Molecular Metabolism最新文献

{"title":"A novel long non-coding RNA connects obesity to impaired adipocyte function","authors":"Aina Lluch ,&nbsp;Jèssica Latorre ,&nbsp;Núria Oliveras-Cañellas ,&nbsp;Ana Fernández-Sánchez ,&nbsp;José M. Moreno-Navarrete ,&nbsp;Anna Castells-Nobau ,&nbsp;Ferran Comas ,&nbsp;Maria Buxò ,&nbsp;José I. Rodríguez-Hermosa ,&nbsp;María Ballester ,&nbsp;Isabel Espadas ,&nbsp;Alejandro Martín-Montalvo ,&nbsp;Birong Zhang ,&nbsp;You Zhou ,&nbsp;Ralph Burkhardt ,&nbsp;Marcus Höring ,&nbsp;Gerhard Liebisch ,&nbsp;Ainara Castellanos-Rubio ,&nbsp;Izortze Santin ,&nbsp;Asha Kar ,&nbsp;Francisco J. Ortega","doi":"10.1016/j.molmet.2024.102040","DOIUrl":"10.1016/j.molmet.2024.102040","url":null,"abstract":"<div><h3>Background</h3><div>Long non-coding RNAs (lncRNAs) can perform tasks of key relevance in fat cells, contributing, when defective, to the burden of obesity and its sequelae. Here, scrutiny of adipose tissue transcriptomes before and after bariatric surgery (GSE53378) granted identification of 496 lncRNAs linked to the obese phenotype. Only expression of linc-GALNTL6-4 displayed an average recovery over 2-fold and FDR-adjusted p-value &lt;0.0001 after weight loss. The aim of the present study was to investigate the impact on adipocyte function and potential clinical value of impaired adipose linc-GALNTL6-4 in obese subjects.</div></div><div><h3>Methods</h3><div>We employed transcriptomic analysis of public dataset GSE199063, and cross validations in two large transversal cohorts to report evidence of a previously unknown association of adipose linc-GALNTL6-4 with obesity. We then performed functional analyses in human adipocyte cultures, genome-wide transcriptomics, and untargeted lipidomics in cell models of loss and gain of function to explore the molecular implications of its associations with obesity and weight loss.</div></div><div><h3>Results</h3><div>The expression of linc-GALNTL6-4 in human adipose tissue is adipocyte-specific and co-segregates with obesity, being normalized upon weight loss. This co-segregation is demonstrated in two longitudinal weight loss studies and two cross-sectional samples. While compromised expression of linc-GALNTL6-4 in obese subjects is primarily due to the inflammatory component in the context of obesity, adipogenesis requires the transcriptional upregulation of linc-GALNTL6-4, the expression of which reaches an apex in terminally differentiated adipocytes. Functionally, we demonstrated that the knockdown of linc-GALNTL6-4 impairs adipogenesis, induces alterations in the lipidome, and leads to the downregulation of genes related to cell cycle, while propelling in adipocytes inflammation, impaired fatty acid metabolism, and altered gene expression patterns, including that of apolipoprotein C1 (APOC1). Conversely, the genetic gain of linc-GALNTL6-4 ameliorated differentiation and adipocyte phenotype, putatively by constraining APOC1, also contributing to the metabolism of triglycerides in adipose.</div></div><div><h3>Conclusions</h3><div>Current data unveil the unforeseen connection of adipocyte-specific linc-GALNTL6-4 as a modulator of lipid homeostasis challenged by excessive body weight and meta-inflammation.</div></div>","PeriodicalId":18765,"journal":{"name":"Molecular Metabolism","volume":"90 ","pages":"Article 102040"},"PeriodicalIF":7.0,"publicationDate":"2024-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142372252","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":"miR-10a regulates cell death and inflammation in adipose tissue of male mice with diet-induced obesity","authors":"Sumin Lee ,&nbsp;Yoon Keun Cho ,&nbsp;Heeseong Kim ,&nbsp;Cheoljun Choi,&nbsp;Sangseob Kim,&nbsp;Yun-Hee Lee","doi":"10.1016/j.molmet.2024.102039","DOIUrl":"10.1016/j.molmet.2024.102039","url":null,"abstract":"<div><h3>Objective</h3><div>Adipose tissue remodeling plays a critical role in obesity-induced metabolic dysfunction, but the underlying molecular mechanisms remain incompletely understood. This study investigates the role of <em>miR-10a-5p</em> in adipose tissue inflammation and metabolic dysfunction induced by a high-fat diet (HFD).</div></div><div><h3>Methods</h3><div>Male <em>miR-10a</em> knockout (KO) mice were fed a HFD to induce obesity for up to 16 weeks. RNA sequencing (RNA-seq) analysis was performed to profile mRNA expression and assess the effects of <em>miR-10a-5p</em> KO in gonadal white adipose tissue (gWAT). Additional analyses included immunoblotting, qPCR, histological examination, and validation of the <em>miR-10a-5p</em> target sequence using a dual-luciferase reporter assay.</div></div><div><h3>Results</h3><div><em>miR-10a-5p</em> was highly expressed in gWAT but decreased after 8 weeks of HFD feeding. Over the 16-week HFD period, <em>miR-10a</em> KO mice exhibited greater weight gain and reduced energy expenditure compared to wild-type (WT) controls. gWAT of <em>miR-10a</em> KO mice on a HFD showed an increased population of proinflammatory macrophages, elevated inflammation, and increased cell death, characterized by upregulated apoptosis and necrosis markers. This was also associated with increased triglyceride accumulation in liver. Mechanistically, the proapoptotic gene <em>Bcl2l11</em> was identified as a direct target of <em>miR-10a-5p</em>. Loss of <em>miR-10a-5p</em> led to BIM-mediated adipocyte death and inflammation, contributing to mitochondrial metabolic dysregulation, increased fibrosis marker expression, and the onset of inflammation in adipose tissue.</div></div><div><h3>Conclusions</h3><div>This study demonstrates the significant role of <em>miR-10a-5p</em> and its downstream target BIM in regulating adipocyte death during diet-induced obesity. This signaling pathway presents a potential therapeutic target for modulating obesity-induced inflammation and cell death in adipose tissue.</div></div>","PeriodicalId":18765,"journal":{"name":"Molecular Metabolism","volume":"90 ","pages":"Article 102039"},"PeriodicalIF":7.0,"publicationDate":"2024-09-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142350339","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":"Identifying targetable metabolic dependencies across colorectal cancer progression","authors":"Danny N. Legge ,&nbsp;Tracey J. Collard ,&nbsp;Ewelina Stanko ,&nbsp;Ashley J. Hoskin ,&nbsp;Amy K. Holt ,&nbsp;Caroline J. Bull ,&nbsp;Madhu Kollareddy ,&nbsp;Jake Bellamy ,&nbsp;Sarah Groves ,&nbsp;Eric H. Ma ,&nbsp;Emma Hazelwood ,&nbsp;David Qualtrough ,&nbsp;Borko Amulic ,&nbsp;Karim Malik ,&nbsp;Ann C. Williams ,&nbsp;Nicholas Jones ,&nbsp;Emma E. Vincent","doi":"10.1016/j.molmet.2024.102037","DOIUrl":"10.1016/j.molmet.2024.102037","url":null,"abstract":"<div><div>Colorectal cancer (CRC) is a multi-stage process initiated through the formation of a benign adenoma, progressing to an invasive carcinoma and finally metastatic spread. Tumour cells must adapt their metabolism to support the energetic and biosynthetic demands associated with disease progression. As such, targeting cancer cell metabolism is a promising therapeutic avenue in CRC. However, to identify tractable nodes of metabolic vulnerability specific to CRC stage, we must understand how metabolism changes during CRC development. Here, we use a unique model system – comprising human early adenoma to late adenocarcinoma. We show that adenoma cells transition to elevated glycolysis at the early stages of tumour progression but maintain oxidative metabolism. Progressed adenocarcinoma cells rely more on glutamine-derived carbon to fuel the TCA cycle, whereas glycolysis and TCA cycle activity remain tightly coupled in early adenoma cells. Adenocarcinoma cells are more flexible with respect to fuel source, enabling them to proliferate in nutrient-poor environments. Despite this plasticity, we identify asparagine (ASN) synthesis as a node of metabolic vulnerability in late-stage adenocarcinoma cells. We show that loss of asparagine synthetase (ASNS) blocks their proliferation, whereas early adenoma cells are largely resistant to ASN deprivation. Mechanistically, we show that late-stage adenocarcinoma cells are dependent on ASNS to support mTORC1 signalling and maximal glycolytic and oxidative capacity. Resistance to ASNS loss in early adenoma cells is likely due to a feedback loop, absent in late-stage cells, allowing them to sense and regulate ASN levels and supplement ASN by autophagy. Together, our study defines metabolic changes during CRC development and highlights ASN synthesis as a targetable metabolic vulnerability in later stage disease.</div></div>","PeriodicalId":18765,"journal":{"name":"Molecular Metabolism","volume":"90 ","pages":"Article 102037"},"PeriodicalIF":7.0,"publicationDate":"2024-09-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142350338","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":"Corrigendum to “The BBSome regulates mitochondria dynamics and function molecular metabolism” [Mol Metabol 67 (2023) 101654]","authors":"Deng-Fu Guo ,&nbsp;Ronald A. Merrill ,&nbsp;Lan Qian ,&nbsp;Ying Hsu ,&nbsp;Qihong Zhang ,&nbsp;Zhihong Lin ,&nbsp;Daniel R. Thedens ,&nbsp;Yuriy M. Usachev ,&nbsp;Isabella Grumbach ,&nbsp;Val C. Sheffield ,&nbsp;Stefan Strack ,&nbsp;Kamal Rahmouni","doi":"10.1016/j.molmet.2024.102038","DOIUrl":"10.1016/j.molmet.2024.102038","url":null,"abstract":"","PeriodicalId":18765,"journal":{"name":"Molecular Metabolism","volume":"90 ","pages":"Article 102038"},"PeriodicalIF":7.0,"publicationDate":"2024-09-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142350340","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":"Acetate drives ovarian cancer quiescence via ACSS2-mediated acetyl-CoA production","authors":"Allison C. Sharrow ,&nbsp;Emily Megill ,&nbsp;Amanda J. Chen ,&nbsp;Afifa Farooqi ,&nbsp;Naveen Kumar Tangudu ,&nbsp;Apoorva Uboveja ,&nbsp;Stacy McGonigal ,&nbsp;Nadine Hempel ,&nbsp;Nathaniel W. Snyder ,&nbsp;Ronald J. Buckanovich ,&nbsp;Katherine M. Aird","doi":"10.1016/j.molmet.2024.102031","DOIUrl":"10.1016/j.molmet.2024.102031","url":null,"abstract":"<div><div>Quiescence is a reversible cell cycle exit traditionally thought to be associated with a metabolically inactive state. Recent work in muscle cells indicates that metabolic reprogramming is associated with quiescence. Whether metabolic changes occur in cancer to drive quiescence is unclear. Using a multi-omics approach, we found that the metabolic enzyme ACSS2, which converts acetate into acetyl-CoA, is both highly upregulated in quiescent ovarian cancer cells and required for their survival. Indeed, quiescent ovarian cancer cells have increased levels of acetate-derived acetyl-CoA, confirming increased ACSS2 activity in these cells. Furthermore, either inducing ACSS2 expression or supplementing cells with acetate was sufficient to induce a reversible quiescent cell cycle exit. RNA-Seq of acetate treated cells confirmed negative enrichment in multiple cell cycle pathways as well as enrichment of genes in a published G0 gene signature. Finally, analysis of patient data showed that ACSS2 expression is upregulated in tumor cells from ascites, which are thought to be more quiescent, compared to matched primary tumors. Additionally, high <em>ACSS2</em> expression is associated with platinum resistance and worse outcomes. Together, this study points to a previously unrecognized ACSS2-mediated metabolic reprogramming that drives quiescence in ovarian cancer. As chemotherapies to treat ovarian cancer, such as platinum, have increased efficacy in highly proliferative cells, our data give rise to the intriguing question that metabolically-driven quiescence may affect therapeutic response.</div></div>","PeriodicalId":18765,"journal":{"name":"Molecular Metabolism","volume":"89 ","pages":"Article 102031"},"PeriodicalIF":7.0,"publicationDate":"2024-09-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142291399","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":"Linking metabolism and histone acetylation dynamics by integrated metabolic flux analysis of Acetyl-CoA and histone acetylation sites","authors":"Anna-Sophia Egger ,&nbsp;Eva Rauch ,&nbsp;Suraj Sharma ,&nbsp;Tobias Kipura ,&nbsp;Madlen Hotze ,&nbsp;Thomas Mair ,&nbsp;Alina Hohenegg ,&nbsp;Philipp Kobler ,&nbsp;Ines Heiland ,&nbsp;Marcel Kwiatkowski","doi":"10.1016/j.molmet.2024.102032","DOIUrl":"10.1016/j.molmet.2024.102032","url":null,"abstract":"<div><h3>Objectives</h3><div>Histone acetylation is an important epigenetic modification that regulates various biological processes and cell homeostasis. Acetyl-CoA, a hub molecule of metabolism, is the substrate for histone acetylation, thus linking metabolism with epigenetic regulation. However, still relatively little is known about the dynamics of histone acetylation and its dependence on metabolic processes, due to the lack of integrated methods that can capture site-specific histone acetylation and deacetylation reactions together with the dynamics of acetyl-CoA synthesis.</div></div><div><h3>Methods</h3><div>In this study, we present a novel proteo-metabo-flux approach that combines mass spectrometry-based metabolic flux analysis of acetyl-CoA and histone acetylation with computational modelling. We developed a mathematical model to describe metabolic label incorporation into acetyl-CoA and histone acetylation based on experimentally measured relative abundances.</div></div><div><h3>Results</h3><div>We demonstrate that our approach is able to determine acetyl-CoA synthesis dynamics and site-specific histone acetylation and deacetylation reaction rate constants, and that consideration of the metabolically labelled acetyl-CoA fraction is essential for accurate determination of histone acetylation dynamics. Furthermore, we show that without correction, changes in metabolic fluxes would be misinterpreted as changes in histone acetylation dynamics, whereas our proteo-metabo-flux approach allows to distinguish between the two processes.</div></div><div><h3>Conclusions</h3><div>Our proteo-metabo-flux approach expands the repertoire of metabolic flux analysis and cross-omics and represents a valuable approach to study the regulatory interplay between metabolism and epigenetic regulation by histone acetylation.</div></div>","PeriodicalId":18765,"journal":{"name":"Molecular Metabolism","volume":"90 ","pages":"Article 102032"},"PeriodicalIF":7.0,"publicationDate":"2024-09-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142291404","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":"HDAC5 controls a hypothalamic STAT5b-TH axis, the sympathetic activation of ATP-consuming futile cycles and adult-onset obesity in male mice","authors":"Raian E. Contreras ,&nbsp;Tim Gruber ,&nbsp;Ismael González-García ,&nbsp;Sonja C. Schriever ,&nbsp;Meri De Angelis ,&nbsp;Noemi Mallet ,&nbsp;Miriam Bernecker ,&nbsp;Beata Legutko ,&nbsp;Dhiraj Kabra ,&nbsp;Mathias Schmidt ,&nbsp;Matthias H. Tschöp ,&nbsp;Ruth Gutierrez-Aguilar ,&nbsp;Jane Mellor ,&nbsp;Cristina García-Cáceres ,&nbsp;Paul T. Pfluger","doi":"10.1016/j.molmet.2024.102033","DOIUrl":"10.1016/j.molmet.2024.102033","url":null,"abstract":"<div><div>With age, metabolic perturbations accumulate to elevate our obesity burden. While age-onset obesity is mostly driven by a sedentary lifestyle and high calorie intake, genetic and epigenetic factors also play a role. Among these, members of the large histone deacetylase (HDAC) family are of particular importance as key metabolic determinants for healthy ageing, or metabolic dysfunction. Here, we aimed to interrogate the role of class 2 family member HDAC5 in controlling systemic metabolism and age-related obesity under non-obesogenic conditions. Starting at 6 months of age, we observed adult-onset obesity in chow-fed male global HDAC5-KO mice, that was accompanied by marked reductions in adrenergic-stimulated ATP-consuming futile cycles, including BAT activity and UCP1 levels, WAT-lipolysis, skeletal muscle, WAT and liver futile creatine and calcium cycles, and ultimately energy expenditure. Female mice did not differ between genotypes. The lower peripheral sympathetic nervous system (SNS) activity in mature male KO mice was linked to higher dopaminergic neuronal activity within the dorsomedial arcuate nucleus (dmARC) and elevated hypothalamic dopamine levels. Mechanistically, we reveal that hypothalamic HDAC5 acts as co-repressor of STAT5b over the control of <em>Tyrosine hydroxylase</em> (TH) gene transactivation, which ultimately orchestrates the activity of dmARH dopaminergic neurons and energy metabolism in male mice under non-obesogenic conditions.</div></div>","PeriodicalId":18765,"journal":{"name":"Molecular Metabolism","volume":"90 ","pages":"Article 102033"},"PeriodicalIF":7.0,"publicationDate":"2024-09-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142291401","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":"CPEB2-activated Prdm16 translation promotes brown adipocyte function and prevents obesity","authors":"Wen-Hsin Lu ,&nbsp;Hui-Feng Chen ,&nbsp;Pei-Chih King,&nbsp;Chi Peng,&nbsp;Yi-Shuian Huang","doi":"10.1016/j.molmet.2024.102034","DOIUrl":"10.1016/j.molmet.2024.102034","url":null,"abstract":"<div><h3>Objective</h3><div>Brown adipose tissue (BAT) plays an important role in mammalian thermogenesis through the expression of uncoupling protein 1 (UCP1). Our previous study identified cytoplasmic polyadenylation element binding protein 2 (CPEB2) as a key regulator that activates the translation of <em>Ucp1</em> with a long 3′-untranslated region (<em>Ucp1L</em>) in response to adrenergic signaling. Mice lacking CPEB2 or <em>Ucp1L</em> exhibited reduced UCP1 expression and impaired thermogenesis; however, only CPEB2-null mice displayed obesogenic phenotypes. Hence, this study aims to investigate how CPEB2-controlled translation impacts body weight.</div></div><div><h3>Methods</h3><div>Body weight measurements were conducted on mice with global knockout (KO) of CPEB2, UCP1 or <em>Ucp1L</em>, as well as those with conditional knockout of CPEB2 in neurons or adipose tissues. RNA sequencing coupled with bioinformatics analysis was used to identify dysregulated gene expression in CPEB2-deficient BAT. The role of CPEB2 in regulating PRD1-BF1-RIZ1 homologous-domain containing 16 (PRDM16) expression was subsequently confirmed by RT-qPCR, Western blotting, polysomal profiling and luciferase reporter assays. Adeno-associated viruses (AAV) expressing CPEB2 or PRDM16 were delivered into BAT to assess their efficacy in mitigating weight gain in CPEB2-KO mice.</div></div><div><h3>Results</h3><div>We validated that defective BAT function contributed to the increased weight gain in CPEB2-KO mice. Transcriptomic profiling revealed upregulated expression of genes associated with muscle development in CPEB2-KO BAT. Given that both brown adipocytes and myocytes stem from myogenic factor 5-expressing precursors, with their cell-fate differentiation regulated by PRDM16, we identified that <em>Prdm16</em> was translationally upregulated by CPEB2. Ectopic expression of PRDM16 in CPEB2-deprived BAT restored gene expression profiles and decreased weight gain in CPEB2-KO mice.</div></div><div><h3>Conclusions</h3><div>In addition to <em>Ucp1L</em>, activation of <em>Prdm16</em> translation by CPEB2 is critical for sustaining brown adipocyte function. These findings unveil a new layer of post-transcriptional regulation governed by CPEB2, fine-tuning thermogenic and metabolic activities of brown adipocytes to control body weight.</div></div>","PeriodicalId":18765,"journal":{"name":"Molecular Metabolism","volume":"89 ","pages":"Article 102034"},"PeriodicalIF":7.0,"publicationDate":"2024-09-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S2212877824001650/pdfft?md5=74d1359d3fcb57a10601c078d6fb0d5b&pid=1-s2.0-S2212877824001650-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142291400","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":"Intestinal gluconeogenesis controls the neonatal development of hypothalamic feeding circuits","authors":"Judith Estrada-Meza ,&nbsp;Jasmine Videlo ,&nbsp;Clara Bron ,&nbsp;Adeline Duchampt ,&nbsp;Cécile Saint-Béat ,&nbsp;Mickael Zergane ,&nbsp;Marine Silva ,&nbsp;Fabienne Rajas ,&nbsp;Sebastien G. Bouret ,&nbsp;Gilles Mithieux ,&nbsp;Amandine Gautier-Stein","doi":"10.1016/j.molmet.2024.102036","DOIUrl":"10.1016/j.molmet.2024.102036","url":null,"abstract":"<div><h3>Objective</h3><div>Intestinal gluconeogenesis (IGN) regulates adult energy homeostasis in part by controlling the same hypothalamic targets as leptin. In neonates, leptin exhibits a neonatal surge controlling axonal outgrowth between the different hypothalamic nuclei involved in feeding circuits and autonomic innervation of peripheral tissues involved in energy and glucose homeostasis. Interestingly, IGN is induced during this specific time-window. We hypothesized that the neonatal pic of IGN also regulates the development of hypothalamic feeding circuits and sympathetic innervation of adipose tissues.</div></div><div><h3>Methods</h3><div>We genetically induced neonatal IGN by overexpressing <em>G6pc1</em> the catalytic subunit of glucose-6-phosphatase (the mandatory enzyme of IGN) at birth or at twelve days after birth. The neonatal development of hypothalamic feeding circuits was studied by measuring Agouti-related protein (AgRP) and Pro-opiomelanocortin (POMC) fiber density in hypothalamic nuclei of 20-day-old pups. The effect of the neonatal induction of intestinal <em>G6pc1</em> on sympathetic innervation of the adipose tissues was studied via tyrosine hydroxylase (TH) quantification. The metabolic consequences of the neonatal induction of intestinal <em>G6pc1</em> were studied in adult mice challenged with a high-fat/high-sucrose (HFHS) diet for 2 months.</div></div><div><h3>Results</h3><div>Induction of intestinal <em>G6pc1</em> at birth caused a neonatal reorganization of AgRP and POMC fiber density in the paraventricular nucleus of the hypothalamus, increased brown adipose tissue tyrosine hydroxylase levels, and protected against high-fat feeding-induced metabolic disorders. In contrast, inducing intestinal <em>G6pc1</em> 12 days after birth did not impact AgRP/POMC fiber densities, adipose tissue innervation or adult metabolism.</div></div><div><h3>Conclusion</h3><div>These findings reveal that IGN at birth but not later during postnatal life controls the development of hypothalamic feeding circuits and sympathetic innervation of adipose tissues, promoting a better management of metabolism in adulthood.</div></div>","PeriodicalId":18765,"journal":{"name":"Molecular Metabolism","volume":"89 ","pages":"Article 102036"},"PeriodicalIF":7.0,"publicationDate":"2024-09-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142291402","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":"Knock-out of CD73 delays the onset of HR-negative breast cancer by reprogramming lipid metabolism and is associated with increased tumor mutational burden","authors":"Paweł Kamil Serafin ,&nbsp;Marta Popęda ,&nbsp;Kamila Bulak ,&nbsp;Agata Zwara ,&nbsp;Barbara Galikowska-Bogut ,&nbsp;Anna Przychodzka ,&nbsp;Adriana Mika ,&nbsp;Tomasz Śledziński ,&nbsp;Marcin Stanisławowski ,&nbsp;Kamila Jendernalik ,&nbsp;Marika Bolcewicz ,&nbsp;Wiktoria Laprus ,&nbsp;Grzegorz Stasiłojć ,&nbsp;Rafał Sądej ,&nbsp;Anna Żaczek ,&nbsp;Leszek Kalinowski ,&nbsp;Patrycja Koszałka","doi":"10.1016/j.molmet.2024.102035","DOIUrl":"10.1016/j.molmet.2024.102035","url":null,"abstract":"<div><h3>Objective</h3><div>CD73 (ecto-5′-nucleotidase, NT5E), a cell-surface enzyme converting 5′-AMP to adenosine, is crucial for cancer progression. However, its role in the tumorigenesis process remains mostly obscure. We aimed to demonstrate CD73's role in breast cancer (BC) tumorigenesis through metabolic rewiring of fatty acid metabolism, a process recently indicated to be regulated by BC major prognostic markers, hormone receptors (HR) for estrogen (ER), and progesterone (PR).</div></div><div><h3>Methods</h3><div>A murine model of chemically induced mammary gland tumorigenesis was applied to analyze CD73 knock-out (KO)-induced changes at the transcriptome (RNA-seq), proteome (IHC, WB), and lipidome (GC-EI-MS) levels. CD73 KO-induced changes were correlated with scRNA-seq and bulk RNA-seq data for human breast tissues and BCs from public collections and confirmed at the proteome level with IHC or WB analysis of BC tissue microarrays and cell lines.</div></div><div><h3>Results</h3><div>CD73 KO delayed the onset of HR/PR-negative mammary tumors in a murine model. This delay correlated with increased expression of genes related to biosynthesis and β-oxidation of fatty acids (FAs) in the CD73 KO group at the initiation stage. STRING analysis based on RNA-seq data indicated an interplay between CD73 KO, up-regulated expression of PR-coding gene, and DEGs involved in FA metabolism, with PPARγ, a main regulator of FA synthesis, as a main connective node. In epithelial cells of mammary glands, PPARγ expression correlated with CD73 at the RNA level. With cancer progression, CD73 KO increased the levels of PUFAn3/6 (polyunsaturated omega 3/6 FAs), known ligands of PPARγ and target for lipid peroxidation, which may lead to oxidative DNA damage. It correlated with the downregulation of genes involved in cellular stress response (<em>Mlh1</em>, <em>Gsta3</em>), PR–or CD73-dependent changes in the intracellular ROS levels and expression or activation of proteins involved in DNA repair or oxidative stress response in mammary tumor or human BC cell lines, increased tumor mutational burden (TMB) and genomic instability markers in CD73 low HR-negative human BCs, and the prolonged onset of tumors in the CD73 KO HR/PR-negative group.</div></div><div><h3>Conclusions</h3><div>CD73 has a significant role in tumorigenesis driving the reprogramming of lipid metabolism through the regulatory loop with PR and PPARγ in epithelial cells of mammary glands. Low CD73 expression/CD73 KO might enhance mutational burden by disrupting this regulatory loop, delaying the onset of HR-negative tumors. Our results support combining therapy targeting the CD73-adenosine axis and tumor lipidome against HR-negative tumors, especially at their earliest developmental stage.</div></div>","PeriodicalId":18765,"journal":{"name":"Molecular Metabolism","volume":"89 ","pages":"Article 102035"},"PeriodicalIF":7.0,"publicationDate":"2024-09-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S2212877824001662/pdfft?md5=27fa9c2e13a7751694f81cf6e399b5ad&pid=1-s2.0-S2212877824001662-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142291403","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}