Molecular Metabolism最新文献

{"title":"Corrigendum to “Kynurenic acid derived from mesentery regulates mesenteritis and colitis via inducing white adipose browning in Crohn's disease” [Mol Metab 99 (2025 Sep) 102203]","authors":"Yongheng Wang , Ritian Lin , Fangtao Wang , Huijun Fu , Xia Wang , Fengshan Jin , Qiao Wang , Weigang Shu","doi":"10.1016/j.molmet.2025.102240","DOIUrl":"10.1016/j.molmet.2025.102240","url":null,"abstract":"","PeriodicalId":18765,"journal":{"name":"Molecular Metabolism","volume":"100 ","pages":"Article 102240"},"PeriodicalIF":6.6,"publicationDate":"2025-08-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144917002","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":"2025-08-29","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}

{"title":"Suppression of adipocyte ABHD6 favors anti-inflammatory and adipogenic programs to preserve adipose tissue fitness in obesity","authors":"Pegah Poursharifi ,&nbsp;Camille Attané ,&nbsp;Isabelle Chenier ,&nbsp;Clemence Schmitt ,&nbsp;Roxane Lussier ,&nbsp;Anfal Al-Mass ,&nbsp;Yat Hei Leung ,&nbsp;Abel Oppong ,&nbsp;Élizabeth Dumais ,&nbsp;Nicolas Flamand ,&nbsp;Mohamed Abu-Farha ,&nbsp;Jehad Abubaker ,&nbsp;Fahd Al-Mulla ,&nbsp;Ying Bai ,&nbsp;Dongwei Zhang ,&nbsp;Marie-Line Peyot ,&nbsp;André Tchernof ,&nbsp;S.R. Murthy Madiraju ,&nbsp;Marc Prentki","doi":"10.1016/j.molmet.2025.102241","DOIUrl":"10.1016/j.molmet.2025.102241","url":null,"abstract":"<div><div>Some individuals exhibit metabolically healthy obesity, characterized by the expansion of white adipose tissue (WAT) without associated complications. The monoacylglycerol (MAG) hydrolase α/β-hydrolase domain-containing 6 (ABHD6) has been implicated in energy metabolism, with its global deletion conferring protection against obesity. However, the immunometabolic roles of adipocyte ABHD6 in WAT remodeling in response to nutri-stress and obesity are not known. Here, we demonstrate that in insulin resistant women, <em>ABHD6</em> mRNA expression is elevated in visceral fat and positively correlates with obesity and metabolic dysregulation. ABHD6 expression is also elevated in the WATs of diet-induced obese and <em>db/db</em> mice. Although adipocyte-specific ABHD6 knockout (AA-KO) mice become obese under high-fat diet, they show higher plasma adiponectin, reduced circulating insulin and inflammatory markers, improved insulin sensitivity, and lower plasma and liver triglycerides. They also show enhanced insulin action in various tissues, but normal glucose tolerance. In addition, AA-KO mice display healthier and less inflamed expansion of visceral fat, with smaller adipocytes and higher stimulated lipolysis and fatty acid oxidation levels. Similar but less prominent phenotype was found in the subcutaneous and brown fat depots. Thus, adipocyte ABHD6 suppression prevents most of the metabolic and inflammatory complications of obesity, but not obesity <em>per se</em>. Mechanistically, this beneficial process involves a rise in MAG levels in mature adipocytes, and their secretion, resulting in a crosstalk among adipocytes, preadipocytes and macrophages in the adipose microenvironment. Elevated intracellular MAG causes PPARs activation in adipocytes, and MAG secreted from adipocytes curtails the inflammatory polarization of macrophages and promotes preadipocyte differentiation. Hence, adipocyte ABHD6 and MAG hydrolysis contribute to unhealthy WAT remodeling and expansion in obesity, and its suppression represents a candidate strategy to uncouple obesity from many of its immunometabolic complications.</div></div>","PeriodicalId":18765,"journal":{"name":"Molecular Metabolism","volume":"101 ","pages":"Article 102241"},"PeriodicalIF":6.6,"publicationDate":"2025-08-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144961659","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":"2025-08-25","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":"Placental mitochondrial calcium uniporter modulates offspring susceptibility to metabolic dysfunction","authors":"Seokwon Jo ,&nbsp;Grace Chung ,&nbsp;Yu-Jin Youn ,&nbsp;Charlotte Hunt ,&nbsp;Ava Hill ,&nbsp;Megan Beetch ,&nbsp;Brian Akhaphong ,&nbsp;Elizabeth A. Morgan ,&nbsp;Perrie F. O'Tierney-Ginn ,&nbsp;Sarah A. Wernimont ,&nbsp;Emilyn U. Alejandro","doi":"10.1016/j.molmet.2025.102236","DOIUrl":"10.1016/j.molmet.2025.102236","url":null,"abstract":"<div><div>Mitochondria are crucial for regulating metabolism, but their role in the placenta and how they may shape offspring metabolism and long-term health remains unclear, despite being commonly associated with pregnancy complications. To investigate this, we used a genetic model with placenta-specific deletion of the mitochondrial calcium uniporter (Pl-MCUKO) and assessed the metabolic trajectory of adult offspring. We found that, at baseline, female placental trophoblasts in wild-type animals exhibited higher respiration rates than males. MCU deletion impaired mitochondrial function specifically in female placentas and was accompanied by distinct changes in the metabolomic profiles of protein and lipid metabolism. Transcriptome analysis revealed reduced placental cellular growth pathways, consistent with smaller placentas and reduced embryonic body weights in Pl-MCUKO. Although <em>in utero</em> MCU deletion affected fetal growth, it was insufficient to cause permanent postnatal changes in body weight, as these deficits normalized in adulthood, with normal glucose homeostasis in Pl-MCUKO offspring. However, when challenged with a high-fat diet, Pl-MCUKO females exhibited reduced weight gain, improved glucose and insulin tolerance, smaller fat depots, and increased ambulatory activity compared to controls. This improved metabolic profile was associated with reduced pancreatic β-cell mass but preserved β-cell function. These findings provide direct evidence that placental mitochondrial function can influence the long-term metabolic health of female offspring by modulating key metabolic tissues.</div></div>","PeriodicalId":18765,"journal":{"name":"Molecular Metabolism","volume":"100 ","pages":"Article 102236"},"PeriodicalIF":6.6,"publicationDate":"2025-08-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144925111","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":"ACAA1 knockout increases the survival rate of KPC mice by activating autophagy","authors":"Ho Lee ,&nbsp;Mingyu Kang ,&nbsp;Sung Hoon Sim ,&nbsp;Joon Hee Kang ,&nbsp;Wonyoung Choi ,&nbsp;Jung Won Chun ,&nbsp;Woosol Hong ,&nbsp;Chaeyoung Kim ,&nbsp;Woojin Ham ,&nbsp;Jeong Hwan Park ,&nbsp;Eun-Byeol Koh ,&nbsp;Yoon Jeon ,&nbsp;Sang Myung Woo ,&nbsp;Soo-Youl Kim","doi":"10.1016/j.molmet.2025.102237","DOIUrl":"10.1016/j.molmet.2025.102237","url":null,"abstract":"<div><h3>Objectives</h3><div>We found that the levels of the peroxisomal fatty acid oxidation (FAO) marker in pancreatic ductal adenocarcinoma (PDAC) patients were higher than those in healthy individuals, based on tissue microarray analysis. This study investigates FAO in preclinical in vitro and in vivo models.</div></div><div><h3>Methods</h3><div>To examine the role of FAO in the peroxisome, we created acetyl-coenzyme A acyltransferase (ACAA1) knockout mice, crossed them with KPC mice, and monitored their survival rates. Additionally, we tested a mouse xenograft model with ACAA1 knockdown in human PDAC cells.</div></div><div><h3>Results</h3><div>In normal cells, <em>ACAA1</em> knockdown did not affect oxygen consumption. In contrast, in PDAC cells, <em>ACAA1</em> knockdown reduced the oxygen consumption rate by up to 60% and decreased ATP production by up to 70%. This suggests that peroxisomes in PDAC supply various acyl-carnitines for FAO in mitochondria. In PDAC cells, <em>ACAA1</em> knockdown lowered ATP levels, resulting in mTOR inactivation and autophagy induction. Additionally, <em>ACAA1</em> knockdown significantly increased LC3-II levels, leading to growth retardation in mouse xenograft models. <em>Acaa1a</em>^{<em>+/−</em>} mice showed a median survival increase of 3 weeks after crossing <em>Acaa1a</em>^{<em>+/−</em>} with KPC mice (<em>Kras</em>^G12D/+; <em>Trp53</em>^R172H/+; <em>Pdx1</em>-Cre, a genetically engineered mice model for PDAC).</div></div><div><h3>Conclusions</h3><div><em>ACAA1</em> knockdown inhibited tumor growth by triggering autophagy, which supported the survival of KPC mice. The most important benefit of targeting ACAA1 is that it blocks tumor growth specifically in cancer cells without harming normal cell energy metabolism.</div></div>","PeriodicalId":18765,"journal":{"name":"Molecular Metabolism","volume":"100 ","pages":"Article 102237"},"PeriodicalIF":6.6,"publicationDate":"2025-08-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144916998","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":"GLP-1R signaling does not modify the severity of experimental graft versus host disease","authors":"Bernardo Yusta,&nbsp;Chi Kin Wong,&nbsp;Dianne Matthews,&nbsp;Jacqueline A. Koehler,&nbsp;Laurie L. Baggio,&nbsp;KW Annie Bang,&nbsp;Daniel J. Drucker","doi":"10.1016/j.molmet.2025.102235","DOIUrl":"10.1016/j.molmet.2025.102235","url":null,"abstract":"<div><h3>Objective</h3><div>Glucagon-like peptide-1 (GLP-1) reduces systemic and gut inflammation. Here we assessed whether gain or loss of GLP-1 receptor (GLP-1R) signaling modifies the extent of gut injury and inflammation in experimental murine acute graft vs. host disease (aGvHD).</div></div><div><h3>Methods</h3><div>Allogeneic hematopoietic cell transplantation (HCT) was performed using bone marrow and splenocytes from BALB/c donors to induce aGvHD in C57BL/6 recipients or vice versa. Chimerism was determined by flow cytometry analysis of immune cell compartments. Inflammation was assessed by histological scoring of gut mucosal damage and by measuring circulating cytokine levels. qPCR was used to quantify gene expression in small intestine immune cells and tissues. The gut microbiome was assessed by 16S rRNA sequencing.</div></div><div><h3>Results</h3><div>Allogeneic chimerism was greater than 90% in peripheral blood and in the gut epithelial compartment. Levels of <em>Glp1r</em> mRNA transcripts were induced in the ileum of both vehicle- and semaglutide-treated allogeneic mice, reflecting that allogeneic T cells homing to the gut express a functional GLP-1R. Nevertheless, semaglutide did not attenuate the severity of systemic cytokine induction, gut injury or inflammation, or the extent of aGvHD in the gut mucosa. Loss of GLP-1R signaling in donor cells had limited effects on overall microbial diversity during acute GvHD, and semaglutide-treated mice exhibited modest changes in proportions of microbial species.</div></div><div><h3>Conclusions</h3><div>Although gut T cells express a functional GLP-1R, GLP-1R signaling has no meaningful impact on systemic or intestinal inflammation or microbiota composition in mice with experimental aGvHD, highlighting that the anti-inflammatory actions of GLP-1 medicines are highly context-dependent.</div></div>","PeriodicalId":18765,"journal":{"name":"Molecular Metabolism","volume":"100 ","pages":"Article 102235"},"PeriodicalIF":6.6,"publicationDate":"2025-08-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144917001","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":"Mice harboring the obesity-associated SNP rs1421085 exhibit increased body weight and reveal an IRX3 neuronal circuit regulating body weight","authors":"Andrew I. Sullivan ,&nbsp;Kyle H. Flippo ,&nbsp;Iltan Aklan ,&nbsp;Kristin E. Claflin ,&nbsp;Donald A. Morgan ,&nbsp;Meghan C. Naber ,&nbsp;Kamal Rahmouni ,&nbsp;Matthew J. Potthoff","doi":"10.1016/j.molmet.2025.102234","DOIUrl":"10.1016/j.molmet.2025.102234","url":null,"abstract":"<div><h3>Objective</h3><div>The single nucleotide polymorphism (SNP) rs1421085 has one of the highest associated risks with obesity of any SNP in the human genome. Through the generation of a novel mouse model harboring rs1421085 (OA-SNP^rs142/rs142), we examined the impact of this SNP on energy balance. Furthermore, we investigated the role of IRX3, a potential mediator of the metabolic effects of rs1421085, in multiple brain regions.</div></div><div><h3>Methods</h3><div>To explore the impact and mechanisms of rs1421085, we monitored body weight, food intake, energy expenditure, and other metabolic parameters of OA-SNP^rs142/rs142 mice under metabolic conditions similar to human obesogenic conditions (thermoneutral housing and 45% high fat diet). We additionally leveraged this model to investigate the impact of rs1421085 on genes that have been suggested to mediate the effects of this SNP on obesity. Finally, we used <em>Irx3</em>-Cre mice in combination with Cre-dependent AAV-<em>Irx3</em> to determine if localized induction of IRX3 in neurons was sufficient to drive the energetic effects of rs1421085.</div></div><div><h3>Results</h3><div>OA-SNP^rs142/rs142 mice are more susceptible to diet-induced obesity and have increased food intake and decreased energy expenditure under human obesogenic conditions. Additionally, OA-SNP^rs142/rs142 mice have elevated <em>Irx3</em> mRNA expression in the brain with prominent expression in metabolically relevant regions such as the posterior hypothalamus (PH) and dorsal vagal complex (DVC). Increased IRX3 in the PH, but not the DVC, resulted in a significant increase in body weight and food intake. Finally, we found that increased expression of IRX3, specifically in IRX3⁺ neurons, decreases excitability and activity of IRX3⁺ neurons in the PH but not the DVC. Interestingly, inhibition of IRX3⁺ PH neurons led to increased body weight and food intake.</div></div><div><h3>Conclusions</h3><div>These data demonstrate that OA-SNP^rs142/rs142 mice recapitulate the body weight phenotype associated with rs1421085 in humans and that increased IRX3 in the posterior hypothalamus, as seen in OA-SNP^rs142/rs142 mice, is sufficient to drive some of the metabolic effects of the SNP.</div></div>","PeriodicalId":18765,"journal":{"name":"Molecular Metabolism","volume":"100 ","pages":"Article 102234"},"PeriodicalIF":6.6,"publicationDate":"2025-08-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144916997","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":"Nuclear functional role of metabolic enzymes and related metabolites: Focus on gene expression regulation","authors":"Simona Todisco ,&nbsp;Dominga Iacobazzi ,&nbsp;Anna Santarsiero ,&nbsp;Paolo Convertini ,&nbsp;Vittoria Infantino","doi":"10.1016/j.molmet.2025.102233","DOIUrl":"10.1016/j.molmet.2025.102233","url":null,"abstract":"<div><h3>Background</h3><div>Many biological processes from physiological development to different pathological conditions are closely linked to dynamic energetic metabolism and its dysregulations. Mounting evidence shows that metabolic rewiring allows cells to adapt to stress conditions, changes in extracellular cues, and nutritional fluctuations in a timely and precise manner by modulating gene expression. Recent studies reveal non-strictly metabolic functions of metabolic enzymes and related metabolites often confined to the nucleus. Indeed, beyond the diffusion of metabolites through nuclear pores, several metabolic enzymes translocate to the nucleus during cellular differentiation, macrophage activation, tumorigenesis, and so on.</div></div><div><h3>Scope of review</h3><div>This review aims to outline recent advances in the nuclear functions of metabolic enzymes, focusing on gene expression regulation through transcription factors and epigenetic mechanisms.</div></div><div><h3>Major conclusions</h3><div>The nuclear localization of metabolic enzymes and metabolites underlines the dual role of metabolism as both a driver and a controller of cellular processes by linking energy metabolism directly to gene expression and cellular reprogramming. The main involvement of respiratory enzymes in nuclear functions suggests a ready interplay between energy status and transcriptional regulation. We trust that these insights will contribute to a more extensive knowledge of the cellular and nuclear landscape and could inspire future investigations on metabolic-mediated gene regulation mechanisms with the aim of developing more effective therapies against diseases.</div></div>","PeriodicalId":18765,"journal":{"name":"Molecular Metabolism","volume":"100 ","pages":"Article 102233"},"PeriodicalIF":6.6,"publicationDate":"2025-08-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144804370","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":"Three-dimensional network of creatine metabolism: From intracellular energy shuttle to systemic metabolic regulatory switch","authors":"Yuhui Su","doi":"10.1016/j.molmet.2025.102228","DOIUrl":"10.1016/j.molmet.2025.102228","url":null,"abstract":"<div><h3>Background</h3><div>Creatine serves as an intracellular shuttle for high-energy phosphate bonds, enabling rapid ATP transfer from energy-producing to energy-consuming cellular compartments. In skeletal muscle, creatine coordinates energy distribution among mitochondrial oxidative phosphorylation, glycolysis, and the phosphagen system. Consequently, creatine supplementation acutely enhances muscular performance and is widely utilized as an ergogenic aid in power-based sports. Recent studies demonstrate that enhanced creatine metabolism in adipose tissue promotes brown adipocyte renewal and boosts energy expenditure in cold environments or sedentary conditions, thereby improving overall systemic metabolism. Beyond its traditional role as an exercise supplement, the creatine metabolic network has emerged as a promising therapeutic target for metabolic disorders.</div></div><div><h3>Scope of review</h3><div>This review begins by revisiting the history and latest advancements in creatine research, and ultimately proposes three dimensions for the current explanation of creatine metabolism: (1) subcellular energy transport; (2) muscle-fat metabolic axis; (3) systemic energy sensing and metabolic reprogramming.</div></div><div><h3>Major conclusions</h3><div>The creatine cycle enables directed energy flow through mitochondrial supercomplexes (VDAC/ANT-CK) and resets systemic metabolism via subcellular energy tunnels and inter-organ interactions. Creatine kinase (CK) condensates, through liquid–liquid phase separation, can rapidly meet energy demands during exercise. Therefore, targeting the dynamics of the CK phase may be promising for enhancing athletic performance and improving metabolic diseases.</div></div>","PeriodicalId":18765,"journal":{"name":"Molecular Metabolism","volume":"100 ","pages":"Article 102228"},"PeriodicalIF":6.6,"publicationDate":"2025-08-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144804372","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}