Molecular Metabolism最新文献

{"title":"Mitochondrial protein deacetylation by SIRT3 in osteoclasts promotes bone resorption with aging in female mice","authors":"Kimberly K. Richardson ,&nbsp;Gareeballah Osman Adam ,&nbsp;Wen Ling ,&nbsp;Aaron Warren ,&nbsp;Adriana Marques-Carvalho ,&nbsp;Jeff D. Thostenson ,&nbsp;Kimberly Krager ,&nbsp;Nukhet Aykin-Burns ,&nbsp;Stephanie D. Byrum ,&nbsp;Maria Almeida ,&nbsp;Ha-Neui Kim","doi":"10.1016/j.molmet.2024.102012","DOIUrl":"10.1016/j.molmet.2024.102012","url":null,"abstract":"<div><h3>Objectives</h3><p>The mitochondrial deacetylase sirtuin-3 (SIRT3) is necessary for the increased bone resorption and enhanced function of mitochondria in osteoclasts that occur with advancing age; how SIRT3 drives bone resorption remains elusive.</p></div><div><h3>Methods</h3><p>To determine the role of SIRT3 in osteoclast mitochondria, we used mice with conditional loss of <em>Sirt3</em> in osteoclast lineage and mice with germline deletion of either <em>Sirt3</em> or its known target <em>Pink</em>1.</p></div><div><h3>Results</h3><p>SIRT3 stimulates mitochondrial quality in osteoclasts in a PINK1-independent manner, promoting mitochondrial activity and osteoclast maturation and function, thereby contributing to bone loss in female but not male mice. Quantitative analyses of global proteomes and acetylomes revealed that deletion of <em>Sirt3</em> dramatically increased acetylation of osteoclast mitochondrial proteins, particularly ATPase inhibitory factor 1 (ATPIF1), an essential protein for mitophagy. Inhibition of mitophagy via mdivi-1 recapitulated the effect of deletion of <em>Sirt3</em> or <em>Atpif1</em> in osteoclast formation and mitochondrial function.</p></div><div><h3>Conclusions</h3><p>Decreasing mitophagic flux in osteoclasts may be a promising pharmacotherapeutic approach to treat osteoporosis in older adults.</p></div>","PeriodicalId":18765,"journal":{"name":"Molecular Metabolism","volume":"88 ","pages":"Article 102012"},"PeriodicalIF":7.0,"publicationDate":"2024-08-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S2212877824001431/pdfft?md5=a9155d0d1cfd89d98d7d2140e9f088ca&pid=1-s2.0-S2212877824001431-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142000340","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":"HSP60 chaperone deficiency disrupts the mitochondrial matrix proteome and dysregulates cholesterol synthesis","authors":"Cagla Cömert ,&nbsp;Kasper Kjær-Sørensen ,&nbsp;Jakob Hansen ,&nbsp;Jasper Carlsen ,&nbsp;Jesper Just ,&nbsp;Brandon F. Meaney ,&nbsp;Elsebet Østergaard ,&nbsp;Yonglun Luo ,&nbsp;Claus Oxvig ,&nbsp;Lisbeth Schmidt-Laursen ,&nbsp;Johan Palmfeldt ,&nbsp;Paula Fernandez-Guerra ,&nbsp;Peter Bross","doi":"10.1016/j.molmet.2024.102009","DOIUrl":"10.1016/j.molmet.2024.102009","url":null,"abstract":"<div><h3>Objective</h3><p>Mitochondrial proteostasis is critical for cellular function. The molecular chaperone HSP60 is essential for cell function and dysregulation of HSP60 expression has been implicated in cancer and diabetes. The few reported patients carrying HSP60 gene variants show neurodevelopmental delay and brain hypomyelination. Hsp60 interacts with more than 260 mitochondrial proteins but the mitochondrial proteins and functions affected by HSP60 deficiency are poorly characterized.</p></div><div><h3>Methods</h3><p>We studied two model systems for HSP60 deficiency: (1) engineered HEK cells carrying an inducible dominant negative HSP60 mutant protein, (2) zebrafish HSP60 knockout larvae. Both systems were analyzed by RNASeq, proteomics, and targeted metabolomics, and several functional assays relevant for the respective model. In addition, skin fibroblasts from patients with disease-associated HSP60 variants were analyzed by proteomics.</p></div><div><h3>Results</h3><p>We show that HSP60 deficiency leads to a differentially downregulated mitochondrial matrix proteome, transcriptional activation of stress responses, and dysregulated cholesterol biosynthesis. This leads to lipid accumulation in zebrafish knockout larvae.</p></div><div><h3>Conclusions</h3><p>Our data provide a compendium of the effects of HSP60 deficiency on the mitochondrial matrix proteome. We show that HSP60 is a master regulator and modulator of mitochondrial functions and metabolic pathways. HSP60 dysfunction also affects cellular metabolism and disrupts the integrated stress response. The effect on cholesterol synthesis explains the effect of HSP60 dysfunction on myelination observed in patients carrying genetic variants of HSP60.</p></div>","PeriodicalId":18765,"journal":{"name":"Molecular Metabolism","volume":"88 ","pages":"Article 102009"},"PeriodicalIF":7.0,"publicationDate":"2024-08-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S2212877824001406/pdfft?md5=d1b8b84d08e9a5261b1d124f08fd7658&pid=1-s2.0-S2212877824001406-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141988378","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 intolerance as a consequence of hematopoietic stem cell dysfunction in offspring of obese mice","authors":"Merve Denizli ,&nbsp;James Ropa ,&nbsp;Lindsay Beasley ,&nbsp;Joydeep Ghosh ,&nbsp;Kelli DeVanna ,&nbsp;Taylor Spice ,&nbsp;Laura S. Haneline ,&nbsp;Maegan Capitano ,&nbsp;Kok Lim Kua","doi":"10.1016/j.molmet.2024.102008","DOIUrl":"10.1016/j.molmet.2024.102008","url":null,"abstract":"<div><h3>Objective</h3><p>Maternal obesity is increasingly common and negatively impacts offspring health. Children of mothers with obesity are at higher risk of developing diseases linked to hematopoietic system abnormalities and metabolism such as type 2 diabetes. Interestingly, disease risks are often dependent on the offspring's sex, suggesting sex-specific reprogramming effect of maternal obesity on offspring hematopoietic stem and progenitor cell (HSPC) function. However, the impact of maternal obesity exposure on offspring HSPC function, and the capability of HSPC to regulate offspring metabolic health is largely understudied. This study aims to test the hypothesis that offspring of obese mice exhibit sex-differences in HSPC function that affect offspring's metabolic health.</p></div><div><h3>Methods</h3><p>We first assessed bone marrow hematopoietic stem and progenitor cell phenotype using postnatal day 21 (P21) and 8-week-old C57BL/6J mice born to control and diet-induced obese dams. We also sorted HSPC (Lineage-, Sca1+, cKit + cells) from P21 mice for competitive primary and secondary transplant, as well as transcriptomic analysis. Body weight, adiposity, insulin tolerance test and glucose tolerance tests were performed in primary and secondary transplant recipient animals.</p></div><div><h3>Results</h3><p>We discovered sex-differences in offspring HSPC function in response to maternal obesity exposure, where male offspring of obese dams (MatOb) showed decreased HSPC numbers and engraftment, while female MatOb offspring remained largely unaffected. RNA-seq revealed immune stimulatory pathways in female MatOb offspring. Finally, only recipients of male MatOb offspring HSPC exhibited glucose intolerance.</p></div><div><h3>Conclusions</h3><p>This study demonstrated the lasting effect of maternal obesity exposure on offspring HSPC function and implicates HSPC in metabolic regulation.</p></div>","PeriodicalId":18765,"journal":{"name":"Molecular Metabolism","volume":"88 ","pages":"Article 102008"},"PeriodicalIF":7.0,"publicationDate":"2024-08-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S221287782400139X/pdfft?md5=f13eb9522ff2b72d9db1a4356fbf8a32&pid=1-s2.0-S221287782400139X-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141982705","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 mitochondrial pyruvate carrier regulates adipose glucose partitioning in female mice","authors":"Christopher E. Shannon ,&nbsp;Terry Bakewell ,&nbsp;Marcel J. Fourcaudot ,&nbsp;Iriscilla Ayala ,&nbsp;Annie A. Smelter ,&nbsp;Edgar A. Hinostroza ,&nbsp;Giovanna Romero ,&nbsp;Mara Asmis ,&nbsp;Leandro C. Freitas Lima ,&nbsp;Martina Wallace ,&nbsp;Luke Norton","doi":"10.1016/j.molmet.2024.102005","DOIUrl":"10.1016/j.molmet.2024.102005","url":null,"abstract":"<div><h3>Objective</h3><p>The mitochondrial pyruvate carrier (MPC) occupies a critical node in intermediary metabolism, prompting interest in its utility as a therapeutic target for the treatment of obesity and cardiometabolic disease. Dysregulated nutrient metabolism in adipose tissue is a prominent feature of obesity pathophysiology, yet the functional role of adipose MPC has not been explored. We investigated whether the MPC shapes the adaptation of adipose tissue to dietary stress in female and male mice.</p></div><div><h3>Methods</h3><p>The impact of pharmacological and genetic disruption of the MPC on mitochondrial pathways of triglyceride assembly (lipogenesis and glyceroneogenesis) was assessed in 3T3L1 adipocytes and murine adipose explants, combined with analyses of adipose MPC expression in metabolically compromised humans. Whole-body and adipose-specific glucose metabolism were subsequently investigated in male and female mice lacking adipocyte MPC1 (<em>Mpc1</em>^AD−/−) and fed either standard chow, high-fat western style, or high-sucrose lipid restricted diets for 24 weeks, using a combination of radiolabeled tracers and GC/MS metabolomics.</p></div><div><h3>Results</h3><p>Treatment with UK5099 or siMPC1 impaired the synthesis of lipids and glycerol-3-phosphate from pyruvate and blunted triglyceride accumulation in 3T3L1 adipocytes, whilst MPC expression in human adipose tissue was negatively correlated with indices of whole-body and adipose tissue metabolic dysfunction. Mature adipose explants from <em>Mpc1</em>^AD−/− mice were intrinsically incapable of incorporating pyruvate into triglycerides. <em>In vivo</em>, MPC deletion restricted the incorporation of circulating glucose into adipose triglycerides, but only in female mice fed a zero fat diet, and this associated with sex-specific reductions in tricarboxylic acid cycle pool sizes and compensatory transcriptional changes in lipogenic and glycerol metabolism pathways. However, whole-body adiposity and metabolic health were preserved in <em>Mpc1</em>^AD−/− mice regardless of sex, even under conditions of zero dietary fat.</p></div><div><h3>Conclusions</h3><p>These findings highlight the greater capacity for mitochondrially driven triglyceride assembly in adipose from female versus male mice and expose a reliance upon MPC-gated metabolism for glucose partitioning in female adipose under conditions of dietary lipid restriction.</p></div>","PeriodicalId":18765,"journal":{"name":"Molecular Metabolism","volume":"88 ","pages":"Article 102005"},"PeriodicalIF":7.0,"publicationDate":"2024-08-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S2212877824001364/pdfft?md5=538729392c0d283f3f722866d7ac9094&pid=1-s2.0-S2212877824001364-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141976150","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 low-density lipoprotein receptor contributes to carotenoid homeostasis by regulating tissue uptake and fecal elimination","authors":"Anthony P. Miller ,&nbsp;Walter C. Monroy ,&nbsp;Gema Soria ,&nbsp;Jaume Amengual","doi":"10.1016/j.molmet.2024.102007","DOIUrl":"10.1016/j.molmet.2024.102007","url":null,"abstract":"<div><h3>Objective</h3><p>Carotenoids are lipophilic plant molecules with antioxidant properties. Some carotenoids such as β-carotene also serve as vitamin A precursors, playing a key role in human health. Carotenoids are transported in lipoproteins with other lipids such as cholesterol, however, the mechanisms responsible for carotenoid storage in tissues and their non-enzymatic elimination remain relatively unexplored. The goal of this study was to examine the contribution of the low-density lipoprotein receptor (LDLR) in the bodily distribution and disposal of carotenoids.</p></div><div><h3>Methods</h3><p>We employed mice lacking one or both carotenoid-cleaving enzymes as suitable models for carotenoid accumulation. We examined the contribution of LDLR in carotenoid distribution by crossbreeding these mice with Ldlr-/- mice or overexpressing LDLR in the liver.</p></div><div><h3>Results</h3><p>Our results show that LDLR plays a dual role in carotenoid homeostasis by simultaneously favoring carotenoid storage in the liver and adipose tissue while facilitating their fecal elimination.</p></div><div><h3>Conclusions</h3><p>Our results highlight a novel role of the LDLR in carotenoid homeostasis, and unveil a previously unrecognized disposal pathway for these important bioactive molecules.</p></div>","PeriodicalId":18765,"journal":{"name":"Molecular Metabolism","volume":"88 ","pages":"Article 102007"},"PeriodicalIF":7.0,"publicationDate":"2024-08-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S2212877824001388/pdfft?md5=c24f61a7aa1444b2b5cd60e3dc7d0f59&pid=1-s2.0-S2212877824001388-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141971441","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":"AT-7687, a novel GIPR peptide antagonist, combined with a GLP-1 agonist, leads to enhanced weight loss and metabolic improvements in cynomolgus monkeys","authors":"Mette H. Jensen ,&nbsp;Samra J. Sanni ,&nbsp;Ditte Riber ,&nbsp;Jens J. Holst ,&nbsp;Mette M. Rosenkilde ,&nbsp;Alexander H. Sparre-Ulrich","doi":"10.1016/j.molmet.2024.102006","DOIUrl":"10.1016/j.molmet.2024.102006","url":null,"abstract":"<div><h3>Objectives</h3><p>Obesity represents a global health crisis with significant patient burdens and healthcare costs. Despite the advances with glucagon-like peptide-1 (GLP-1) receptor agonists in treating obesity, unmet needs remain. This study characterizes a novel glucose-dependent insulinotropic polypeptide receptor (GIPR) peptide antagonist, AT-7687, evaluating its potential to enhance obesity treatment.</p></div><div><h3>Methods</h3><p>We assessed the in vitro potency and pharmacokinetics of AT-7687, alongside its therapeutic effects when administered subcutaneously (SC) alone and in combination with liraglutide to high-fat-diet-fed obese non-human primates (NHP). The study spanned a 42-day treatment period and a 15-day washout period.</p></div><div><h3>Results</h3><p>AT-7687 demonstrated a subnanomolar cAMP antagonistic potency (pKB of 9.5) in HEK-293 cells and a 27.4 h half-life in NHPs. It effectively maintained weight stability in obese monkeys, whereas placebo recipients had an 8.6% weight increase by day 42 (<em>P</em> = 0.01). Monotherapy with liraglutide resulted in a 12.4% weight reduction compared to placebo (<em>P</em> = 0.03) and combining AT-7687 with liraglutide led to a 16.3% weight reduction (<em>P</em> = 0.0002). The combination therapy significantly improved metabolic markers, reducing insulin levels by 52% (<em>P</em> = 0.008), glucose by 30% (<em>P</em> = 0.02), triglycerides by 39% (<em>P</em> = 0.05), total cholesterol by 29% (<em>P</em> = 0.03), and LDL cholesterol by 48% (<em>P</em> = 0.003) compared to placebo. AT-7687 treatment was well tolerated and not associated with any side effects.</p></div><div><h3>Conclusions</h3><p>This study underscores the potential of AT-7687 as a promising addition to current obesity treatments.</p></div>","PeriodicalId":18765,"journal":{"name":"Molecular Metabolism","volume":"88 ","pages":"Article 102006"},"PeriodicalIF":7.0,"publicationDate":"2024-08-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S2212877824001376/pdfft?md5=d4e3ed6d91b514b386ce580c9aecd09d&pid=1-s2.0-S2212877824001376-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141917128","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":"Maternal gut Bifidobacterium breve modifies fetal brain metabolism in germ-free mice","authors":"Jorge Lopez-Tello ,&nbsp;Raymond Kiu ,&nbsp;Zoe Schofield ,&nbsp;Cindy X.W. Zhang ,&nbsp;Douwe van Sinderen ,&nbsp;Gwénaëlle Le Gall ,&nbsp;Lindsay J. Hall ,&nbsp;Amanda N. Sferruzzi-Perri","doi":"10.1016/j.molmet.2024.102004","DOIUrl":"10.1016/j.molmet.2024.102004","url":null,"abstract":"<div><h3>Background</h3><p>Recent advances have significantly expanded our understanding of the gut microbiome's influence on host physiology and metabolism. However, the specific role of certain microorganisms in gestational health and fetal development remains underexplored.</p></div><div><h3>Objective</h3><p>This study investigates the impact of <em>Bifidobacterium breve</em> UCC2003 on fetal brain metabolism when colonized in the maternal gut during pregnancy.</p></div><div><h3>Methods</h3><p>Germ-free pregnant mice were colonized with or without <em>B. breve</em> UCC2003 during pregnancy. The metabolic profiles of fetal brains were analyzed, focusing on the presence of key metabolites and the expression of critical metabolic and cellular pathways.</p></div><div><h3>Results</h3><p>Maternal colonization with <em>B. breve</em> resulted in significant metabolic changes in the fetal brain. Specifically, ten metabolites, including citrate, 3-hydroxyisobutyrate, and carnitine, were reduced in the fetal brain. These alterations were accompanied by increased abundance of transporters involved in glucose and branched-chain amino acid uptake. Furthermore, supplementation with this bacterium was associated with elevated expression of critical metabolic pathways such as PI3K-AKT, AMPK, STAT5, and Wnt-β-catenin signaling, including its receptor Frizzled-7. Additionally, there was stabilization of HIF-2 protein and modifications in genes and proteins related to cellular growth, axogenesis, and mitochondrial function.</p></div><div><h3>Conclusions</h3><p>The presence of maternal <em>B. breve</em> during pregnancy plays a crucial role in modulating fetal brain metabolism and growth. These findings suggest that <em>Bifidobacterium</em> could modify fetal brain development, potentially offering new avenues for enhancing gestational health and fetal development through microbiota-targeted interventions.</p></div>","PeriodicalId":18765,"journal":{"name":"Molecular Metabolism","volume":"88 ","pages":"Article 102004"},"PeriodicalIF":7.0,"publicationDate":"2024-08-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S2212877824001352/pdfft?md5=3e90f92db17997955d5e68124ce516ef&pid=1-s2.0-S2212877824001352-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141913309","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":"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}