Molecular Metabolism最新文献

{"title":"Impact of sleep deprivation on colon cancer: Unraveling the KynA-P4HA2-HIF-1α axis in tumor lipid metabolism and metastasis","authors":"Zuojie Peng ,&nbsp;Jia Song ,&nbsp;Wenzhong Zhu ,&nbsp;Haijun Bao ,&nbsp;Yuan Hu ,&nbsp;Yongping Shi ,&nbsp;Xukai Cheng ,&nbsp;Mi Jiang ,&nbsp;Feifei Fang ,&nbsp;Jinhuang Chen ,&nbsp;Xiaogang Shu","doi":"10.1016/j.molmet.2025.102109","DOIUrl":"10.1016/j.molmet.2025.102109","url":null,"abstract":"<div><h3>Objective</h3><div>There is growing evidence that sleep deprivation promotes cancer progression. In addition, colon cancer patients often experience sleep deprivation due to factors such as cancer pain and side effects of treatment. The occurrence of liver metastases is an important factor in the mortality of colon cancer patients. However, the relationship between sleep deprivation and liver metastases from colon cancer has not been elucidated.</div></div><div><h3>Methods</h3><div>A sleep deprivation liver metastasis model was constructed to evaluate the effect of sleep deprivation on liver metastasis of colon cancer. Subsequently, mice feces were collected for untargeted metabolomics to screen and identify the key mediator, Kynurenic acid (KynA). Furthermore, HILPDA was screened by transcriptomics, and its potential mechanism was explored through ChIP, co-IP, ubiquitination experiments, phenotyping experiments, etc.</div></div><div><h3>Results</h3><div>Sleep deprivation promotes liver metastases in colon cancer. Functionally, sleep deprivation aggravates lipid accumulation and decreases the production of the microbiota metabolite KynA. In contrast, KynA inhibited colon cancer progression <em>in vitro</em>. <em>In vivo</em>, KynA supplementation reversed the promoting effects of sleep deprivation on liver metastases from colon cancer. Mechanistically, KynA downregulates the expression of P4HA2 to promote the ubiquitination and degradation of HIF-1α, which leads to a decrease in the transcription of HILPDA, and ultimately leads to an increase in lipolysis of colon cancer cells.</div></div><div><h3>Conclusions</h3><div>Our findings reveal that sleep deprivation impairs intracellular lipolysis by KynA, leading to lipid droplets accumulation in colon cancer cells. This process ultimately promotes colon cancer liver metastasis. This suggests a promising strategy for colon cancer treatment.</div></div>","PeriodicalId":18765,"journal":{"name":"Molecular Metabolism","volume":"93 ","pages":"Article 102109"},"PeriodicalIF":7.0,"publicationDate":"2025-02-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143374327","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":"Altered thermal preference by preoptic estrogen receptor alpha neurons in postpartum females","authors":"Nan Zhang ,&nbsp;Meng Yu ,&nbsp;Qianru Zhao ,&nbsp;Bing Feng ,&nbsp;Yue Deng ,&nbsp;Jonathan C. Bean ,&nbsp;Qingzhuo Liu ,&nbsp;Benjamin P. Eappen ,&nbsp;Yang He ,&nbsp;Kristine M. Conde ,&nbsp;Hailan Liu ,&nbsp;Yongjie Yang ,&nbsp;Longlong Tu ,&nbsp;Mengjie Wang ,&nbsp;Yongxiang Li ,&nbsp;Na Yin ,&nbsp;Hesong Liu ,&nbsp;Junying Han ,&nbsp;Darah Ave Threat ,&nbsp;Nathan Xu ,&nbsp;Chunmei Wang","doi":"10.1016/j.molmet.2025.102108","DOIUrl":"10.1016/j.molmet.2025.102108","url":null,"abstract":"<div><h3>Objective</h3><div>This study aims to investigate how reproductive experience (RE) alters thermal preference and thermoregulation in female mice, with a focus on estrogen receptor alpha (ERα)-expressing neurons in the preoptic area (POA).</div></div><div><h3>Methods</h3><div>Thermal preference and body temperature were measured in female mice with and without RE, and virgin female mice with selective deletion of ERα from the POA (ERα^POA-KO). The number and activity of ERα-expressing POA neurons (ERα^POA) were assessed using immunohistochemistry and in vitro electrophysiology in response to temperature changes and ERα agonist.</div></div><div><h3>Results</h3><div>We showed that female mice prefer a cooler environment starting from late pregnancy and persisting long term postpartum. Female mice with RE (&gt;4 weeks post-weaning) displayed lower body temperature and a lower thermal preferred temperature, and lost preference for warm environments (30 °C) but preserved avoidance of cold environments (15 °C). This was associated with a significant decrease in the number of ERα^POA neurons. Importantly, virgin female ERα^POA-KO mice displayed lower thermal preferred temperature and impaired warm preference, mimicking RE mice. We further found that distinct ERα^POA subpopulations can be regulated by temperature changes with or without presynaptic blockers, and by ERα agonist. More importantly, RE decreased the number of warm-activated ERα^POA neurons and reduced the excitatory effects of warmth and estrogen-ERα signaling, while cold-activated ERα^POA neurons were slightly enhanced in female mice with RE.</div></div><div><h3>Conclusion</h3><div>Our results support that the thermosensing ability and estrogenic effects in ERα^POA neurons are regulated by reproductive experience, altering thermal preference.</div></div>","PeriodicalId":18765,"journal":{"name":"Molecular Metabolism","volume":"93 ","pages":"Article 102108"},"PeriodicalIF":7.0,"publicationDate":"2025-02-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143256011","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":"HINT1 suppression protects against age-related cardiac dysfunction by enhancing mitochondrial biogenesis","authors":"Michio Sato ,&nbsp;Tsuyoshi Kadomatsu ,&nbsp;Jun Morinaga ,&nbsp;Yuya Kinoshita ,&nbsp;Daisuke Torigoe ,&nbsp;Haruki Horiguchi ,&nbsp;Sumio Ohtsuki ,&nbsp;Shuji Yamamura ,&nbsp;Ryoko Kusaba ,&nbsp;Takanori Yamaguchi ,&nbsp;Goro Yoshioka ,&nbsp;Kimi Araki ,&nbsp;Tomohiko Wakayama ,&nbsp;Keishi Miyata ,&nbsp;Koichi Node ,&nbsp;Yuichi Oike","doi":"10.1016/j.molmet.2025.102107","DOIUrl":"10.1016/j.molmet.2025.102107","url":null,"abstract":"<div><h3>Objective</h3><div>Cardiac function declines with age, impairing exercise tolerance and negatively impacting healthy aging. However, mechanisms driving age-related declines in cardiac function are not fully understood.</div></div><div><h3>Methods</h3><div>We examined mechanisms underlying age-related cardiac dysfunction using 3- and 24-month-old wild-type mice fed ad libitum or 24-month-old wild-type mice subjected to 70% calorie restriction (CR) starting at 2-month-old. In addition, cardiac aging phenotypes and mitochondrial biogenesis were also analyzed in 25-month-old cardiac-specific Hint1 knockout mice, 24-month-old CAG-Caren Tg mice, and 24-month-old wild-type mice injected with AAV6-Caren.</div></div><div><h3>Results</h3><div>We observed inactivation of mitochondrial biogenesis in hearts of aged mice. We also showed that activity of the BAF chromatin remodeling complex is repressed by HINT1, whose expression in heart increases with age, leading to decreased transcription of Tfam, which promotes mitochondrial biogenesis. Interestingly, CR not only suppressed age-related declines in cardiac function and mitochondrial biogenesis but blocked concomitant increases in cardiac HINT1 protein levels and maintained Tfam transcription. Furthermore, expression of the lncRNA Caren, which inhibits Hint1 mRNA translation, decreased with age in heart, and CR suppressed this effect. Finally, decreased HINT1 expression due to Caren overexpression antagonized age-related declines in mitochondrial biogenesis, ameliorating age-related cardiac dysfunction, exercise intolerance, and exercise-induced cardiac damage and subsequent death of mice.</div></div><div><h3>Conclusion</h3><div>Our findings suggest that mitochondrial biogenesis in cardiomyocytes decreases with age and could underlie cardiac dysfunction, and that the Caren-HINT1-mitochondrial biogenesis axis may constitute a mechanism linking CR to resistance to cardiac aging. We also show that ameliorating declines in mitochondrial biogenesis in cardiomyocytes could counteract age-related declines in cardiac function, and that this strategy may improve exercise tolerance and extend so-called \"healthy life span\".</div></div>","PeriodicalId":18765,"journal":{"name":"Molecular Metabolism","volume":"93 ","pages":"Article 102107"},"PeriodicalIF":7.0,"publicationDate":"2025-02-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143256019","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":"Epigenetic suppression of creatine kinase B in adipocytes links endoplasmic reticulum stress to obesity-associated inflammation","authors":"Gianluca Renzi ,&nbsp;Ivan Vlassakev ,&nbsp;Mattias Hansen ,&nbsp;Romane Higos ,&nbsp;Simon Lecoutre ,&nbsp;Merve Elmastas ,&nbsp;Ondrej Hodek ,&nbsp;Thomas Moritz ,&nbsp;Lynn M. Alaeddine ,&nbsp;Scott Frendo–Cumbo ,&nbsp;Ingrid Dahlman ,&nbsp;Alastair Kerr ,&nbsp;Salwan Maqdasy ,&nbsp;Niklas Mejhert ,&nbsp;Mikael Rydén","doi":"10.1016/j.molmet.2024.102082","DOIUrl":"10.1016/j.molmet.2024.102082","url":null,"abstract":"<div><div>In white adipose tissue, disturbed creatine metabolism through reduced creatine kinase B (CKB) transcription contributes to obesity-related inflammation. However, the mechanisms regulating <em>CKB</em> expression in human white adipocytes remain unclear. By screening conditions perturbed in obesity, we identified endoplasmic reticulum (ER) stress as a key suppressor of <em>CKB</em> transcription across multiple cell types. Through follow-up studies, we found that ER stress through the IRE1–XBP1s pathway, promotes <em>CKB</em> promoter methylation via the methyltransferase DNMT3A. This epigenetic change represses <em>CKB</em> transcription, shifting metabolism towards glycolysis and increasing the production of the pro-inflammatory chemokine CCL2. We validated our findings in vivo, demonstrating that individuals living with obesity show an inverse relationship between <em>CKB</em> expression and promoter methylation in white adipocytes, along with elevated CCL2 secretion. Overall, our study uncovers a regulatory axis where ER stress drives inflammation in obesity by reducing CKB abundance, and consequently altering the bioenergetic state of the cell.</div></div>","PeriodicalId":18765,"journal":{"name":"Molecular Metabolism","volume":"92 ","pages":"Article 102082"},"PeriodicalIF":7.0,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11731883/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142829429","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":"TMEM135 deficiency improves hepatic steatosis by suppressing CD36 in a SIRT1-dependent manner","authors":"Arun Chhetri ,&nbsp;Channy Park ,&nbsp;Hyunsoo Kim ,&nbsp;Laxman Manandhar ,&nbsp;Chagtsalmaa Chuluunbaatar ,&nbsp;Jaetaek Hwang ,&nbsp;Xiaofan Wei ,&nbsp;Gyuho Jang ,&nbsp;Batching Chinbold ,&nbsp;Hyug Moo Kwon ,&nbsp;Sang-wook Lee ,&nbsp;Raekil Park","doi":"10.1016/j.molmet.2024.102080","DOIUrl":"10.1016/j.molmet.2024.102080","url":null,"abstract":"<div><h3>Objectives</h3><div>Dysregulation of lipid homeostasis pathway causes many liver diseases, including hepatic steatosis. One of the primary factors contributing to lipid accumulation is fatty acid uptake by the liver. Transmembrane protein 135 (TMEM135), which exists in mitochondria and peroxisomes, participates in intracellular lipid metabolism. This study aims to investigate the role of TMEM135 on regulating cellular lipid import in the liver.</div></div><div><h3>Methods</h3><div>We used <em>in vivo, ex vivo</em>, and <em>in vitro</em> models of steatosis. TMEM135 knockout (TMEM135KO) and wild type (WT) mice were fed a high-fat diet (HFD) to induce hepatic steatosis. Primary mouse hepatocytes and AML12 cells were treated with free fatty acid (FFA). Additionally, TMEM135-deficient stable cells and overexpressed cells were established using AML12 cells.</div></div><div><h3>Results</h3><div>TMEM135 deficiency mitigated lipid accumulation in the liver of HFD-fed TMEM135KO mice. TMEM135-depleted primary hepatocytes and AML12 cells exhibited less lipid accumulation when treated with FFA compared to control cells, as shown as lipid droplets. Consistently, the effect of TMEM135 depletion on lipid accumulation was completely reversed under TMEM135 overexpression conditions. CD36 expression was markedly induced by HFD or FFA, which was reduced by TMEM135 depletion. Among the SIRT family proteins, only SIRT1 expression definitely increased in the liver of HFD-fed TMEM135KO mice along with a significant increase in NAD⁺/NADH ratio. However, inhibition of SIRT1 in TMEM135-depleted cells using siSIRT1 or the SIRT1 inhibitor EX-527 resulted in an increase of CD36 expression and consequent TG levels.</div></div><div><h3>Conclusions</h3><div>TMEM135 depletion attenuates CD36 expression in a SIRT1-dependent manner, thereby reducing cellular lipid uptake and hepatic steatosis.</div></div>","PeriodicalId":18765,"journal":{"name":"Molecular Metabolism","volume":"92 ","pages":"Article 102080"},"PeriodicalIF":7.0,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11728970/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142794981","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-dependent upregulation of Agrp in glomus type I cells of the carotid body","authors":"Luis Leon-Mercado ,&nbsp;Ivan Menendez-Montes ,&nbsp;Jonathan Tao ,&nbsp;Bandy Chen ,&nbsp;David P. Olson ,&nbsp;C. Mackaaij ,&nbsp;C.G.J. Cleypool ,&nbsp;Laurent Gautron","doi":"10.1016/j.molmet.2025.102095","DOIUrl":"10.1016/j.molmet.2025.102095","url":null,"abstract":"<div><div>Agouti-related peptide (AgRP) is a well-established potent orexigenic peptide primarily expressed in hypothalamic neurons. Nevertheless, the expression and functional significance of extrahypothalamic AgRP remain poorly understood. In this study, utilizing histological and molecular biology techniques, we have identified a significant expression of <em>Agrp</em> mRNA and AgRP peptide production in glomus type I cells within the mouse carotid body (CB). Furthermore, we have uncovered evidence supporting the expression of the AgRP receptor melanocortin receptor 3 (Mc3r) in adjacent sympathetic neurons, suggesting a potential local paracrine role for AgRP within the CB. Importantly, AgRP immunoreactivity was also identified in glomus type I cells of the human CB. Given the unexpected abundance of AgRP in glomus type I cells, a chemoreceptor cell specialized in oxygen sensing, we proceeded to investigate whether <em>Agrp</em> expression in the CB is regulated by hypoxemia and associated oxygen-sensing molecular mechanisms. <em>In vitro</em> luciferase assays reveal that hypoxia stimulates the human and mouse Agrp promoters in a Hypoxia Inducible Factor (HIF1/2)-dependent manner. Our <em>in vivo</em> experiments further demonstrate that exposure to environmental hypoxia (10%) robustly induces <em>Agrp</em> expression in type I glomus cells of mice. Furthermore, these findings collectively highlight the hitherto unknown source of AgRP in murine and human type I glomus cells and underscore the direct control of <em>Agrp</em> transcription by HIF signaling.</div></div>","PeriodicalId":18765,"journal":{"name":"Molecular Metabolism","volume":"92 ","pages":"Article 102095"},"PeriodicalIF":7.0,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11786784/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142964702","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":"Muscarinic acetylcholine type 1 receptor antagonism activates TRPM3 to augment mitochondrial function and drive axonal repair in adult sensory neurons","authors":"Sanjana Chauhan ,&nbsp;Darrell R. Smith ,&nbsp;Shiva Shariati-Ievari ,&nbsp;Abhay Srivastava ,&nbsp;Sanjiv Dhingra ,&nbsp;Michel Aliani ,&nbsp;Paul Fernyhough","doi":"10.1016/j.molmet.2024.102083","DOIUrl":"10.1016/j.molmet.2024.102083","url":null,"abstract":"<div><h3>Objective</h3><div>Antagonism of the muscarinic acetylcholine type 1 receptor (M₁R) promotes sensory axon repair and is protective in peripheral neuropathy, however, the mechanism remains elusive. We investigated the role of the heat-sensing transient receptor potential melastatin-3 (TRPM3) cation channel in M₁R antagonism-mediated nerve regeneration and explored the potential of TRPM3 activation to facilitate axonal plasticity.</div></div><div><h3>Methods</h3><div>Dorsal root ganglion (DRG) neurons from adult control or diabetic rats were cultured and treated with TRPM3 agonists (CIM0216, pregnenolone sulfate) and M₁R antagonists pirenzepine (PZ) or muscarinic toxin 7 (MT7). Ca²⁺ transients, mitochondrial respiration, AMP-activated protein kinase (AMPK) expression, and mitochondrial inner membrane potential were analyzed. The effect of M₁R activation or blockade on TRPM3 activity mediated by phosphatidylinositol 4,5-bisphosphate (PIP₂) was studied. Metabolic profiling of DRG neurons and human neuroblastoma SH-SY5Y cells was conducted.</div></div><div><h3>Results</h3><div>M₁R antagonism induced by PZ or MT7 increased Ca²⁺ influx in DRG neurons and was inhibited by TRPM3 antagonists or in the absence of extracellular Ca²⁺. TRPM3 agonists elevated Ca²⁺ levels, augmented mitochondrial respiration, AMPK activation and neurite outgrowth. M₁R antagonism stimulated TRPM3 channel activity through inhibition of PIP₂ hydrolysis to activate Ca²⁺/calmodulin-dependent protein kinase kinase β (CaMKKβ)/AMPK, leading to augmented mitochondrial function and neuronal metabolism. DRG neurons with AAV-mediated shRNA knockdown of TRPM3 exhibited suppressed antimuscarinic drug-induced neurite outgrowth. TRPM3 agonists increased glycolysis and TCA cycle metabolites, indicating enhanced metabolism in DRG neurons and SH-SY5Y cells.</div></div><div><h3>Conclusions</h3><div>Activation of the TRPM3/CaMKKβ/AMPK pathway promoted collateral sprouting of sensory axons, positioning TRPM3 as a promising therapeutic target for peripheral neuropathy.</div></div>","PeriodicalId":18765,"journal":{"name":"Molecular Metabolism","volume":"92 ","pages":"Article 102083"},"PeriodicalIF":7.0,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11732569/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142854825","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":"Synthetic inhibition of SREBP2 and the mevalonate pathway blocks rhabdomyosarcoma tumor growth in vitro and in vivo and promotes chemosensitization","authors":"Silvia Codenotti ,&nbsp;Michela Asperti ,&nbsp;Maura Poli ,&nbsp;Luisa Lorenzi ,&nbsp;Alberto Pietrantoni ,&nbsp;Matteo Cassandri ,&nbsp;Francesco Marampon ,&nbsp;Alessandro Fanzani","doi":"10.1016/j.molmet.2024.102085","DOIUrl":"10.1016/j.molmet.2024.102085","url":null,"abstract":"<div><h3>Objective</h3><div>The aim of the present study was to investigate the effects of targeting the mevalonate pathway (MVP) in rhabdomyosarcoma (RMS), a soft tissue tumor with a prevalence in young people.</div></div><div><h3>Methods</h3><div><em>In silico</em> analyses of RNA datasets were performed to correlate MVP with RMS patient survival. The sensitivity of RMS cell lines to MVP inhibitors was assessed <em>in vitro</em> by analysis of cell growth (crystal violet and clonogenic assays), cell migration (wound healing assay), cell survival (neutral red assay), and oxidative stress (ROS assay). The effects of MVP inhibitors were tested <em>in vivo</em> by analyzing RMS xenografts grown in NOD/SCID mice. Quantification of protein targets was performed using immunoblotting or immunohistochemistry analyses.</div></div><div><h3>Results</h3><div><em>In silico</em> analysis showed upregulation of sterol regulatory element-binding protein 2 (SREBP2) and MVP genes, including 3-Hydroxy-3-Methylglutaryl-CoA Reductase (HMGCR), farnesyl-diphosphate synthase (FDPS), squalene epoxidase (SQLE), which correlated with worse overall patient survival. Targeting of MVP in human RD and RH30 lines by inhibitors of SREBP2 (fatostatin), HMGCR (lovastatin and simvastatin), and FDPS (zoledronic acid) resulted in impaired cell growth, migration, and viability, and increased oxidative cell death in combination with actinomycin D. Conversely, cholesterol (CHO) supplementation enhanced cell growth and migration. Fatostatin and lovastatin produced rapid attenuation of Erk1/2 and Akt1 signaling in RMS lines, and oral administration of lovastatin reduced tumor mass growth of xenografted RD cells in NOD/SCID mice. Finally, we found that forced Akt1 activation in RD cells was sufficient to drive SREBP2, HMGCR and SQLE protein expression, promoting increased susceptibility to MVP inhibitors.</div></div><div><h3>Conclusions</h3><div>These data suggest that the Akt1, SREBP2 and MVP axis is critical for RMS tumor growth, migration, and oxidative stress protection primarily through maintaining adequate CHO levels that enable proper intracellular signaling. Therefore, stimulating CHO depletion via SREBP2 and MVP inhibition may represent a viable option to improve the combination therapy protocol, especially in pAkt1-positive RMS.</div></div>","PeriodicalId":18765,"journal":{"name":"Molecular Metabolism","volume":"92 ","pages":"Article 102085"},"PeriodicalIF":7.0,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11750561/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142872707","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":"Enhanced dynorphin expression and secretion in pancreatic beta-cells under hyperglycemic conditions","authors":"Miranda Movahed,&nbsp;Ruy A. Louzada,&nbsp;Manuel Blandino-Rosano","doi":"10.1016/j.molmet.2024.102088","DOIUrl":"10.1016/j.molmet.2024.102088","url":null,"abstract":"<div><h3>Objective</h3><div>Dynorphin, an endogenous opioid peptide predominantly expressed in the central nervous system and involved in stress response, pain, and addiction, has intrigued researchers due to its expression in pancreatic β-cells. In this study, we aimed to characterize dynorphin expression in mouse and human islets and explore the mechanisms regulating its expression.</div></div><div><h3>Methods</h3><div>We used primary mouse and human islets with unbiased published datasets to examine how glucose and other nutrients regulate dynorphin expression and secretion in islets.</div></div><div><h3>Results</h3><div>The prodynorphin gene is significantly upregulated in β-cells under hyperglycemic conditions. <em>In vitro</em> studies revealed that increased glucose concentrations correlate with increased dynorphin expression, indicating a critical interplay involving Ca²⁺, CamKII, and CREB pathways in β-cells. Perifusion studies allowed us to measure the dynamic secretion of dynorphin in response to glucose from mouse and human islets for the first time. Furthermore, we confirmed that increased dynorphin content within the β-cells directly correlates with enhanced dynorphin secretion. Finally, our findings demonstrate a synergistic effect of palmitate in conjunction with high glucose, further amplifying dynorphin levels and secretion in pancreatic islets.</div></div><div><h3>Conclusions</h3><div>This study demonstrates that the opioid peptide prodynorphin is expressed in mouse and human β-cells. Prodynorphin levels are regulated in parallel with insulin in response to glucose, palmitate, and amino acids. Our findings elucidate the signaling pathways involved, with CamKII playing a key role in regulating prodynorphin levels in β-cells. Finally, our findings are the first to demonstrate active dynorphin secretion from mouse and human islets in response to glucose.</div></div>","PeriodicalId":18765,"journal":{"name":"Molecular Metabolism","volume":"92 ","pages":"Article 102088"},"PeriodicalIF":7.0,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142907272","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":"SF1-specific deletion of the energy sensor AMPKγ2 induces obesity","authors":"Óscar Freire-Agulleiro ,&nbsp;Ánxela Estévez-Salguero ,&nbsp;Vitor Ferreira ,&nbsp;Cassie Lynn Holleman ,&nbsp;Julia García-Currás ,&nbsp;Ismael González-García ,&nbsp;Rubén Nogueiras ,&nbsp;Manuel Tena-Sempere ,&nbsp;Cristina García-Cáceres ,&nbsp;Carlos Diéguez ,&nbsp;Miguel López","doi":"10.1016/j.molmet.2024.102091","DOIUrl":"10.1016/j.molmet.2024.102091","url":null,"abstract":"<div><h3>Objective</h3><div>AMP-activated protein kinase (AMPK) is a heterotrimer complex consisting of a catalytic α subunit (α1, α2) with a serine/threonine kinase domain, and two regulatory subunits, β (β1, β2) and γ (γ1, γ2, γ3), encoded by different genes. In the hypothalamus, AMPK plays a crucial role in regulating energy balance, including feeding, energy expenditure, peripheral glucose and lipid metabolism. However, most research on hypothalamic AMPK has concentrated on the catalytic subunits AMPKα1 and AMPKα2, with little focus on the regulatory subunits.</div></div><div><h3>Methods</h3><div>To fill this gap of knowledge, we investigated the effects of selectively deleting the regulatory isoform AMPKγ2, which is a primary “energy sensor”, in steroidogenic factor 1 (SF1) neurons of the ventromedial hypothalamic nucleus (VMH). Complete metabolic phenotyping and molecular analyses in brown adipose tissue (BAT), white adipose tissue (WAT) and liver were carried out.</div></div><div><h3>Results</h3><div>Our findings reveal that, in contrast to the obesity-protective effect of the genetic deletion of AMPKα subunits, the loss of AMPKγ2 in SF1 neurons leads to a sex-independent and feeding-independent obesity-prone phenotype due to decreased thermogenesis in brown adipose tissue (BAT) and reduced browning of WAT, resulting in lower energy expenditure. Additionally, SF1-Cre AMPKγ2 mice exhibit hepatic lipid accumulation, but surprisingly maintain normal glucose homeostasis.</div></div><div><h3>Conclusions</h3><div>Overall, these results highlight the distinct roles of AMPK subunits within the hypothalamus.</div></div>","PeriodicalId":18765,"journal":{"name":"Molecular Metabolism","volume":"92 ","pages":"Article 102091"},"PeriodicalIF":7.0,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11782900/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142921106","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}