Molecular Metabolism最新文献

{"title":"The role of intestinal microbiota in physiologic and body compositional changes that accompany CLA-mediated weight loss in obese mice","authors":"Meifan Zhang ,&nbsp;Yue S. Yin ,&nbsp;Karolline S. May ,&nbsp;Shari Wang ,&nbsp;Hayley Purcell ,&nbsp;Xue-Song Zhang ,&nbsp;Martin J. Blaser ,&nbsp;Laura J. den Hartigh","doi":"10.1016/j.molmet.2024.102029","DOIUrl":"10.1016/j.molmet.2024.102029","url":null,"abstract":"<div><h3>Objective</h3><div>Obesity continues to be a major problem, despite known treatment strategies such as lifestyle modifications, pharmaceuticals, and surgical options, necessitating the development of novel weight loss approaches. The naturally occurring fatty acid, 10,12 conjugated linoleic acid (10,12 CLA), promotes weight loss by increasing fat oxidation and browning of white adipose tissue, leading to increased energy expenditure in obese mice. Coincident with weight loss, 10,12 CLA also alters the murine gut microbiota by enriching for microbes that produce short chain fatty acids (SCFAs), with concurrent elevations in fecal butyrate and plasma acetate.</div></div><div><h3>Methods</h3><div>To determine if the observed microbiota changes are required for 10,12 CLA-mediated weight loss, adult male mice with diet-induced obesity were given broad-spectrum antibiotics (ABX) to perturb the microbiota prior to and during 10,12 CLA-mediated weight loss. Conversely, to determine whether gut microbes were sufficient to induce weight loss, conventionally-raised and germ-free mice were transplanted with cecal contents from mice that had undergone weight loss by 10,12 CLA supplementation.</div></div><div><h3>Results</h3><div>While body weight was minimally modulated by ABX-mediated perturbation of gut bacterial populations, adult male mice given ABX were more resistant to the increased energy expenditure and fat loss that are induced by 10,12 CLA supplementation. Transplanting cecal contents from donor mice losing weight due to oral 10,12 CLA consumption into conventional or germ-free mice led to improved glucose metabolism with increased butyrate production.</div></div><div><h3>Conclusions</h3><div>These data suggest a critical role for the microbiota in diet-modulated changes in energy balance and glucose metabolism, and distinguish the metabolic effects of orally delivered 10,12 CLA from cecal transplantation of the resulting microbiota.</div></div>","PeriodicalId":18765,"journal":{"name":"Molecular Metabolism","volume":"89 ","pages":"Article 102029"},"PeriodicalIF":7.0,"publicationDate":"2024-09-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S2212877824001601/pdfft?md5=326aab8e1d24d56e61a94eb34363b447&pid=1-s2.0-S2212877824001601-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142266787","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":"Reversing Pdgfrβ signaling restores metabolically active beige adipocytes by alleviating ILC2 suppression in aged and obese mice","authors":"Abigail M. Benvie,&nbsp;Daniel C. Berry","doi":"10.1016/j.molmet.2024.102028","DOIUrl":"10.1016/j.molmet.2024.102028","url":null,"abstract":"<div><h3>Objective</h3><div>Platelet Derived Growth Factor Receptor Beta (Pdgfrβ) suppresses the formation of cold temperature-induced beige adipocytes in aged mammals. We aimed to determine if deleting Pdgfrβ in aged mice could rejuvenate metabolically active beige adipocytes by activating group 2 innate lymphoid cells (ILC2), and whether this effect could counteract diet-induced obesity-associated beige fat decline.</div></div><div><h3>Methods</h3><div>We employed Pdgfrβ gain-of-function and loss-of-function mouse models targeting beige adipocyte progenitor cells (APCs). Our approach included cold exposure, metabolic cage analysis, and age and diet-induced obesity models to examine beige fat development and metabolic function under varied Pdgfrβ activity.</div></div><div><h3>Results</h3><div>Acute cold exposure alone enhanced metabolic benefits in aged mice, irrespective of beige fat generation. However, Pdgfrβ deletion in aged mice reestablished the formation of metabolically functional beige adipocytes, enhancing metabolism. Conversely, constitutive Pdgfrβ activation in young mice stymied beige fat development. Mechanistically, Pdgfrβ deletion upregulated IL-33, promoting ILC2 recruitment and activation, whereas Pdgfrβ activation reduced IL-33 levels and suppressed ILC2 activity. Notably, diet-induced obesity markedly increased Pdgfrβ expression and Stat1 signaling, which inhibited IL-33 induction and ILC2 activation. Genetic deletion of Pdgfrβ restored beige fat formation in obese mice, improving whole-body metabolism.</div></div><div><h3>Conclusions</h3><div>This study reveals that cold temperature exposure alone can trigger metabolic activation in aged mammals. However, reversing Pdgfrβ signaling in aged and obese mice not only restores beige fat formation but also renews metabolic function and enhances the immunological environment of white adipose tissue (WAT). These findings highlight Pdgfrβ as a crucial target for therapeutic strategies aimed at combating age- and obesity-related metabolic decline.</div></div>","PeriodicalId":18765,"journal":{"name":"Molecular Metabolism","volume":"89 ","pages":"Article 102028"},"PeriodicalIF":7.0,"publicationDate":"2024-09-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S2212877824001595/pdfft?md5=cb448e89b880c761ea3e309209359700&pid=1-s2.0-S2212877824001595-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142269759","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":"Lead-in calorie restriction enhances the weight-lowering efficacy of incretin hormone-based pharmacotherapies in mice","authors":"Jonas Petersen ,&nbsp;Christoffer Merrild ,&nbsp;Jens Lund ,&nbsp;Stephanie Holm ,&nbsp;Christoffer Clemmensen","doi":"10.1016/j.molmet.2024.102027","DOIUrl":"10.1016/j.molmet.2024.102027","url":null,"abstract":"<div><h3>Objectives</h3><p>The potential benefits of combining lifestyle changes with weight loss pharmacotherapies for obesity treatment are underexplored. Building on recent clinical observations, this study aimed to determine whether “lead-in” calorie restriction before administering clinically approved weight loss medications enhances the maximum achievable weight loss in preclinical models.</p></div><div><h3>Methods</h3><p>Diet-induced obese mice (DIO) were exposed to 7 or 14 days of calorie restriction before initiating treatment with semaglutide (a glucagon-like peptide-1 receptor (GLP-1R) agonist), tirzepatide (a GLP-1R/glucose insulinotropic peptide receptor (GIPR) co-agonist), or setmelanotide (a melanocortin-4 receptor (MC4R) agonist). Follow-up assessments using indirect calorimetry determined the contributions of energy intake and expenditure linked to consecutive exposure to dieting followed by pharmacotherapy.</p></div><div><h3>Results</h3><p>Calorie restriction prior to treatment with semaglutide or tirzepatide enhanced the weight loss magnitude of both incretin-based therapies in DIO mice, reflected by a reduction in fat mass and linked to reduced energy intake and a less pronounced adaptive drop in energy expenditure. These benefits were not observed with the MC4R agonist, setmelanotide.</p></div><div><h3>Conclusions</h3><p>Our findings provide compelling evidence that calorie restriction prior to incretin-based therapy enhances the achievable extent of weight loss, as reflected in a weight loss plateau at a lower level compared to that of treatment without prior calorie reduction. This work suggests that more intensive lifestyle interventions should be considered prior to pharmacological treatment, encouraging further exploration and discussion of the current standard of care.</p></div>","PeriodicalId":18765,"journal":{"name":"Molecular Metabolism","volume":"89 ","pages":"Article 102027"},"PeriodicalIF":7.0,"publicationDate":"2024-09-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S2212877824001583/pdfft?md5=91443792b8ef4914b7d96a3c61e31acb&pid=1-s2.0-S2212877824001583-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142241977","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Corrigendum to “Results from three phase 1 trials of NNC9204-1177, a glucagon/GLP-1 receptor co-agonist: effects on weight loss and safety in adults with overweight or obesity” [Mol Metab 78 (2023) 101801]","authors":"Martin Haljeta Friedrichsen ,&nbsp;Lars Endahl ,&nbsp;Frederik Flindt Kreiner ,&nbsp;Ronald Goldwater ,&nbsp;Martin Kankam ,&nbsp;Søren Toubro ,&nbsp;Sune Boris Nygård","doi":"10.1016/j.molmet.2024.102023","DOIUrl":"10.1016/j.molmet.2024.102023","url":null,"abstract":"","PeriodicalId":18765,"journal":{"name":"Molecular Metabolism","volume":"89 ","pages":"Article 102023"},"PeriodicalIF":7.0,"publicationDate":"2024-09-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S2212877824001546/pdfft?md5=de4a09727093a03c43a16621279f3aa8&pid=1-s2.0-S2212877824001546-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142154597","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 protein defends lean mass and maintains the metabolic benefits of glucagon receptor agonism in mice","authors":"Tatiana Lopes ,&nbsp;David CD. Hope ,&nbsp;Jose M. Ramos-Pittol ,&nbsp;Anna Curtis ,&nbsp;Jed V. Shrewsbury ,&nbsp;Iona Davies ,&nbsp;Zijing Zhou ,&nbsp;Alessandro Sardini ,&nbsp;James S. Minnion ,&nbsp;Dirk Dormann ,&nbsp;Gavin A. Bewick ,&nbsp;Kevin G. Murphy ,&nbsp;David Carling ,&nbsp;Stephen R. Bloom ,&nbsp;Tricia MM. Tan ,&nbsp;Bryn M. Owen","doi":"10.1016/j.molmet.2024.102024","DOIUrl":"10.1016/j.molmet.2024.102024","url":null,"abstract":"<div><h3>Objective</h3><p>Glucagon has long been proposed as a component of multi-agonist obesity therapeutics due to its ability to induce energy expenditure and cause weight loss. However, chronic glucagon-receptor agonism has been associated with a reduction in circulating amino acids and loss of lean mass. Importantly, it is currently not known whether the metabolic benefits of glucagon can be maintained under contexts that allow the defence of lean mass.</p></div><div><h3>Methods</h3><p>We investigate the metabolic effects of the long-acting glucagon receptor agonist, G108, when administered to obese mice at low-doses, and with dietary protein supplementation.</p></div><div><h3>Results</h3><p>Dietary protein supplementation can only fully defend lean mass at a low dose of G108 that is sub-anorectic and does not reduce fat mass. However, in this context, G108 is still highly effective at improving glucose tolerance and reducing liver fat in obese mice. Mechanistically, liver RNA-Seq analysis reveals that dietary protein supplementation defends anabolic processes in low-dose G108-treated mice, and its effects on treatment-relevant glucose and lipid pathways are preserved.</p></div><div><h3>Conclusion</h3><p>Glucagon-mediated energy expenditure and weight loss may be mechanistically coupled to hypoaminocidemia and lean mass loss. However, our data suggest that glucagon can treat MAFLD at doses which allow full defence of lean mass given sufficient dietary protein intake. Therefore, proportionate glucagon therapy may be safe and effective in targeting hepatocytes and improving in glycaemia and liver fat.</p></div>","PeriodicalId":18765,"journal":{"name":"Molecular Metabolism","volume":"89 ","pages":"Article 102024"},"PeriodicalIF":7.0,"publicationDate":"2024-09-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S2212877824001558/pdfft?md5=e47d0ea2bc85e42d642f1908efcd0e02&pid=1-s2.0-S2212877824001558-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142140470","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":"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}