Molecular Metabolism最新文献

{"title":"Sustained diabetes remission induced by FGF1 involves a shift in transcriptionally distinct AgRP neuron subpopulations","authors":"Nadia N. Aalling ,&nbsp;Petar V. Todorov ,&nbsp;Shad Hassan ,&nbsp;Dylan M. Belmont-Rausch ,&nbsp;Oliver Pugerup Christensen ,&nbsp;Claes Ottzen Laurentiussen ,&nbsp;Anja M. Jørgensen ,&nbsp;Kimberly M. Alonge ,&nbsp;Jarrad M. Scarlett ,&nbsp;Zaman Mirzadeh ,&nbsp;Jenny M. Brown ,&nbsp;Michael W. Schwartz ,&nbsp;Tune H. Pers","doi":"10.1016/j.molmet.2025.102300","DOIUrl":"10.1016/j.molmet.2025.102300","url":null,"abstract":"<div><div>In rodent models of type 2 diabetes, a single intracerebroventricular (icv) injection of fibroblast growth factor 1 (FGF1) induces sustained remission of hyperglycemia. Overactive agouti-related peptide (AgRP) neurons, located in the hypothalamic arcuate nucleus, are a hallmark of diabetic states, and their long-term inhibition has been linked to FGF1's antidiabetic effects. To investigate the underlying mechanism(s), we performed single-nucleus RNA sequencing of the mediobasal hypothalamus at Days 5 and 14 post-injection in wild-type and diabetic (Lep^{<em>ob/ob</em>}) mice treated with FGF1 or vehicle. We found that AgRP neurons from Lep^{<em>ob/ob</em>} mice form a transcriptionally distinct, hyperactive subpopulation. By Day 5, icv FGF1 induced a subset of these neurons to shift toward a less active, wild-type-like state, characterized by reduced activity-linked gene expression that persisted through Day 14. Spatial transcriptomics revealed that this FGF1-responsive AgRP subset is positioned dorsally within the arcuate nucleus. The transcriptional shift was accompanied by transcriptional processes indicative of increased GABAergic signaling, axonogenesis, and astrocyte–AgRP and oligodendrocyte–AgRP interactions. These glial inputs involve astrocytic neurexins and the perineuronal net (PNN) component phosphacan, suggesting both intrinsic and extrinsic mechanisms underlie FGF1-induced AgRP silencing. Combined with evidence that FGF1 increases PNN assembly in the arcuate nucleus, our findings reveal a cell-type–specific model for how FGF1 elicits long-term reprogramming of hypothalamic circuits to achieve diabetes remission.</div></div>","PeriodicalId":18765,"journal":{"name":"Molecular Metabolism","volume":"103 ","pages":"Article 102300"},"PeriodicalIF":6.6,"publicationDate":"2026-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145724524","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}

{"title":"Corrigendum to “Transient juvenile hypoglycemia in GH insensitive Laron syndrome pigs is associated with insulin hypersensitivity” [Mol Metabol (2025) 102273]","authors":"Arne Hinrichs ,&nbsp;Kalliopi Pafili ,&nbsp;Gencer Sancar ,&nbsp;Laeticia Laane ,&nbsp;Silja Zettler ,&nbsp;Malek Torgeman ,&nbsp;Barbara Kessler ,&nbsp;Judith Leonie Nono ,&nbsp;Sonja Kunz ,&nbsp;Birgit Rathkolb ,&nbsp;Cristina Barosa ,&nbsp;Cornelia Prehn ,&nbsp;Alexander Cecil ,&nbsp;Simone Renner ,&nbsp;Elisabeth Kemter ,&nbsp;Sabine Kahl ,&nbsp;Julia Szendroedi ,&nbsp;Martin Bidlingmaier ,&nbsp;John Griffith Jones ,&nbsp;Martin Hrabĕ de Angelis ,&nbsp;Eckhard Wolf","doi":"10.1016/j.molmet.2025.102286","DOIUrl":"10.1016/j.molmet.2025.102286","url":null,"abstract":"","PeriodicalId":18765,"journal":{"name":"Molecular Metabolism","volume":"103 ","pages":"Article 102286"},"PeriodicalIF":6.6,"publicationDate":"2026-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145596811","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}

{"title":"Multi-omics atlas of ovarian cellular and molecular responses to diabetes","authors":"Zheng-Hui Zhao ,&nbsp;Xue-Ying Chen ,&nbsp;Cheng-Yan Zhuo,&nbsp;Xiang-Hong Ou,&nbsp;Qing-Yuan Sun","doi":"10.1016/j.molmet.2025.102307","DOIUrl":"10.1016/j.molmet.2025.102307","url":null,"abstract":"<div><div>Diabetes is associated with compromised reproductive health; however, the cellular and molecular mechanisms underlying its impact on ovarian function remain largely unclear. In this study, we integrated single-cell RNA sequencing, DNA methylation profiling, and metabolomic analyses to comprehensively characterize the ovarian cellular landscape, epigenetic alterations, and metabolic reprogramming in diabetic female mice, with a focus on identifying diabetes-induced changes in ovarian cells. Our cell type-specific transcriptomic analysis revealed that dysregulated steroid hormone biosynthesis and impaired fatty acid metabolism are prominent features of diabetic ovarian dysfunction. Notably, key genes including <em>Cyp11a1</em>, <em>Fshr</em>, and <em>Lhcgr</em> exhibited reduced expression accompanied by increased DNA methylation levels in their gene regions within granulosa cells under diabetic conditions. Furthermore, disrupted granulosa cell differentiation was evident, leading to aberrant luteal cell formation and compromised luteal function. In parallel, metabolomic profiling revealed profound metabolic reprogramming in diabetic ovaries, with significant alterations in lipid metabolism pathways, including elevated unsaturated fatty acid and reduced glycerophospholipid metabolism. Taken together, these findings provide novel insights into the molecular pathways underlying ovarian dysfunction in the context of diabetes, thereby enhancing our understanding of folliculogenesis in metabolic disorders.</div></div>","PeriodicalId":18765,"journal":{"name":"Molecular Metabolism","volume":"103 ","pages":"Article 102307"},"PeriodicalIF":6.6,"publicationDate":"2026-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145763324","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}

{"title":"The transcription factor CUX1 exerts opposing roles in human and mouse adipocyte differentiation","authors":"Yang Chen ,&nbsp;Lin Liu ,&nbsp;Ryan P. Calhoun ,&nbsp;Lan Cheng ,&nbsp;David Steger ,&nbsp;Patrick Seale","doi":"10.1016/j.molmet.2025.102290","DOIUrl":"10.1016/j.molmet.2025.102290","url":null,"abstract":"<div><h3>Objective</h3><div>Adipocyte differentiation is critical for the metabolically protective expansion of adipose tissue. Impaired differentiation drives lipodystrophy and pathologic tissue remodeling, major contributors to cardiometabolic diseases. The differentiation process is governed by master transcription factors, including the pioneer factor C/EBPβ, which initiates the adipogenic program. Here, we sought to identify novel C/EBPβ-associated factors that regulate human adipocyte differentiation.</div></div><div><h3>Methods</h3><div>We used chromatin immunoprecipitation followed by selective isolation of chromatin-associated proteins (ChIP-SICAP) to identify proteins that interact with C/EBPβ on chromatin during human adipocyte differentiation. Candidate factors were assessed for their effects on differentiation, through conducting a CRISPR/Cas9-based knockout screen in human adipocyte precursor cells (hAPCs). The transcription factor CUX1 emerged as a top candidate. We performed gain- and loss-of-function studies in primary human and mouse adipocyte differentiation models, coupled with RNA-seq and ChIP-seq, to define CUX1-regulated genes and pathways. <em>In vivo</em> relevance was tested using adipocyte precursor–selective <em>Cux1</em> knockout and lineage reporter mice.</div></div><div><h3>Results</h3><div>Loss of CUX1 impaired, whereas its overexpression enhanced, adipocyte differentiation in hAPCs. RNA-seq and ChIP-seq analyses revealed that CUX1 promotes the expression of key adipogenic genes, including <em>PPARG</em> in hAPCs. By contrast, CUX1 exerted the opposite effect in mouse adipocyte differentiation. <em>Cux1</em> deletion enhanced, while CUX1 overexpression suppressed, differentiation in mouse APCs (mAPCs). CUX1 exhibited distinct chromatin-binding patterns and motif enrichment profiles in mouse versus human cells. <em>In vivo</em>, <em>Cux1</em> deletion in APCs of mice increased <em>de novo</em> adipocyte formation during early stages of obesity development.</div></div><div><h3>Conclusions</h3><div>The transcription factor CUX1 regulates adipocyte differentiation in opposite directions in humans and mice, emphasizing the need for species-specific models in metabolic disease research,</div></div>","PeriodicalId":18765,"journal":{"name":"Molecular Metabolism","volume":"103 ","pages":"Article 102290"},"PeriodicalIF":6.6,"publicationDate":"2026-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145636144","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}

{"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 ,&nbsp;Ruben Rodriguez ,&nbsp;Anne Hergarden ,&nbsp;Michael A. Elliott ,&nbsp;Juan P. Frias ,&nbsp;Federico A. Argüelles-Tello ,&nbsp;Edgar Tenorio ,&nbsp;Jonathan E. Rankin ,&nbsp;Jingtao Wu ,&nbsp;Shyam Krishnan ,&nbsp;Daniel A. Erlanson ,&nbsp;Raymond V. Fucini ,&nbsp;Derek Bone ,&nbsp;Jeffrey S. Iwig ,&nbsp;Luis Acosta ,&nbsp;Ashley Untereiner ,&nbsp;Asmita Pant ,&nbsp;Avalon Patton ,&nbsp;Leyla L. Sanchez-Sanchez ,&nbsp;Jian Luo ,&nbsp;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":"2026-01-01","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}

{"title":"Increased TGF-β/Activin-Smad2 signaling is associated with pancreatic β-cell dysfunction and glucose intolerance in gestational diabetes mellitus","authors":"Talía Boronat-Belda ,&nbsp;Hilda Ferrero ,&nbsp;Sergi Soriano ,&nbsp;Elena Ribes-García ,&nbsp;Rubén Betoret-Gustems ,&nbsp;Daniel Martínez-Bañón ,&nbsp;Mónica Serrano-Selva ,&nbsp;Juan Martínez-Pinna ,&nbsp;Ángel Nadal ,&nbsp;Iván Quesada ,&nbsp;Paloma Alonso-Magdalena","doi":"10.1016/j.molmet.2025.102274","DOIUrl":"10.1016/j.molmet.2025.102274","url":null,"abstract":"<div><h3>Background</h3><div>Gestational diabetes mellitus (GDM) is the most common metabolic disease during pregnancy and increases the prevalence of type 2 diabetes in both mothers and children. GDM management provides an opportunity to prevent and lower the global burden of diabetes across life. Molecular mechanisms underlying GDM are not completely understood. In this study, we explore the role of transforming growth factor beta (TGF-β) signaling in GDM, as this pathway reportedly affects pancreatic β-cell development, function, and proliferation.</div></div><div><h3>Methods</h3><div>We developed a GDM animal model. Serum circulating levels of TGF-β family ligands were measured in mice and human GDM. Pancreatic TGF-β signaling was investigated via gene and protein expression.</div></div><div><h3>Results</h3><div>Our GDM animal model recapitulates the main pathophysiological features of human GDM, including glucose intolerance, decreased insulin sensitivity and pancreatic β-cell malfunction. Islets from GDM mice showed impaired insulin secretion and content, altered ion channel activity, and decreased β-cell replication rate. This was accompanied by increased Smad2 signaling activation. Elevated serum activin-A and inhibin levels were found in mice and human GDM, suggesting their role as upstream signaling transducers of pancreatic Smad2 activation. Pharmacological inhibition of TGF-β/Activin-Smad2 signaling in mouse pancreatic islets resulted in improved pancreatic β-cell function and regeneration capacity.</div></div><div><h3>Conclusions</h3><div>Our data suggest that disruption of the pancreatic Smad2 pathway plays a critical role in the pathogenesis of GDM, contributing to abnormal glucose homeostasis and inadequate insulin secretion. Attenuation of this signaling pathway may represent a putative therapeutic target for GDM.</div></div>","PeriodicalId":18765,"journal":{"name":"Molecular Metabolism","volume":"103 ","pages":"Article 102274"},"PeriodicalIF":6.6,"publicationDate":"2026-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145337345","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}

{"title":"Transient juvenile hypoglycemia in GH insensitive Laron syndrome pigs is associated with insulin hypersensitivity","authors":"Arne Hinrichs ,&nbsp;Kalliopi Pafili ,&nbsp;Gencer Sancar ,&nbsp;Laeticia Laane ,&nbsp;Silja Zettler ,&nbsp;Malek Torgeman ,&nbsp;Barbara Kessler ,&nbsp;Judith Leonie Nono ,&nbsp;Sonja Kunz ,&nbsp;Birgit Rathkolb ,&nbsp;Cristina Barosa ,&nbsp;Cornelia Prehn ,&nbsp;Alexander Cecil ,&nbsp;Simone Renner ,&nbsp;Elisabeth Kemter ,&nbsp;Sabine Kahl ,&nbsp;Julia Szendroedi ,&nbsp;Martin Bidlingmaier ,&nbsp;John Griffith Jones ,&nbsp;Martin Hrabĕ de Angelis ,&nbsp;Eckhard Wolf","doi":"10.1016/j.molmet.2025.102273","DOIUrl":"10.1016/j.molmet.2025.102273","url":null,"abstract":"<div><h3>Background and aims</h3><div>Fasting hypoglycemia has clinical implications for children with growth hormone (GH)-insensitivity syndrome. This study investigates the pathophysiology of juvenile hypoglycemia in a large animal model for GH receptor (GHR) deficiency (the <em>GHR</em>-KO pig) and elucidates mechanisms underlying the transition to normoglycemia in adulthood.</div></div><div><h3>Methods</h3><div>Insulin sensitivity was assessed in juvenile and adult <em>GHR</em>-KO pigs and wild-type (WT) controls via hyperinsulinemic-euglycemic clamp (HEC) tests. Glucose turnover was measured using D-[6,6-²H₂] glucose and ²H₂O. Clinical chemical and targeted metabolomics parameters in blood serum were correlated with qPCR and western blot analyses of liver and adipose tissue.</div></div><div><h3>Results</h3><div><em>GHR</em>-KO pigs showed increased insulin sensitivity (p = 0.0019), especially at young age (M-value +34% vs. WT), insignificantly reduced insulin levels, and reduced endogenous glucose production (p = 0.0007), leading to fasting hypoglycemia with depleted liver glycogen, elevated β-hydroxybutyrate, but no increase in NEFA levels. Low hormone-sensitive lipase phosphorylation in adipose tissue suggested impaired lipolysis in young <em>GHR</em>-KO pigs. Metabolomics indicated enhanced fatty acid beta-oxidation and use of glucogenic amino acids, likely serving as compensatory pathways to maintain energy homeostasis. In adulthood, insulin sensitivity remained elevated but less pronounced (M-value +20%), while insulin levels were significantly reduced, enabling normoglycemia and improved NEFA availability. Increased fat mass, but not sex hormones, appeared key to this metabolic transition, as early castration had no effect.</div></div><div><h3>Conclusions</h3><div>Juvenile hypoglycemia in GH insensitivity results from excessive insulin sensitivity, reduced glucose production, and impaired lipolysis. Normoglycemia in adulthood emerges through increased adiposity and moderated insulin sensitivity, independently of sex hormones. These findings elucidate the age-dependent metabolic adaptations in GH insensitivity.</div></div>","PeriodicalId":18765,"journal":{"name":"Molecular Metabolism","volume":"103 ","pages":"Article 102273"},"PeriodicalIF":6.6,"publicationDate":"2026-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145346213","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}

{"title":"Corrigendum to “Insulin receptor-mediated signaling regulates pluripotency markers and lineage differentiation” [Mol Metab 18 (2018) 153–163]","authors":"Manoj K. Gupta ,&nbsp;Dario F. De Jesus ,&nbsp;Sevim Kahraman ,&nbsp;Ivan A. Valdez ,&nbsp;Farnaz Shamsi ,&nbsp;Lian Yi ,&nbsp;Adam C. Swensen ,&nbsp;Yu-Hua Tseng ,&nbsp;Wei-Jun Qian ,&nbsp;Rohit N. Kulkarni","doi":"10.1016/j.molmet.2025.102285","DOIUrl":"10.1016/j.molmet.2025.102285","url":null,"abstract":"","PeriodicalId":18765,"journal":{"name":"Molecular Metabolism","volume":"103 ","pages":"Article 102285"},"PeriodicalIF":6.6,"publicationDate":"2026-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145596873","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}

{"title":"Loss of GLP-2R signaling in Glp2r−/− mice increases the long-term severity of graft versus host disease","authors":"Bernardo Yusta,&nbsp;Chi Kin Wong,&nbsp;Dianne Matthews,&nbsp;Jacqueline A. Koehler,&nbsp;Laurie L. Baggio,&nbsp;Daniel J. Drucker","doi":"10.1016/j.molmet.2025.102311","DOIUrl":"10.1016/j.molmet.2025.102311","url":null,"abstract":"<div><h3>Background</h3><div>Glucagon-like peptide-2 (GLP-2) reduces systemic and gut inflammation while preserving mucosal integrity. Preclinical and clinical reports implicate GLP-2 receptor (GLP-2R) agonism as a potential therapy for graft vs. host disease (GvHD).</div></div><div><h3>Methods</h3><div>Here we assessed whether enhanced vs. loss of GLP-2R signaling modifies gut injury and inflammation in experimental murine acute GvHD (aGvHD). Allogeneic hematopoietic cell transplantation (HCT) was performed using bone marrow and splenocytes from BALB/cJ donor mice to induce aGvHD in C57BL/6J recipients. Chimerism was determined by flow cytometry of immune cell compartments. Inflammation was assessed by measuring circulating cytokines and histological scoring of gut mucosal damage. GLP-2 responsivity was assessed using histology and gene expression analyses. The gut microbiome was assessed by 16S rRNA sequencing.</div></div><div><h3>Results</h3><div>Allogeneic chimerism was &gt;90% in peripheral blood and in the gut epithelial compartment. Gut GLP-2R signaling was preserved following allogeneic bone marrow transplantation. Surprisingly, GLP-2R agonism using teduglutide did not reduce circulating cytokines, gut injury, immune cell infiltration or the severity of aGvHD. In contrast, transplant recipient <em>Glp2r</em>^−/− mice exhibited reduced survival, associated with increased bacteremia. Shifts in microbial species abundance with gain or loss of GLP-2R signaling were not correlated with aGvHD clinical outcomes.</div></div><div><h3>Conclusions</h3><div>Activation of GLP-2R signaling did not reduce the severity of experimental aGvHD, failing to replicate a previous study using an identical aGvHD protocol. Nevertheless, loss of GLP-2R signaling in transplant recipients decreased survival and increased bacteremia, implicating an essential role for endogenous GLP-2R signaling in maintaining barrier function in the context of immune-mediated gut epithelial injury.</div></div>","PeriodicalId":18765,"journal":{"name":"Molecular Metabolism","volume":"103 ","pages":"Article 102311"},"PeriodicalIF":6.6,"publicationDate":"2026-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145794410","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}

{"title":"Protective role of soluble CD52 in obesity-associated steatotic liver disease and glucose dysregulation in mice","authors":"Yuichiro Miyazawa ,&nbsp;Tsutomu Wada ,&nbsp;Yuichi Iwasa ,&nbsp;Kento Fuse ,&nbsp;Hisafumi Shioneri ,&nbsp;Yasuhiro Onogi ,&nbsp;Azusa Sameshima ,&nbsp;Tomoyuki Yoshida ,&nbsp;Ichiro Takasaki ,&nbsp;Hisashi Mori ,&nbsp;Keiichi Koizumi ,&nbsp;Hiroshi Tsuneki ,&nbsp;Shigeru Saito ,&nbsp;Toshiyasu Sasaoka","doi":"10.1016/j.molmet.2025.102279","DOIUrl":"10.1016/j.molmet.2025.102279","url":null,"abstract":"<div><h3>Objectives</h3><div>Soluble CD52 (sCD52) derived from activated CD4⁺ T cells regulates T cell immunity under autoimmune conditions; however, its role in obesity-associated chronic inflammation and glucose metabolism remains unclear. Therefore, we herein investigated the significance of CD52 in obesity.</div></div><div><h3>Methods</h3><div>CD52-knockout mice (KO) and their wild-type littermates were fed a high-fat diet (HFD) for 12 weeks and analyzed.</div></div><div><h3>Results</h3><div>sCD52 preferentially suppressed chronic liver inflammation and protected against impaired glucose tolerance and metabolic dysfunction-associated steatotic liver disease (MASLD) in obesity. No significant differences were observed in weight gain or energy metabolism in KO mice; however, glucose metabolism was impaired. A histological examination revealed more severe chronic inflammation and steatosis in KO mice, accompanied by changes in liver transcriptome profiles, but no significant differences in epididymal white adipose tissue (eWAT). In contrast, CD52 expression was significantly up-regulated in eWAT, with slightly higher levels in the liver and skeletal muscle in HFD-fed obese C57BL/6 mice than in chow-fed controls. sCD52 was released from the cultured eWAT of obese mice, but not lean mice, and circulating sCD52 levels were higher in obese mice. A re-analysis of a public single-nucleus RNA sequencing library revealed that increased CD52 in eWAT was linked to immune cells and adipocytes. T cell-derived purified sCD52 suppressed macrophage activation <em>in vitro</em>. In contrast, sCD52 was not secreted from 3T3-L1 adipocytes, although its protein levels increased with differentiation.</div></div><div><h3>Conclusions</h3><div>T cell-derived sCD52 mitigates the obesity-associated development of MASLD and glucose intolerance in mice.</div></div>","PeriodicalId":18765,"journal":{"name":"Molecular Metabolism","volume":"103 ","pages":"Article 102279"},"PeriodicalIF":6.6,"publicationDate":"2026-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145458837","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}