Molecular Metabolism最新文献

{"title":"Peroxiredoxin 2 regulates DAF-16/FOXO mediated mitochondrial remodelling in response to exercise that is disrupted in ageing","authors":"Qin Xia ,&nbsp;Penglin Li ,&nbsp;José C. Casas-Martinez ,&nbsp;Antonio Miranda-Vizuete ,&nbsp;Emma McDermott ,&nbsp;Peter Dockery ,&nbsp;Katarzyna Goljanek-Whysall ,&nbsp;Brian McDonagh","doi":"10.1016/j.molmet.2024.102003","DOIUrl":"10.1016/j.molmet.2024.102003","url":null,"abstract":"<div><h3>Objectives</h3><p>A decline in mitochondrial function and increased susceptibility to oxidative stress is a hallmark of ageing. Exercise endogenously generates reactive oxygen species (ROS) in skeletal muscle and promotes mitochondrial remodelling resulting in improved mitochondrial function. It is unclear how exercise induced redox signalling results in alterations in mitochondrial dynamics and morphology.</p></div><div><h3>Methods</h3><p>In this study, a <em>Caenorhabditis elegans</em> model of exercise and ageing was used to determine the mechanistic role of Peroxiredoxin 2 (PRDX-2) in regulating mitochondrial morphology. Mitochondrial morphology was analysed using transgenic reporter strains and transmission electron microscopy, complimented with the analysis of the effects of ageing and exercise on physiological activity.</p></div><div><h3>Results</h3><p>The redox state of PRDX-2 was altered with exercise and ageing, hyperoxidised peroxiredoxins were detected in old worms along with basally elevated intracellular ROS. Exercise generated intracellular ROS and rapid mitochondrial remodelling, which was disrupted with age. The exercise intervention promoted mitochondrial ER contact sites (MERCS) assembly and increased DAF-16/FOXO nuclear localisation. The <em>prdx-2</em> mutant strain had a disrupted mitochondrial network as evidenced by increased mitochondrial fragmentation. In the <em>prdx-2</em> mutant strain, exercise did not activate DAF-16/FOXO, mitophagy or increase MERCS assembly. The results demonstrate that exercise generated ROS increased DAF-16/FOXO transcription factor nuclear localisation required for activation of mitochondrial fusion events that were blunted with age.</p></div><div><h3>Conclusions</h3><p>The data demonstrate the critical role of PRDX-2 in orchestrating mitochondrial remodelling in response to a physiological stress by regulating redox dependent DAF-16/FOXO nuclear localisation.</p></div>","PeriodicalId":18765,"journal":{"name":"Molecular Metabolism","volume":"88 ","pages":"Article 102003"},"PeriodicalIF":7.0,"publicationDate":"2024-08-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S2212877824001340/pdfft?md5=82765dfb901b6b5a5d971370c33ba848&pid=1-s2.0-S2212877824001340-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141907067","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":"Bitter-tasting drugs tune GDF15 and GLP-1 expression via bitter taste or motilin receptors in the intestine of patients with obesity","authors":"Qian Wang ,&nbsp;Mona Farhadipour ,&nbsp;Theo Thijs ,&nbsp;Emily Ruilova Sosoranga ,&nbsp;Bart Van der Schueren ,&nbsp;Laurens J. Ceulemans ,&nbsp;Ellen Deleus ,&nbsp;Matthias Lannoo ,&nbsp;Jan Tack ,&nbsp;Inge Depoortere","doi":"10.1016/j.molmet.2024.102002","DOIUrl":"10.1016/j.molmet.2024.102002","url":null,"abstract":"<div><h3>Objective</h3><p>Growth differentiation factor 15 (GDF15), a stress related cytokine, was recently identified as a novel satiety signal acting via the GFRAL receptor located in the hindbrain. Bitter compounds are known to induce satiety via the release of glucagon-like peptide 1 (GLP-1) through activation of bitter taste receptors (TAS2Rs, 25 subtypes) on enteroendocrine cells in the gut. This study aimed to investigate whether and how bitter compounds induce a stress response in intestinal epithelial cells to affect GDF15 expression in patients with obesity, thereby facilitating satiety signaling from the gut.</p></div><div><h3>Methods</h3><p>The acute effect of oral intake of the bitter-containing medication Plaquenil (hydroxychloroquine sulfate) on plasma GDF15 levels was evaluated in a placebo-controlled, double-blind, randomized, two-visit crossover study in healthy volunteers. Primary crypts isolated from the jejunal mucosa from patients with obesity were stimulated with vehicle or bitter compounds, and the effect on GDF15 expression was evaluated using RT-qPCR or ELISA. Immunofluorescence colocalization studies were performed between GDF15, epithelial cell type markers and TAS2Rs. The role of TAS2Rs was tested by 1) pretreatment with a TAS2R antagonist, GIV3727; 2) determining TAS2R4/43 polymorphisms that affect taste sensitivity to TAS2R4/43 agonists.</p></div><div><h3>Results</h3><p>Acute intake of hydroxychloroquine sulfate increased GDF15 plasma levels, which correlated with reduced hunger scores and plasma ghrelin levels in healthy volunteers. This effect was mimicked in primary jejunal cultures from patients with obesity. GDF15 was expressed in enteroendocrine and goblet cells with higher expression levels in patients with obesity. Various bitter-tasting compounds (medicinal, plant extracts, bacterial) either increased or decreased GDF15 expression, with some also affecting GLP-1. The effect was mediated by specific intestinal TAS2R subtypes and the unfolded protein response pathway. The bitter-induced effect on GDF15/GLP-1 expression was influenced by the existence of TAS2R4 amino acid polymorphisms and TAS2R43 deletion polymorphisms that may predict patient's therapeutic responsiveness. However, the effect of the bitter-tasting antibiotic azithromycin on GDF15 release was mediated via the motilin receptor, possibly explaining some of its aversive side effects.</p></div><div><h3>Conclusions</h3><p>Bitter chemosensory and pharmacological receptors regulate the release of GDF15 from human gut epithelial cells and represent potential targets for modulating metabolic disorders or cachexia.</p></div>","PeriodicalId":18765,"journal":{"name":"Molecular Metabolism","volume":"88 ","pages":"Article 102002"},"PeriodicalIF":7.0,"publicationDate":"2024-08-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S2212877824001339/pdfft?md5=f5827da181b705475d7efd75b5003692&pid=1-s2.0-S2212877824001339-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141902353","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":"An efficient AAV vector system of Rec2 serotype for intravenous injection to study metabolism in brown adipocytes in vivo","authors":"Janina Behrens ,&nbsp;Ingke Braren ,&nbsp;Michelle Y. Jaeckstein ,&nbsp;Luka Lilie ,&nbsp;Markus Heine ,&nbsp;Finnja Sass ,&nbsp;Judith Sommer ,&nbsp;Dagmar Silbert-Wagner ,&nbsp;Marceline M. Fuh ,&nbsp;Anna Worthmann ,&nbsp;Leon Straub ,&nbsp;Tarek Moustafa ,&nbsp;Joerg Heeren ,&nbsp;Ludger Scheja","doi":"10.1016/j.molmet.2024.101999","DOIUrl":"10.1016/j.molmet.2024.101999","url":null,"abstract":"<div><h3>Objective</h3><p>Recombinant adeno-associated virus (rAAV) vectors are powerful tools for the sustained expression of proteins <em>in vivo</em> and have been successfully used for mechanistic studies in mice. A major challenge associated with this method is to obtain tissue specificity and high expression levels without need of local virus administration.</p></div><div><h3>Methods</h3><p>To achieve this goal for brown adipose tissue (BAT), we developed a rAAV vector for intravenous bolus injection, which includes an expression cassette comprising an uncoupling protein-1 enhancer-promoter for transcription in brown adipocytes and miR122 target sequences for suppression of expression in the liver, combined with packaging in serotype Rec2 capsid protein. To test tissue specificity, we used a version of this vector expressing Cre recombinase to transduce mice with floxed alleles to knock out MLXIPL (ChREBP) or tdTomato-Cre reporter mice.</p></div><div><h3>Results</h3><p>We demonstrated efficient Cre-dependent recombination in interscapular BAT and variable effects in minor BAT depots, but little or no efficacy in white adipose tissues, liver and other organs. Direct overexpression of glucose transporter SLC2A1 (GLUT1) using the rAAV vector in wild type mice resulted in increased glucose uptake and glucose-dependent gene expression in BAT, indicating usefulness of this vector to increase the function even of abundant proteins.</p></div><div><h3>Conclusion</h3><p>Taken together, we describe a novel brown adipocyte-specific rAAV method to express proteins for loss-of-function and gain-of-function metabolic studies. The approach will enable researchers to access brown fat swiftly, reduce animal breeding time and costs, as well as enable the creation of new transgenic mouse models combining multiple transgenes.</p></div>","PeriodicalId":18765,"journal":{"name":"Molecular Metabolism","volume":"88 ","pages":"Article 101999"},"PeriodicalIF":7.0,"publicationDate":"2024-07-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S2212877824001303/pdfft?md5=38dc7ebd6ff1f7b186786795d0ba5fd8&pid=1-s2.0-S2212877824001303-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141879105","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":"PPARG in osteocytes controls cell bioenergetics and systemic energy metabolism independently of sclerostin levels in circulation","authors":"Sudipta Baroi ,&nbsp;Piotr J. Czernik ,&nbsp;Mohd Parvez Khan ,&nbsp;Joshua Letson ,&nbsp;Emily Crowe ,&nbsp;Amit Chougule ,&nbsp;Patrick R. Griffin ,&nbsp;Clifford J. Rosen ,&nbsp;Beata Lecka-Czernik","doi":"10.1016/j.molmet.2024.102000","DOIUrl":"10.1016/j.molmet.2024.102000","url":null,"abstract":"<div><h3>Objective</h3><p>The skeleton is one of the largest organs in the body, wherein metabolism is integrated with systemic energy metabolism. However, the bioenergetic programming of osteocytes, the most abundant bone cells coordinating bone metabolism, is not well defined. Here, using a mouse model with partial penetration of an osteocyte-specific PPARG deletion, we demonstrate that PPARG controls osteocyte bioenergetics and their contribution to systemic energy metabolism independently of circulating sclerostin levels, which were previously correlated with metabolic status of extramedullary fat depots.</p></div><div><h3>Methods</h3><p><em>In vivo</em> and <em>in vitro</em> models of osteocyte-specific PPARG deletion, i.e. <em>Dmp</em>1^Cre<em>Pparγ</em>^flfl male and female mice (γOT^KO) and MLO-Y4 osteocyte-like cells with either siRNA-silenced or CRISPR/Cas9-edited <em>Pparγ</em>. As applicable, the models were analyzed for levels of energy metabolism, glucose metabolism, and metabolic profile of extramedullary adipose tissue, as well as the osteocyte transcriptome, mitochondrial function, bioenergetics, insulin signaling, and oxidative stress.</p></div><div><h3>Results</h3><p>Circulating sclerostin levels of γOT^KO male and female mice were not different from control mice. Male γOT^KO mice exhibited a high energy phenotype characterized by increased respiration, heat production, locomotion and food intake. This high energy phenotype in males did not correlate with “beiging” of peripheral adipose depots. However, both sexes showed a trend for reduced fat mass and apparent insulin resistance without changes in glucose tolerance, which correlated with decreased osteocytic responsiveness to insulin measured by AKT activation. The transcriptome of osteocytes isolated from γOT^KO males suggested profound changes in cellular metabolism, fuel transport, mitochondria dysfunction, insulin signaling and increased oxidative stress. In MLO-Y4 osteocytes, PPARG deficiency correlated with highly active mitochondria, increased ATP production, and accumulation of reactive oxygen species (ROS).</p></div><div><h3>Conclusions</h3><p>PPARG in male osteocytes acts as a molecular break on mitochondrial function, and protection against oxidative stress and ROS accumulation. It also regulates osteocyte insulin signaling and fuel usage to produce energy. These data provide insight into the connection between osteocyte bioenergetics and their sex-specific contribution to the balance of systemic energy metabolism. These findings support the concept that the skeleton controls systemic energy expenditure <em>via</em> osteocyte metabolism.</p></div>","PeriodicalId":18765,"journal":{"name":"Molecular Metabolism","volume":"88 ","pages":"Article 102000"},"PeriodicalIF":7.0,"publicationDate":"2024-07-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S2212877824001315/pdfft?md5=9f2ed9e5e20593fdd3d7b911bd63c9c5&pid=1-s2.0-S2212877824001315-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141792880","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":"Decoding the immune dance: Unraveling the interplay between beta cells and type 1 diabetes","authors":"Saptarshi Roy,&nbsp;Pravil Pokharel,&nbsp;Jon D. Piganelli","doi":"10.1016/j.molmet.2024.101998","DOIUrl":"10.1016/j.molmet.2024.101998","url":null,"abstract":"<div><h3>Background</h3><p>Type 1 diabetes (T1D) is an autoimmune disease characterized by the specific destruction of insulin-producing beta cells in the pancreas by the immune system, including CD4 cells which orchestrate the attack and CD8 cells which directly destroy the beta cells, resulting in the loss of glucose homeostasis.</p></div><div><h3>Scope of review</h3><p>This comprehensive document delves into the complex interplay between the immune system and beta cells, aiming to shed light on the mechanisms driving their destruction in T1D. Insights into the genetic predisposition, environmental triggers, and autoimmune responses provide a foundation for understanding the autoimmune attack on beta cells. From the role of viral infections as potential triggers to the inflammatory response of beta cells, an intricate puzzle starts to unfold. This exploration highlights the importance of beta cells in breaking immune tolerance and the factors contributing to their targeted destruction. Furthermore, it examines the potential role of autophagy and the impact of cytokine signaling on beta cell function and survival.</p></div><div><h3>Major conclusions</h3><p>This review collectively represents current research findings on T1D which offers valuable perspectives on novel therapeutic approaches for preserving beta cell mass, restoring immune tolerance, and ultimately preventing or halting the progression of T1D. By unraveling the complex dynamics between the immune system and beta cells, we inch closer to a comprehensive understanding of T1D pathogenesis, paving the way for more effective treatments and ultimately a cure.</p></div>","PeriodicalId":18765,"journal":{"name":"Molecular Metabolism","volume":"88 ","pages":"Article 101998"},"PeriodicalIF":7.0,"publicationDate":"2024-07-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S2212877824001297/pdfft?md5=72aad796a1e12605d8fbedd7339234fd&pid=1-s2.0-S2212877824001297-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141788688","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":"Tissue Inhibitor of Metalloproteinase 3 (TIMP3) mutations increase glycolytic activity and dysregulate glutamine metabolism in RPE cells","authors":"Allison Grenell ,&nbsp;Charandeep Singh ,&nbsp;Monisha Raju ,&nbsp;Alyson Wolk ,&nbsp;Sonal Dalvi ,&nbsp;Geeng-Fu Jang ,&nbsp;John S. Crabb ,&nbsp;Courtney E. Hershberger ,&nbsp;Kannan V. Manian ,&nbsp;Karen Hernandez ,&nbsp;John W. Crabb ,&nbsp;Ruchira Singh ,&nbsp;Jianhai Du ,&nbsp;Bela Anand-Apte","doi":"10.1016/j.molmet.2024.101995","DOIUrl":"10.1016/j.molmet.2024.101995","url":null,"abstract":"<div><h3>Objectives</h3><p>Mutations in Tissue Inhibitor of Metalloproteinases 3 (TIMP3) cause Sorsby's Fundus Dystrophy (SFD), a dominantly inherited, rare form of macular degeneration that results in vision loss. TIMP3 is synthesized primarily by retinal pigment epithelial (RPE) cells, which constitute the outer blood-retinal barrier. One major function of RPE is the synthesis and transport of vital nutrients, such as glucose, to the retina. Recently, metabolic dysfunction in RPE cells has emerged as an important contributing factor in retinal degenerations. We set out to determine if RPE metabolic dysfunction was contributing to SFD pathogenesis.</p></div><div><h3>Methods</h3><p>Quantitative proteomics was conducted on RPE of mice expressing the S179C variant of TIMP3, known to be causative of SFD in humans. Proteins found to be differentially expressed (P &lt; 0.05) were analyzed using statistical overrepresentation analysis to determine enriched pathways, processes, and protein classes using g:profiler and PANTHER Gene Ontology. We examined the effects of mutant TIMP3 on RPE metabolism using human ARPE-19 cells expressing mutant S179C TIMP3 and patient-derived induced pluripotent stem cell-derived RPE (iRPE) carrying the S204C TIMP3 mutation. RPE metabolism was directly probed using isotopic tracing coupled with GC/MS analysis. Steady state [U–¹³C₆] glucose isotopic tracing was preliminarily conducted on S179C ARPE-19 followed by [U–¹³C₆] glucose and [U–¹³C₅] glutamine isotopic tracing in SFD iRPE cells.</p></div><div><h3>Results</h3><p>Quantitative proteomics and enrichment analysis conducted on RPE of mice expressing mutant S179C TIMP3 identified differentially expressed proteins that were enriched for metabolism-related pathways and processes. Notably these results highlighted dysregulated glycolysis and glucose metabolism. Stable isotope tracing experiments with [U–¹³C₆] glucose demonstrated enhanced glucose utilization and glycolytic activity in S179C TIMP3 APRE-19 cells. Similarly, [U–¹³C₆] glucose tracing in SFD iRPE revealed increased glucose contribution to glycolysis and the TCA cycle. Additionally, [U–¹³C₅] glutamine tracing found evidence of altered malic enzyme activity.</p></div><div><h3>Conclusions</h3><p>This study provides important information on the dysregulation of RPE glucose metabolism in SFD and implicates a potential commonality with other retinal degenerative diseases, emphasizing RPE cellular metabolism as a therapeutic target.</p></div>","PeriodicalId":18765,"journal":{"name":"Molecular Metabolism","volume":"88 ","pages":"Article 101995"},"PeriodicalIF":7.0,"publicationDate":"2024-07-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S2212877824001261/pdfft?md5=f27c912d6cfdad145dbd8ae7a0e9f38f&pid=1-s2.0-S2212877824001261-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141759763","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":"Tanycytic transcytosis inhibition disrupts energy balance, glucose homeostasis and cognitive function in male mice","authors":"Manon Duquenne ,&nbsp;Eleonora Deligia ,&nbsp;Cintia Folgueira ,&nbsp;Cyril Bourouh ,&nbsp;Emilie Caron ,&nbsp;Frank Pfrieger ,&nbsp;Markus Schwaninger ,&nbsp;Ruben Nogueiras ,&nbsp;Jean-Sébastien Annicotte ,&nbsp;Monica Imbernon ,&nbsp;Vincent Prévot","doi":"10.1016/j.molmet.2024.101996","DOIUrl":"10.1016/j.molmet.2024.101996","url":null,"abstract":"<div><h3>Objectives</h3><p>In Western society, high-caloric diets rich in fats and sugars have fueled the obesity epidemic and its related disorders. Disruption of the body-brain communication, crucial for maintaining glucose and energy homeostasis, arises from both obesogenic and genetic factors, leading to metabolic disorders. Here, we investigate the role of hypothalamic tanycyte shuttles between the pituitary portal blood and the third ventricle cerebrospinal fluid in regulating energy balance.</p></div><div><h3>Methods</h3><p>We inhibited vesicle-associated membrane proteins (VAMP1-3)-mediated release in tanycytes by expressing the botulinum neurotoxin type B light chain (BoNT/B) in a Cre-dependent manner in tanycytes. This was achieved by injecting either TAT-Cre in the third ventricle or an AAV1/2 expressing Cre under the control of the tanycyte-specific promoter iodothyronine deiodinase 2 into the lateral ventricle of adult male mice.</p></div><div><h3>Results</h3><p>In male mice fed a standard diet, targeted expression of BoNT/B in adult tanycytes blocks leptin transport into the mediobasal hypothalamus and results in normal-weight central obesity, including increased food intake, abdominal fat deposition, and elevated leptin levels but no marked change in body weight. Furthermore, BoNT/B expression in adult tanycytes promotes fatty acid storage, leading to glucose intolerance and insulin resistance. Notably, these metabolic disturbances occur despite a compensatory increase in insulin secretion, observed both in response to exogenous glucose boluses in vivo and in isolated pancreatic islets. Intriguingly, these metabolic alterations are associated with impaired spatial memory in BoNT/B-expressing mice.</p></div><div><h3>Conclusions</h3><p>These findings underscore the central role of tanycytes in brain-periphery communication and highlight their potential implication in the age-related development of type 2 diabetes and cognitive decline. Our tanycytic BoNT/B mouse model provides a robust platform for studying how these conditions progress over time, from prediabetic states to full-blown metabolic and cognitive disorders, and the mechanistic contribution of tanycytes to their development. The recognition of the impact of tanycytic transcytosis on hormone transport opens new avenues for developing targeted therapies that could address both metabolic disorders and their associated cognitive comorbidities, which often emerge or worsen with advancing age.</p></div>","PeriodicalId":18765,"journal":{"name":"Molecular Metabolism","volume":"87 ","pages":"Article 101996"},"PeriodicalIF":7.0,"publicationDate":"2024-07-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S2212877824001273/pdfft?md5=7ddfd5fe6a0a906adec81a436dcca3d8&pid=1-s2.0-S2212877824001273-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141759762","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":"Esrra regulates Rplp1-mediated translation of lysosome proteins suppressed in metabolic dysfunction-associated steatohepatitis and reversed by alternate day fasting","authors":"Madhulika Tripathi ,&nbsp;Karine Gauthier ,&nbsp;Reddemma Sandireddy ,&nbsp;Jin Zhou ,&nbsp;Priyanka Guptta ,&nbsp;Suganya Sakthivel ,&nbsp;Wei Wen Teo ,&nbsp;Yadanar Than Naing ,&nbsp;Kabilesh Arul ,&nbsp;Keziah Tikno ,&nbsp;Sung-Hee Park ,&nbsp;Yajun Wu ,&nbsp;Lijin Wang ,&nbsp;Boon-Huat Bay ,&nbsp;Lei Sun ,&nbsp;Vincent Giguere ,&nbsp;Pierce K.H. Chow ,&nbsp;Sujoy Ghosh ,&nbsp;Donald P. McDonnell ,&nbsp;Paul M. Yen ,&nbsp;Brijesh K. Singh","doi":"10.1016/j.molmet.2024.101997","DOIUrl":"10.1016/j.molmet.2024.101997","url":null,"abstract":"<div><h3>Objective</h3><p>Currently, little is known about the mechanism(s) regulating global and specific protein translation during metabolic dysfunction-associated steatohepatitis (MASH; previously known as non-alcoholic steatohepatitis, NASH).</p></div><div><h3>Methods</h3><p>Unbiased label-free quantitative proteome, puromycin-labelling and polysome profiling were used to understand protein translation activity <em>in vitro</em> and <em>in vivo</em>.</p></div><div><h3>Results</h3><p>We observed a global decrease in protein translation during lipotoxicity in human primary hepatocytes, mouse hepatic AML12 cells, and livers from a dietary mouse model of MASH. Interestingly, proteomic analysis showed that Rplp1, which regulates ribosome and translation pathways, was one of the most downregulated proteins. Moreover, decreased Esrra expression and binding to the Rplp1 promoter, diminished Rplp1 gene expression during lipotoxicity. This, in turn, reduced global protein translation and Esrra/Rplp1-dependent translation of lysosome (Lamp2, Ctsd) and autophagy (sqstm1, Map1lc3b) proteins. Of note, Esrra did not increase its binding to these gene promoters or their gene transcription, confirming its regulation of their translation during lipotoxicity. Notably, hepatic Esrra-Rplp1-dependent translation of lysosomal and autophagy proteins also was impaired in MASH patients and liver-specific <em>Esrra</em> knockout mice. Remarkably, alternate day fasting induced Esrra-Rplp1-dependent expression of lysosomal proteins, restored autophagy, and reduced lipotoxicity, inflammation, and fibrosis in hepatic cell culture and <em>in vivo</em> models of MASH.</p></div><div><h3>Conclusions</h3><p>Esrra regulation of Rplp1-mediated translation of lysosome/autolysosome proteins was downregulated during MASH. Alternate day fasting activated this novel pathway and improved MASH, suggesting that Esrra and Rplp1 may serve as therapeutic targets for MASH. Our findings also provided the first example of a nuclear hormone receptor, Esrra, to not only regulate transcription but also protein translation, via induction of Rplp1.</p></div>","PeriodicalId":18765,"journal":{"name":"Molecular Metabolism","volume":"87 ","pages":"Article 101997"},"PeriodicalIF":7.0,"publicationDate":"2024-07-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S2212877824001285/pdfft?md5=81df0324e8a5b092148f5e4c0dd213eb&pid=1-s2.0-S2212877824001285-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141734634","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Metabolic plasticity in a Pde6bSTOP/STOP retinitis pigmentosa mouse model following rescue","authors":"Monika Ayten ,&nbsp;Nundehui Díaz-Lezama ,&nbsp;Hanaa Ghanawi ,&nbsp;Felia C. Haffelder ,&nbsp;Jacqueline Kajtna ,&nbsp;Tobias Straub ,&nbsp;Marco Borso ,&nbsp;Axel Imhof ,&nbsp;Stefanie M. Hauck ,&nbsp;Susanne F. Koch","doi":"10.1016/j.molmet.2024.101994","DOIUrl":"10.1016/j.molmet.2024.101994","url":null,"abstract":"<div><h3>Objective</h3><p>Retinitis pigmentosa (RP) is a hereditary retinal disease characterized by progressive photoreceptor degeneration, leading to vision loss. The best hope for a cure for RP lies in gene therapy. However, given that RP patients are most often diagnosed in the midst of ongoing photoreceptor degeneration, it is unknown how the retinal proteome changes as RP disease progresses, and which changes can be prevented, halted, or reversed by gene therapy.</p></div><div><h3>Methods</h3><p>Here, we used a <em>Pde6b</em>-deficient RP gene therapy mouse model and performed untargeted proteomic analysis to identify changes in protein expression during degeneration and after treatment.</p></div><div><h3>Results</h3><p>We demonstrated that <em>Pde6b</em> gene restoration led to a novel form of homeostatic plasticity in rod phototransduction which functionally compensates for the decreased number of rods. By profiling protein levels of metabolic genes and measuring metabolites, we observed an upregulation of proteins associated with oxidative phosphorylation in mutant and treated photoreceptors.</p></div><div><h3>Conclusion</h3><p>In conclusion, the metabolic demands of the retina differ in our <em>Pde6b</em>-deficient RP mouse model and are not rescued by gene therapy treatment. These findings provide novel insights into features of both RP disease progression and long-term rescue with gene therapy.</p></div>","PeriodicalId":18765,"journal":{"name":"Molecular Metabolism","volume":"88 ","pages":"Article 101994"},"PeriodicalIF":7.0,"publicationDate":"2024-07-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S221287782400125X/pdfft?md5=6010579f47431b45363c3e5b7663bbf8&pid=1-s2.0-S221287782400125X-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141734645","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":"The homeodomain transcription factor Six3 regulates hypothalamic Pomc expression and its absence from POMC neurons induces hyperphagia and mild obesity in male mice","authors":"Hui Yu ,&nbsp;Angelika Chiang ,&nbsp;Marcelo Rubinstein ,&nbsp;Malcolm J. Low","doi":"10.1016/j.molmet.2024.101993","DOIUrl":"10.1016/j.molmet.2024.101993","url":null,"abstract":"<div><h3>Objective</h3><p>Proopiomelanocortin (POMC) neurons release potent anorexigenic neuropeptides, which suppress food intake and enhance energy expenditure via melanocortin receptors. Although the importance of central melanocortin in physiological regulation is well established, the underlying genetic mechanisms that define the functional identity of melanocortin neurons and maintain hypothalamic <em>Pomc</em> expression remain to be fully determined. In this study, we investigate the functional significance of <em>Six3,</em> a transcriptional regulator notably expressed in embryonic and adult mouse POMC neurons, in the regulation of hypothalamic <em>Pomc</em> expression and downstream physiological consequences.</p></div><div><h3>Methods</h3><p>We first evaluated the expression of <em>Six3</em> in the developing and adult hypothalamus by double fluorescence <em>in situ</em> hybridization. Next, we assessed POMC immunoreactivity in mutant mice selectively lacking <em>Six3</em> from <em>Pomc</em>-expressing neurons and quantified <em>Pomc</em> mRNA levels in a tamoxifen-inducible <em>Six3</em> knockout mouse model activated at embryonic E9.5 days. We also determined glucose and insulin sensitivity, daily food intake, body composition and body weight in adult male and female mice lacking <em>Six3</em> specifically from POMC neurons. Lastly, we assessed the physiological consequences of ablating <em>Six3</em> from POMC neurons in adult mice.</p></div><div><h3>Results</h3><p><em>Six3</em> and <em>Pomc</em> were co-expressed in mouse hypothalamic neurons during development and adulthood. Mouse embryos deficient in <em>Six3</em> showed reduced <em>Pomc</em> expression in the developing hypothalamus. Targeted deletion of <em>Six3</em> specifically from POMC neurons resulted in decreased hypothalamic <em>Pomc</em> expression, increased daily food intake, enhanced glucose sensitivity and mild obesity in male but not in female mice. Finally, conditional removal of <em>Six3</em> from POMC neurons in adult mice led to a reduction in hypothalamic POMC immunoreactivity with no significant effects in body weight or food intake.</p></div><div><h3>Conclusions</h3><p>Altogether, our results demonstrate that <em>Six3</em> plays an essential role in the early establishment of POMC neuron identity and the maintenance of physiological levels of hypothalamic <em>Pomc</em> expression. In addition, our study demonstrates that the functional significance of <em>Six3</em> expression in POMC neurons is sexually dimorphic and age-dependent.</p></div>","PeriodicalId":18765,"journal":{"name":"Molecular Metabolism","volume":"87 ","pages":"Article 101993"},"PeriodicalIF":7.0,"publicationDate":"2024-07-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S2212877824001248/pdfft?md5=e1f7da9c342a933d0153229da82b53ed&pid=1-s2.0-S2212877824001248-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141697099","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}