bioRxiv : the preprint server for biology最新文献

{"title":"Gamma-burst cortical activity in awake behaving macaques.","authors":"Benjamin T Acland, Ben Julian A Palanca, Janine Bijsterbosch, Lawrence H Snyder","doi":"10.1101/2023.09.26.559594","DOIUrl":"10.1101/2023.09.26.559594","url":null,"abstract":"<p><p>Electrophysiological recordings during ketamine anesthesia have revealed a slow alternating pattern of high- and low- frequency activity (a \"gamma-burst\" pattern) that develops with the onset of general anesthesia. We examine the role of NMDA receptor antagonism in generating the gamma-burst pattern and the link between gamma-bursts and dissociative anesthesia. We compare the effects of ketamine with those of the highly selective NMDA receptor antagonist CGS 19755 on multi-site intracranial electrophysiology and behavior in rhesus macaques. Remarkably, we find that animals given a moderate dose of CGS 19755 are able to perform a difficult memory task, while at the same time showing electrophysiological activity similar to ketamine anesthesia, with one key difference: a lack of delta-band LFP modulation. This difference demonstrates that ketamine's ability to drive strong delta-band oscillations relies on additional mechanisms beyond NMDA receptor antagonism alone, and points to a key role for the activity underlying delta-band oscillations in causing anesthesia.</p>","PeriodicalId":72407,"journal":{"name":"bioRxiv : the preprint server for biology","volume":" ","pages":""},"PeriodicalIF":0.0,"publicationDate":"2025-02-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10557640/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"41173593","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"ATP-release pannexin channels are gated by lysophospholipids.","authors":"Erik Henze, Russell N Burkhardt, Bennett W Fox, Tyler J Schwertfeger, Eric Gelsleichter, Kevin Michalski, Lydia Kramer, Margret Lenfest, Jordyn M Boesch, Hening Lin, Frank C Schroeder, Toshimitsu Kawate","doi":"10.1101/2023.10.23.563601","DOIUrl":"10.1101/2023.10.23.563601","url":null,"abstract":"<p><p>In addition to its role as cellular energy currency, adenosine triphosphate (ATP) serves as an extracellular messenger that mediates diverse cell-to-cell communication. Compelling evidence supports that ATP is released from cells through pannexins, a family of membrane proteins that form heptameric large-pore channels. However, the activation mechanisms that trigger ATP release by pannexins remain poorly understood. Here, we discover lysophospholipids as endogenous pannexin activators, using activity-guided fractionation of mouse tissue extracts combined with untargeted metabolomics and electrophysiology. We show that lysophospholipids directly and reversibly activate pannexins in the absence of other proteins. Secretomics experiments reveal that lysophospholipid-activated pannexin 1 leads to the release of not only ATP but also other signaling metabolites, such as 5'-methylthioadenosine, which is important for immunomodulation. We also demonstrate that lysophospholipids activate endogenous pannexin 1 in human monocytes, leading to the release of IL-1β through inflammasome activation. Our results provide a connection between lipid metabolism and purinergic signaling, both of which play major roles in immune responses.</p>","PeriodicalId":72407,"journal":{"name":"bioRxiv : the preprint server for biology","volume":" ","pages":""},"PeriodicalIF":0.0,"publicationDate":"2025-02-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10634739/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"92157625","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"H3.3-G34R Mutation-Mediated Epigenetic Reprogramming Leads to Enhanced Efficacy of Immune Stimulatory Gene Therapy in Diffuse Hemispheric Gliomas.","authors":"Maria B Garcia-Fabiani, Santiago Haase, Kaushik Banerjee, Ziwen Zhu, Brandon L McClellan, Anzar A Mujeeb, Yingxiang Li, Claire E Tronrud, Maria L Varela, Molly E J West, Jin Yu, Padma Kadiyala, Ayman W Taher, Felipe J Núñez, Mahmoud S Alghamri, Andrea Comba, Flor M Mendez, Alejandro J Nicola Candia, Brittany Salazar, Fernando M Nunez, Marta B Edwards, Tingting Qin, Rodrigo T Cartaxo, Michael Niculcea, Carl Koschmann, Sriram Venneti, Montserrat Puigdelloses Vallcorba, Emon Nasajpour, Giulia Pericoli, Maria Vinci, Claudia L Kleinman, Nada Jabado, James P Chandler, Adam M Sonabend, Michael DeCuypere, Dolores Hambardzumyan, Laura M Prolo, Kelly B Mahaney, Gerald A Grant, Claudia K Petritsch, Joshua D Welch, Maureen A Sartor, Pedro R Lowenstein, Maria G Castro","doi":"10.1101/2023.06.13.544658","DOIUrl":"10.1101/2023.06.13.544658","url":null,"abstract":"<p><p>Diffuse hemispheric glioma (DHG), H3 G34-mutant, representing 9-15% of cases, are aggressive Central Nervous System (CNS) tumors with poor prognosis. This study examines the role of epigenetic reprogramming of the immune microenvironment and the response to immune-mediated therapies in G34-mutant DHG. To this end, we utilized human G34-mutant DHG biopsies, primary G34-mutant DHG cultures, and genetically engineered G34-mutant mouse models (GEMMs). Our findings show that the G34 mutation alters histone marks' deposition at promoter and enhancer regions, leading to the activation of the JAK/STAT pathway, which in turn results in an immune-permissive tumor microenvironment. The implementation of Ad-TK/Ad-Flt3L immunostimulatory gene therapy significantly improved median survival, and lead to over 50% long term survivors. Upon tumor rechallenge in the contralateral hemisphere without any additional treatment, the long-term survivors exhibited robust anti-tumor immunity and immunological memory. These results indicate that immune-mediated therapies hold significant potential for clinical translation in treating patients harboring H3.3-G34 mutant DHGs, offering a promising strategy for improving outcomes in this challenging cancer subtype affecting adolescents and young adults (AYA).</p><p><strong>Statement of significance: </strong>This study uncovers the role of the H3.3-G34 mutation in reprogramming the tumor immune microenvironment in diffuse hemispheric gliomas. Our findings support the implementation of precision medicine informed immunotherapies, aiming at improving enhanced therapeutic outcomes in adolescents and young adults harboring H3.3-G34 mutant DHGs.</p>","PeriodicalId":72407,"journal":{"name":"bioRxiv : the preprint server for biology","volume":" ","pages":""},"PeriodicalIF":0.0,"publicationDate":"2025-02-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://ftp.ncbi.nlm.nih.gov/pub/pmc/oa_pdf/11/20/nihpp-2023.06.13.544658v1.PMC10312611.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"10149707","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Somatodendritic orientation determines tDCS-induced neuromodulation of Purkinje cell activity in awake mice.","authors":"Carlos A Sánchez-León, Guillermo Sánchez-Garrido Campos, Marta Fernández, Alvaro Sánchez-López, Javier F Medina, Javier Márquez-Ruiz","doi":"10.1101/2023.02.18.529047","DOIUrl":"10.1101/2023.02.18.529047","url":null,"abstract":"<p><p>Transcranial direct-current stimulation (tDCS) of the cerebellum is a promising non-invasive neuromodulatory technique being proposed for the treatment of neurological and neuropsychiatric disorders. However, there is a lack of knowledge about how externally applied currents affect neuronal spiking activity in cerebellar circuits <i>in vivo</i>. We investigated how Cb-tDCS affects the firing rate of Purkinje cells (PC) and non-PC in the mouse cerebellar cortex to understand the underlying mechanisms behind the polarity-dependent modulation of neuronal activity induced by tDCS. Mice (n = 9) were prepared for the chronic recording of LFPs to assess the actual electric field gradient imposed by Cb-tDCS in our experimental design. Single-neuron extracellular recording of PCs in awake (n = 24) and anesthetized (n = 27) mice was combined with juxtacellular recordings and subsequent staining of PC with neurobiotin under anesthesia (n = 8) to correlate their neuronal orientation with their response to Cb-tDCS. Finally, a high-density Neuropixels recording system was used to demonstrate the relevance of neuronal orientation during the application of Cb-tDCS in awake mice (n = 6). In this study, we observe that Cb-tDCS induces a heterogeneous polarity-dependent modulation of the firing rate of Purkinje cells (PC) and non-PC in the mouse cerebellar cortex. We demonstrate that the apparently heterogeneous effects of tDCS on PC activity can be explained by taking into account the somatodendritic orientation relative to the electric field. Our findings highlight the need to consider neuronal orientation and morphology to improve tDCS computational models, enhance stimulation protocol reliability, and optimize effects in both basic and clinical applications.</p>","PeriodicalId":72407,"journal":{"name":"bioRxiv : the preprint server for biology","volume":" ","pages":""},"PeriodicalIF":0.0,"publicationDate":"2025-02-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://ftp.ncbi.nlm.nih.gov/pub/pmc/oa_pdf/33/a9/nihpp-2023.02.18.529047v1.PMC9949160.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"9081424","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Organoid-based <i>in vitro</i> system and reporter for the study of <i>Cryptosporidium parvum</i> sexual reproduction.","authors":"Bethany R Korwin-Mihavics, Emmett A Dews, Peter Miller, Alexandra Cameron, Bruno Martorelli di Genova, Christopher D Huston","doi":"10.1101/2023.09.29.560165","DOIUrl":"10.1101/2023.09.29.560165","url":null,"abstract":"<p><p>Many advances have been made recently in our understanding of <i>Cryptosporidium</i>'s asexual cycle and sexual differentiation. However, the process of fertilization, which is required for transmission of infectious oocysts, is not well understood. Typical cancer cell-based culture only allows robust exploration of asexual cycle and sexual differentiation of <i>Cryptosporidium</i>. To facilitate exploration of sexual reproduction in <i>C. parvum</i> we developed an organoid-based culture system that supports <i>Cryptosporidium's</i> full life cycle and a novel fertilization reporter. Organoid derived monolayers (ODMs) supported fertilization and oocyst production and maintained the infection for up to 3 weeks. ODM derived oocysts were infectious <i>in vivo</i>. Fertilization was confirmed by successfully mating two strains of <i>C. parvum</i> and with a novel fertilization switch reporter. The fertilization switch reporter utilizes a DiCre system in which cre fragments are expressed under the control of sexual stage promoters resulting in a rapamycin-inducible switch in fluorescent protein expression from mCherry to mNeonGreen after fertilization that is spatially and temporally controlled. This results in mCherry positive parasites in the first generation and offspring that express mNeonGreen. <i>In vivo</i> validation of the fertilization switch reporter demonstrated the precision and efficiency of the fertilization switch reporter and confirmed excision of the mCherry gene sequence only after rapamycin treatment. The start of a second generation of parasites was also shown in the ODMs and rarely in HCT8s. Use of this reporter in ODMs can help investigate the <i>Cryptosporidium</i> lifecycle post sexual differentiation in a physiologically relevant <i>in vitro</i> system.</p>","PeriodicalId":72407,"journal":{"name":"bioRxiv : the preprint server for biology","volume":" ","pages":""},"PeriodicalIF":0.0,"publicationDate":"2025-02-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://ftp.ncbi.nlm.nih.gov/pub/pmc/oa_pdf/e8/4b/nihpp-2023.09.29.560165v1.PMC10557739.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"41175379","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Control adjustment costs limit goal flexibility: Empirical evidence and a computational account.","authors":"Ivan Grahek, Xiamin Leng, Sebastian Musslick, Amitai Shenhav","doi":"10.1101/2023.08.22.554296","DOIUrl":"10.1101/2023.08.22.554296","url":null,"abstract":"<p><p>A cornerstone of human intelligence is the ability to flexibly adjust our cognition and behavior as our goals change. For instance, achieving some goals requires efficiency, while others require caution. Different goals require us to engage different control processes, such as adjusting how attentive and cautious we are. Here, we show that performance incurs control adjustment costs when people adjust control to meet changing goals. Across four experiments, we provide evidence of these costs, and validate a dynamical systems model explaining the source of these costs. Participants performed a single cognitively demanding task under varying performance goals (e.g., being fast or accurate). We modeled control allocation to include a dynamic process of adjusting from one's current control state to a target state for a given performance goal. By incorporating inertia into this adjustment process, our model accounts for our empirical finding that people under-shoot their target control state more (i.e., exhibit larger adjustment costs) when goals switch rather than remain fixed (Study 1). Further validating our model, we show that the magnitude of this cost is increased when: distances between target states are larger (Study 2), there is less time to adjust to the new goal (Study 3), and goal switches are more frequent (Study 4). Our findings characterize the costs of adjusting control to meet changing goals, and show that these costs emerge directly from cognitive control dynamics. In so doing, they shed new light on the sources of and constraints on flexibility of goal-directed behavior.</p>","PeriodicalId":72407,"journal":{"name":"bioRxiv : the preprint server for biology","volume":" ","pages":""},"PeriodicalIF":0.0,"publicationDate":"2025-02-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://ftp.ncbi.nlm.nih.gov/pub/pmc/oa_pdf/e8/b9/nihpp-2023.08.22.554296v1.PMC10473589.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"10240836","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Performance of <i>qpAdm</i> -based screens for genetic admixture on admixture-graph-shaped histories and stepping-stone landscapes.","authors":"Olga Flegontova, Ulaş Işıldak, Eren Yüncü, Matthew P Williams, Christian D Huber, Jan Kočí, Leonid A Vyazov, Piya Changmai, Pavel Flegontov","doi":"10.1101/2023.04.25.538339","DOIUrl":"10.1101/2023.04.25.538339","url":null,"abstract":"<p><p><i>qpAdm</i> is a statistical tool that is often used for testing large sets of alternative admixture models for a target population. Despite its popularity, <i>qpAdm</i> remains untested on two-dimensional stepping-stone landscapes and in situations with low pre-study odds (low ratio of true to false models). We tested high-throughput <i>qpAdm</i> protocols with typical properties such as number of source combinations per target, model complexity, model feasibility criteria, etc. Those protocols were applied to admixture-graph-shaped and stepping-stone simulated histories sampled randomly or systematically. We demonstrate that false discovery rates of high-throughput <i>qpAdm</i> protocols exceed 50% for many parameter combinations since: 1) pre-study odds are low and fall rapidly with increasing model complexity; 2) complex migration networks violate the assumptions of the method, hence there is poor correlation between <i>qpAdm p</i> -values and model optimality, contributing to low but non-zero false positive rate and low power; 3) although admixture fraction estimates between 0 and 1 are largely restricted to symmetric configurations of sources around a target, a small fraction of asymmetric highly non-optimal models have estimates in the same interval, contributing to the false positive rate. We also re-interpret large sets of <i>qpAdm</i> models from two studies in terms of source-target distance and symmetry and suggest improvements to <i>qpAdm</i> protocols: 1) temporal stratification of targets and proxy sources in the case of admixture-graph-shaped histories; 2) focused exploration of few models for increasing pre-study odds; dense landscape sampling for increasing power and stringent conditions on estimated admixture fractions for decreasing the false positive rate.</p><p><strong>Article summary: </strong>Proliferation in the archaeogenetic literature of protocols for detection of admixed groups based a so-called <i>qpAdm</i> algorithm became disconnected from performance testing: the only extensive study of <i>qpAdm</i> on simulated data showed that it performs well under an unrealistically simple demographic scenario. We found that false discoveries of gene flows by <i>qpAdm</i> on a collection of random admixture-graph-shaped histories and on complex stepping-stone landscapes are very common and provide guidelines for design of <i>qpAdm</i> protocols in archaeogenetic studies.</p>","PeriodicalId":72407,"journal":{"name":"bioRxiv : the preprint server for biology","volume":" ","pages":""},"PeriodicalIF":0.0,"publicationDate":"2025-02-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10614728/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"71415627","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Collagen IV of basement membranes: I. Origin and diversification of COL4 genes enabling animal evolution and adaptation.","authors":"Patrick S Page-McCaw, Elena N Pokidysheva, Carl E Darris, Sergei Chetyrkin, Aaron L Fidler, Julianna Gallup, Prayag Murawala, Julie K Hudson, Sergei Boudko, Billy G Hudson","doi":"10.1101/2023.10.18.563013","DOIUrl":"10.1101/2023.10.18.563013","url":null,"abstract":"<p><p>Collagen IV is a major component of basement membranes, a specialized form of extracellular matrix that enabled the assembly of multicellular epithelial tissues. In mammals, collagen IV assembles from a family of six α-chains (α1 to α6), forming three supramolecular scaffolds: Col-IVα121, Col-IVα345 and Col-IVα121-α556. The α-chains are encoded by six genes (COL4A1-6) that occur in pairs in a head-to-head arrangement. In Alport syndrome, variants in COL4A3, 4 or 5 genes, encoding Col-IVα345 scaffold in glomerular basement membrane (GBM), the kidney ultrafilter, cause progressive renal failure in millions of people worldwide. How variants cause dysfunction remains obscure. Here, we gained insights into Col-IVα345 function by determining its evolutionary lineage, as revealed from phylogenetic analyses and tissue expression of COL4 gene-pairs. We found that the COL4A⟨1|2⟩ gene-pair emerged in basal Ctenophores and Cnidaria phyla and is highly conserved across metazoans. The COL4A⟨1|2⟩ duplicated and arose as the progenitor to the COL4A⟨3|4⟩ gene-pair in cyclostomes, coinciding with emergence of kidney GBM, and expressed and conserved in jawed-vertebrates, except for amphibians, and a second duplication as the progenitor to the COL4A⟨5|6⟩ gene-pair and conserved in jawed-vertebrates. These findings revealed that Col-IVα121 is the progenitor scaffold, expressed ubiquitously in metazoan basement membranes, and which evolved into vertebrate Col-IVα345 and expressed in GBM. The Col-IVα345 scaffold, in comparison, has an increased number of cysteine residues, varying in number with osmolarity of the environment. Cysteines mediate disulfide crosslinks between protomers, an adaptation enabling a compact GBM that withstands the high hydrostatic pressure associated with glomerular ultrafiltration.</p>","PeriodicalId":72407,"journal":{"name":"bioRxiv : the preprint server for biology","volume":" ","pages":""},"PeriodicalIF":0.0,"publicationDate":"2025-02-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10614949/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"71415511","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Self-supervised segmentation and characterization of fiber bundles in anatomic tracing data.","authors":"Vaanathi Sundaresan, Julia F Lehman, Chiara Maffei, Suzanne N Haber, Anastasia Yendiki","doi":"10.1101/2023.09.30.560310","DOIUrl":"10.1101/2023.09.30.560310","url":null,"abstract":"<p><p>Anatomic tracing is the gold standard tool for delineating brain connections and for validating more recently developed imaging approaches such as diffusion MRI tractography. A key step in the analysis of data from tracer experiments is the careful, manual charting of fiber trajectories on histological sections. This is a very time-consuming process, which limits the amount of annotated tracer data that are available for validation studies. Thus, there is a need to accelerate this process by developing a method for computer-assisted segmentation. Such a method must be robust to the common artifacts in tracer data, including variations in the intensity of stained axons and background, as well as spatial distortions introduced by sectioning and mounting the tissue. The method should also achieve satisfactory performance using limited manually charted data for training. Here we propose the first deep-learning method, with a self-supervised loss function, for segmentation of fiber bundles on histological sections from macaque brains that have received tracer injections. We address the limited availability of manual labels with a semi-supervised training technique that takes advantage of unlabeled data to improve performance. We also introduce anatomic and across-section continuity constraints to improve accuracy. We show that our method can be trained on manually charted sections from a single case and segment unseen sections from different cases, with a true positive rate of ~0.80. We further demonstrate the utility of our method by quantifying the density of fiber bundles as they travel through different white-matter pathways. We show that fiber bundles originating in the same injection site have different levels of density when they travel through different pathways, a finding that can have implications for microstructure-informed tractography methods. The code for our method is available at https://github.com/v-sundaresan/fiberbundle_seg_tracing.</p>","PeriodicalId":72407,"journal":{"name":"bioRxiv : the preprint server for biology","volume":" ","pages":""},"PeriodicalIF":0.0,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10592842/pdf/nihpp-2023.09.30.560310v1.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"49694680","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Loss of CTRP10 results in female obesity with preserved metabolic health.","authors":"Fangluo Chen, Dylan C Sarver, Muzna Saqib, Leandro M Velez, Susan Aja, Marcus M Seldin, G William Wong","doi":"10.1101/2023.11.01.565163","DOIUrl":"10.1101/2023.11.01.565163","url":null,"abstract":"<p><p>Obesity is a major risk factor for type 2 diabetes, dyslipidemia, cardiovascular disease, and hypertension. Intriguingly, there is a subset of metabolically healthy obese (MHO) individuals who are seemingly able to maintain a healthy metabolic profile free of metabolic syndrome. The molecular underpinnings of MHO, however, are not well understood. Here, we report that CTRP10/C1QL2-deficient mice represent a unique female model of MHO. CTRP10 modulates weight gain in a striking and sexually dimorphic manner. Female, but not male, mice lacking CTRP10 develop obesity with age on a low-fat diet while maintaining an otherwise healthy metabolic profile. When fed an obesogenic diet, female <i>Ctrp10</i> knockout (KO) mice show rapid weight gain. Despite pronounced obesity, <i>Ctrp10</i> KO female mice do not develop steatosis, dyslipidemia, glucose intolerance, insulin resistance, oxidative stress, or low-grade inflammation. Obesity is largely uncoupled from metabolic dysregulation in female KO mice. Multi-tissue transcriptomic analyses highlighted gene expression changes and pathways associated with insulin-sensitive obesity. Transcriptional correlation of the differentially expressed gene (DEG) orthologous in humans also shows sex differences in gene connectivity within and across metabolic tissues, underscoring the conserved sex-dependent function of CTRP10. Collectively, our findings suggest that CTRP10 negatively regulates body weight in females, and that loss of CTRP10 results in benign obesity with largely preserved insulin sensitivity and metabolic health. This female MHO mouse model is valuable for understanding sex-biased mechanisms that uncouple obesity from metabolic dysfunction.</p>","PeriodicalId":72407,"journal":{"name":"bioRxiv : the preprint server for biology","volume":" ","pages":""},"PeriodicalIF":0.0,"publicationDate":"2025-01-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10635050/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"92157802","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}