Molecular Metabolism最新文献

{"title":"Adipocyte heparan sulfate determines type 2 diabetes susceptibility in mice via FGF1-Mediated glucose regulation","authors":"Chung-Jui Yu ,&nbsp;Ariane R. Pessentheiner ,&nbsp;Sihao Liu ,&nbsp;Sarah Wax ,&nbsp;Marissa L. Maciej-Hulme ,&nbsp;Chelsea D. Painter ,&nbsp;Bastian Ramms ,&nbsp;Daniel R. Sandoval ,&nbsp;Anthony Quach ,&nbsp;Natalie DeForest ,&nbsp;G. Michelle Ducasa ,&nbsp;Chiara Tognaccini ,&nbsp;Caroline Labib ,&nbsp;Norah Al-Azzam ,&nbsp;Friederike Haumann ,&nbsp;Greg Trieger ,&nbsp;Patrick Secrest ,&nbsp;Amit Majithia ,&nbsp;Aaron C. Petrey ,&nbsp;Kamil Godula ,&nbsp;Philip L.S.M. Gordts","doi":"10.1016/j.molmet.2025.102267","DOIUrl":"10.1016/j.molmet.2025.102267","url":null,"abstract":"<div><div>Obesity is the principal driver of insulin resistance, and lipodystrophy is also linked with insulin resistance, emphasizing the vital role of adipose tissue in glucose homeostasis. The quality of adipose tissue expansion is a critical determinant of insulin resistance predisposition, with individuals suffering from metabolic unhealthy adipose expansion exhibiting greater risk. Adipocytes are pivotal in orchestrating metabolic adjustments in response to nutrient intake and cell intrinsic factors that positively regulate these adjustments are key to prevent Type-2 diabetes. Employing unique genetic mouse models, we established the critical involvement of heparan sulfate (HS), a fundamental element of the adipocyte glycocalyx, in upholding glucose homeostasis during dietary stress. Genetic models that compromise adipocyte HS accelerate the development of high-fat diet-induced hyperglycemia and insulin resistance, independent of weight gain. Mechanistically, we show that perturbations in adipocyte HS disrupts endogenous FGF1 signaling, a key nutrient-sensitive effector. Furthermore, compromising adipocyte HS composition detrimentally impacts FGF1-FGFR1-mediated endocrinization, with no significant improvement observed in glucose homeostasis. Our data establish adipocyte HS composition as a determinant of Type 2 diabetes susceptibility and the critical dependency of the endogenous adipocyte FGF1 metabolic pathway on HS.</div></div>","PeriodicalId":18765,"journal":{"name":"Molecular Metabolism","volume":"102 ","pages":"Article 102267"},"PeriodicalIF":6.6,"publicationDate":"2025-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145275255","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":"Comparative transcriptomics of lateral hypothalamic cell types reveals conserved growth hormone-tachykinin dynamics in feeding","authors":"Vindhya Chaganty ,&nbsp;Ruey-Kuang Cheng ,&nbsp;Kimberle Shen ,&nbsp;Na Zhang ,&nbsp;Gaynah Javier Doblado ,&nbsp;Sarah Ong ,&nbsp;Sandra Tan ,&nbsp;Valarie Yu Yan Tham ,&nbsp;Jung-Hwa Choi ,&nbsp;Marnie E. Halpern ,&nbsp;Wei Leong Chew ,&nbsp;Anand Kumar Andiappan ,&nbsp;Sarah Xinwei Luo ,&nbsp;Caroline Lei Wee","doi":"10.1016/j.molmet.2025.102251","DOIUrl":"10.1016/j.molmet.2025.102251","url":null,"abstract":"<div><h3>Objectives</h3><div>The lateral hypothalamus (LH) plays a central role in appetite control, however the functional and evolutionary conservation of its subcircuits remain unclear. This study aimed to define the molecular and cellular identities of zebrafish LH neurons, identify conserved LH cell types across vertebrates, and investigate their roles in appetite regulation.</div></div><div><h3>Methods</h3><div>We performed the Act-seq method of single-cell RNA sequencing in the larval zebrafish LH under food-deprived and voracious feeding states to capture activity-dependent transcriptional signatures. Using integrative comparative transcriptomics, we aligned zebrafish neuronal clusters with a published mouse LH dataset to identify conserved neuronal sub-populations, and performed functional and molecular characterisation of a highly-conserved cell type in both zebrafish and mice.</div></div><div><h3>Results</h3><div>We identified several LH neuronal subtypes in zebrafish that are differentially activated during voracious feeding. Cross-species mapping revealed overlapping cellular clusters, especially for GABAergic neurons. We report a conserved GABAergic cluster co-expressing growth hormone (GH) receptors and tachykinin. In both species, feeding activates these neurons and elevates GH receptor and tachykinin expression. In zebrafish, upstream GH signaling is similarly regulated by feeding state, and acute GH administration both activates this cluster and enhances food intake.</div></div><div><h3>Conclusions</h3><div>These findings uncover a conserved GH receptor-tachykinin LH population which may link metabolic hormone signaling to appetite control. Beyond its established long-term roles in growth and metabolism, we propose that GH exerts acute appetite-enhancing effects through activation of this neuronal pathway. Our comparative LH atlas highlights the evolutionary biology of hypothalamic appetite circuits.</div></div>","PeriodicalId":18765,"journal":{"name":"Molecular Metabolism","volume":"102 ","pages":"Article 102251"},"PeriodicalIF":6.6,"publicationDate":"2025-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145065109","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":"Reframing metformin as a gut-targeted glucose-lowering therapy: Mechanistic insights and translational relevance","authors":"Tongzhi Wu ,&nbsp;Michael Horowitz ,&nbsp;Karen L. Jones ,&nbsp;Christopher K. Rayner","doi":"10.1016/j.molmet.2025.102276","DOIUrl":"10.1016/j.molmet.2025.102276","url":null,"abstract":"","PeriodicalId":18765,"journal":{"name":"Molecular Metabolism","volume":"102 ","pages":"Article 102276"},"PeriodicalIF":6.6,"publicationDate":"2025-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145458891","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 diet-derived gut microbial metabolite 3-phenylpropionic acid reverses insulin resistance and obesity-associated metabolic dysfunction","authors":"Sara Alqudah ,&nbsp;Beckey DeLucia ,&nbsp;Lucas J. Osborn ,&nbsp;Rachel L. Markley ,&nbsp;Viharika Bobba ,&nbsp;Sarah M. Preston ,&nbsp;Tharika Thambidurai ,&nbsp;Layan Hamidi Nia ,&nbsp;Clifton G. Fulmer ,&nbsp;Naseer Sangwan ,&nbsp;Ina Nemet ,&nbsp;Jan Claesen","doi":"10.1016/j.molmet.2025.102272","DOIUrl":"10.1016/j.molmet.2025.102272","url":null,"abstract":"<div><h3>Background/Purpose</h3><div>Obesity-associated metabolic disorders, including type 2 diabetes and metabolic dysfunction associated fatty liver disease (MAFLD), are major global health burdens. While dietary polyphenols have shown promise in ameliorating these conditions, their efficacy is dependent on specialized gut microbial metabolism, and the underlying molecular mechanisms remain mostly elusive. Here, we demonstrate that dietary supplementation with polyphenol-rich elderberry (Eld) extract abrogates the effects of an obesogenic diet in a gut microbiota-dependent manner, preventing insulin resistance and reducing hepatic steatosis in mice.</div></div><div><h3>Methods</h3><div>We developed a targeted, quantitative liquid chromatography-tandem mass spectrometry method for detection of gut bacterial polyphenol catabolites and identified 3-phenylpropionic acid as a key microbial metabolite in the portal plasma of Eld supplemented animals.</div></div><div><h3>Results</h3><div>We showed that 3-phenylpropionic acid potently activates hepatic AMP-activated protein kinase α, explaining its role in improved liver lipid homeostasis. We further uncovered the metabolic pathway cumulating in 3-phenylpropionic acid for the common gut commensal <em>Clostridium sporogenes</em>.</div></div><div><h3>Conclusion</h3><div>Our findings establish 3-phenylpropionic acid as a diet-derived, microbiota-dependent metabolite with insulin-sensitizing and anti-steatotic activities and provide a molecular basis for prebiotic interventions to improve host metabolic health.</div></div>","PeriodicalId":18765,"journal":{"name":"Molecular Metabolism","volume":"102 ","pages":"Article 102272"},"PeriodicalIF":6.6,"publicationDate":"2025-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145329570","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":"KAT6A acetylation regulates AMPK function and hypertrophic remodeling in the heart","authors":"Mariko Aoyagi Keller ,&nbsp;Andreas Ivessa ,&nbsp;Tong Liu ,&nbsp;Hong Li ,&nbsp;Peter J. Romanienko ,&nbsp;Michinari Nakamura","doi":"10.1016/j.molmet.2025.102239","DOIUrl":"10.1016/j.molmet.2025.102239","url":null,"abstract":"<div><div>Diets influence metabolism and disease susceptibility, with lysine acetyltransferases (KATs) serving as key regulators through acetyl-CoA. We have previously demonstrated that a ketogenic diet alleviates cardiac pathology, though the underlying mechanisms remain largely unknown. Here we show that KAT6A acetylation is crucial for mitochondrial function and cell growth. Proteomic analysis revealed that KAT6A is acetylated at lysine (K)816 in the hearts of mice fed a ketogenic diet under hypertension, which enhances its interaction with AMPK regulatory subunits. RNA-sequencing analysis demonstrated that the KAT6A acetylation-mimetic mutant stimulates AMPK signaling in cardiomyocytes. Moreover, the acetylation-mimetic mutant mitigated phenylephrine-induced mitochondrial dysfunction and cardiomyocyte hypertrophy via AMPK activation. However, KAT6A-K816R acetylation-resistant knock-in mice unexpectedly exhibited smaller hearts with enhanced AMPK activity, conferring protection against neurohumoral stress-induced cardiac hypertrophy and remodeling. These findings indicate that KAT6A regulates metabolism and cellular growth by interacting with and modulating AMPK activity through K816-acetylation in a cell type-specific manner.</div></div>","PeriodicalId":18765,"journal":{"name":"Molecular Metabolism","volume":"101 ","pages":"Article 102239"},"PeriodicalIF":6.6,"publicationDate":"2025-11-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144961656","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":"Dietary isoleucine content modulates the metabolic and molecular response to a Western diet in mice","authors":"Michaela E. Trautman ,&nbsp;Cara L. Green ,&nbsp;Michael R. MacArthur ,&nbsp;Krittisak Chaiyakul ,&nbsp;Yasmine H. Alam ,&nbsp;Chung-Yang Yeh ,&nbsp;Reji Babygirija ,&nbsp;Isabella James ,&nbsp;Michael Gilpin ,&nbsp;Esther Zelenovskiy ,&nbsp;Madelyn Green ,&nbsp;Ryan N. Marshall ,&nbsp;Alexander Raskin ,&nbsp;Michelle M. Sonsalla ,&nbsp;Victoria Flores ,&nbsp;Judith A. Simcox ,&nbsp;Irene M. Ong ,&nbsp;Kristen C. Malecki ,&nbsp;Cholsoon Jang ,&nbsp;Dudley W. Lamming","doi":"10.1016/j.molmet.2025.102248","DOIUrl":"10.1016/j.molmet.2025.102248","url":null,"abstract":"<div><div>The amino acid composition of the diet has recently emerged as a critical regulator of metabolic health. Consumption of the branched-chain amino acid isoleucine is positively correlated with body mass index in humans, and reducing dietary levels of isoleucine rapidly improves the metabolic health of diet-induced obese male C57BL/6J mice. However, there are some reports that dietary supplementation with extra BCAAs has health benefits. Further, the interactions between sex, genetic background, and dietary isoleucine levels in response to a Western Diet (WD) remain incompletely understood. Here, we find that although the magnitude of the effect varies by sex and strain, reducing dietary levels of isoleucine protects C57BL/6J and DBA/2J mice of both sexes from the deleterious metabolic effects of a WD, while increasing dietary levels of isoleucine impairs aspects of metabolic health. Despite broadly positive responses across all sexes and strains to reduced isoleucine, the molecular response of each sex and strain is highly distinctive. Using a multi-omics approach, we identify a core sex- and strain-independent molecular response to dietary isoleucine, and identify mega-clusters of differentially expressed hepatic genes, metabolites, and lipids associated with each phenotype. Intriguingly, the metabolic effects of reduced isoleucine in mice are not associated with FGF21 – and we find that in humans, plasma FGF21 levels are likewise not associated with dietary levels of isoleucine. Finally, an analysis of human NHANES data shows that isoleucine content varies widely across foods, and that individuals with higher Healthy Eating Index scores tend to consume lower amounts of isoleucine. Our results suggest that the dietary level of isoleucine is a potential mediator of the metabolic and molecular response to a WD, and imply that reducing dietary isoleucine may represent a theoretically translatable strategy to protect from the negative metabolic consequences of a WD.</div></div>","PeriodicalId":18765,"journal":{"name":"Molecular Metabolism","volume":"101 ","pages":"Article 102248"},"PeriodicalIF":6.6,"publicationDate":"2025-11-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145054381","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":"Pde5a deficiency prevents diet-induced obesity via adipose cAMP-PKA activation enhancing fat browning","authors":"Federica Campolo ,&nbsp;Ottavia Giampaoli ,&nbsp;Federica Barbagallo ,&nbsp;Biagio Palmisano ,&nbsp;Anna Di Maio ,&nbsp;Francesca Sciarra ,&nbsp;Flavio Rizzo ,&nbsp;Serena Monti ,&nbsp;Sandra Albanese ,&nbsp;Silvia Cardarelli ,&nbsp;Maria Rita Assenza ,&nbsp;Eleonora Poggiogalle ,&nbsp;Adriano Patriarca ,&nbsp;Fabio Sciubba ,&nbsp;Antonio Filippini ,&nbsp;Andrea Lenzi ,&nbsp;Daniele Gianfrilli ,&nbsp;Mauro Giorgi ,&nbsp;Susanna Dolci ,&nbsp;Fabio Naro ,&nbsp;Andrea M. Isidori","doi":"10.1016/j.molmet.2025.102243","DOIUrl":"10.1016/j.molmet.2025.102243","url":null,"abstract":"<div><h3>Objective</h3><div>Cyclic nucleotides are central regulators of adipogenesis and adaptive thermogenesis, with their intracellular concentrations tightly controlled by phosphodiesterases (PDEs). Among them, phosphodiesterase type 5 (PDE5A) regulates cyclic guanosine monophosphate (cGMP) turnover in adipocytes. Although PDE5A inhibition has been explored in diabetes, its role in systemic metabolism remains poorly defined.</div></div><div><h3>Methods</h3><div>We employed different <em>Pde5a</em> knockout mouse models to investigate the impact of PDE5A deficiency on adipose tissue biology and whole-body energy homeostasis. Phenotypic, histological, and metabolic assessments were performed under chow and high-fat diet conditions, with a focus on thermogenic activation, hepatic lipid accumulation, and glucose metabolism.</div></div><div><h3>Results</h3><div>Loss of <em>Pde5a</em> resulted in robust activation of brown adipose tissue and moderate browning of white adipose depots, accompanied by a reduction in hepatic lipid content. Upon high-fat diet challenge, <em>Pde5a</em>-deficient mice exhibited resistance to obesity, improved glucose handling, and enhanced thermogenic capacity. Mechanistically, these protective effects originated from early developmental knockdown of <em>Pde5a</em>, which induced metabolic reprogramming via activation of the cAMP–protein kinase A (PKA) signaling pathway. The convergence of cGMP and cAMP signaling cascades orchestrated systemic metabolic adaptations.</div></div><div><h3>Conclusions</h3><div>Our study identifies PDE5A as a previously unrecognized regulator of thermogenesis and energy balance. Targeting PDE5A may therefore represent a promising adjuvant therapeutic approach for the treatment of metabolic disorders.</div></div>","PeriodicalId":18765,"journal":{"name":"Molecular Metabolism","volume":"101 ","pages":"Article 102243"},"PeriodicalIF":6.6,"publicationDate":"2025-11-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145006372","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":"Dual leucine zipper-bearing kinase DLK is necessary for cell autonomous regulation of insulin sensitivity","authors":"Hetty N. Wong ,&nbsp;Nathan Qi ,&nbsp;Edward B. Arias ,&nbsp;Kae Won Cho ,&nbsp;Deepak Nihalani ,&nbsp;Gregory D. Cartee ,&nbsp;Lawrence B. Holzman","doi":"10.1016/j.molmet.2025.102244","DOIUrl":"10.1016/j.molmet.2025.102244","url":null,"abstract":"<div><div>Metabolic syndrome and insulin resistance are driven in part by dysregulated signaling through the c-Jun N-terminal kinase (JNK) pathway. The scaffold protein JIP1 and its upstream kinase DLK (dual leucine zipper kinase) form a dynamic signaling complex that modulates JNK activity, yet the physiological role of DLK in glucose metabolism remains undefined. Here, we identify DLK as a critical regulator of insulin sensitivity using three genetically modified mouse models: a hypomorphic DLK allele, a tamoxifen-inducible whole-body DLK knockout, and a high-fat diet–induced obese model with DLK ablation. All models exhibited enhanced insulin sensitivity independent of adiposity, characterized by increased glucose uptake in muscle and adipose tissue, and improved suppression of hepatic glucose production during hyperinsulinemic-euglycemic clamp studies. Mechanistically, we demonstrate that DLK functions in a cell-autonomous manner, limiting insulin signaling through modulation of AKT and IRS1 phosphorylation downstream of insulin stimulation. In cultured myoblasts and fibroblasts, DLK was required for JNK activation and subsequent dampening of insulin signaling. These findings establish DLK as a regulator of whole-body insulin sensitivity, independent of obesity through a JIP-JNK signaling module. The results suggest that targeting DLK could represent a therapeutic strategy for improving insulin sensitivity in metabolic disease.</div></div>","PeriodicalId":18765,"journal":{"name":"Molecular Metabolism","volume":"101 ","pages":"Article 102244"},"PeriodicalIF":6.6,"publicationDate":"2025-11-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144993012","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":"Myeloid-specific CAMKK2 deficiency protects against diet-induced obesity and insulin resistance by rewiring metabolic gene expression and enhancing energy expenditure","authors":"Andrea R. Ortiz ,&nbsp;Kevin Nay ,&nbsp;Brittany A. Stork ,&nbsp;Adam M. Dean ,&nbsp;Sean M. Hartig ,&nbsp;Cristian Coarfa ,&nbsp;Surafel Tegegne ,&nbsp;Christopher RM. Asquith ,&nbsp;Daniel E. Frigo ,&nbsp;Brian York ,&nbsp;Anthony R. Means ,&nbsp;Mark A. Febbraio ,&nbsp;John W. Scott","doi":"10.1016/j.molmet.2025.102250","DOIUrl":"10.1016/j.molmet.2025.102250","url":null,"abstract":"<div><h3>Objective</h3><div>Obesity is associated with chronic, low-grade inflammation in metabolic tissues such as liver, adipose tissue and skeletal muscle implicating insulin resistance and type 2 diabetes as inflammatory diseases. This inflammatory response involves the accumulation of pro-inflammatory macrophages in these metabolically relevant organs. The Ca²⁺-calmodulin-dependent protein kinase kinase-2 (CAMKK2) is a key regulator of cellular and systemic energy metabolism, and a coordinator of macrophage-mediated inflammatory responses. However, its role in obesity-associated metabolic dysfunction is not fully defined. The aim of this study was to determine the contribution of CAMKK2 to the regulation of inflammation and systemic metabolism during diet-induced obesity.</div></div><div><h3>Methods</h3><div>Mice with myeloid-specific deletion of <em>Camkk2</em> were generated and challenged with a high-fat diet. Metabolic phenotyping, histological analyses, and transcriptomic profiling were used to assess whole-body metabolism, liver lipid accumulation, and gene expression in macrophages and adipose tissue.</div></div><div><h3>Results</h3><div>Myeloid-specific <em>Camkk2</em> deficiency protected mice from high fat diet-induced obesity, insulin resistance and liver steatosis. These protective effects were associated with rewiring of metabolic and inflammatory gene expression in both macrophages and adipose tissue, along with enhanced whole-body energy expenditure.</div></div><div><h3>Conclusions</h3><div>Our data establish CAMKK2 as an important regulator of macrophage function and putative therapeutic target for treating obesity and related metabolic disorders.</div></div>","PeriodicalId":18765,"journal":{"name":"Molecular Metabolism","volume":"101 ","pages":"Article 102250"},"PeriodicalIF":6.6,"publicationDate":"2025-11-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145058505","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":"DYRK1A inhibition restores pancreatic functions and improves glucose metabolism in a preclinical model of type 2 diabetes","authors":"Romane Bertrand ,&nbsp;Stefania Tolu ,&nbsp;Delphine Picot ,&nbsp;Cécile Tourrel-Cuzin ,&nbsp;Ayoub Ouahab ,&nbsp;Julien Dairou ,&nbsp;Emmanuel Deau ,&nbsp;Mattias F. Lindberg ,&nbsp;Laurent Meijer ,&nbsp;Jamileh Movassat ,&nbsp;Benjamin Uzan","doi":"10.1016/j.molmet.2025.102242","DOIUrl":"10.1016/j.molmet.2025.102242","url":null,"abstract":"<div><h3>Objectives</h3><div>Insulin deficiency caused by the loss of β cells and/or impaired insulin secretion is a key factor in the pathogenesis of type 2 diabetes (T2D). The restoration of β cell number and function is thus a promising strategy to combat diabetes. Dual-specificity tyrosine-regulated kinase 1A (DYRK1A) has been shown to regulate human β cell proliferation. DYRK1A inhibitors are potential therapeutic tools, due to their ability to induce β cell proliferation. However, their anti-diabetic effects in the complex setting of type 2 diabetes remains unexplored. The aim of this study was to determine the impact of chronic DYRK1A inhibition on the remission of diabetes in pre-diabetic and overtly diabetic Goto-Kakizaki (GK) rats.</div></div><div><h3>Methods</h3><div>We assessed the impact of <em>in vivo</em> treatment with a DYRK1A inhibitor, Leucettinib-92, on β cell proliferation and insulin secretion in GK rats. Further, we evaluated the effects of long-term Leucettinib-92 treatment on the whole-body glucose metabolism in overtly diabetic GK rats through the assessment of fasting and post-absorptive glycemia, glucose tolerance and insulin sensitivity.</div></div><div><h3>Results</h3><div>Short-term <em>in vivo</em> treatment of prediabetic GK rats with Leucettinb-92 stimulated β cell proliferation <em>in vivo</em>, and sustainably prevented the development of overt hyperglycemia. Long-term treatment of adult GK rats with established diabetes increased the β cell mass and reduced basal hyperglycemia. Leucettinib-92 treatment also improved glucose tolerance, and glucose-induced insulin secretion <em>in vivo</em>.</div></div><div><h3>Conclusions</h3><div>We show that DYRK1A inhibition restores the β cell mass and function in a preclinical model of T2D, leading to the improvement of body's global glucose homeostasis.</div></div>","PeriodicalId":18765,"journal":{"name":"Molecular Metabolism","volume":"101 ","pages":"Article 102242"},"PeriodicalIF":6.6,"publicationDate":"2025-11-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144961608","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}