Molecular Metabolism最新文献

{"title":"Hunger signalling in the olfactory bulb primes exploration, food-seeking and peripheral metabolism","authors":"Romana Stark ,&nbsp;Harry Dempsey ,&nbsp;Elizabeth Kleeman ,&nbsp;Martina Sassi ,&nbsp;Sherri Osborne-Lawrence ,&nbsp;Sepideh Sheybani-Deloui ,&nbsp;Helen J. Rushby ,&nbsp;Christen K. Mirth ,&nbsp;Karl Austin-Muttitt ,&nbsp;Jonathan Mullins ,&nbsp;Jeffrey M. Zigman ,&nbsp;Jeffrey S. Davies ,&nbsp;Zane B. Andrews","doi":"10.1016/j.molmet.2024.102025","DOIUrl":"10.1016/j.molmet.2024.102025","url":null,"abstract":"<div><h3>Objective</h3><div>Although the metabolic state of an organism affects olfactory function, the precise mechanisms and their impact on behavior and metabolism remain unknown. Here, we assess whether ghrelin receptors (GHSRs) in the olfactory bulb (OB) increase olfactory function and influence foraging behaviors and metabolism.</div></div><div><h3>Methods</h3><div>We performed a detailed behavioural and metabolic analysis in mice lacking GHSRs in the OB (OB^GHSR deletion). We also analsyed OB scRNA-seq and spatial transcriptomic datasets to assess GHSR+ cells in the main and accessory olfactory bulbs, as well as the anterior olfactory nucleus.</div></div><div><h3>Results</h3><div>OB^GHSR deletion affected olfactory discrimination and habituation to both food and non-food odors. Anxiety-like and depression-like behaviors were significantly greater after OB^GHSR deletion, whereas exploratory behavior was reduced, with the greatest effect under fasted conditions. OB^GHSR deletion impacted feeding behavior as evidenced by altered bout number and duration, as well as buried food-seeking. OB^GHSR deletion increased body weight and fat mass, spared fat utilisation on a chow diet and impaired glucose metabolism indicating metabolic dysfunction. Cross referenced analysis of OB scRNA-seq and spatial transcriptomic datasets revealed GHSR+ glutamate neurons in the main and accessory olfactory bulbs, as well as the anterior olfactory nucleus. Ablation of glutamate neurons in the OB reduced ghrelin-induced food finding and phenocopied results seen after OB^GHSR deletion.</div></div><div><h3>Conclusions</h3><div>OB^GHSRs help to maintain olfactory function, particularly during hunger, and facilitate behavioral adaptations that optimise food-seeking in anxiogenic environments, priming metabolic pathways in preparation for food consumption.</div></div>","PeriodicalId":18765,"journal":{"name":"Molecular Metabolism","volume":"89 ","pages":"Article 102025"},"PeriodicalIF":7.0,"publicationDate":"2024-09-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142140471","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":"Polyribonucleotide nucleotidyltransferase 1 participates in metabolic-associated fatty liver disease pathogenesis by affecting lipid metabolism and mitochondrial homeostasis","authors":"Canghai Guan ,&nbsp;Xinlei Zou ,&nbsp;Chengru Yang ,&nbsp;Wujiang Shi ,&nbsp;Jianjun Gao ,&nbsp;Yifei Ge ,&nbsp;Zhaoqiang Xu ,&nbsp;Shaowu Bi ,&nbsp;Xiangyu Zhong","doi":"10.1016/j.molmet.2024.102022","DOIUrl":"10.1016/j.molmet.2024.102022","url":null,"abstract":"<div><h3>Objective</h3><p>Metabolic-associated fatty liver disease (MAFLD) represents one of the most prevalent chronic liver conditions worldwide, but its precise pathogenesis remains unclear. This research endeavors to elucidate the involvement and molecular mechanisms of polyribonucleotide nucleotidyltransferase 1 (PNPT1) in the progression of MAFLD.</p></div><div><h3>Methods</h3><p>The study employed western blot and qRT-PCR to evaluate PNPT1 levels in liver specimens from individuals diagnosed with MAFLD and in mouse models subjected to a high-fat diet. Cellular studies investigated the effects of PNPT1 on lipid metabolism, apoptosis, and mitochondrial stability in hepatocytes. Immunofluorescence was utilized to track the subcellular movement of PNPT1 under high lipid conditions. RNA immunoprecipitation and functional assays were conducted to identify interactions between PNPT1 and Mcl-1 mRNA. The role of PPARα as an upstream transcriptional regulator of PNPT1 was investigated. Recombinant adenoviral vectors were utilized to modulate PNPT1 expression <em>in vivo</em>.</p></div><div><h3>Results</h3><p>PNPT1 was found to be markedly reduced in liver tissues from MAFLD patients and HFD mice. <em>In vitro</em>, PNPT1 directly regulated hepatic lipid metabolism, apoptosis, and mitochondrial stability. Under conditions of elevated lipids, PNPT1 relocated from mitochondria to cytoplasm, modifying its physiological functions. RNA immunoprecipitation revealed that the KH and S1 domains of PNPT1 bind to and degrade Mcl-1 mRNA, which in turn affects mitochondrial permeability. The transcriptional regulator PPARα was identified as a significant influencer of PNPT1, impacting both its expression and subsequent cellular functions. Alterations in PNPT1 expression were directly correlated with the progression of MAFLD in mice.</p></div><div><h3>Conclusions</h3><p>The study confirms the pivotal function of PNPT1 in the development of MAFLD through its interactions with Mcl-1 and its regulatory effects on lipid metabolism and mitochondrial stability. These insights highlight the intricate association between PNPT1 and MAFLD, shedding light on its molecular pathways and presenting a potential new therapeutic avenue for MAFLD management.</p></div>","PeriodicalId":18765,"journal":{"name":"Molecular Metabolism","volume":"89 ","pages":"Article 102022"},"PeriodicalIF":7.0,"publicationDate":"2024-08-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S2212877824001534/pdfft?md5=c768d52bcbc8757adc124df47bd1cce5&pid=1-s2.0-S2212877824001534-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142109594","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":"Dietary fat content and absorption shape standard diet devaluation through hunger circuits","authors":"Ames K. Sutton Hickey ,&nbsp;Jordan Becker ,&nbsp;Eva O. Karolczak ,&nbsp;Andrew Lutas ,&nbsp;Michael J. Krashes","doi":"10.1016/j.molmet.2024.102021","DOIUrl":"10.1016/j.molmet.2024.102021","url":null,"abstract":"<div><h3>Objective</h3><p>Exposure to 60% high fat diet (HFD) leads to a robust consummatory preference over well-balanced chow standard diet (SD) when mice are presented with a choice. This passive HFD-induced SD devaluation following HFD challenge and withdrawal is highlighted by the significant reduction in SD food intake even in states of caloric deprivation. The elements of HFD that lead to this SD depreciation remains unclear. Possibly important factors include the amount and type of fat contained in a diet as well as past eating experiences dependent on sensory properties including taste and post ingestive feedback. We aimed to explore the role of these components to HFD-induced SD devaluation.</p></div><div><h3>Methods</h3><p>Wildtype mice were longitudinally presented discrete HFDs in conjunction with SD and feeding and metabolic parameters were analyzed. A separate cohort of animals were assessed for acute HFD preference in 3 conditions: 1) <em>ad libitum</em> fed (sated), 2) overnight fasted (physiologically hungry), and 3) <em>ad libitum</em> fed (artificially hungry), elicited through chemogenetic Agouti-related peptide (AgRP) neuron activation. Population dynamics of AgRP neurons were recorded to distinct inaccessible and accessible diets both before and after consummatory experience. Transient receptor potential channel type M5 (TRPM5) knockout mice were used to investigate the role of fat taste perception and preference to HFD-induced SD devaluation. The clinically approved lipase inhibitor orlistat was used to test the contribution of fat absorption to HFD-induced SD devaluation.</p></div><div><h3>Results</h3><p>HFD-induced SD devaluation is dependent on fat content, composition, and preference. This effect scaled both in strength and latency with higher percentages of animal fat. 60% HFD was preferred and almost exclusively consumed in preference to other diets across hours and days, but this was not as evident upon initial introduction over seconds and minutes, suggesting ingestive experience is critical. Optical fiber photometry recordings of AgRP activity supported this notion as neuronal suppression by the different diets was contingent on prior intake. While taste transduced via TRPM5 influenced HFD-evoked weight gain, it failed to impact either HFD preference or HFD-induced SD devaluation. Perturbation of post ingestive feedback through orlistat-mediated diminishment of fat absorption prevented HFD-evoked weight gain and abolished HFD-induced SD devaluation.</p></div><div><h3>Conclusions</h3><p>Post ingestive feedback via fat digestion is vital for expression of HFD-induced SD devaluation.</p></div>","PeriodicalId":18765,"journal":{"name":"Molecular Metabolism","volume":"89 ","pages":"Article 102021"},"PeriodicalIF":7.0,"publicationDate":"2024-08-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S2212877824001522/pdfft?md5=1a4bed330b6aeb8ffaac555cda916624&pid=1-s2.0-S2212877824001522-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142109593","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 GLP-1 medicines semaglutide and tirzepatide do not alter disease-related pathology, behaviour or cognitive function in 5XFAD and APP/PS1 mice","authors":"Leticia Forny Germano,&nbsp;Jacqueline A. Koehler,&nbsp;Laurie L. Baggio,&nbsp;Fiona Cui,&nbsp;Chi Kin Wong,&nbsp;Nikolaj Rittig,&nbsp;Xiemin Cao,&nbsp;Dianne Matthews,&nbsp;Daniel J. Drucker","doi":"10.1016/j.molmet.2024.102019","DOIUrl":"10.1016/j.molmet.2024.102019","url":null,"abstract":"<div><h3>Objective</h3><p>The development of glucagon-like peptide-1 receptor (GLP-1R) agonists for the treatment of type 2 diabetes and obesity has been accompanied by evidence for anti-inflammatory and cytoprotective actions in the heart, blood vessels, kidney, and brain. Whether GLP-1R agonists might be useful clinically for attenuating deterioration of cognitive dysfunction and reducing the progression of Alzheimer's disease remains uncertain.</p></div><div><h3>Methods</h3><p>Here we evaluated the actions of semaglutide and tirzepatide, clinically distinct GLP-1 medicines, in two mouse models of neurodegeneration.</p></div><div><h3>Results</h3><p>Semaglutide reduced body weight and improved glucose tolerance in 12-month-old male and female 5XFAD and APP/PS1 mice, consistent with pharmacological engagement of the GLP-1R. Nevertheless, amyloid plaque density was not different in the cerebral cortex, hippocampus, or subiculum of semaglutide-treated 12-month-old 5XFAD and APP/PS1 mice. IBA1 and GFAP expression were increased in the hippocampus of 5XFAD and APP/PS1 mice but were not reduced by semaglutide. Moreover, parameters of neurobehavioral and cognitive function evaluated using Open Field testing or the Morris water maze were not improved following treatment with semaglutide. To explore whether incretin therapies might be more effective in younger mice, we studied semaglutide and tirzepatide action in 6-month-old male and female 5XFAD mice. Neither semaglutide nor tirzepatide modified the extent of plaque accumulation, hippocampal IBA1+ or GFAP+ cells, or parameters of neurobehavioral testing, despite improving glucose tolerance and reducing body weight. mRNA biomarkers of inflammation and neurodegeneration were increased in the hippocampus of male and female 5XFAD mice but were not reduced after treatment with semaglutide or tirzepatide.</p></div><div><h3>Conclusions</h3><p>Collectively, these findings reveal preservation of the metabolic actions of two GLP-1 medicines, semaglutide and tirzepatide, yet inability to detect improvement in structural and functional parameters of neurodegeneration in two mouse models of Alzheimer's disease.</p></div>","PeriodicalId":18765,"journal":{"name":"Molecular Metabolism","volume":"89 ","pages":"Article 102019"},"PeriodicalIF":7.0,"publicationDate":"2024-08-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S2212877824001509/pdfft?md5=12155cdd102ffb422b4aa79f1663591d&pid=1-s2.0-S2212877824001509-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142109595","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":"Arginine deprivation/citrulline augmentation with ADI-PEG20 as novel therapy for complications in type 2 diabetes","authors":"Ammar A. Abdelrahman ,&nbsp;Porsche V. Sandow ,&nbsp;Jing Wang ,&nbsp;Zhimin Xu ,&nbsp;Modesto Rojas ,&nbsp;John S. Bomalaski ,&nbsp;Tahira Lemtalsi ,&nbsp;Ruth B. Caldwell ,&nbsp;Robert W. Caldwell","doi":"10.1016/j.molmet.2024.102020","DOIUrl":"10.1016/j.molmet.2024.102020","url":null,"abstract":"<div><h3>Objective</h3><p>Chronic inflammation and oxidative stress mediate the pathological progression of diabetic complications, like diabetic retinopathy (DR), peripheral neuropathy (DPN) and impaired wound healing. Studies have shown that treatment with a stable form of arginase 1 that reduces <span>l</span>-arginine levels and increases ornithine and urea limits retinal injury and improves visual function in DR. We tested the therapeutic efficacy of PEGylated arginine deiminase (ADI-PEG20) that depletes <span>l</span>-arginine and elevates <span>l</span>-citrulline on diabetic complications in the <em>db/db</em> mouse model of type 2 diabetes (T2D).</p></div><div><h3>Methods</h3><p>Mice received intraperitoneal (IP), intramuscular (IM), or intravitreal (IVT) injections of ADI-PEG20 or PEG20 as control. Effects on body weight, fasting blood glucose levels, blood-retinal-barrier (BRB) function, visual acuity, contrast sensitivity, thermal sensitivity, and wound healing were determined. Studies using bone marrow-derived macrophages (BMDM) examined the underlying signaling pathway.</p></div><div><h3>Results</h3><p>Systemic injections of ADI-PEG20 reduced body weight and blood glucose and decreased oxidative stress and inflammation in <em>db/db</em> retinas. These changes were associated with improved BRB and visual function along with thermal sensitivity and wound healing. IVT injections of either ADI-PEG20, anti-VEGF antibody or their combination also improved BRB and visual function. ADI-PEG20 treatment also prevented LPS/IFNℽ-induced activation of BMDM <em>in vitro</em> as did depletion of <span>l</span>-arginine and elevation of <span>l</span>-citrulline.</p></div><div><h3>Conclusions/interpretation</h3><p>ADI-PEG20 treatment limited signs of DR and DPN and enhanced wound healing in <em>db/db</em> mice. Studies using BMDM suggest that the anti-inflammatory effects of ADI-PEG20 involve blockade of the JAK2-STAT1 signaling pathway via <span>l</span>-arginine depletion and <span>l</span>-citrulline production.</p></div>","PeriodicalId":18765,"journal":{"name":"Molecular Metabolism","volume":"89 ","pages":"Article 102020"},"PeriodicalIF":7.0,"publicationDate":"2024-08-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S2212877824001510/pdfft?md5=c962c8036e363d7ea0bab17c65e01441&pid=1-s2.0-S2212877824001510-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142109592","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":"Loss of mitochondria long-chain fatty acid oxidation impairs skeletal muscle contractility by disrupting myofibril structure and calcium homeostasis","authors":"Andrea S. Pereyra,&nbsp;Regina F. Fernandez,&nbsp;Adam Amorese,&nbsp;Jasmine N. Castro,&nbsp;Chien-Te Lin,&nbsp;Espen E. Spangenburg,&nbsp;Jessica M. Ellis","doi":"10.1016/j.molmet.2024.102015","DOIUrl":"10.1016/j.molmet.2024.102015","url":null,"abstract":"<div><h3>Objective</h3><p>Abnormal lipid metabolism in mammalian tissues can be highly deleterious, leading to organ failure. Carnitine Palmitoyltransferase 2 (CPT2) deficiency is an inherited metabolic disorder affecting the liver, heart, and skeletal muscle due to impaired mitochondrial oxidation of long-chain fatty acids (mLCFAO) for energy production.</p></div><div><h3>Methods</h3><p>However, the basis of tissue damage in mLCFAO disorders is not fully understood. Mice lacking CPT2 in skeletal muscle (<em>Cpt2</em>^{<em>Sk−/−</em>}) were generated to investigate the nexus between mFAO deficiency and myopathy.</p></div><div><h3>Results</h3><p>Compared to controls, ex-vivo contractile force was reduced by 70% in <em>Cpt2</em>^{<em>Sk−/−</em>} oxidative soleus muscle despite the preserved capacity to couple ATP synthesis to mitochondrial respiration on alternative substrates to long-chain fatty acids. Increased mitochondrial biogenesis, lipid accumulation, and the downregulation of 80% of dystrophin-related and contraction-related proteins severely compromised the structure and function of <em>Cpt2</em>^{<em>Sk−/−</em>} soleus. CPT2 deficiency affected oxidative muscles more than glycolytic ones. Exposing isolated sarcoplasmic reticulum to long-chain acylcarnitines (LCACs) inhibited calcium uptake. In agreement, <em>Cpt2</em>^{<em>Sk−/−</em>} soleus had decreased calcium uptake and significant accumulation of palmitoyl-carnitine, suggesting that LCACs and calcium dyshomeostasis are linked in skeletal muscle.</p></div><div><h3>Conclusions</h3><p>Our data demonstrate that loss of CPT2 and mLCFAO compromise muscle structure and function due to excessive mitochondrial biogenesis, downregulation of the contractile proteome, and disruption of calcium homeostasis.</p></div>","PeriodicalId":18765,"journal":{"name":"Molecular Metabolism","volume":"89 ","pages":"Article 102015"},"PeriodicalIF":7.0,"publicationDate":"2024-08-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S2212877824001467/pdfft?md5=d42ff98ff5c63323ab6632c688dc4f53&pid=1-s2.0-S2212877824001467-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142056054","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":"Picalm, a novel regulator of GLUT4-trafficking in adipose tissue","authors":"Jasmin Gaugel ,&nbsp;Neele Haacke ,&nbsp;Ratika Sehgal ,&nbsp;Markus Jähnert ,&nbsp;Wenke Jonas ,&nbsp;Anne Hoffmann ,&nbsp;Matthias Blüher ,&nbsp;Adhideb Ghosh ,&nbsp;Falko Noé ,&nbsp;Christian Wolfrum ,&nbsp;Joycelyn Tan ,&nbsp;Annette Schürmann ,&nbsp;Daniel J. Fazakerley ,&nbsp;Heike Vogel","doi":"10.1016/j.molmet.2024.102014","DOIUrl":"10.1016/j.molmet.2024.102014","url":null,"abstract":"<div><h3>Objective</h3><p><em>Picalm</em> (phosphatidylinositol-binding clathrin assembly protein), a ubiquitously expressed clathrin-adapter protein, is a well-known susceptibility gene for Alzheimer's disease, but its role in white adipose tissue (WAT) function has not yet been studied. Transcriptome analysis revealed differential expression of <em>Picalm</em> in WAT of diabetes-prone and diabetes-resistant mice, hence we aimed to investigate the potential link between <em>Picalm</em> expression and glucose homeostasis, obesity-related metabolic phenotypes, and its specific role in insulin-regulated GLUT4 trafficking in adipocytes.</p></div><div><h3>Methods</h3><p><em>Picalm</em> expression and epigenetic regulation by microRNAs (miRNAs) and DNA methylation were analyzed in WAT of diabetes-resistant (DR) and diabetes-prone (DP) female New Zealand Obese (NZO) mice and in male NZO after time-restricted feeding (TRF) and alternate-day fasting (ADF). <em>PICALM</em> expression in human WAT was evaluated in a cross-sectional cohort and assessed before and after weight loss induced by bariatric surgery. siRNA-mediated knockdown of <em>Picalm</em> in 3T3-L1-cells was performed to elucidate functional outcomes on GLUT4-translocation as well as insulin signaling and adipogenesis.</p></div><div><h3>Results</h3><p><em>Picalm</em> expression in WAT was significantly lower in DR compared to DP female mice, as well as in insulin-sensitive vs. resistant NZO males, and was also reduced in NZO males following TRF and ADF. Four miRNAs (let-7c, miR-30c, miR-335, miR-344) were identified as potential mediators of diabetes susceptibility-related differences in <em>Picalm</em> expression, while 11 miRNAs (including miR-23a, miR-29b, and miR-101a) were implicated in TRF and ADF effects. Human <em>PICALM</em> expression in adipose tissue was lower in individuals without obesity vs. with obesity and associated with weight-loss outcomes post-bariatric surgery. siRNA-mediated knockdown of <em>Picalm</em> in mature 3T3-L1-adipocytes resulted in amplified insulin-stimulated translocation of the endogenous glucose transporter GLUT4 to the plasma membrane and increased phosphorylation of Akt and Tbc1d4. Moreover, depleting Picalm before and during 3T3-L1 differentiation significantly suppressed adipogenesis, suggesting that Picalm may have distinct roles in the biology of pre- and mature adipocytes.</p></div><div><h3>Conclusions</h3><p>Picalm is a novel regulator of GLUT4-translocation in WAT, with its expression modulated by both genetic predisposition to diabetes and dietary interventions. These findings suggest a potential role for Picalm in improving glucose homeostasis and highlight its relevance as a therapeutic target for metabolic disorders.</p></div>","PeriodicalId":18765,"journal":{"name":"Molecular Metabolism","volume":"88 ","pages":"Article 102014"},"PeriodicalIF":7.0,"publicationDate":"2024-08-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S2212877824001455/pdfft?md5=e2b8a1ea0ed49dcb7aee2bbf9c855b30&pid=1-s2.0-S2212877824001455-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142056055","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":"Glucose-1,6-bisphosphate: A new gatekeeper of cerebral mitochondrial pyruvate uptake","authors":"Motahareh Solina Safari ,&nbsp;Priska Woerl ,&nbsp;Carolin Garmsiri ,&nbsp;Dido Weber ,&nbsp;Marcel Kwiatkowski ,&nbsp;Madlen Hotze ,&nbsp;Louisa Kuenkel ,&nbsp;Luisa Lang ,&nbsp;Matthias Erlacher ,&nbsp;Ellen Gelpi ,&nbsp;Johannes A. Hainfellner ,&nbsp;Gottfried Baier ,&nbsp;Gabriele Baier-Bitterlich ,&nbsp;Stephanie zur Nedden","doi":"10.1016/j.molmet.2024.102018","DOIUrl":"10.1016/j.molmet.2024.102018","url":null,"abstract":"<div><h3>Objective</h3><p>Glucose-1,6-bisphosphate (G-1,6-BP), a byproduct of glycolysis that is synthesized by phosphoglucomutase 2 like 1 (PGM2L1), is particularly abundant in neurons. G-1,6-BP is sensitive to the glycolytic flux, due to its dependence on 1,3-bisphosphoglycerate as phosphate donor, and the energy state, due to its degradation by inosine monophosphate-activated phosphomannomutase 1. Since the exact role of this metabolite remains unclear, our aim was to elucidate the specific function of G-1,6-BP in the brain.</p></div><div><h3>Methods</h3><p>The effect of PGM2L1 on neuronal post-ischemic viability was assessed by siRNA-mediated knockdown of PGM2L1 in primary mouse neurons. Acute mouse brain slices were used to correlate the reduction in G-1,6-BP upon ischemia to changes in carbon metabolism by ¹³C₆-glucose tracing. A drug affinity responsive target stability assay was used to test if G-1,6-BP interacts with the mitochondrial pyruvate carrier (MPC) subunits in mouse brain protein extracts. Human embryonic kidney cells expressing a MPC bioluminescence resonance energy transfer sensor were used to analyze how PGM2L1 overexpression affects MPC activity. The effect of G-1,6-BP on mitochondrial pyruvate uptake and oxygen consumption rates was analyzed in isolated mouse brain mitochondria. PGM2L1 and a predicted upstream kinase were overexpressed in a human neuroblastoma cell line and G-1,6-BP levels were measured.</p></div><div><h3>Results</h3><p>We found that G-1,6-BP in mouse brain slices was quickly degraded upon ischemia and reperfusion. Knockdown of PGM2L1 in mouse neurons reduced post-ischemic viability, indicating that PGM2L1 plays a neuroprotective role. The reduction in G-1,6-BP upon ischemia was not accompanied by alterations in glycolytic rates but we did see a reduced ¹³C₆-glucose incorporation into citrate, suggesting a potential role in mitochondrial pyruvate uptake or metabolism. Indeed, G-1,6-BP interacted with both MPC subunits and overexpression of PGM2L1 increased MPC activity. G-1,6-BP, at concentrations found in the brain, enhanced mitochondrial pyruvate uptake and pyruvate-induced oxygen consumption rates. Overexpression of a predicted upstream kinase inhibited PGM2L1 activity, showing that besides metabolism, also signaling pathways can regulate G-1,6-BP levels.</p></div><div><h3>Conclusions</h3><p>We provide evidence that G-1,6-BP positively regulates mitochondrial pyruvate uptake and post-ischemic neuronal viability. These compelling data reveal a novel mechanism by which neurons can couple glycolysis-derived pyruvate to the tricarboxylic acid cycle. This process is sensitive to the glycolytic flux, the cell's energetic state, and upstream signaling cascades, offering many regulatory means to fine-tune this critical metabolic step.</p></div>","PeriodicalId":18765,"journal":{"name":"Molecular Metabolism","volume":"88 ","pages":"Article 102018"},"PeriodicalIF":7.0,"publicationDate":"2024-08-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S2212877824001492/pdfft?md5=d3ddfdcae295b2a907fbeca55458a897&pid=1-s2.0-S2212877824001492-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142056098","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":"Renal L-2-hydroxyglutarate dehydrogenase activity promotes hypoxia tolerance and mitochondrial metabolism in Drosophila melanogaster","authors":"Nader H. Mahmoudzadeh ,&nbsp;Yasaman Heidarian ,&nbsp;Jason P. Tourigny ,&nbsp;Alexander J. Fitt ,&nbsp;Katherine Beebe ,&nbsp;Hongde Li ,&nbsp;Arthur Luhur ,&nbsp;Kasun Buddika ,&nbsp;Liam Mungcal ,&nbsp;Anirban Kundu ,&nbsp;Robert A. Policastro ,&nbsp;Garrett J. Brinkley ,&nbsp;Gabriel E. Zentner ,&nbsp;Travis Nemkov ,&nbsp;Robert Pepin ,&nbsp;Geetanjali Chawla ,&nbsp;Sunil Sudarshan ,&nbsp;Aylin R. Rodan ,&nbsp;Angelo D'Alessandro ,&nbsp;Jason M. Tennessen","doi":"10.1016/j.molmet.2024.102013","DOIUrl":"10.1016/j.molmet.2024.102013","url":null,"abstract":"<div><h3>Objectives</h3><p>The mitochondrial enzyme L-2-hydroxyglutarate dehydrogenase (L2HGDH) regulates the abundance of L-2-hydroxyglutarate (L-2HG), a potent signaling metabolite capable of influencing chromatin architecture, mitochondrial metabolism, and cell fate decisions. Loss of L2hgdh activity in humans induces ectopic L-2HG accumulation, resulting in neurodevelopmental defects, altered immune cell function, and enhanced growth of clear cell renal cell carcinomas. To better understand the molecular mechanisms that underlie these disease pathologies, we used the fruit fly <em>Drosophila melanogaster</em> to investigate the endogenous functions of L2hgdh.</p></div><div><h3>Methods</h3><p><em>L2hgdh</em> mutant adult male flies were analyzed under normoxic and hypoxic conditions using a combination of semi-targeted metabolomics and RNA-seq. These multi-omic analyses were complemented by tissue-specific genetic studies that examined the effects of <em>L2hgdh</em> mutations on the <em>Drosophila</em> renal system (Malpighian tubules; MTs).</p></div><div><h3>Results</h3><p>Our studies revealed that while L2hgdh is not essential for growth or viability under standard culture conditions, <em>L2hgdh</em> mutants are hypersensitive to hypoxia and expire during the reoxygenation phase with severe disruptions of mitochondrial metabolism. Moreover, we find that the fly renal system is a key site of L2hgdh activity, as <em>L2hgdh</em> mutants that express a rescuing transgene within the MTs survive hypoxia treatment and exhibit normal levels of mitochondrial metabolites. We also demonstrate that even under normoxic conditions, <em>L2hgdh</em> mutant MTs experience significant metabolic stress and are sensitized to aberrant growth upon Egfr activation.</p></div><div><h3>Conclusions</h3><p>These findings present a model in which renal L2hgdh activity limits systemic L-2HG accumulation, thus indirectly regulating the balance between glycolytic and mitochondrial metabolism, enabling successful recovery from hypoxia exposure, and ensuring renal tissue integrity.</p></div>","PeriodicalId":18765,"journal":{"name":"Molecular Metabolism","volume":"89 ","pages":"Article 102013"},"PeriodicalIF":7.0,"publicationDate":"2024-08-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S2212877824001443/pdfft?md5=da641ce779f9a0413df75505970159c0&pid=1-s2.0-S2212877824001443-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142056056","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 INSULIN and IAPP dual reporter enables tracking of functional maturation of stem cell-derived insulin producing cells","authors":"Carmen L. Bayly ,&nbsp;Xiao-Qing Dai ,&nbsp;Cuilan Nian ,&nbsp;Paul C. Orban ,&nbsp;C. Bruce Verchere ,&nbsp;Patrick E. MacDonald ,&nbsp;Francis C. Lynn","doi":"10.1016/j.molmet.2024.102017","DOIUrl":"10.1016/j.molmet.2024.102017","url":null,"abstract":"<div><h3>Objective</h3><p>Human embryonic stem cell (hESC; SC)-derived pancreatic β cells can be used to study diabetes pathologies and develop cell replacement therapies. Although current differentiation protocols yield SCβ cells with varying degrees of maturation, these cells still differ from deceased donor human β cells in several respects. We sought to develop a reporter cell line that could be used to dynamically track SCβ cell functional maturation.</p></div><div><h3>Methods</h3><p>To monitor SCβ cell maturation <em>in vitro</em>, we created an IAPP-2A-mScar and INSULIN-2A-EGFP dual fluorescent reporter (<em>INS</em>^{<em>2A-EGFP/+</em>}<em>;IAPP</em>^{<em>2A-mScarlet/+</em>}) hESC line using CRISPR/Cas9. Pluripotent SC were then differentiated using a 7-stage protocol to islet-like cells. Immunohistochemistry, flow cytometry, qPCR, GSIS and electrophysiology were used to characterise resulting cell populations.</p></div><div><h3>Results</h3><p>We observed robust expression of EGFP and mScarlet fluorescent proteins in insulin- and IAPP-expressing cells without any compromise to their differentiation. We show that the proportion of insulin-producing cells expressing IAPP increases over a 4-week maturation period, and that a subset of insulin-expressing cells remain IAPP-free. Compared to this IAPP-free population, we show these insulin- and IAPP-expressing cells are less polyhormonal, more glucose-sensitive, and exhibit decreased action potential firing in low (2.8 mM) glucose.</p></div><div><h3>Conclusions</h3><p>The <em>INS</em>^{<em>2A-EGFP/+</em>}<em>;IAPP</em>^{<em>2A-mScarlet/+</em>} hESC line provides a useful tool for tracking populations of maturing hESC-derived β cells <em>in vitro</em>. This tool has already been shared with 3 groups and is freely available to all.</p></div>","PeriodicalId":18765,"journal":{"name":"Molecular Metabolism","volume":"89 ","pages":"Article 102017"},"PeriodicalIF":7.0,"publicationDate":"2024-08-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S2212877824001480/pdfft?md5=77d7ce5f2d48e33486470a8cc9668837&pid=1-s2.0-S2212877824001480-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142056097","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}