Molecular Metabolism最新文献

{"title":"Pre-operative DNA methylation marks as predictors of weight loss outcomes after sleeve gastrectomy","authors":"Guillermo Paz-López ,&nbsp;Teresa M. Linares-Pineda ,&nbsp;Andrés González-Jiménez ,&nbsp;Raquel Sancho-Marín ,&nbsp;Luis Ocaña-Wilhelmi ,&nbsp;Francisco J. Tinahones ,&nbsp;Sonsoles Morcillo ,&nbsp;Carolina Gutiérrez-Repiso","doi":"10.1016/j.molmet.2024.102087","DOIUrl":"10.1016/j.molmet.2024.102087","url":null,"abstract":"<div><h3>Objective</h3><div>Although DNA methylation has been suggested to be a potential predictor of the progression of obesity and obesity-related diseases, little is known about its potential role as predictive marker of successful weight loss after bariatric surgery.</div></div><div><h3>Methods</h3><div>20 patients who underwent sleeve gastrectomy were classified according to the percentage of excess weight loss (%EWL) 1 year after bariatric surgery, using 60% as the cut-off point. Blood DNA methylation was analyzed prior to surgery using the Infinium Methylation EPIC Bead Chip array-based platform.</div></div><div><h3>Results</h3><div>A total number of 76,559 differentially methylated positions (DMPs) (p &lt; 0.05) were found between &lt;60% EWL and &gt;60% EWL groups. Of them, 59,308 DMPs were annotated to genes. KEGG enrichment analysis showed that pathways involved in the signalling of MAPK, Wnt, mTor, FoxO and AMPK, among others, were involved in weight loss trajectory.</div><div>A stepwise logistic regression using the DMPs with an absolute Δβ &gt;0.2 showed that higher methylation levels in the CpG sites cg02405213 (mapping to <em>JAK2</em>) (OR: 1.20098, [0.9586, 1.5044]) and cg01702330 (OR: 2.4426, [0.5761, 10.3567]), were shown to be associated with a higher probability of achieving &gt;60 %EWL after sleeve gastrectomy, whereas higher methylation levels in the CpG site cg04863892 (mapping to <em>HOXA5</em>) were associated with lower probability of achieving &gt;60 %EWL after sleeve gastrectomy (OR: 0.7966, [0.5637, 1.1259]).</div></div><div><h3>Conclusions</h3><div>Our results show a different pre-surgery methylation pattern according to %EWL. We identified three CpG sites (cg04863892, cg02405213, cg01702330) with potential value as predictor markers of weight loss response to bariatric surgery.</div></div>","PeriodicalId":18765,"journal":{"name":"Molecular Metabolism","volume":"92 ","pages":"Article 102087"},"PeriodicalIF":7.0,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11780120/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142895388","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Metabolic plasticity in pancreatic cancer: The mitochondrial connection","authors":"Noemi Ghiglione ,&nbsp;Damiano Abbo ,&nbsp;Anastasia Bushunova ,&nbsp;Andrea Costamagna,&nbsp;Paolo Ettore Porporato,&nbsp;Miriam Martini","doi":"10.1016/j.molmet.2024.102089","DOIUrl":"10.1016/j.molmet.2024.102089","url":null,"abstract":"<div><h3>Background</h3><div>Cellular metabolism plays a pivotal role in the development and progression of pancreatic ductal adenocarcinoma (PDAC), with dysregulated metabolic pathways contributing to tumorigenesis and therapeutic resistance. Distinct metabolic heterogeneity in pancreatic cancer significantly impacts patient prognosis, as variations in metabolic profiles influence tumor behavior and treatment responses.</div><div>Scope of the Review: This review explores the intricate interplay between mitochondrial dynamics, mitophagy, and cellular metabolism in PDAC. We discuss the significance of mitophagy dysregulation in PDAC pathogenesis, emphasizing its influence on treatment responses and prognosis. Furthermore, we analyze the impact of mitochondrial dynamics alterations, including fission and fusion processes, on PDAC progression and tumorigenesis.</div></div><div><h3>Major Conclusion</h3><div>Targeting mitochondrial metabolism holds promise for advancing PDAC therapeutics. Ongoing clinical trials underscore the therapeutic potential of modulating key regulators of mitochondrial dynamics and mitophagy. Despite inherent challenges, these approaches offer diverse strategies to enhance treatment efficacy and improve patient outcomes.</div></div>","PeriodicalId":18765,"journal":{"name":"Molecular Metabolism","volume":"92 ","pages":"Article 102089"},"PeriodicalIF":7.0,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142907273","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Bioenergetic adaptations of small intestinal epithelial cells reduce cell differentiation enhancing intestinal permeability in obese mice","authors":"Thomas Guerbette ,&nbsp;Vincent Ciesielski ,&nbsp;Manon Brien ,&nbsp;Daniel Catheline ,&nbsp;Roselyne Viel ,&nbsp;Mégane Bostoën ,&nbsp;Jean-Baptiste Perrin ,&nbsp;Agnès Burel ,&nbsp;Régis Janvier ,&nbsp;Vincent Rioux ,&nbsp;Annaïg Lan ,&nbsp;Gaëlle Boudry","doi":"10.1016/j.molmet.2025.102098","DOIUrl":"10.1016/j.molmet.2025.102098","url":null,"abstract":"<div><h3><strong>Objective</strong></h3><div>Obesity and overweight are associated with low-grade inflammation induced by adipose tissue expansion and perpetuated by altered intestinal homeostasis, including increased epithelial permeability. Intestinal epithelium functions are supported by intestinal epithelial cells (IEC) mitochondria function. However, diet-induced obesity (DIO) may impair mitochondrial activity of IEC and consequently, intestinal homeostasis. The aim of the project was to determine whether DIO alters the mitochondrial function of IEC, and what are the consequences on intestinal homeostasis.</div></div><div><h3>Methods</h3><div>C57Bl/6J mice were fed a control diet for 22 weeks or a high fat diet (58 kcal% fat). Bioenergetic adaptations of IEC were evaluated on isolated crypts and villi from mouse jejunum. To determine the link between mitochondrial function and alterations of intestinal homeostasis in response to lipid overload, we used the jejunal epithelial cell line IPEC-J2 <em>in vitro</em> and mouse jejunum organoids.</div></div><div><h3>Results</h3><div>Here, we report that DIO in mice induced lipid metabolism adaptations favoring lipid storage in IEC together with reduced number, altered dynamics and diminished oxidative phosphorylation activity of IEC mitochondria. Using the IPEC-J2 cell line, we showed that IEC lipid metabolism and oxidative stress machinery adaptations preceded mitochondrial bioenergetic ones. Moreover, we unraveled the intricate link between IEC energetic status and proliferation / differentiation balance since enhancing mitochondrial function with the AMPK activator AICAR in jejunal organoids reduced proliferation and initiated IEC differentiation and conversely. We confirmed that the reduced IEC mitochondrial function observed in DIO mice was associated with increased proliferation and reduced differentiation, promoting expression of the permissive <em>Cldn2</em> in the jejunal epithelium of DIO mice.</div></div><div><h3>Conclusions</h3><div>Our study provides new insights into metabolic adaptations of IEC in obesity by revealing that excess lipid intake diminishes mitochondrial number in IEC, reducing IEC differentiation that contribute to increased epithelial permeability.</div></div>","PeriodicalId":18765,"journal":{"name":"Molecular Metabolism","volume":"92 ","pages":"Article 102098"},"PeriodicalIF":7.0,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143008090","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Intrahepatic levels of microbiome-derived hippurate associates with improved metabolic dysfunction-associated steatotic liver disease","authors":"Maxime Deslande ,&nbsp;Francesc Puig-Castellvi ,&nbsp;Inés Castro-Dionicio ,&nbsp;Romina Pacheco-Tapia ,&nbsp;Violeta Raverdy ,&nbsp;Robert Caiazzo ,&nbsp;Guillaume Lassailly ,&nbsp;Audrey Leloire ,&nbsp;Petros Andrikopoulos ,&nbsp;Yasmina Kahoul ,&nbsp;Nawel Zaïbi ,&nbsp;Bénédicte Toussaint ,&nbsp;Frédérik Oger ,&nbsp;Nicolas Gambardella ,&nbsp;Philippe Lefebvre ,&nbsp;Mehdi Derhourhi ,&nbsp;Souhila Amanzougarene ,&nbsp;Bart Staels ,&nbsp;François Pattou ,&nbsp;Philippe Froguel ,&nbsp;Marc-Emmanuel Dumas","doi":"10.1016/j.molmet.2024.102090","DOIUrl":"10.1016/j.molmet.2024.102090","url":null,"abstract":"<div><h3>Objective</h3><div>Metabolic dysfunction-associated steatotic liver disease (MASLD) is characterised by lipid accumulation in the liver and is often associated with obesity and type 2 diabetes. The gut microbiome recently emerged as a significant player in liver metabolism and health. Hippurate, a host-microbial co-metabolite has been associated with human gut microbial gene richness and with metabolic health. However, its role on liver metabolism and homeostasis is poorly understood.</div></div><div><h3>Methods</h3><div>We characterised liver biospies from 318 patients with obesity using RNAseq and metabolomics in liver and plasma to derive associations among hepatic hippurate, hepatic gene expression and MASLD and phenotypes. To test a potential beneficial role for hippurate in hepatic insulin resistance, we profile the metabolome of (IHH) using ultra-high-performance liquid chromatography coupled to high-resolution tandem mass spectrometry (UHPLC-MS/MS), and characterised intracellular triglyceride accumulation and glucose internalisation after a 24 h insulin exposure.</div></div><div><h3>Results</h3><div>We first report significant associations among MASLD traits, plasma and hepatic hippurate. Further analysis of the hepatic transcriptome shows that liver and plasma hippurate are inversely associated with MASLD, implicating lipid metabolism and regulation of inflammatory responses pathways. Hippurate treatment inhibits lipid accumulation and rescues insulin resistance induced by 24-hour chronic insulin in IHH. Hippurate also improves hepatocyte metabolic profiles by increasing the abundance of metabolites involved in energy homeostasis that are depleted by chronic insulin treatment while decreasing those involved in inflammation.</div></div><div><h3>Conclusions</h3><div>Altogether, our results further highlight hippurate as a mechanistic marker of metabolic health, by its ability to improve metabolic homeostasis as a postbiotic candidate.</div></div>","PeriodicalId":18765,"journal":{"name":"Molecular Metabolism","volume":"92 ","pages":"Article 102090"},"PeriodicalIF":7.0,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11772989/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142921096","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Deficiency of the mitochondrial transporter SLC25A47 minimally impacts hepatic lipid metabolism in fasted and diet-induced obese mice","authors":"Brecht Attema ,&nbsp;Montserrat A. de la Rosa Rodriguez ,&nbsp;Evert M. van Schothorst ,&nbsp;Sander Grefte ,&nbsp;Guido JEJ. Hooiveld ,&nbsp;Sander Kersten","doi":"10.1016/j.molmet.2024.102092","DOIUrl":"10.1016/j.molmet.2024.102092","url":null,"abstract":"<div><h3>Objective</h3><div>The peroxisome proliferator-activated receptor-alpha (PPARα) plays a central role in lipid metabolism in the liver by stimulating the expression of hundreds of genes. Accordingly, regulation by PPARα could be a screening tool to identify novel genes involved in hepatic lipid metabolism. Previously, the mitochondrial transporter SLC25A47 was suggested to play a role in energy metabolism and liver-specific uncoupling, but further research is lacking.</div></div><div><h3>Methods</h3><div>We explored the potential role of SLC25A47 through in vitro studies and using mice overexpressing and lacking SLC25A47.</div></div><div><h3>Results</h3><div><em>SLC25A47</em> was identified as a PPARα-regulated and fasting-induced gene in human and mouse hepatocytes. Adenoviral-mediated overexpression of SLC25A47 minimally impacted metabolic parameters during fasting and high-fat feeding. During high-fat feeding, SLC25A47 ablation also did not influence any metabolic parameters, apart from a minor improvement in glucose tolerance. In fasted mice, SLC25A47 ablation was associated with modest, reproducible, and likely indirect reductions in plasma triglycerides and glycerol. SLC25A47 ablation did not influence energy expenditure. Depending on the nutritional status, metabolomic analysis showed modest alterations in plasma, liver, and hepatic mitochondrial levels of various metabolites related to amino acid metabolism, TCA cycle, and fatty acid metabolism. No major and consistent alterations in levels of specific metabolites were found that establish the substrate for and function of SLC25A47.</div></div><div><h3>Conclusion</h3><div>Collectively, our results hint at a role of SLC25A47 in amino acid and fatty acid metabolism, yet suggest that SLC25A47 is dispensable for hepatic lipid homeostasis during fasting and high-fat feeding.</div></div>","PeriodicalId":18765,"journal":{"name":"Molecular Metabolism","volume":"92 ","pages":"Article 102092"},"PeriodicalIF":7.0,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11773045/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142920573","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Cannabinoid type-1 receptors in CaMKII neurons drive impulsivity in pathological eating behavior","authors":"Elena Martin-Garcia ,&nbsp;Laura Domingo-Rodriguez ,&nbsp;Beat Lutz ,&nbsp;Rafael Maldonado ,&nbsp;Inigo Ruiz de Azua","doi":"10.1016/j.molmet.2025.102096","DOIUrl":"10.1016/j.molmet.2025.102096","url":null,"abstract":"<div><h3>Objectives</h3><div>Overconsumption of palatable food and energy accumulation are evolutionary mechanisms of survival when food is scarce. These innate mechanisms becom detrimental in obesogenic environment promoting obesity and related comorbidities, including mood disorders. This study aims at elucidating the role of the endocannabinoid system in energy accumulation and hedonic feeding.</div></div><div><h3>Methods</h3><div>We applied a genetic strategy to reconstitute cannabinoid type-1 receptor (CB1) expression at functional levels specifically in CaMKII+ neurons (CaMKII-CB1-RS) and adipocytes (Ati-CB1-RS), respectively, in a CB1 deficient background.</div></div><div><h3>Results</h3><div>Rescued CB1 expression in CaMKII+ neurons, but not in adipocytes, promotes feeding behavior, leading to fasting-induced hyperphagia, increased motivation, and impulsivity to palatable food seeking. In a diet-induced obesity model, CB1 re-expression in CaMKII+ neurons, but not in adipocytes, compared to complete CB1 deficiency, was sufficient to largely restore weight gain, food intake without any effect on glucose intolerance associated with high-fat diet consumption. In a model of glucocorticoid-mediated metabolic syndrome, CaMKII-CB1-RS mice showed all metabolic alterations linked to the human metabolic syndrome except of glucose intolerance. In a binge-eating model mimicking human pathological feeding, CaMKII-CB1-RS mice showed increased seeking and compulsive behavior to palatable food, suggesting crucial roles in foraging and an enhanced susceptibility to addictive-like eating behaviors. Importantly, other contingent behaviors, including increased cognitive flexibility and reduced anxiety-like behaviors, but not depressive-like behaviors, were also observed.</div></div><div><h3>Conclusions</h3><div>CB1 in CaMKII+ neurons is instrumental in feeding behavior and energy storage under physiological conditions. The exposure to risk factors (hypercaloric diet, glucocorticoid dysregulation) leads to obesity, metabolic syndrome, binge-eating and food addiction.</div></div>","PeriodicalId":18765,"journal":{"name":"Molecular Metabolism","volume":"92 ","pages":"Article 102096"},"PeriodicalIF":7.0,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11787564/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142951447","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Exercise-induced methylation of the Serhl2 promoter and implication for lipid metabolism in rat skeletal muscle","authors":"Mutsumi Katayama ,&nbsp;Kazuhiro Nomura ,&nbsp;Jonathan M. Mudry ,&nbsp;Alexander V. Chibalin ,&nbsp;Anna Krook ,&nbsp;Juleen R. Zierath","doi":"10.1016/j.molmet.2024.102081","DOIUrl":"10.1016/j.molmet.2024.102081","url":null,"abstract":"<div><h3>Objectives</h3><div>Environmental factors such as physical activity induce epigenetic modifications, with exercise-responsive DNA methylation changes occurring in skeletal muscle. To determine the skeletal muscle DNA methylation signature of endurance swim training, we used whole-genome methylated DNA immunoprecipitation (MeDIP) sequencing.</div></div><div><h3>Methods</h3><div>We utilized endurance-trained rats, cultured L6 myotubes, and human skeletal muscle cells, employing MeDIP sequencing, gene silencing, and palmitate oxidation assays. Additional methods included promoter luciferase assays, fluorescence microscopy, and RNA/DNA analysis to investigate exercise-induced molecular changes.</div></div><div><h3>Results</h3><div>Gene set enrichment analysis (GSEA) of differentially methylated promoter regions identified an enrichment of four gene sets, including those linked to lipid metabolic processes, with hypermethylated or hypomethylated promoter regions in skeletal muscle of exercise-trained rats. Bisulfite sequencing confirmed hypomethylation of CpGs in the <em>Serhl2</em> (Serine Hydrolase Like 2) transcription start site in exercise-trained rats. <em>Serhl2</em> gene expression was upregulated in both exercise-trained rats and an \"exercise-in-a-dish\" model of L6 myotubes subjected to electrical pulse stimulation (EPS). <em>Serhl2</em> promoter activity was regulated by methylation and EPS. A <em>Nr4a</em> binding motif in the <em>Serhl2</em> promoter, when deleted, reduced promoter activity and sensitivity to methylation in L6 myotubes. Silencing <em>Serhl2</em> in L6 myotubes reduced intracellular lipid oxidation and triacylglycerol synthesis in response to EPS.</div></div><div><h3>Conclusions</h3><div>Exercise-training enhances intracellular lipid metabolism and phenotypic changes in skeletal muscle through epigenomic modifications on <em>Serhl2</em>. Hypomethylation of the <em>Serhl2</em> promoter influences <em>Nr4a</em> transcription factor binding, promoter activity, and gene expression, linking exercise-induced epigenomic regulation of <em>Serhl2</em> to lipid oxidation and triacylglycerol synthesis.</div></div>","PeriodicalId":18765,"journal":{"name":"Molecular Metabolism","volume":"92 ","pages":"Article 102081"},"PeriodicalIF":7.0,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11732562/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142807643","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Hypoxia-inducible factor 1α is required to establish the larval glycolytic program in Drosophila melanogaster","authors":"Yasaman Heidarian ,&nbsp;Tess D. Fasteen ,&nbsp;Liam Mungcal ,&nbsp;Kasun Buddika ,&nbsp;Nader H. Mahmoudzadeh ,&nbsp;Travis Nemkov ,&nbsp;Angelo D'Alessandro ,&nbsp;Jason M. Tennessen","doi":"10.1016/j.molmet.2025.102106","DOIUrl":"10.1016/j.molmet.2025.102106","url":null,"abstract":"<div><h3>Objectives</h3><div>The rapid growth that occurs during <em>Drosophila</em> larval development requires a dramatic rewiring of central carbon metabolism to support biosynthesis. Larvae achieve this metabolic state, in part, by coordinately up-regulating the expression of genes involved in carbohydrate metabolism. The resulting metabolic program exhibits hallmark characteristics of aerobic glycolysis and establishes a physiological state that supports growth. To date, the only factor known to activate the larval glycolytic program is the <em>Drosophila</em> Estrogen-Related Receptor (dERR). However, dERR is dynamically regulated during the onset of this metabolic switch, indicating that other factors must be involved. Here we examine the possibility that the <em>Drosophila</em> ortholog of Hypoxia inducible factor 1α (Hif1α) is also required to activate the larval glycolytic program.</div></div><div><h3>Methods</h3><div>CRISPR/Cas9 was used to generate new loss-of-function alleles in the <em>Drosophila</em> gene <em>similar</em> (<em>sima</em>), which encodes the sole fly ortholog of Hif1α. The resulting mutant strains were analyzed using a combination of metabolomics and RNAseq for defects in carbohydrate metabolism.</div></div><div><h3>Results</h3><div>Our studies reveal that <em>sima</em> mutants fail to activate aerobic glycolysis and die during larval development with metabolic phenotypes that mimic those displayed by <em>dERR</em> mutants. Moreover, we demonstrate that dERR and Sima/Hif1α protein accumulation is mutually dependent, as loss of either transcription factor results in decreased abundance of the other protein.</div></div><div><h3>Conclusions</h3><div>These findings demonstrate that Sima/HIF1α is required during embryogenesis to coordinately up-regulate carbohydrate metabolism in preparation for larval growth. Notably, our study also reveals that the Sima/HIF1α-dependent gene expression program shares considerable overlap with that observed in <em>dERR</em> mutant, suggesting that Sima/HIF1α and dERR cooperatively regulate embryonic and larval glycolytic gene expression.</div></div>","PeriodicalId":18765,"journal":{"name":"Molecular Metabolism","volume":"93 ","pages":"Article 102106"},"PeriodicalIF":7.0,"publicationDate":"2025-01-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143080515","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Characterization of subcutaneous and visceral de-differentiated fat cells","authors":"Yan Li ,&nbsp;Houyu Zhang ,&nbsp;Carlos F. Ibáñez ,&nbsp;Meng Xie","doi":"10.1016/j.molmet.2025.102105","DOIUrl":"10.1016/j.molmet.2025.102105","url":null,"abstract":"<div><h3>Objective</h3><div>The capacity of mature adipocytes to de-differentiate into fibroblast-like cells has been demonstrated in vitro and a few, rather specific in vivo conditions. A detailed comparison between de-differentiated fat (DFAT) cells and adipose stem and progenitor cells (ASPCs) from different adipose depots is yet to be conducted. Moreover, whether de-differentiation of mature adipocytes from classical subcutaneous and visceral depots occurs under physiological conditions remains unknown.</div></div><div><h3>Methods</h3><div>Here, we used in vitro \"ceiling culture\", single cell/nucleus RNA sequencing, epigenetic anaysis and genetic lineage tracing to address these unknowns.</div></div><div><h3>Results</h3><div>We show that in vitro-derived DFAT cells have lower adipogenic potential and distinct cellular composition compared to ASPCs. In addition, DFAT cells derived from adipocytes of inguinal origin have dramatically higher adipogenic potential than DFAT cells of the epididymal origin, due in part to enhanced NF-KB signaling in the former. We also show that high-fat diet (HFD) feeding enhances DFAT cell colony formation and re-differentiation into adipocytes, while switching from HFD to chow diet (CD) only reverses their re-differentiation. Moreover, HFD deposits epigenetic changes in DFAT cells and ASPCs that are not reversed after returning to CD. Finally, combining genetic lineage tracing and single cell/nucleus RNA sequencing, we demonstrate the existence of DFAT cells in inguinal and epididymal adipose depots in vivo, with transcriptomes resembling late-stage ASPCs.</div></div><div><h3>Conclusions</h3><div>These data uncover the cell type- and depot-specific properties of DFAT cells, as well as their plasticity in response to dietary intervention. This knowledge may shed light on their role in life style change-induced weight loss and regain.</div></div>","PeriodicalId":18765,"journal":{"name":"Molecular Metabolism","volume":"93 ","pages":"Article 102105"},"PeriodicalIF":7.0,"publicationDate":"2025-01-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143066766","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Nutrient control of splice site selection contributes to methionine addiction of cancer","authors":"Da-Wei Lin ,&nbsp;Francisco G. Carranza ,&nbsp;Stacey Borrego ,&nbsp;Linda Lauinger ,&nbsp;Lucas Dantas de Paula ,&nbsp;Harika R. Pulipelli ,&nbsp;Anna Andronicos ,&nbsp;Klemens J. Hertel ,&nbsp;Peter Kaiser","doi":"10.1016/j.molmet.2025.102103","DOIUrl":"10.1016/j.molmet.2025.102103","url":null,"abstract":"<div><h3>Objective</h3><div>Many cancer cells depend on exogenous methionine for proliferation, whereas non-tumorigenic cells can divide in media supplemented with the metabolic precursor homocysteine. This phenomenon is known as methionine dependence of cancer or methionine addiction. The underlying mechanisms driving this cancer-specific metabolic addiction are poorly understood. Here we find that methionine dependence is associated with severe dysregulation of pre-mRNA splicing.</div></div><div><h3>Methods</h3><div>We used triple-negative breast cancer cells and their methionine-independent derivatives R8 to compare RNA expression profiles in methionine and homocysteine growth media. The data set was also analyzed for alternative splicing.</div></div><div><h3>Results</h3><div>When tumorigenic cells were cultured in homocysteine medium, cancer cells failed to efficiently methylate the spliceosomal snRNP component SmD1, which resulted in reduced binding to the Survival-of-Motor-Neuron protein SMN leading to aberrant splicing. These effects were specific for cancer cells as neither Sm protein methylation nor splicing fidelity was affected when non-tumorigenic cells were cultured in homocysteine medium. Sm protein methylation is catalyzed by Protein Arginine Methyl Transferase 5 (Prmt5). Reducing methionine concentrations in the culture medium sensitized cancer cells to Prmt5 inhibition supporting a mechanistic link between methionine dependence of cancer and splicing.</div></div><div><h3>Conclusions</h3><div>Our results link nutritional demands to splicing changes and thereby provide a link between the cancer-specific metabolic phenomenon, described as methionine addiction over 40 years ago, with a defined cellular pathway that contributes to cancer cell proliferation.</div></div>","PeriodicalId":18765,"journal":{"name":"Molecular Metabolism","volume":"93 ","pages":"Article 102103"},"PeriodicalIF":7.0,"publicationDate":"2025-01-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143040294","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}