Molecular Metabolism最新文献

{"title":"Pyruvate kinase deficiency links metabolic perturbations to neurodegeneration and axonal protection","authors":"Thomas J. Waller ,&nbsp;Catherine A. Collins ,&nbsp;Monica Dus","doi":"10.1016/j.molmet.2025.102187","DOIUrl":"10.1016/j.molmet.2025.102187","url":null,"abstract":"<div><h3>Objective</h3><div>Metabolic disruption is a central feature to many neurodegenerative diseases. Despite this, many gaps exist in our understanding of how these perturbations link to the mechanisms of neural disease. In this study, we sought to understand how genetically-controlled, cell-specific loss of pyruvate kinase (PyK) impacts motor neuron synaptic integrity and how the canonical neurodegenerative proteins DLK and SARM1 respond to this break in homeostasis.</div></div><div><h3>Methods</h3><div>This study made use of the genetically-tractable <em>Drosophila melanogaster</em> to cell-specifically express proteins (via the GAL4/UAS binary system), knockdown gene transcripts (via RNA interference), and knockout gene loci (via guide RNA-directed Cas9). Synaptic and axonal degeneration were measured through immunohistochemistry, microscopy, and blinded scoring of fly larvae at both early and later 3rd instar stages to test for progressive phenotypes. Nervous system injury through a physical nerve crush assay was used to assay functional outcomes of protective stress responses.</div></div><div><h3>Results</h3><div>We found that knockdown or knockout of <em>PyK</em> results in progressive axonal and synaptic degeneration, dependent on signaling through DLK and SARM1. This degeneration is preceded by nuclear transcriptional activation by DLK and the downstream AP-1 transcription factor Fos. We also found evidence of a neuroprotective response through injury of PyK-deficient axons (before progressive degeneration has occurred), which results in delayed Wallerian degeneration. This delay shows dependence on DLK and Fos, and coincides with reduced axonal localization of SARM1 whose overexpression fully restores degeneration speed.</div></div><div><h3>Conclusions</h3><div>These data support a rheostat model of DLK signaling that both promotes and inhibits axon degeneration in response to metabolic disruption. This rheostat likely converges on regulation of SARM1, which is required for the progressive synapse loss following PyK, but also abolishes the protective delay in injury-induced Wallerian degeneration when overexpressed. Overall, we conclude that metabolic signaling through PyK is essential for the integrity of motor neuron axons and synapses, and that its disruption activates both neurodegenerative and neuroprotective mechanisms</div></div>","PeriodicalId":18765,"journal":{"name":"Molecular Metabolism","volume":"98 ","pages":"Article 102187"},"PeriodicalIF":7.0,"publicationDate":"2025-06-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144285509","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":"Deletion of PPARα in mouse brown adipocytes increases their De Novo Lipogenesis","authors":"Pierre-Louis Batrow ,&nbsp;Sylvie Caspar-Bauguil ,&nbsp;Nathalie Rochet ,&nbsp;Nadine Gautier ,&nbsp;Anne-Sophie Rousseau ,&nbsp;Marielle Maret ,&nbsp;Samah Rekima ,&nbsp;Etienne Mouisel ,&nbsp;Emmanuel Van Obberghen ,&nbsp;Christian H. Roux ,&nbsp;Hervé Guillou ,&nbsp;Catherine Postic ,&nbsp;Christian Wolfrum ,&nbsp;Dominique Langin ,&nbsp;Ez-Zoubir Amri ,&nbsp;Isabelle Mothe-Satney","doi":"10.1016/j.molmet.2025.102184","DOIUrl":"10.1016/j.molmet.2025.102184","url":null,"abstract":"<div><h3>Objective</h3><div>Peroxisome Proliferator-Activated Receptors (PPARs) are nuclear receptors involved in the control of lipid metabolism. The PPARα isoform is highly expressed in brown adipose tissue (BAT). However, its precise role in BAT remains unclear. Here, we aimed to investigate the role of PPARα in BAT of high fat diet-induced obese mice in a thermoneutral environment.</div></div><div><h3>Methods</h3><div>We used tamoxifen-inducible-BAT specific PPARα knockout mice (PPARαBATKO) that were housed at thermoneutrality to minimize BAT basal activation, fed a high-fat diet for 20 weeks and challenged with a β₃-adrenergic agonist (CL316,243) during the last week. Both male and female mice were studied.</div></div><div><h3>Results</h3><div>Body weight and glucose tolerance tests were similar in both sexes and genotypes. However, BAT morphology was altered in PPARαBATKO mice, with more unilocular and larger lipid droplets compared to control mice, suggesting BAT impaired function. Indeed, when treated with CL316,243, both male and female mice had increased De Novo Lipogenesis (DNL), reflected by an increased expression of ChREBPβ and lipogenic enzymes ACLY, ACC1, FASN and SCD1. These changes were accompanied by an increase in fatty acids in triglycerides, and thus an increase in lipid storage. Moreover, lipid profiles in phospholipids were different, suggesting a modification in the membrane content with an increase of palmitoleate.</div></div><div><h3>Conclusions</h3><div>Altogether, our results reveal a key role for PPARα in DNL in BAT and in the regulation of lipid metabolism in HFD-induced obesity.</div></div>","PeriodicalId":18765,"journal":{"name":"Molecular Metabolism","volume":"98 ","pages":"Article 102184"},"PeriodicalIF":7.0,"publicationDate":"2025-06-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144275345","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":"RNA editing deficiency models differential immunogenicity of pancreatic α- and β-cells","authors":"Shani Peleg ,&nbsp;Liza Zamashanski ,&nbsp;Jonathan Belin ,&nbsp;Roy Novoselsky ,&nbsp;Roni Cohen-Fultheim ,&nbsp;Udi Ehud Knebel ,&nbsp;Benjamin Glaser ,&nbsp;Shalev Itzkovitz ,&nbsp;Klaus H. Kaestner ,&nbsp;Alvin C. Powers ,&nbsp;Erez Y. Levanon ,&nbsp;Agnes Klochendler ,&nbsp;Yuval Dor","doi":"10.1016/j.molmet.2025.102183","DOIUrl":"10.1016/j.molmet.2025.102183","url":null,"abstract":"<div><h3>Objective</h3><div>A longstanding question in type 1 diabetes (T1D) research pertains to the selective loss of β-cells whilst neighboring islet α-cells remain unharmed. We examined molecular mechanisms that may underly this differential vulnerability, by investigating the role of RNA editing, a cellular process that prevents double-stranded RNA (dsRNA)-mediated interferon response, in mouse α- and β-cells.</div></div><div><h3>Methods</h3><div>The enzyme responsible for RNA editing, Adar, was selectively deleted in vivo in mouse β-cells, α-cells, or in both cell types. Subsequent analyses were performed to investigate the impact of deficient RNA editing in α- or β-cells on the interferon response, islet inflammation, cell viability and metabolic outcomes.</div></div><div><h3>Results</h3><div>Mosaic disruption of the Adar gene in mouse β-cells triggers a massive interferon response, islet inflammation and mutant β-cell destruction. Surprisingly, wild type β-cells are also eliminated, whereas neighboring α-cells are unaffected. α-cell Adar deletion leads to only a slight elevation in interferon signature and does not elicit inflammation nor a metabolic phenotype. Concomitant deletion of Adar in α- and β-cells leads to elimination of both cell populations, suggesting that in contrast to β-cells, α-cell death requires both cell autonomous deficiency in RNA editing and exogenous cytokines.</div></div><div><h3>Conclusions</h3><div>We demonstrate differential sensitivity of mouse α- and β-cells to deficient RNA editing. The resistance of α-cells to RNA editing deficiency and to cytokines mirrors their persistence in T1D, and constitutes a molecularly defined model of differential islet cell vulnerability.</div></div>","PeriodicalId":18765,"journal":{"name":"Molecular Metabolism","volume":"98 ","pages":"Article 102183"},"PeriodicalIF":7.0,"publicationDate":"2025-06-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144275347","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":"Methylglyoxal-induced RNA modifications decrease RNA stability and translation and are associated with type 2 diabetes","authors":"Edwin De Jesus Lopez Gonzalez ,&nbsp;Seigmund Wai Tsuen Lai ,&nbsp;Kelani Sun ,&nbsp;Caree R. Carson ,&nbsp;Carlos Hernandez-Castillo ,&nbsp;Tala Zoukari ,&nbsp;Kassandra Lopez ,&nbsp;Jianying Zhang ,&nbsp;Thomas Blevins ,&nbsp;John Termini ,&nbsp;Sarah C. Shuck","doi":"10.1016/j.molmet.2025.102186","DOIUrl":"10.1016/j.molmet.2025.102186","url":null,"abstract":"<div><h3>Objectives</h3><div>Methylglyoxal (MG), a reactive aldehyde generated as a byproduct of glucose and lipid metabolism, is known to modify nucleic acids and proteins, altering their structure and function. While MG-induced DNA and protein adducts have been extensively studied and associated with type 2 diabetes (T2D) and its complications, the formation, biological relevance, and functional consequences of MG-induced RNA adducts remain poorly understood. This study aimed to define the chemical structures of MG-derived RNA adducts, assess their presence in clinical samples, and determine their impact on RNA stability and translation.</div></div><div><h3>Methods</h3><div>We employed liquid chromatography-tandem mass spectrometry (LC-MS/MS), nuclear magnetic resonance (NMR), and other spectroscopic techniques to characterize MG-induced RNA adducts formed in vitro and in biological samples. RNA was isolated from cultured cells and clinical urine specimens from individuals with and without T2D. RNA stability and translation were assessed using firefly luciferase reporter mRNAs modified with MG in cell-based assays.</div></div><div><h3>Results</h3><div><em>In vitro</em> MG treatment resulted in the formation of an unstable product, tentatively identified as <em>N²</em>-(1,2-dihydroxy-2-methyl)ethano-guanosine (cMG-guanosine), and two stable adducts: <em>N²</em>-(1-carboxyethyl)-guanosine (CEG) and <em>N²</em>-(1-carboxyethyl)-7–1-hydroxy-2-oxopropyl-guanosine (MG-CEG). In cellular RNA and urine from patients, only the stereoisomers of CEG were detected. CEG levels were significantly elevated in patients with T2D compared to controls and showed a stronger association with T2D than the DNA adduct <em>N²</em>-(1-carboxyethyl)-deoxyguanosine (CEdG). Furthermore, CEG levels were higher in T2D patients who had developed complications compared to those without complications. Functionally, MG-modified luciferase mRNA exhibited decreased stability and reduced translational efficiency relative to unmodified mRNA.</div></div><div><h3>Conclusions</h3><div>This study provides the first structural and functional characterization of MG-induced RNA adducts and demonstrates their accumulation in individuals with T2D, particularly in those with disease complications. These findings highlight RNA MG-adducts as clinically relevant epitranscriptomic modifications that may contribute to RNA destabilization and impaired translation, suggesting a novel molecular mechanism by which metabolic stress may exacerbate disease progression.</div></div>","PeriodicalId":18765,"journal":{"name":"Molecular Metabolism","volume":"98 ","pages":"Article 102186"},"PeriodicalIF":7.0,"publicationDate":"2025-06-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144275346","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":"Adiponectin-receptor agonism prevents right ventricular tissue pathology in a mouse model of Duchenne muscular dystrophy","authors":"Shivam Gandhi ,&nbsp;Luca J. Delfinis ,&nbsp;Parashar D. Bhatt ,&nbsp;Madison C. Garibotti ,&nbsp;Catherine A. Bellissimo ,&nbsp;Amireza N. Goli ,&nbsp;Brooke A. Morris ,&nbsp;Aditya N. Brahmbhatt ,&nbsp;Simona Yakobov-Shimonov ,&nbsp;Fasih A. Rahman ,&nbsp;Joe Quadrilatero ,&nbsp;Jeremy A. Simpson ,&nbsp;Gary Sweeney ,&nbsp;Ali A. Abdul-Sater ,&nbsp;Peter H. Backx ,&nbsp;Henry H. Hsu ,&nbsp;Christopher G.R. Perry","doi":"10.1016/j.molmet.2025.102179","DOIUrl":"10.1016/j.molmet.2025.102179","url":null,"abstract":"<div><h3>Objective</h3><div>Cardiac fibrosis during Duchenne muscular dystrophy (DMD) arises from cellular damage and inflammation and is associated with metabolic dysfunction. The extent to which these relationships develop across all 4 cardiac chambers, particularly during early-stage disease, remains unknown.</div></div><div><h3>Methods and Results</h3><div>We discovered that very young D2.mdx mice exhibit fibrosis exclusively in the right ventricle (RV) and left atrium. Concurrent myocardial disorganization in the RV was related to a highly specific inflammatory signature of increased infiltrating pro-inflammatory macrophages (CD11b+CD45+CD64+F4/80+CCR2+), myofibre mitochondrial-linked apoptosis, and reduced carbohydrate and fat oxidation. This relationship did not occur in the left ventricle. Short-term daily administration of a peptidomimetic adiponectin receptor agonist, ALY688, prevented RV fibrosis, infiltrating macrophages, and mitochondrial stress as well as left atrial fibrosis.</div></div><div><h3>Conclusions</h3><div>Our discoveries demonstrate early-stage cardiac tissue pathology occurs in a chamber-specific manner and is prevented by adiponectin receptor agonism, thereby opening a new direction for developing therapies that prevent tissue remodeling during DMD.</div></div>","PeriodicalId":18765,"journal":{"name":"Molecular Metabolism","volume":"99 ","pages":"Article 102179"},"PeriodicalIF":7.0,"publicationDate":"2025-06-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144258584","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":"microRNA-1 regulates metabolic flexibility by programming adult skeletal muscle pyruvate metabolism","authors":"Ahmed Ismaeel ,&nbsp;Bailey D. Peck ,&nbsp;McLane M. Montgomery ,&nbsp;Benjamin I. Burke ,&nbsp;Jensen Goh ,&nbsp;Abigail B. Franco ,&nbsp;Qin Xia ,&nbsp;Katarzyna Goljanek-Whysall ,&nbsp;Brian McDonagh ,&nbsp;Jared M. McLendon ,&nbsp;Pieter J. Koopmans ,&nbsp;Daniel Jacko ,&nbsp;Kirill Schaaf ,&nbsp;Wilhelm Bloch ,&nbsp;Sebastian Gehlert ,&nbsp;Kevin A. Murach ,&nbsp;Kelsey H. Fisher–Wellman ,&nbsp;Ryan L. Boudreau ,&nbsp;Yuan Wen ,&nbsp;John J. McCarthy","doi":"10.1016/j.molmet.2025.102182","DOIUrl":"10.1016/j.molmet.2025.102182","url":null,"abstract":"<div><h3>Objective</h3><div>Metabolic flexibility refers to the ability of tissues to adjust cellular fuel choice in response to conditional changes in metabolic demand and activity. A loss of metabolic flexibility is a defining feature of various diseases and cellular dysfunction. This study investigated the role of microRNA-1 (miR-1), the most abundant microRNA in skeletal muscle, in maintaining whole-body metabolic flexibility.</div></div><div><h3>Methods</h3><div>We used an inducible, skeletal muscle-specific knockout (KO) mouse model to examine miR-1 function. Argonaute 2 enhanced crosslinking and immunoprecipitation sequencing (AGO2 eCLIP-seq) and RNA-seq analyses identified miR-1 target genes. Metabolism was investigated using metabolomics, proteomics, and comprehensive bioenergetic and activity phenotyping. Corroborating information was provided from cell culture, <em>C. elegans</em>, and exercised human muscle tissue.</div></div><div><h3>Results</h3><div>miR-1 KO mice demonstrated loss of diurnal oscillations in whole-body respiratory exchange ratio and higher fasting blood glucose. For the first time, we identified bona fide miR-1 target genes in adult skeletal muscle that regulated pyruvate metabolism through mechanisms including the alternative splicing of pyruvate kinase (<em>Pkm</em>). The maintenance of metabolic flexibility by miR-1 was necessary for sustained endurance activity in mice and in <em>C. elegans</em>. Loss of metabolic flexibility in the miR-1 KO mouse was rescued by pharmacological inhibition of the miR-1 target, monocarboxylate transporter 4 (MCT4), which redirects glycolytic carbon flux toward oxidation. The physiological down-regulation of miR-1 in response to hypertrophic stimuli caused a similar metabolic reprogramming necessary for muscle cell growth.</div></div><div><h3>Conclusions</h3><div>These data identify a novel post-transcriptional mechanism of whole-body metabolism regulation mediated by a tissue-specific miRNA.</div></div>","PeriodicalId":18765,"journal":{"name":"Molecular Metabolism","volume":"98 ","pages":"Article 102182"},"PeriodicalIF":7.0,"publicationDate":"2025-06-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144258585","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":"Gut microbiota-derived extracellular vesicles exhibit diurnal regulation and activate hepatic gluconeogenesis","authors":"Jian Tan ,&nbsp;Jemma Justine Taitz ,&nbsp;Duan Ni ,&nbsp;Camille Potier-Villette ,&nbsp;Gabriela Pinget ,&nbsp;Tamara Pulpitel ,&nbsp;Dragana Stanley ,&nbsp;Ralph Nanan ,&nbsp;Laurence Macia","doi":"10.1016/j.molmet.2025.102180","DOIUrl":"10.1016/j.molmet.2025.102180","url":null,"abstract":"<div><div>The circadian clock regulates tissue-specific homeostasis, and its disruption is associated with metabolic disorders. Both host metabolic processes and the gut microbiota exhibit diurnal regulation, and both contribute to the maintenance of glucose homeostasis (Thaiss et al., 2014; Bishehsari et al., 2020; Frazier et al., 2023) [1–3]. However, how the gut microbiota and the circadian rhythm interplay to control host glucose homeostasis is not fully understood. Here, we identified gut microbiota-derived extracellular vesicles (MEV) as a potential peripheral Zeitgeber (time cue) for the hepatic circadian clock, controlling hepatic gluconeogenesis. Host feeding patterns influence the gut microbiota, driving the diurnal production of MEV. Gut MEV levels coincide with the activity of hepatic gluconeogenesis, with overnight fasting associated with increased production of MEV by gut bacteria. MEV directly activates hepatic gluconeogenesis and chronic increase in MEV exposure impairs glucose homeostasis <em>in vivo</em>. Our finding highlights a mechanism by which the gut microbiota has co-evolved with the host to support its glucose needs during periods of energy demands (such as during fasting or starvation). On the contrary, an abnormal increase in MEV production, leading to dysregulated gluconeogenesis, may underlie various glucose-associated disorders, such as type 2 or gestational diabetes. Together, our data reconcile the gut microbiota and circadian rhythm in the control of host glucose homeostasis and metabolic health.</div></div>","PeriodicalId":18765,"journal":{"name":"Molecular Metabolism","volume":"98 ","pages":"Article 102180"},"PeriodicalIF":7.0,"publicationDate":"2025-06-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144248802","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":"VGluT3 BNST neurons transmit GABA and restrict sucrose consumption","authors":"Annie Ly ,&nbsp;Rachel Karnosky ,&nbsp;Emily D. Prévost ,&nbsp;Hayden Hotchkiss ,&nbsp;Julianne M. Pelletier ,&nbsp;Robert L. Spencer ,&nbsp;Christopher P. Ford ,&nbsp;David H. Root","doi":"10.1016/j.molmet.2025.102178","DOIUrl":"10.1016/j.molmet.2025.102178","url":null,"abstract":"<div><h3>Objective</h3><div>The bed nucleus of the stria terminalis (BNST) is involved in feeding, reward, aversion, and anxiety-like behavior. We identify BNST neurons defined by the expression of vesicular glutamate transporter 3, VGluT3.</div></div><div><h3>Methods</h3><div>A combination of <em>in situ</em> hybridization, tract tracing, <em>ex vivo</em> whole-cell electrophysiology, <em>in vivo</em> recording, optogenetic, and behavioral approaches were used.</div></div><div><h3>Results</h3><div>VGluT3 neurons were localized to anteromedial BNST, were molecularly distinct from accumbal VGluT3 neurons, and co-express vesicular GABA transporter (VGaT). BNST VGluT3 neurons projected to arcuate nucleus (ARC) and paraventricular nucleus of the hypothalamus (PVN), regions critical for feeding and homeostatic regulation. Most single BNST VGluT3 neurons projected to either PVN or ARC and a subset projected to both. BNST VGluT3 neurons functionally transmit GABA to both ARC and PVN, with rare glutamate co-transmission to ARC. <em>In vivo</em>, VGluT3 BNST neurons showed greater neuronal activity in response to sucrose consumption while sated compared with fasted. When fasted, optogenetic stimulation of BNST VGluT3 neurons decreased sucrose consumption using several stimulation conditions but not when stimulation occurred prior to sucrose access, suggesting that BNST VGluT3 activation concurrent with consumption in the fasted state reduces feeding. BNST VGluT3 activation had no effect on anxiety-like behavior in several paradigms (novelty-suppressed feeding, open field, and elevated zero maze). BNST VGluT3 activation also did not result in real-time place preference or aversion.</div></div><div><h3>Conclusions</h3><div>We interpret these data such that VGluT3 BNST neurons represent a unique cellular population within the BNST that provides inhibitory input to hypothalamic regions to decrease sucrose consumption.</div></div>","PeriodicalId":18765,"journal":{"name":"Molecular Metabolism","volume":"98 ","pages":"Article 102178"},"PeriodicalIF":7.0,"publicationDate":"2025-06-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144248814","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":"Stress and high fat diet reconfigure the active translatome of CeA-NPY neurons","authors":"Chi Kin Ip ,&nbsp;Lei Zhang ,&nbsp;Ramon Tasan ,&nbsp;Herbert Herzog","doi":"10.1016/j.molmet.2025.102176","DOIUrl":"10.1016/j.molmet.2025.102176","url":null,"abstract":"<div><h3>Objective</h3><div>The interplay between calorie-dense food and chronic stress significantly accelerates obesity development, with neural circuits expressing Neuropeptide Y (NPY) in the central amygdala (CeA) emerging as the key mediator of this process. While these circuits are known to enhance hedonic feeding behavior and promote weight gain, the precise molecular mechanisms regulating NPY neuron activity at the translational level under the combined influence of high fat diet and stress conditions have remained poorly understood.</div></div><div><h3>Methods</h3><div>We employed translational ribosome affinity purification coupled with Next-Generation Sequencing (TRAPseq), allowing us to specifically identify RNA transcripts actively undergoing protein translation in NPY neurons under high fat diet (HFD) or high fat diet combined with stress conditions (HFDS).</div></div><div><h3>Results</h3><div>Our molecular profiling demonstrates that NPY neurons specifically co-express with genes marking the orexigenic (appetite-stimulating) population, while showing minimal overlap with anorexigenic (appetite-suppressing) markers. Gene ontology analysis identified distinct clusters involved in fatty acid metabolic processes, stress response pathways, and the production of feeding-related neuropeptides specifically under HFDS. Immunohistochemical investigations revealed in addition to local CeA (CeA^m) NPY connection pathways, long-range projections, to the lateral habenula (LHb), the periaqueductal gray (PAG) and parvicellular reticular formation (PCRt). These projections suggest a specific role for CeA NPY neurons in coordinating feeding and emotional responses.</div></div><div><h3>Conclusion</h3><div>Collectively, our findings identify specific lipid-sensing mechanisms and synaptic modulating pathways as principal targets of stress within the CeA-NPY circuit, revealing novel molecular mechanisms through which NPY neurons integrate and process both dietary and stress signals.</div></div>","PeriodicalId":18765,"journal":{"name":"Molecular Metabolism","volume":"98 ","pages":"Article 102176"},"PeriodicalIF":7.0,"publicationDate":"2025-06-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144248813","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":"RNA binding proteins PCBP1 and PCBP2 regulate pancreatic β cell translation","authors":"Matthew W. Haemmerle ,&nbsp;Kirill Batmanov ,&nbsp;Sabyasachi Sen ,&nbsp;Matthew J. Varney ,&nbsp;Alexander T. Utecht ,&nbsp;Austin L. Good ,&nbsp;Andrea V. Scota ,&nbsp;Sarah A. Tersey ,&nbsp;Louis R. Ghanem ,&nbsp;Caroline C. Philpott ,&nbsp;Doris A. Stoffers","doi":"10.1016/j.molmet.2025.102175","DOIUrl":"10.1016/j.molmet.2025.102175","url":null,"abstract":"<div><h3>Objectives</h3><div>Tight control of β cell mRNA translation plays a central role in regulating glucose homoeostasis and β cell health. RNA binding proteins (RBPs) impact translational dynamics and function in networks to achieve their regulatory outcomes, yet an understanding of the RBPs and nature of their interplay in directing β cell translation remain limited. We recently established that the RBP PCBP2 is a key post-transcriptional regulator of β cell function. Here, we investigate the relationship of PCBP2 and its sister-isoform PCBP1 in shaping β cell homeostasis and translation.</div></div><div><h3>Methods</h3><div>Mice with β cell-specific deletion of <em>Pcbp1</em> and combined <em>Pcbp1/2</em> were generated to examine the influence of these factors on blood glucose and β cell homeostasis. Gene expression was interrogated with single-cell RNA sequencing, qRT-PCR, and western blot. RNA-protein interactions were measured using RNA immunoprecipitation. Gene depletion studies were performed using CRISPR-Cas9 or shRNAs. Puromycin labeling was used to monitor global translation.</div></div><div><h3>Results</h3><div><em>Pcbp1</em> deletion preserved glucose homeostasis whereas <em>Pcbp</em> co-deletion resulted in severe diabetes due to compromised β cell viability. Single-cell RNA sequencing of <em>Pcbp</em> co-deficient β cells revealed downregulation of a network of core translation initiation factors and ribosomal mRNAs. Motif enrichment analysis, mRNA-protein interaction, and mRNA stability studies identified that the PCBPs co-impact these mRNAs in part through binding and stabilization. Accordingly, protein translational monitoring demonstrated a requirement for the PCBPs in sustaining global mRNA translation in β cells.</div></div><div><h3>Conclusions</h3><div>Our findings demonstrate a requirement for the PCBPs in sustaining the global rates of mRNA translation critical for β cell control of glucose homeostasis.</div></div>","PeriodicalId":18765,"journal":{"name":"Molecular Metabolism","volume":"98 ","pages":"Article 102175"},"PeriodicalIF":7.0,"publicationDate":"2025-05-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144199632","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}