导的NKA电流，增加超极化后动作电位振幅，加速动作电位频率。NKAβ1的缺失通过损害糖酵解依赖的NKA激活来延迟葡萄糖刺激的Ca2+进入，并降低Ca2+振荡期间Na+的清除效率，导致沉默期延长。因此，Na+内流的糖酵解刺激通过NKA清除Na+的动力学决定了沉默期的持续时间，而在没有NKAβ1的β-细胞中Na+清除会减少。此外，NKAβ1通过减弱Gi-GPCR效应和增强gs -偶联GLP-1受体介导的cAMP产生和Ca2+进入来差异性调节β-细胞G蛋白偶联受体（GPCR）信号传导。人假胰岛NKAβ1βKD导致细胞内Ca2+强直性升高和胰岛素分泌增加。这些发现表明含有NKAβ1的NKA复合物是β细胞电活动、Ca2+振荡和分泌模式的关键调节因子，对全身葡萄糖稳态有直接影响。

{"title":"Glycolytic activation of β-cell Na+/K+-ATPases containing β1-subunits accelerates Na+ extrusion, prolonging the duration of Ca2+ oscillations but decreasing insulin secretion","authors":"Matthew T. Dickerson , Prasanna K. Dadi , Reagan P. McDevitt , Jordyn R. Dobson , Soma Behera , Spencer J. Peachee , Shannon E. Gibson , Tenzin Wangmo , David A. Jacobson","doi":"10.1016/j.molmet.2025.102296","DOIUrl":"10.1016/j.molmet.2025.102296","url":null,"abstract":"<div><div>Electrogenic Na<sup>+</sup>/K<sup>+</sup> ATPases (NKAs) control β-cell Ca<sup>2+</sup> influx and insulin secretion by integrating the signal strength of stimulatory G protein (G<sub>s</sub>)-coupled ligands (e.g., GLP-1, glucagon) and inhibitory G protein (G<sub>i</sub>)-coupled ligands (e.g., somatostatin, epinephrine). However, there is a significant gap in our understanding of how specific NKA subunits contribute to β-cell function. Here, we demonstrate that the NKA β1-subunit (NKAβ1) is highly expressed and functional at the plasma membrane of mouse and human β-cells. β-cell-specific NKAβ1 knockout improves glucose tolerance and hepatic insulin sensitivity, coinciding with enhanced first- and second-phase glucose-stimulated insulin secretion (GSIS). Electrophysiological studies reveal that β-cell NKAβ1 enhances somatostatin-induced NKA currents, increases action potential afterhyperpolarization amplitude, and accelerates action potential frequency. Loss of NKAβ1 delays glucose-stimulated Ca<sup>2+</sup> entry by impairing glycolysis-dependent NKA activation and reduces Na<sup>+</sup> clearance efficiency during Ca<sup>2+</sup> oscillations, resulting in prolonged silent phases. Thus, glycolytic stimulation of Na<sup>+</sup> influx dictates silent phase duration via the kinetics of Na<sup>+</sup> clearance by NKA, which is diminished in β-cells without NKAβ1. Furthermore, NKAβ1 differentially modulates β-cell G protein-coupled receptor (GPCR) signaling by attenuating G<sub>i</sub>-GPCR effects and augmenting G<sub>s</sub>-coupled GLP-1 receptor-mediated cAMP production and Ca<sup>2+</sup> entry. β-cell NKAβ1 knockdown in human pseudoislets led to tonically elevated intracellular Ca<sup>2+</sup> and increased insulin secretion. These findings establish NKAβ1-containing NKA complexes as critical regulators of β-cell electrical activity, Ca<sup>2+</sup> oscillations, and secretory patterns, with direct consequences for systemic glucose homeostasis.</div></div>","PeriodicalId":18765,"journal":{"name":"Molecular Metabolism","volume":"103 ","pages":"Article 102296"},"PeriodicalIF":6.6,"publicationDate":"2025-12-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145695663","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"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

Protein kinase D deficiency induces a senescence-like phenotype in β-cells and improves glucose and insulin tolerance under high-fat diet conditions 蛋白激酶D缺乏诱导β细胞衰老样表型，并在高脂肪饮食条件下改善葡萄糖和胰岛素耐受性。

IF 6.6 2区医学 Q1 ENDOCRINOLOGY & METABOLISM

Molecular Metabolism

Pub Date : 2025-12-03 DOI: 10.1016/j.molmet.2025.102297

Wolfgang S. Lieb , Carlos O. Oueslati Morales , Kornelia Ellwanger , Claudia Koch , Sylke Lutz , Stephan A. Eisler , Annika M. Möller , Veronika Leiss , Angelika Hausser

Insulin secretion from pancreatic β-cells is essential for maintaining glucose homeostasis and preventing type 2 diabetes, a condition closely associated with aging. Although previous studies in mice have shown that both basal and glucose-stimulated insulin secretion increase with age, the underlying mechanisms remained poorly understood. In this study, we identify protein kinase D (PKD) as a critical regulator of β-cell function during aging through its control of cellular senescence. Using β-cell–specific expression of dominant-negative PKDkd-EGFP and the selective PKD inhibitor CRT0066101, we demonstrate that inhibition of PKD activity in mature adult mice induced a senescent-like β-cell phenotype characterized by enlarged cell size and elevated β-galactosidase activity. These changes were associated with decreased expression of the antioxidant enzyme superoxide dismutase 2 and increased levels of reactive oxygen species. Surprisingly, despite promoting a senescent-like phenotype, PKD inhibition significantly improved glucose tolerance, enhanced glucose-stimulated insulin secretion, and protected against high-fat diet–induced glucose and insulin intolerance. These findings highlight the importance of PKD in preserving β-cell function under aging and metabolic stress conditions.

胰腺β细胞分泌胰岛素对于维持葡萄糖稳态和预防与衰老密切相关的2型糖尿病至关重要。尽管先前对小鼠的研究表明，基础和葡萄糖刺激的胰岛素分泌都随着年龄的增长而增加，但其潜在的机制仍然知之甚少。在这项研究中，我们发现蛋白激酶D （PKD）通过控制细胞衰老，在衰老过程中作为β细胞功能的关键调节因子。通过β细胞特异性表达显性阴性PKDkd-EGFP和选择性PKD抑制剂CRT0066101，我们证明了成熟成年小鼠中PKD活性的抑制诱导了衰老样β细胞表型，其特征是细胞大小增大和β-半乳糖苷酶活性升高。这些变化与抗氧化酶超氧化物歧化酶2的表达降低和活性氧水平升高有关。令人惊讶的是，尽管促进了类似衰老的表型，PKD抑制显著改善了葡萄糖耐量，增强了葡萄糖刺激的胰岛素分泌，并防止高脂肪饮食诱导的葡萄糖和胰岛素不耐受。这些发现强调了PKD在衰老和代谢应激条件下保持β细胞功能的重要性。

{"title":"Protein kinase D deficiency induces a senescence-like phenotype in β-cells and improves glucose and insulin tolerance under high-fat diet conditions","authors":"Wolfgang S. Lieb , Carlos O. Oueslati Morales , Kornelia Ellwanger , Claudia Koch , Sylke Lutz , Stephan A. Eisler , Annika M. Möller , Veronika Leiss , Angelika Hausser","doi":"10.1016/j.molmet.2025.102297","DOIUrl":"10.1016/j.molmet.2025.102297","url":null,"abstract":"<div><div>Insulin secretion from pancreatic β-cells is essential for maintaining glucose homeostasis and preventing type 2 diabetes, a condition closely associated with aging. Although previous studies in mice have shown that both basal and glucose-stimulated insulin secretion increase with age, the underlying mechanisms remained poorly understood. In this study, we identify protein kinase D (PKD) as a critical regulator of β-cell function during aging through its control of cellular senescence. Using β-cell–specific expression of dominant-negative PKDkd-EGFP and the selective PKD inhibitor CRT0066101, we demonstrate that inhibition of PKD activity in mature adult mice induced a senescent-like β-cell phenotype characterized by enlarged cell size and elevated β-galactosidase activity. These changes were associated with decreased expression of the antioxidant enzyme superoxide dismutase 2 and increased levels of reactive oxygen species. Surprisingly, despite promoting a senescent-like phenotype, PKD inhibition significantly improved glucose tolerance, enhanced glucose-stimulated insulin secretion, and protected against high-fat diet–induced glucose and insulin intolerance. These findings highlight the importance of PKD in preserving β-cell function under aging and metabolic stress conditions.</div></div>","PeriodicalId":18765,"journal":{"name":"Molecular Metabolism","volume":"103 ","pages":"Article 102297"},"PeriodicalIF":6.6,"publicationDate":"2025-12-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145687531","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"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

Reprogramming of cholesterol sensing in epithelial cells supports pancreatic inflammation 上皮细胞中胆固醇感知的重编程支持胰腺炎症。

IF 6.6 2区医学 Q1 ENDOCRINOLOGY & METABOLISM

Molecular Metabolism

Pub Date : 2025-12-02 DOI: 10.1016/j.molmet.2025.102292

Giulia Milan , Olga A. Mareninova , Marco Fantuz , Martina Spacci , Carlotta Paoli , Jerik A. Pineda , Roberta Noè , Beatrice Calciolari , Roberto Zoncu , Anna S. Gukovskaya , Alessandro Carrer

Pancreatitis is a common cause of hospitalization that necessitates attentive clinical management. Affected individuals are at risk for pancreatic cancer due to aberrant signaling and empowered cell plasticity. Yet, molecular and cellular dynamics that govern epithelial cell behavior in response to inflammation remain largely elusive.

Here we found that inflammation induces Endoplasmic Reticulum-Associated Degradation protein (ERAD)-mediated downregulation of Niemann-Pick type C protein 1 (NPC1), which leads to the sequestration of free cholesterol within acinar cells’ lysosomes. Reducing intra-pancreatic cholesterol levels through genetic ablation of Acly ameliorates cerulein-induced pancreatitis, while pharmacological targeting of NPC1 exacerbates tissue damage.

Mechanistically, the accumulation of lysosomal cholesterol is sensed by the mechanistic Target of Rapamycin Complex 1 (mTORC1) that promotes metaplasia of pancreatic acinar cells, an event commonly associated to pancreatitis and tissue regeneration. Indeed, cholesterol supplementation or NPC1 inhibition facilitate acinar-to-ductal metaplasia (ADM) both ex vivo and in vivo, in an mTORC1-dependent manner.

These results identify a metabolic/signaling axis driving the reprogramming of pancreatic epithelial cells in response to inflammation. This hinges on a nutrient sensing paradigm, previously documented exclusively in pathological conditions.

胰腺炎是住院治疗的常见原因，需要细心的临床管理。由于信号异常和细胞可塑性增强，受影响的个体有患胰腺癌的风险。然而，控制上皮细胞对炎症反应行为的分子和细胞动力学在很大程度上仍然难以捉摸。本研究发现，炎症诱导内质网相关降解蛋白（ERAD）介导的Niemann-Pick型C蛋白1 （NPC1）下调，导致游离胆固醇在腺泡细胞溶酶体中被隔离。通过基因消融Acly降低胰腺内胆固醇水平可改善cerulein诱导的胰腺炎，而药物靶向NPC1会加重组织损伤。从机制上讲，溶酶体胆固醇的积累是由雷帕霉素复合物1 （mTORC1）的机制靶标感知的，该靶标促进胰腺腺泡细胞的化生，这一事件通常与胰腺炎和组织再生有关。事实上，补充胆固醇或抑制NPC1以mtorc1依赖的方式促进体外和体内的腺泡到导管化生（ADM）。这些结果确定了代谢/信号轴驱动胰腺上皮细胞对炎症反应的重编程。这取决于以前仅在病理条件下记录的营养感知范式。

{"title":"Reprogramming of cholesterol sensing in epithelial cells supports pancreatic inflammation","authors":"Giulia Milan , Olga A. Mareninova , Marco Fantuz , Martina Spacci , Carlotta Paoli , Jerik A. Pineda , Roberta Noè , Beatrice Calciolari , Roberto Zoncu , Anna S. Gukovskaya , Alessandro Carrer","doi":"10.1016/j.molmet.2025.102292","DOIUrl":"10.1016/j.molmet.2025.102292","url":null,"abstract":"<div><div>Pancreatitis is a common cause of hospitalization that necessitates attentive clinical management. Affected individuals are at risk for pancreatic cancer due to aberrant signaling and empowered cell plasticity. Yet, molecular and cellular dynamics that govern epithelial cell behavior in response to inflammation remain largely elusive.</div><div>Here we found that inflammation induces Endoplasmic Reticulum-Associated Degradation protein (ERAD)-mediated downregulation of Niemann-Pick type C protein 1 (NPC1), which leads to the sequestration of free cholesterol within acinar cells’ lysosomes. Reducing intra-pancreatic cholesterol levels through genetic ablation of <em>Acly</em> ameliorates cerulein-induced pancreatitis, while pharmacological targeting of NPC1 exacerbates tissue damage.</div><div>Mechanistically, the accumulation of lysosomal cholesterol is sensed by the mechanistic Target of Rapamycin Complex 1 (mTORC1) that promotes metaplasia of pancreatic acinar cells, an event commonly associated to pancreatitis and tissue regeneration. Indeed, cholesterol supplementation or NPC1 inhibition facilitate acinar-to-ductal metaplasia (ADM) both <em>ex vivo</em> and <em>in vivo</em>, in an mTORC1-dependent manner.</div><div>These results identify a metabolic/signaling axis driving the reprogramming of pancreatic epithelial cells in response to inflammation. This hinges on a nutrient sensing paradigm, previously documented exclusively in pathological conditions.</div></div>","PeriodicalId":18765,"journal":{"name":"Molecular Metabolism","volume":"103 ","pages":"Article 102292"},"PeriodicalIF":6.6,"publicationDate":"2025-12-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145677682","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"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

High-fat diet induces senescence in ADSCs via CDK4 ubiquitination-mediated cell cycle disruption, contributing to impaired glucose tolerance 高脂肪饮食通过CDK4泛素化介导的细胞周期破坏诱导ADSCs衰老，导致糖耐量受损。

IF 6.6 2区医学 Q1 ENDOCRINOLOGY & METABOLISM

Molecular Metabolism

Pub Date : 2025-11-29 DOI: 10.1016/j.molmet.2025.102293

Zheng Ge , Zitian Liu , Shuohui Dong , Xiang Zhao , Guangwei Yang , Ao Yu , Wei Guo , Xiang Zhang , Qunzheng Wu , Kexin Wang

High-fat diet (HFD) promotes adipose tissue senescence, which in turn disrupts insulin-mediated glycemic homeostasis. The underlying mechanisms remain unclear. Through clinical survey data, animal models, and primary adipose-derived mesenchymal stem cells (ADSC), we investigated how dietary patterns influence adipocyte senescence. We found that elevated fatty acid levels enhance the interaction between the E3 ubiquitin ligase TRIP12 and Cyclin-dependent kinase 4 (CDK4) in ADSCs, triggering CDK4 ubiquitination and degradation. As a process associated with this disruption in cell cycle progression, cellular senescence may represent a key outcome. Consequently, senescent ADSC-derived mature adipocytes (ADSC-MA) exhibit impaired insulin-stimulated GLUT4 membrane translocation and reduced glucose uptake. In contrast, within an HFD setting, dietary fiber supplementation is associated with the reversal of cellular senescence. The gut microbiota–short-chain fatty acids (SCFAs) axis may be involved in the restoration of cell cycle progression and the amelioration of ADSC senescence, correlating with a partial recovery of glucose uptake capacity in ADSC-MAs. Our study highlights potential strategies to reverse cellular senescence and identifies promising therapeutic targets for impaired glucose tolerance.

高脂肪饮食（HFD）促进脂肪组织衰老，这反过来破坏胰岛素介导的血糖稳态。其潜在机制尚不清楚。通过临床调查数据、动物模型和原代脂肪源性间充质干细胞（ADSC），我们研究了饮食模式如何影响脂肪细胞衰老。我们发现，升高的脂肪酸水平增强了ADSCs中E3泛素连接酶TRIP12和细胞周期蛋白依赖性激酶4 （CDK4）之间的相互作用，触发CDK4泛素化和降解。作为与细胞周期进程中断相关的一个过程，细胞衰老可能是一个关键的结果。因此，衰老的adsc来源的成熟脂肪细胞（ADSC-MA）表现出胰岛素刺激的GLUT4膜易位受损和葡萄糖摄取减少。相反，在高热量饮食的情况下，膳食纤维的补充与细胞衰老的逆转有关。肠道微生物群-短链脂肪酸（SCFAs）轴可能参与细胞周期进程的恢复和ADSC衰老的改善，与ADSC- mas中葡萄糖摄取能力的部分恢复有关。我们的研究强调了逆转细胞衰老的潜在策略，并确定了葡萄糖耐量受损的有希望的治疗靶点。

{"title":"High-fat diet induces senescence in ADSCs via CDK4 ubiquitination-mediated cell cycle disruption, contributing to impaired glucose tolerance","authors":"Zheng Ge , Zitian Liu , Shuohui Dong , Xiang Zhao , Guangwei Yang , Ao Yu , Wei Guo , Xiang Zhang , Qunzheng Wu , Kexin Wang","doi":"10.1016/j.molmet.2025.102293","DOIUrl":"10.1016/j.molmet.2025.102293","url":null,"abstract":"<div><div>High-fat diet (HFD) promotes adipose tissue senescence, which in turn disrupts insulin-mediated glycemic homeostasis. The underlying mechanisms remain unclear. Through clinical survey data, animal models, and primary adipose-derived mesenchymal stem cells (ADSC), we investigated how dietary patterns influence adipocyte senescence. We found that elevated fatty acid levels enhance the interaction between the E3 ubiquitin ligase TRIP12 and Cyclin-dependent kinase 4 (CDK4) in ADSCs, triggering CDK4 ubiquitination and degradation. As a process associated with this disruption in cell cycle progression, cellular senescence may represent a key outcome. Consequently, senescent ADSC-derived mature adipocytes (ADSC-MA) exhibit impaired insulin-stimulated GLUT4 membrane translocation and reduced glucose uptake. In contrast, within an HFD setting, dietary fiber supplementation is associated with the reversal of cellular senescence. The gut microbiota–short-chain fatty acids (SCFAs) axis may be involved in the restoration of cell cycle progression and the amelioration of ADSC senescence, correlating with a partial recovery of glucose uptake capacity in ADSC-MAs. Our study highlights potential strategies to reverse cellular senescence and identifies promising therapeutic targets for impaired glucose tolerance.</div></div>","PeriodicalId":18765,"journal":{"name":"Molecular Metabolism","volume":"103 ","pages":"Article 102293"},"PeriodicalIF":6.6,"publicationDate":"2025-11-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145649040","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"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

The impact of gut-liver-derived mediators on the organ crosstalk with brain, heart, and kidney: A systematic review 肠-肝源介质对脑、心、肾器官串扰的影响：系统综述。

IF 6.6 2区医学 Q1 ENDOCRINOLOGY & METABOLISM

Molecular Metabolism

Pub Date : 2025-11-29 DOI: 10.1016/j.molmet.2025.102295

Shruti Bhargava , Zhuangting Rao , Raymond Vanholder , Frank Tacke , Heidi Noels , Vera Jankowski , Juliane Hermann , Joachim Jankowski

Introduction

The current understanding of interactions and crosstalk among essential organs remains incomplete, mainly due to the limitations of studies on the systemic mechanisms at play. The gut and the liver are essential for the functioning of the entire body, and their derived mediators circulate through blood or lymph, impacting other organs like the brain, heart, and kidneys.

Aim

This publication reviews gut-liver-derived mediators, which were tested and validated in vivo in humans and rodents, together with the current knowledge of their systemic effects on key vital organs.

Method

Original articles published up to February 2025, based on clinical trials or in vivo experimental models, were retrieved from PubMed and Web of Science.

Results

During this systematic analysis, 28 gut-liver-derived mediators were identified from 52 publications and classified into five distinct groups based on their molecular characteristics: (a) low molecular weight metabolites, (b) endotoxins, (c) hormones, (d) lipids and (e) proteins. Additionally, the mechanism of action for each of these molecules was specified, aimed at providing a mechanistic overview of their effects on the brain, heart, and kidneys.

Discussion

The diverse and occasionally conflicting impact of the identified mediators on comorbidities necessitates further investigations pinpointing key mechanisms influencing disease genesis and progression.

Conclusion

Our research shows the necessity of a thorough examination of these mediators, exploring their diagnostic and therapeutic potential in a holistic multi-organ setting, to elucidate inter-organ crosstalk.

目前对重要器官之间的相互作用和串扰的理解仍然不完整，主要是由于对系统机制的研究有限。肠道和肝脏对整个身体的功能至关重要，它们衍生的介质通过血液或淋巴循环，影响其他器官，如大脑、心脏和肾脏。本出版物回顾了在人类和啮齿类动物体内进行测试和验证的肠道-肝脏来源的介质，以及它们对关键重要器官的系统性影响的最新知识。截至2025年2月发表的基于临床试验或体内实验模型的原创文章，从PubMed和Web of Science检索。在这项系统分析中，从52份出版物中鉴定出28种肠-肝源性介质，并根据其分子特征将其分为五组：(a)低分子量代谢物，(b)内毒素，(c)激素，(d)脂质和(e)蛋白质。此外，每种分子的作用机制都被指定，旨在提供它们对大脑、心脏和肾脏影响的机制概述。已确定的介质对合并症的影响多种多样，有时相互冲突，因此需要进一步研究确定影响疾病发生和进展的关键机制。我们的研究表明，有必要对这些介质进行彻底的检查，探索它们在整体多器官环境中的诊断和治疗潜力，以阐明器官间的串扰。

{"title":"The impact of gut-liver-derived mediators on the organ crosstalk with brain, heart, and kidney: A systematic review","authors":"Shruti Bhargava , Zhuangting Rao , Raymond Vanholder , Frank Tacke , Heidi Noels , Vera Jankowski , Juliane Hermann , Joachim Jankowski","doi":"10.1016/j.molmet.2025.102295","DOIUrl":"10.1016/j.molmet.2025.102295","url":null,"abstract":"<div><h3>Introduction</h3><div>The current understanding of interactions and crosstalk among essential organs remains incomplete, mainly due to the limitations of studies on the systemic mechanisms at play. The gut and the liver are essential for the functioning of the entire body, and their derived mediators circulate through blood or lymph, impacting other organs like the brain, heart, and kidneys.</div></div><div><h3>Aim</h3><div>This publication reviews gut-liver-derived mediators, which were tested and validated <em>in vivo</em> in humans and rodents, together with the current knowledge of their systemic effects on key vital organs.</div></div><div><h3>Method</h3><div>Original articles published up to February 2025, based on clinical trials or in vivo experimental models, were retrieved from PubMed and Web of Science.</div></div><div><h3>Results</h3><div>During this systematic analysis, 28 gut-liver-derived mediators were identified from 52 publications and classified into five distinct groups based on their molecular characteristics: (a) low molecular weight metabolites, (b) endotoxins, (c) hormones, (d) lipids and (e) proteins. Additionally, the mechanism of action for each of these molecules was specified, aimed at providing a mechanistic overview of their effects on the brain, heart, and kidneys.</div></div><div><h3>Discussion</h3><div>The diverse and occasionally conflicting impact of the identified mediators on comorbidities necessitates further investigations pinpointing key mechanisms influencing disease genesis and progression.</div></div><div><h3>Conclusion</h3><div>Our research shows the necessity of a thorough examination of these mediators, exploring their diagnostic and therapeutic potential in a holistic multi-organ setting, to elucidate inter-organ crosstalk.</div></div>","PeriodicalId":18765,"journal":{"name":"Molecular Metabolism","volume":"103 ","pages":"Article 102295"},"PeriodicalIF":6.6,"publicationDate":"2025-11-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145654711","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"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

Common and distinct roles of AMPKγ isoforms in small-molecule activator-stimulated glucose uptake in mouse skeletal muscle AMPKγ亚型在小鼠骨骼肌小分子激活剂刺激的葡萄糖摄取中的共同和独特作用。

IF 6.6 2区医学 Q1 ENDOCRINOLOGY & METABOLISM

Molecular Metabolism

Pub Date : 2025-11-29 DOI: 10.1016/j.molmet.2025.102294

Dipsikha Biswas , Ever Espino-Gonzalez , Danial Ahwazi , Jordana B. Freemantle , Amy M. Ehrlich , Charline Jomard , Jonas Brorson , Agnete N. Schou , Jean Farup , Julien Gondin , Jesper Just , Marc Foretz , Jonas T. Treebak , Marianne Agerholm , Kei Sakamoto

Objectives

Small-molecule activators targeting the allosteric drug and metabolite (ADaM) site of AMPK enhance insulin-independent glucose uptake in skeletal muscle and lower glucose in preclinical models of hyperglycemia. The regulatory AMPKγ subunit plays a central role in energy sensing. While the skeletal muscle-selective γ3 isoform is essential for AMP/ZMP-induced glucose uptake, it is dispensable for ADaM site-binding activators. We hypothesized that the predominant γ1 isoform is required for ADaM site activator-stimulated glucose uptake in skeletal muscle.

Methods

Single-nucleus RNA sequencing (snRNA-seq) was performed on mouse and human skeletal muscle mapping AMPK subunit isoform distribution across resident cell types. To determine γ isoform-specific requirements for activator-stimulated glucose uptake, skeletal muscle-specific inducible AMPKγ1/γ3 double knockout (imγ1^−/−/γ3^−/−) and single knockout (imγ1^−/− and imγ3^−/−) mice were generated. Ex vivo glucose uptake was measured following treatment with AICAR (AMP-mimetic) or MK-8722 (ADaM site activator), and in vivo MK-8722-induced blood glucose lowering was assessed.

Results

snRNA-seq revealed distinct AMPK isoform distribution: γ1 was ubiquitously expressed, whereas γ3 was enriched in glycolytic myofibers in both mouse and human skeletal muscle. Ex vivo, glucose uptake stimulated by either AICAR or MK-8722 was severely blunted in imγ1^−/−/γ3^−/− muscle, and MK-8722-induced blood glucose lowering was significantly blunted in vivo. AICAR but not MK-8722-stimulated muscle glucose uptake was abolished in imγ3^−/−, whereas both activators fully retained effects on glucose uptake and glucose lowering in imγ1^−/− mice.

Conclusions

While γ1 predominates in stabilizing the AMPKα2β2γ1 complex, it is dispensable for AMPK activator-stimulated glucose uptake in skeletal muscle, whether mediated via the nucleotide-binding or ADaM site.

目的：在临床前高血糖模型中，靶向AMPK变抗药和代谢物（ADaM）位点的小分子激活剂可增强骨骼肌胰岛素不依赖型葡萄糖摄取并降低血糖。调控AMPKγ亚基在能量传感中起核心作用。虽然骨骼肌选择性γ - 3异构体对于AMP/ zmp诱导的葡萄糖摄取是必不可少的，但对于ADaM位点结合激活剂来说是必不可少的。我们假设主要的γ - 1亚型是ADaM位点激活剂刺激的骨骼肌葡萄糖摄取所必需的。方法：对小鼠和人类骨骼肌进行单核RNA测序（snRNA-seq），绘制AMPK亚基亚型在各常驻细胞类型中的分布。为了确定激活剂刺激葡萄糖摄取的γ异构体特异性需求，我们制造了骨骼肌特异性诱导的AMPKγ1/γ3双敲除（imγ1-/-/γ3-/-）和单敲除（imγ1-/-和imγ3-/-）小鼠。在AICAR （AMP-mimetic）或MK-8722 （ADaM位点激活剂）治疗后测量体外葡萄糖摄取，并评估MK-8722诱导的体内血糖降低。结果：snRNA-seq显示AMPK在小鼠和人类骨骼肌中普遍表达γ - 1，而γ - 3在糖酵解肌纤维中富集。在体外，AICAR或MK-8722刺激的imγ - 1-/-/γ - 3-/-肌肉的葡萄糖摄取严重钝化，MK-8722诱导的血糖降低在体内明显钝化。在imγ - 3-/-小鼠中，AICAR刺激的肌肉葡萄糖摄取被消除，而mk -8722刺激的肌肉葡萄糖摄取未被消除，而这两种激活剂对imγ - 1-/-小鼠的葡萄糖摄取和葡萄糖降低作用完全保留。结论：虽然γ - 1在稳定AMPKα2β2γ1复合物中起主导作用，但无论是通过核苷酸结合位点还是通过ADaM位点介导，它对于AMPK激活剂刺激的骨骼肌葡萄糖摄取都是必不可少的。

{"title":"Common and distinct roles of AMPKγ isoforms in small-molecule activator-stimulated glucose uptake in mouse skeletal muscle","authors":"Dipsikha Biswas , Ever Espino-Gonzalez , Danial Ahwazi , Jordana B. Freemantle , Amy M. Ehrlich , Charline Jomard , Jonas Brorson , Agnete N. Schou , Jean Farup , Julien Gondin , Jesper Just , Marc Foretz , Jonas T. Treebak , Marianne Agerholm , Kei Sakamoto","doi":"10.1016/j.molmet.2025.102294","DOIUrl":"10.1016/j.molmet.2025.102294","url":null,"abstract":"<div><h3>Objectives</h3><div>Small-molecule activators targeting the allosteric drug and metabolite (ADaM) site of AMPK enhance insulin-independent glucose uptake in skeletal muscle and lower glucose in preclinical models of hyperglycemia. The regulatory AMPKγ subunit plays a central role in energy sensing. While the skeletal muscle-selective γ3 isoform is essential for AMP/ZMP-induced glucose uptake, it is dispensable for ADaM site-binding activators. We hypothesized that the predominant γ1 isoform is required for ADaM site activator-stimulated glucose uptake in skeletal muscle.</div></div><div><h3>Methods</h3><div>Single-nucleus RNA sequencing (snRNA-seq) was performed on mouse and human skeletal muscle mapping AMPK subunit isoform distribution across resident cell types. To determine γ isoform-specific requirements for activator-stimulated glucose uptake, skeletal muscle-specific inducible AMPKγ1/γ3 double knockout (imγ1<sup>−/−</sup>/γ3<sup>−/−</sup>) and single knockout (imγ1<sup>−/−</sup> and imγ3<sup>−/−</sup>) mice were generated<em>. Ex vivo</em> glucose uptake was measured following treatment with AICAR (AMP-mimetic) or MK-8722 (ADaM site activator), and <em>in vivo</em> MK-8722-induced blood glucose lowering was assessed.</div></div><div><h3>Results</h3><div>snRNA-seq revealed distinct AMPK isoform distribution: γ1 was ubiquitously expressed, whereas γ3 was enriched in glycolytic myofibers in both mouse and human skeletal muscle. <em>Ex vivo</em>, glucose uptake stimulated by either AICAR or MK-8722 was severely blunted in imγ1<sup>−/−</sup>/γ3<sup>−/−</sup> muscle, and MK-8722-induced blood glucose lowering was significantly blunted <em>in vivo</em>. AICAR but not MK-8722-stimulated muscle glucose uptake was abolished in imγ3<sup>−/−</sup>, whereas both activators fully retained effects on glucose uptake and glucose lowering in imγ1<sup>−/−</sup> mice.</div></div><div><h3>Conclusions</h3><div>While γ1 predominates in stabilizing the AMPKα2β2γ1 complex, it is dispensable for AMPK activator-stimulated glucose uptake in skeletal muscle, whether mediated via the nucleotide-binding or ADaM site.</div></div>","PeriodicalId":18765,"journal":{"name":"Molecular Metabolism","volume":"103 ","pages":"Article 102294"},"PeriodicalIF":6.6,"publicationDate":"2025-11-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145654769","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"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

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 : 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。

{"title":"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","authors":"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","doi":"10.1016/j.molmet.2025.102291","DOIUrl":"10.1016/j.molmet.2025.102291","url":null,"abstract":"<div><div>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.</div></div>","PeriodicalId":18765,"journal":{"name":"Molecular Metabolism","volume":"103 ","pages":"Article 102291"},"PeriodicalIF":6.6,"publicationDate":"2025-11-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145649092","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"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