{"gene":"C1QL3","run_date":"2026-04-28T17:12:38","timeline":{"discoveries":[{"year":2011,"finding":"CTRP13 (C1QL3) is secreted as a disulfide-linked oligomeric protein and forms heteromeric complexes with CTRP10; recombinant CTRP13 promotes glucose uptake in adipocytes, myotubes, and hepatocytes via activation of the AMPK signaling pathway, and suppresses lipid-induced JNK stress signaling to ameliorate insulin resistance in hepatocytes.","method":"Heterologous expression, purified recombinant protein functional assays, glucose uptake assays, signaling pathway analysis (AMPK, JNK) in cultured cells","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1-2 — multiple orthogonal in vitro assays with purified recombinant protein, replicated across cell types","pmids":["21378161"],"is_preprint":false},{"year":2016,"finding":"C1QL3 is a secreted neuronal protein that binds to BAI3 (ADGRB3), an adhesion-class GPCR; C1QL3 expression is activity-dependent in cultured neurons and supports excitatory synapse density. Conditional and constitutive C1QL3 knockout mice exhibit fewer excitatory synapses and behavioral abnormalities including impaired fear memories; C1QL3 expressed in basolateral amygdala neurons projecting to medial prefrontal cortex is required for formation and/or maintenance of these synapses.","method":"Knockout mouse generation, circuit-tracing, conditional ablation, electrophysiology/synapse counting, behavioral assays, cultured neuron experiments","journal":"Neuron","confidence":"High","confidence_rationale":"Tier 2 — multiple orthogonal methods (KO mice, conditional ablation, circuit tracing, behavioral phenotyping), replicated across brain regions","pmids":["27478018"],"is_preprint":false},{"year":2013,"finding":"Central administration of recombinant CTRP13 suppresses food intake and reduces body weight in mice; CTRP13 and the orexigenic neuropeptide AgRP reciprocally regulate each other's expression in the hypothalamus, forming a hypothalamic feedback loop modulating food intake.","method":"Intracerebroventricular delivery of recombinant protein, quantitative PCR of neuropeptide gene expression, food restriction and activity-based anorexia mouse models","journal":"PloS one","confidence":"Medium","confidence_rationale":"Tier 2 — in vivo central delivery with defined molecular phenotype (AgRP/CTRP13 reciprocal regulation), single lab","pmids":["23638159"],"is_preprint":false},{"year":2017,"finding":"C1QL3 is highly expressed in SCN neurons; C1QL3 knockout mice have reduced excitatory synapse density in the SCN and exhibit less consolidated circadian activity and period lengthening following a phase-delaying light pulse, establishing C1QL3 as required for glutamatergic synapse formation/maintenance and circadian behavior in the SCN.","method":"Knockout mouse, synapse counting, circadian behavioral assays (light pulse phase-shifting)","journal":"Journal of biological rhythms","confidence":"Medium","confidence_rationale":"Tier 2 — KO mouse with defined synaptic and behavioral phenotype, single lab","pmids":["28553739"],"is_preprint":false},{"year":2018,"finding":"CTRP13 reduces CD36 protein levels via autophagy-lysosome-dependent degradation (post-transcriptional), thereby decreasing oxidized LDL uptake, foam-cell formation, and macrophage trapping; blocking autophagy-lysosome induction abolishes CTRP13's protective effects against atherosclerosis.","method":"In vivo ApoE-/- mouse model with CTRP13 infusion, primary peritoneal macrophage assays, pharmacological autophagy blockade, Western blot","journal":"FASEB journal","confidence":"Medium","confidence_rationale":"Tier 2 — in vivo and in vitro evidence with pharmacological rescue experiment identifying mechanism","pmids":["30222079"],"is_preprint":false},{"year":2019,"finding":"CTRP13 preserves endothelial function in diabetic models by increasing GTP cyclohydrolase 1 (GCH1) expression and tetrahydrobiopterin (BH4) levels, ameliorating eNOS coupling; mechanistically, CTRP13 rescues high-glucose-induced inhibition of PKA activity, and increased PKA phosphorylates PPARα, promoting its recruitment to the GCH1 promoter and activating GCH1 transcription.","method":"Diabetic mouse models (db/db, STZ), ex vivo aortic relaxation assays, HUVEC culture, PKA activity assay, ChIP-like promoter recruitment, Western blot","journal":"Diabetes","confidence":"Medium","confidence_rationale":"Tier 2 — multiple orthogonal assays in vivo and in vitro with mechanistic pathway identified, single lab","pmids":["31676569"],"is_preprint":false},{"year":2019,"finding":"CTRP13 attenuates vascular calcification by repressing phosphorylation of tristetraprolin (TTP), thereby activating TTP and increasing its binding to the 3'UTR of Runx2 mRNA, accelerating Runx2 mRNA destabilization and degradation, and preventing VSMC transition from contractile to osteogenic phenotype.","method":"CRF rat model, VSMC culture, beta-glycerophosphate calcification assay, Runx2 overexpression rescue, TTP binding assay, Western blot","journal":"FASEB journal","confidence":"Medium","confidence_rationale":"Tier 2 — in vivo and in vitro with epistasis (Runx2 overexpression reversal) and RNA-binding mechanism identified, single lab","pmids":["31145871"],"is_preprint":false},{"year":2019,"finding":"miR-124 targets C1ql3 in the hippocampus; lentivirus-mediated overexpression of miR-124 or C1 inhibitor (C1INH) rescued blood-brain barrier breakdown, promoted angiogenesis, and reduced Aβ deposition in APP/PS1 transgenic mice, placing C1QL3 downstream of miR-124 in cerebromicrovascular regulation.","method":"APP/PS1 transgenic mice, lentivirus-mediated miR-124 overexpression, C1INH treatment, BBB integrity assays, angiogenesis quantification","journal":"Brain research bulletin","confidence":"Medium","confidence_rationale":"Tier 2 — genetic epistasis (miR-124 overexpression rescues C1QL3-associated phenotype) with functional readouts in vivo","pmids":["31499089"],"is_preprint":false},{"year":2020,"finding":"CTRP13 activates the CaMKKβ/AMPK pathway in rat liver sinusoidal endothelial cells (rLSECs) to attenuate high-glucose-induced increases in laminin (LN) and caveolin-1 (CAV-1) expression; pharmacological inhibition of CaMKKβ or AMPK abolished the protective effects of CTRP13 overexpression.","method":"Lentiviral CTRP13 overexpression in rLSECs, pharmacological inhibitors (STO-609, Compound C), Western blot, qRT-PCR","journal":"Aging","confidence":"Medium","confidence_rationale":"Tier 2 — pharmacological rescue identifies CaMKKβ/AMPK as downstream pathway of CTRP13, single lab","pmids":["32554851"],"is_preprint":false},{"year":2020,"finding":"CTRP13 mitigates abdominal aortic aneurysm formation; mechanistically, CTRP13 stabilizes NAMPT1 protein by preventing its ubiquitination-proteasome-dependent degradation, and NAMPT1 knockdown abolishes the anti-inflammatory and anti-apoptotic effects of CTRP13 in vascular SMCs.","method":"ApoE-/- angiotensin II and CaCl2 AAA mouse models, CTRP13 infusion, NAMPT1 siRNA knockdown, ubiquitination assay, Western blot","journal":"Molecular therapy","confidence":"Medium","confidence_rationale":"Tier 2 — in vivo and in vitro with epistasis (NAMPT1 KD reversal) and ubiquitination mechanism identified, single lab","pmids":["32966772"],"is_preprint":false},{"year":2021,"finding":"C1QL3 mediates a novel trans-synaptic cell-cell adhesion complex involving ADGRB3 (BAI3) and two neuronal pentraxins, NPTX1 and NPTXR; C1ql3, Nptx1, and Nptxr are highly co-expressed in the same excitatory neurons in the cerebral cortex, suggesting presynaptic secretion and formation of a complex that binds postsynaptically localized ADGRB3.","method":"In vivo interactome study (Co-IP/pulldown), single-cell RNA-seq data analysis, cell-cell adhesion assays","journal":"FASEB journal","confidence":"Medium","confidence_rationale":"Tier 2-3 — in vivo interactome plus cell adhesion assay identifies novel binding partners, single lab","pmids":["33337553"],"is_preprint":false},{"year":2021,"finding":"CTRP13 overexpression protects H9c2 cardiomyocytes from hypoxia/reoxygenation-induced oxidative stress and apoptosis via activation of the AMPK/Nrf2/ARE signaling pathway; AMPK inhibition reverses CTRP13-mediated Nrf2/ARE activation and cardioprotection, and Nrf2 silencing abolishes the protective effects of CTRP13.","method":"H9c2 cell H/R model, CTRP13 overexpression/silencing, AMPK inhibitor (Compound C), Nrf2 siRNA, ROS assays, apoptosis assays; in vivo rat I/R model with recombinant CTRP13","journal":"Cell transplantation","confidence":"Medium","confidence_rationale":"Tier 2 — epistasis via pharmacological inhibition and siRNA knockdown identifies pathway, single lab","pmids":["34338573"],"is_preprint":false},{"year":2023,"finding":"Loss of CTRP13 (Ctrp13 knockout mice) paradoxically improved systemic metabolic profiles: KO mice were more active, leaner, had reduced hepatic glucose output, improved glucose tolerance, insulin sensitivity, and triglyceride clearance, indicating CTRP13 functions as a negative metabolic regulator in vivo.","method":"Ctrp13 knockout mouse comprehensive metabolic phenotyping, RNA-seq of multiple tissues, integration with human METSIM cohort data","journal":"Molecular metabolism","confidence":"High","confidence_rationale":"Tier 2 — rigorous KO mouse metabolic phenotyping with transcriptomic analysis and human data integration, multiple metabolic readouts","pmids":["37844630"],"is_preprint":false},{"year":2024,"finding":"C1QL3 is upregulated in the basolateral amygdala (BLA) following chronic morphine withdrawal conditioning; C1QL3 co-localizes with BAI3 in the BLA; downregulation of C1QL3 in the BLA impairs chronic morphine withdrawal memory formation; C1QL3 modulates ubiquitination-mediated degradation of PSD95, decreasing PSD95 protein levels as a downstream mechanism.","method":"Conditioned place aversion, chemogenetics, immunofluorescence co-localization, C1QL3 knockdown via viral vector, PSD95 pharmacological blockade, ubiquitination assay","journal":"Biochemical and biophysical research communications","confidence":"Medium","confidence_rationale":"Tier 2-3 — in vivo knockdown with behavioral phenotype and molecular mechanism (PSD95 ubiquitination), single lab","pmids":["38772224"],"is_preprint":false},{"year":2024,"finding":"C1QL3 knockout in rats increases ramified microglia and decreases hypertrophic microglia at baseline; after LPS stimulation, KO brains have more amoeboid microglia and higher Arg-1 expression; KO also damages neuronal dendritic arbors and spine density, and results in hyperactive behavior and impaired short-term working memory.","method":"CRISPR/Cas9 C1ql3 KO rats, immunohistochemistry, Golgi staining, MRI, behavioral tests (open field, Morris water maze, Y maze)","journal":"Animal models and experimental medicine","confidence":"Medium","confidence_rationale":"Tier 2 — KO rat model with defined cellular (microglial, neuronal) and behavioral phenotypes, single lab","pmids":["38379452"],"is_preprint":false},{"year":2024,"finding":"CTRP13 inhibits ferroptosis of endothelial cells by activating GCH1/BH4 signaling, upregulating GPX4 and downregulating ACSL4; GCH1 silencing or BH4 inhibition counteracts CTRP13's protective effect on ox-LDL-induced endothelial ferroptosis, thereby inhibiting atherosclerosis progression.","method":"ApoE-/- mouse model with C1ql3 AAV overexpression, mouse aortic endothelial cell (MAEC) culture, GCH1 siRNA, BH4 inhibitor, ferroptosis markers (GPX4, ACSL4), lipid peroxidation assays","journal":"International immunopharmacology","confidence":"Medium","confidence_rationale":"Tier 2 — in vivo and in vitro with GCH1 siRNA and BH4 inhibitor rescue experiments identifying mechanism, single lab","pmids":["39541845"],"is_preprint":false},{"year":2025,"finding":"Using an epitope-tagged knock-in mouse (C1ql3-2HA), native PAGE determined the endogenous oligomeric state of C1QL3; brain-wide light-sheet microscopy identified an expanded neuroanatomical map of C1QL3 expression including cortical, subcortical regions and retina; super-resolution STED microscopy localized C1QL3 to hippocampal mossy fiber synapses positioned between pre- and post-synaptic markers, supporting its role in trans-synaptic complexes.","method":"Epitope-tagged knock-in mouse (C1ql3-2HA), native PAGE, light-sheet microscopy, STED super-resolution microscopy, dual immunohistochemistry","journal":"bioRxiv","confidence":"Medium","confidence_rationale":"Tier 1-2 — novel knock-in mouse with native protein detection, multiple structural/localization methods; preprint not yet peer-reviewed","pmids":["41959109"],"is_preprint":true}],"current_model":"C1QL3 is a secreted, oligomeric gC1q-domain protein expressed presynaptically by excitatory neurons that binds to the adhesion GPCR BAI3/ADGRB3 and neuronal pentraxins NPTX1/NPTXR to form trans-synaptic adhesion complexes, thereby regulating excitatory synapse density and strength across multiple brain circuits (amygdala-PFC, SCN, hippocampal mossy fibers), and controlling diverse behaviors including fear memory, circadian rhythms, and cognitive flexibility; peripherally, as an adipokine (CTRP13), it acts as a negative metabolic regulator by activating AMPK signaling to modulate glucose uptake, hepatic glucose output, lipid metabolism, and endothelial function via downstream targets including GCH1/BH4, Runx2 mRNA stability, NAMPT1 ubiquitination, and CD36 autophagy-lysosomal degradation."},"narrative":{"teleology":[{"year":2011,"claim":"Identification of CTRP13 as a secreted oligomeric adipokine that activates AMPK signaling established C1QL3 as a metabolic hormone capable of promoting glucose uptake and suppressing lipid-induced stress signaling across multiple cell types.","evidence":"Recombinant protein functional assays measuring glucose uptake and AMPK/JNK signaling in adipocytes, myotubes, and hepatocytes","pmids":["21378161"],"confidence":"High","gaps":["Receptor mediating metabolic signaling unidentified","No in vivo metabolic phenotyping of loss-of-function models","Oligomeric state of native endogenous protein not determined"]},{"year":2013,"claim":"Central administration of CTRP13 demonstrated that C1QL3 acts in the hypothalamus to suppress food intake and reciprocally regulates AgRP, establishing a central anorexigenic role beyond its peripheral metabolic effects.","evidence":"Intracerebroventricular delivery of recombinant protein in mice with qPCR of hypothalamic neuropeptide expression","pmids":["23638159"],"confidence":"Medium","gaps":["Hypothalamic receptor for CTRP13 not identified","No genetic loss-of-function confirmation of feeding phenotype","Single lab finding"]},{"year":2016,"claim":"Discovery that C1QL3 binds BAI3/ADGRB3 and is required for excitatory synapse maintenance in the BLA-PFC circuit transformed understanding of C1QL3 from a purely metabolic factor to a trans-synaptic organizer controlling synapse number and fear memory.","evidence":"Constitutive and conditional C1QL3 knockout mice, electrophysiology, synapse counting, circuit tracing, and behavioral assays","pmids":["27478018"],"confidence":"High","gaps":["Mechanism by which C1QL3–BAI3 interaction promotes synapse formation unknown","Whether C1QL3 signals through BAI3 GPCR activity or purely as adhesion molecule unresolved"]},{"year":2017,"claim":"Extension of the synaptic role to the suprachiasmatic nucleus demonstrated that C1QL3's synaptogenic function is not circuit-specific and that synapse loss in the SCN has functional consequences for circadian behavioral consolidation.","evidence":"C1QL3 knockout mice with SCN synapse quantification and circadian phase-shift behavioral assays","pmids":["28553739"],"confidence":"Medium","gaps":["Molecular mechanism of C1QL3-dependent synapse maintenance in SCN not dissected","Single lab replication"]},{"year":2018,"claim":"Identification of autophagy-lysosomal degradation of CD36 as a downstream effector of CTRP13 provided the first specific vascular protective mechanism, explaining how CTRP13 reduces foam cell formation and atherosclerosis.","evidence":"ApoE−/− mice with CTRP13 infusion, peritoneal macrophage assays, pharmacological autophagy blockade","pmids":["30222079"],"confidence":"Medium","gaps":["Direct receptor or upstream signal linking CTRP13 to autophagy pathway not identified","Single lab"]},{"year":2019,"claim":"Three studies collectively delineated CTRP13's vascular protective mechanisms: preservation of eNOS coupling via PKA-PPARα-GCH1/BH4 transcriptional axis, attenuation of vascular calcification via TTP-mediated Runx2 mRNA destabilization, and regulation of cerebrovascular integrity downstream of miR-124.","evidence":"Diabetic mouse aortic relaxation and HUVEC ChIP assays (GCH1); CRF rat VSMC calcification with TTP binding and Runx2 overexpression rescue; APP/PS1 mice with lentiviral miR-124 overexpression and BBB assays","pmids":["31676569","31145871","31499089"],"confidence":"Medium","gaps":["Whether these vascular pathways converge on a common receptor unknown","TTP regulation mechanism (which kinase/phosphatase) not fully resolved","miR-124–C1QL3 link lacks direct target validation by reporter assay"]},{"year":2020,"claim":"Discovery that CTRP13 stabilizes NAMPT1 by preventing its ubiquitination and that CTRP13 signals through CaMKKβ/AMPK in liver sinusoidal endothelial cells expanded the catalogue of downstream effectors and confirmed AMPK as a conserved signaling node across tissues.","evidence":"ApoE−/− AAA mouse models with NAMPT1 siRNA epistasis and ubiquitination assays; rLSEC overexpression with CaMKKβ/AMPK pharmacological inhibition","pmids":["32966772","32554851"],"confidence":"Medium","gaps":["Direct CTRP13 receptor on vascular SMCs and LSECs unidentified","Whether NAMPT1 stabilization is AMPK-dependent not tested"]},{"year":2021,"claim":"Identification of NPTX1 and NPTXR as C1QL3 binding partners that co-assemble into a trans-synaptic adhesion complex with BAI3 provided a molecular framework for how C1QL3 bridges pre- and post-synaptic compartments at excitatory synapses.","evidence":"In vivo co-immunoprecipitation/pulldown, cell–cell adhesion assays, single-cell RNA-seq co-expression analysis","pmids":["33337553"],"confidence":"Medium","gaps":["Stoichiometry and structure of the C1QL3–NPTX–BAI3 complex not determined","Functional necessity of NPTX1/NPTXR for C1QL3 synaptogenic activity not tested by combined loss-of-function"]},{"year":2023,"claim":"Comprehensive metabolic phenotyping of Ctrp13 knockout mice revealed that CTRP13 paradoxically acts as a negative metabolic regulator in vivo, resolving the apparent contradiction between gain-of-function studies showing metabolic benefit and the actual physiological role.","evidence":"Ctrp13 KO mouse metabolic phenotyping (body composition, glucose/insulin tolerance, triglyceride clearance), RNA-seq, integration with human METSIM cohort","pmids":["37844630"],"confidence":"High","gaps":["Tissue-specific contributions (adipose vs. brain vs. liver) to the metabolic phenotype not dissected","Mechanism by which CTRP13 restrains metabolic fitness not identified"]},{"year":2024,"claim":"Studies in 2024 extended C1QL3's neural functions: C1QL3 knockout rats showed altered microglial morphology, dendritic damage, and cognitive deficits, while BLA-specific knockdown revealed C1QL3 modulates PSD95 ubiquitination during morphine withdrawal memory, linking synapse remodeling to substance-use-related behavior.","evidence":"CRISPR/Cas9 C1ql3 KO rats with Golgi staining, microglial immunohistochemistry, MRI, behavioral tests; BLA viral knockdown with conditioned place aversion, PSD95 ubiquitination assays","pmids":["38379452","38772224"],"confidence":"Medium","gaps":["Whether PSD95 ubiquitination is a direct or indirect effect of C1QL3 unknown","Microglial phenotype could be secondary to synapse loss rather than direct C1QL3 action on microglia","Rat KO findings not yet replicated across species"]},{"year":2024,"claim":"Demonstration that CTRP13 inhibits endothelial ferroptosis through GCH1/BH4-dependent upregulation of GPX4 unified the earlier eNOS-coupling mechanism with a new cell-death modality, establishing GCH1/BH4 as a central node in CTRP13's vascular protection.","evidence":"ApoE−/− mice with C1ql3 AAV overexpression, MAEC culture with GCH1 siRNA and BH4 inhibitor rescue, ferroptosis marker quantification","pmids":["39541845"],"confidence":"Medium","gaps":["Whether ferroptosis inhibition operates through AMPK or an independent pathway not tested","Single lab"]},{"year":null,"claim":"The identity of the peripheral receptor(s) mediating CTRP13's metabolic and vascular signaling remains unknown, and the structural basis and stoichiometry of the C1QL3–NPTX–BAI3 trans-synaptic complex have not been determined.","evidence":"","pmids":[],"confidence":"Low","gaps":["No receptor identified for CTRP13 in metabolic or vascular tissues","No high-resolution structure of C1QL3 or its complexes","Tissue-specific conditional knockouts needed to decouple neural vs. peripheral phenotypes"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0098631","term_label":"cell adhesion mediator activity","supporting_discovery_ids":[1,10,16]},{"term_id":"GO:0098772","term_label":"molecular function regulator activity","supporting_discovery_ids":[0,12]},{"term_id":"GO:0048018","term_label":"receptor ligand activity","supporting_discovery_ids":[0,2,5]}],"localization":[{"term_id":"GO:0005576","term_label":"extracellular region","supporting_discovery_ids":[0,1,10]},{"term_id":"GO:0005886","term_label":"plasma membrane","supporting_discovery_ids":[1,10,16]}],"pathway":[{"term_id":"R-HSA-112316","term_label":"Neuronal System","supporting_discovery_ids":[1,3,10,14]},{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[0,5,8,11]},{"term_id":"R-HSA-1430728","term_label":"Metabolism","supporting_discovery_ids":[0,12]},{"term_id":"R-HSA-1500931","term_label":"Cell-Cell communication","supporting_discovery_ids":[1,10,16]},{"term_id":"R-HSA-9612973","term_label":"Autophagy","supporting_discovery_ids":[4]}],"complexes":["C1QL3–NPTX1–NPTXR–BAI3 trans-synaptic complex","CTRP13–CTRP10 heteromeric complex"],"partners":["ADGRB3","NPTX1","NPTXR","CTRP10","GCH1","NAMPT1","PSD95"],"other_free_text":[]},"mechanistic_narrative":"C1QL3 is a secreted, oligomeric gC1q-domain protein that functions as a trans-synaptic organizer in the brain and as a metabolic regulator (adipokine CTRP13) in peripheral tissues. In excitatory neurons, C1QL3 binds the adhesion GPCR BAI3/ADGRB3 and neuronal pentraxins NPTX1/NPTXR to form trans-synaptic adhesion complexes that maintain excitatory synapse density in the amygdala-prefrontal cortex circuit, suprachiasmatic nucleus, and hippocampal mossy fibers, with knockout animals exhibiting reduced synapse numbers, impaired fear memory, disrupted circadian consolidation, hyperactivity, and working memory deficits [PMID:27478018, PMID:28553739, PMID:38379452, PMID:33337553]. Peripherally, CTRP13 activates CaMKKβ/AMPK signaling to promote glucose uptake and suppress hepatic glucose output, and loss-of-function studies in knockout mice reveal it acts as a negative metabolic regulator whose absence paradoxically improves glucose tolerance, insulin sensitivity, and triglyceride clearance [PMID:21378161, PMID:37844630]. CTRP13 also exerts vascular protective effects by upregulating GCH1/BH4 to preserve eNOS coupling and inhibit endothelial ferroptosis, by promoting autophagy-lysosomal degradation of CD36 to reduce foam cell formation, and by stabilizing NAMPT1 protein to attenuate aortic aneurysm formation [PMID:31676569, PMID:39541845, PMID:30222079, PMID:32966772]."},"prefetch_data":{"uniprot":{"accession":"Q5VWW1","full_name":"Complement C1q-like protein 3","aliases":["C1q and tumor necrosis factor-related protein 13","C1q/TNF-related protein 13"],"length_aa":255,"mass_kda":26.7,"function":"May regulate the number of excitatory synapses that are formed on hippocampus neurons. Has no effect on inhibitory synapses (By similarity). Plays a role in glucose homeostasis. Via AMPK signaling pathway, stimulates glucose uptake in adipocytes, myotubes and hepatocytes and enhances insulin-stimulated glucose uptake. In a hepatoma cell line, reduces the expression of gluconeogenic enzymes G6PC1 and PCK1 and hence decreases de novo glucose production (By similarity)","subcellular_location":"Secreted","url":"https://www.uniprot.org/uniprotkb/Q5VWW1/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/C1QL3","classification":"Not Classified","n_dependent_lines":0,"n_total_lines":1208,"dependency_fraction":0.0},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[],"url":"https://opencell.sf.czbiohub.org/search/C1QL3","total_profiled":1310},"omim":[{"mim_id":"615229","title":"COMPLEMENT COMPONENT 1, q SUBCOMPONENT-LIKE 4; C1QL4","url":"https://www.omim.org/entry/615229"},{"mim_id":"615227","title":"COMPLEMENT COMPONENT 1, q SUBCOMPONENT-LIKE 3; C1QL3","url":"https://www.omim.org/entry/615227"},{"mim_id":"614330","title":"COMPLEMENT COMPONENT 1, q SUBCOMPONENT-LIKE 2; C1QL2","url":"https://www.omim.org/entry/614330"},{"mim_id":"611586","title":"COMPLEMENT COMPONENT 1, q SUBCOMPONENT-LIKE 1; C1QL1","url":"https://www.omim.org/entry/611586"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Approved","locations":[{"location":"Vesicles","reliability":"Approved"},{"location":"Cytosol","reliability":"Additional"}],"tissue_specificity":"Group enriched","tissue_distribution":"Detected in some","driving_tissues":[{"tissue":"brain","ntpm":26.1},{"tissue":"retina","ntpm":6.9}],"url":"https://www.proteinatlas.org/search/C1QL3"},"hgnc":{"alias_symbol":["K100","C1ql","C1QTNF13","CTRP13"],"prev_symbol":[]},"alphafold":{"accession":"Q5VWW1","domains":[],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q5VWW1","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q5VWW1-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q5VWW1-F1-predicted_aligned_error_v6.png","plddt_mean":79.06},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=C1QL3","jax_strain_url":"https://www.jax.org/strain/search?query=C1QL3"},"sequence":{"accession":"Q5VWW1","fasta_url":"https://rest.uniprot.org/uniprotkb/Q5VWW1.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q5VWW1/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q5VWW1"}},"corpus_meta":[{"pmid":"21378161","id":"PMC_21378161","title":"Metabolic regulation by C1q/TNF-related protein-13 (CTRP13): activation OF AMP-activated protein kinase and suppression of fatty acid-induced JNK signaling.","date":"2011","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/21378161","citation_count":119,"is_preprint":false},{"pmid":"27478018","id":"PMC_27478018","title":"Expression of C1ql3 in Discrete Neuronal Populations Controls Efferent Synapse Numbers and Diverse Behaviors.","date":"2016","source":"Neuron","url":"https://pubmed.ncbi.nlm.nih.gov/27478018","citation_count":89,"is_preprint":false},{"pmid":"6140224","id":"PMC_6140224","title":"Lipopolysaccharide, capsule, and fimbriae as virulence factors among O1, O7, O16, O18, or O75 and K1, K5, or K100 Escherichia coli.","date":"1984","source":"Infection and immunity","url":"https://pubmed.ncbi.nlm.nih.gov/6140224","citation_count":88,"is_preprint":false},{"pmid":"1677349","id":"PMC_1677349","title":"Virulence patterns and long-range genetic mapping of extraintestinal Escherichia coli K1, K5, and K100 isolates: use of pulsed-field gel electrophoresis.","date":"1991","source":"Infection and immunity","url":"https://pubmed.ncbi.nlm.nih.gov/1677349","citation_count":65,"is_preprint":false},{"pmid":"28207876","id":"PMC_28207876","title":"Circulating C1q complement/TNF-related protein (CTRP) 1, CTRP9, CTRP12 and CTRP13 concentrations in Type 2 diabetes mellitus: In vivo regulation by glucose.","date":"2017","source":"PloS one","url":"https://pubmed.ncbi.nlm.nih.gov/28207876","citation_count":57,"is_preprint":false},{"pmid":"28033351","id":"PMC_28033351","title":"Association of C1q/TNF-Related Protein-3 (CTRP3) and CTRP13 Serum Levels with Coronary Artery Disease in Subjects with and without Type 2 Diabetes Mellitus.","date":"2016","source":"PloS one","url":"https://pubmed.ncbi.nlm.nih.gov/28033351","citation_count":55,"is_preprint":false},{"pmid":"23638159","id":"PMC_23638159","title":"A central role for C1q/TNF-related protein 13 (CTRP13) in modulating food intake and body weight.","date":"2013","source":"PloS one","url":"https://pubmed.ncbi.nlm.nih.gov/23638159","citation_count":49,"is_preprint":false},{"pmid":"30222079","id":"PMC_30222079","title":"CTRP13 inhibits atherosclerosis via autophagy-lysosome-dependent degradation of CD36.","date":"2018","source":"FASEB journal : official publication of the Federation of American Societies for Experimental Biology","url":"https://pubmed.ncbi.nlm.nih.gov/30222079","citation_count":40,"is_preprint":false},{"pmid":"33337553","id":"PMC_33337553","title":"C1QL3 promotes cell-cell adhesion by mediating complex formation between ADGRB3/BAI3 and neuronal pentraxins.","date":"2021","source":"FASEB journal : official publication of the Federation of American Societies for Experimental Biology","url":"https://pubmed.ncbi.nlm.nih.gov/33337553","citation_count":35,"is_preprint":false},{"pmid":"31676569","id":"PMC_31676569","title":"CTRP13 Preserves Endothelial Function by Targeting GTP Cyclohydrolase 1 in Diabetes.","date":"2019","source":"Diabetes","url":"https://pubmed.ncbi.nlm.nih.gov/31676569","citation_count":24,"is_preprint":false},{"pmid":"31499089","id":"PMC_31499089","title":"miR-124 regulates cerebromicrovascular function in APP/PS1 transgenic mice via C1ql3.","date":"2019","source":"Brain research bulletin","url":"https://pubmed.ncbi.nlm.nih.gov/31499089","citation_count":23,"is_preprint":false},{"pmid":"28553739","id":"PMC_28553739","title":"Anatomical and Behavioral Investigation of C1ql3 in the Mouse Suprachiasmatic Nucleus.","date":"2017","source":"Journal of biological rhythms","url":"https://pubmed.ncbi.nlm.nih.gov/28553739","citation_count":21,"is_preprint":false},{"pmid":"32966772","id":"PMC_32966772","title":"CTRP13 Mitigates Abdominal Aortic Aneurysm Formation via NAMPT1.","date":"2020","source":"Molecular therapy : the journal of the American Society of Gene 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purified recombinant protein functional assays, glucose uptake assays, signaling pathway analysis (AMPK, JNK) in cultured cells\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 — multiple orthogonal in vitro assays with purified recombinant protein, replicated across cell types\",\n      \"pmids\": [\"21378161\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"C1QL3 is a secreted neuronal protein that binds to BAI3 (ADGRB3), an adhesion-class GPCR; C1QL3 expression is activity-dependent in cultured neurons and supports excitatory synapse density. Conditional and constitutive C1QL3 knockout mice exhibit fewer excitatory synapses and behavioral abnormalities including impaired fear memories; C1QL3 expressed in basolateral amygdala neurons projecting to medial prefrontal cortex is required for formation and/or maintenance of these synapses.\",\n      \"method\": \"Knockout mouse generation, circuit-tracing, conditional ablation, electrophysiology/synapse counting, behavioral assays, cultured neuron experiments\",\n      \"journal\": \"Neuron\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — multiple orthogonal methods (KO mice, conditional ablation, circuit tracing, behavioral phenotyping), replicated across brain regions\",\n      \"pmids\": [\"27478018\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"Central administration of recombinant CTRP13 suppresses food intake and reduces body weight in mice; CTRP13 and the orexigenic neuropeptide AgRP reciprocally regulate each other's expression in the hypothalamus, forming a hypothalamic feedback loop modulating food intake.\",\n      \"method\": \"Intracerebroventricular delivery of recombinant protein, quantitative PCR of neuropeptide gene expression, food restriction and activity-based anorexia mouse models\",\n      \"journal\": \"PloS one\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — in vivo central delivery with defined molecular phenotype (AgRP/CTRP13 reciprocal regulation), single lab\",\n      \"pmids\": [\"23638159\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"C1QL3 is highly expressed in SCN neurons; C1QL3 knockout mice have reduced excitatory synapse density in the SCN and exhibit less consolidated circadian activity and period lengthening following a phase-delaying light pulse, establishing C1QL3 as required for glutamatergic synapse formation/maintenance and circadian behavior in the SCN.\",\n      \"method\": \"Knockout mouse, synapse counting, circadian behavioral assays (light pulse phase-shifting)\",\n      \"journal\": \"Journal of biological rhythms\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — KO mouse with defined synaptic and behavioral phenotype, single lab\",\n      \"pmids\": [\"28553739\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"CTRP13 reduces CD36 protein levels via autophagy-lysosome-dependent degradation (post-transcriptional), thereby decreasing oxidized LDL uptake, foam-cell formation, and macrophage trapping; blocking autophagy-lysosome induction abolishes CTRP13's protective effects against atherosclerosis.\",\n      \"method\": \"In vivo ApoE-/- mouse model with CTRP13 infusion, primary peritoneal macrophage assays, pharmacological autophagy blockade, Western blot\",\n      \"journal\": \"FASEB journal\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — in vivo and in vitro evidence with pharmacological rescue experiment identifying mechanism\",\n      \"pmids\": [\"30222079\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"CTRP13 preserves endothelial function in diabetic models by increasing GTP cyclohydrolase 1 (GCH1) expression and tetrahydrobiopterin (BH4) levels, ameliorating eNOS coupling; mechanistically, CTRP13 rescues high-glucose-induced inhibition of PKA activity, and increased PKA phosphorylates PPARα, promoting its recruitment to the GCH1 promoter and activating GCH1 transcription.\",\n      \"method\": \"Diabetic mouse models (db/db, STZ), ex vivo aortic relaxation assays, HUVEC culture, PKA activity assay, ChIP-like promoter recruitment, Western blot\",\n      \"journal\": \"Diabetes\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — multiple orthogonal assays in vivo and in vitro with mechanistic pathway identified, single lab\",\n      \"pmids\": [\"31676569\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"CTRP13 attenuates vascular calcification by repressing phosphorylation of tristetraprolin (TTP), thereby activating TTP and increasing its binding to the 3'UTR of Runx2 mRNA, accelerating Runx2 mRNA destabilization and degradation, and preventing VSMC transition from contractile to osteogenic phenotype.\",\n      \"method\": \"CRF rat model, VSMC culture, beta-glycerophosphate calcification assay, Runx2 overexpression rescue, TTP binding assay, Western blot\",\n      \"journal\": \"FASEB journal\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — in vivo and in vitro with epistasis (Runx2 overexpression reversal) and RNA-binding mechanism identified, single lab\",\n      \"pmids\": [\"31145871\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"miR-124 targets C1ql3 in the hippocampus; lentivirus-mediated overexpression of miR-124 or C1 inhibitor (C1INH) rescued blood-brain barrier breakdown, promoted angiogenesis, and reduced Aβ deposition in APP/PS1 transgenic mice, placing C1QL3 downstream of miR-124 in cerebromicrovascular regulation.\",\n      \"method\": \"APP/PS1 transgenic mice, lentivirus-mediated miR-124 overexpression, C1INH treatment, BBB integrity assays, angiogenesis quantification\",\n      \"journal\": \"Brain research bulletin\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — genetic epistasis (miR-124 overexpression rescues C1QL3-associated phenotype) with functional readouts in vivo\",\n      \"pmids\": [\"31499089\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"CTRP13 activates the CaMKKβ/AMPK pathway in rat liver sinusoidal endothelial cells (rLSECs) to attenuate high-glucose-induced increases in laminin (LN) and caveolin-1 (CAV-1) expression; pharmacological inhibition of CaMKKβ or AMPK abolished the protective effects of CTRP13 overexpression.\",\n      \"method\": \"Lentiviral CTRP13 overexpression in rLSECs, pharmacological inhibitors (STO-609, Compound C), Western blot, qRT-PCR\",\n      \"journal\": \"Aging\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — pharmacological rescue identifies CaMKKβ/AMPK as downstream pathway of CTRP13, single lab\",\n      \"pmids\": [\"32554851\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"CTRP13 mitigates abdominal aortic aneurysm formation; mechanistically, CTRP13 stabilizes NAMPT1 protein by preventing its ubiquitination-proteasome-dependent degradation, and NAMPT1 knockdown abolishes the anti-inflammatory and anti-apoptotic effects of CTRP13 in vascular SMCs.\",\n      \"method\": \"ApoE-/- angiotensin II and CaCl2 AAA mouse models, CTRP13 infusion, NAMPT1 siRNA knockdown, ubiquitination assay, Western blot\",\n      \"journal\": \"Molecular therapy\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — in vivo and in vitro with epistasis (NAMPT1 KD reversal) and ubiquitination mechanism identified, single lab\",\n      \"pmids\": [\"32966772\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"C1QL3 mediates a novel trans-synaptic cell-cell adhesion complex involving ADGRB3 (BAI3) and two neuronal pentraxins, NPTX1 and NPTXR; C1ql3, Nptx1, and Nptxr are highly co-expressed in the same excitatory neurons in the cerebral cortex, suggesting presynaptic secretion and formation of a complex that binds postsynaptically localized ADGRB3.\",\n      \"method\": \"In vivo interactome study (Co-IP/pulldown), single-cell RNA-seq data analysis, cell-cell adhesion assays\",\n      \"journal\": \"FASEB journal\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2-3 — in vivo interactome plus cell adhesion assay identifies novel binding partners, single lab\",\n      \"pmids\": [\"33337553\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"CTRP13 overexpression protects H9c2 cardiomyocytes from hypoxia/reoxygenation-induced oxidative stress and apoptosis via activation of the AMPK/Nrf2/ARE signaling pathway; AMPK inhibition reverses CTRP13-mediated Nrf2/ARE activation and cardioprotection, and Nrf2 silencing abolishes the protective effects of CTRP13.\",\n      \"method\": \"H9c2 cell H/R model, CTRP13 overexpression/silencing, AMPK inhibitor (Compound C), Nrf2 siRNA, ROS assays, apoptosis assays; in vivo rat I/R model with recombinant CTRP13\",\n      \"journal\": \"Cell transplantation\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — epistasis via pharmacological inhibition and siRNA knockdown identifies pathway, single lab\",\n      \"pmids\": [\"34338573\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"Loss of CTRP13 (Ctrp13 knockout mice) paradoxically improved systemic metabolic profiles: KO mice were more active, leaner, had reduced hepatic glucose output, improved glucose tolerance, insulin sensitivity, and triglyceride clearance, indicating CTRP13 functions as a negative metabolic regulator in vivo.\",\n      \"method\": \"Ctrp13 knockout mouse comprehensive metabolic phenotyping, RNA-seq of multiple tissues, integration with human METSIM cohort data\",\n      \"journal\": \"Molecular metabolism\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — rigorous KO mouse metabolic phenotyping with transcriptomic analysis and human data integration, multiple metabolic readouts\",\n      \"pmids\": [\"37844630\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"C1QL3 is upregulated in the basolateral amygdala (BLA) following chronic morphine withdrawal conditioning; C1QL3 co-localizes with BAI3 in the BLA; downregulation of C1QL3 in the BLA impairs chronic morphine withdrawal memory formation; C1QL3 modulates ubiquitination-mediated degradation of PSD95, decreasing PSD95 protein levels as a downstream mechanism.\",\n      \"method\": \"Conditioned place aversion, chemogenetics, immunofluorescence co-localization, C1QL3 knockdown via viral vector, PSD95 pharmacological blockade, ubiquitination assay\",\n      \"journal\": \"Biochemical and biophysical research communications\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2-3 — in vivo knockdown with behavioral phenotype and molecular mechanism (PSD95 ubiquitination), single lab\",\n      \"pmids\": [\"38772224\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"C1QL3 knockout in rats increases ramified microglia and decreases hypertrophic microglia at baseline; after LPS stimulation, KO brains have more amoeboid microglia and higher Arg-1 expression; KO also damages neuronal dendritic arbors and spine density, and results in hyperactive behavior and impaired short-term working memory.\",\n      \"method\": \"CRISPR/Cas9 C1ql3 KO rats, immunohistochemistry, Golgi staining, MRI, behavioral tests (open field, Morris water maze, Y maze)\",\n      \"journal\": \"Animal models and experimental medicine\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — KO rat model with defined cellular (microglial, neuronal) and behavioral phenotypes, single lab\",\n      \"pmids\": [\"38379452\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"CTRP13 inhibits ferroptosis of endothelial cells by activating GCH1/BH4 signaling, upregulating GPX4 and downregulating ACSL4; GCH1 silencing or BH4 inhibition counteracts CTRP13's protective effect on ox-LDL-induced endothelial ferroptosis, thereby inhibiting atherosclerosis progression.\",\n      \"method\": \"ApoE-/- mouse model with C1ql3 AAV overexpression, mouse aortic endothelial cell (MAEC) culture, GCH1 siRNA, BH4 inhibitor, ferroptosis markers (GPX4, ACSL4), lipid peroxidation assays\",\n      \"journal\": \"International immunopharmacology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — in vivo and in vitro with GCH1 siRNA and BH4 inhibitor rescue experiments identifying mechanism, single lab\",\n      \"pmids\": [\"39541845\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"Using an epitope-tagged knock-in mouse (C1ql3-2HA), native PAGE determined the endogenous oligomeric state of C1QL3; brain-wide light-sheet microscopy identified an expanded neuroanatomical map of C1QL3 expression including cortical, subcortical regions and retina; super-resolution STED microscopy localized C1QL3 to hippocampal mossy fiber synapses positioned between pre- and post-synaptic markers, supporting its role in trans-synaptic complexes.\",\n      \"method\": \"Epitope-tagged knock-in mouse (C1ql3-2HA), native PAGE, light-sheet microscopy, STED super-resolution microscopy, dual immunohistochemistry\",\n      \"journal\": \"bioRxiv\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1-2 — novel knock-in mouse with native protein detection, multiple structural/localization methods; preprint not yet peer-reviewed\",\n      \"pmids\": [\"41959109\"],\n      \"is_preprint\": true\n    }\n  ],\n  \"current_model\": \"C1QL3 is a secreted, oligomeric gC1q-domain protein expressed presynaptically by excitatory neurons that binds to the adhesion GPCR BAI3/ADGRB3 and neuronal pentraxins NPTX1/NPTXR to form trans-synaptic adhesion complexes, thereby regulating excitatory synapse density and strength across multiple brain circuits (amygdala-PFC, SCN, hippocampal mossy fibers), and controlling diverse behaviors including fear memory, circadian rhythms, and cognitive flexibility; peripherally, as an adipokine (CTRP13), it acts as a negative metabolic regulator by activating AMPK signaling to modulate glucose uptake, hepatic glucose output, lipid metabolism, and endothelial function via downstream targets including GCH1/BH4, Runx2 mRNA stability, NAMPT1 ubiquitination, and CD36 autophagy-lysosomal degradation.\"\n}\n```","stage2_raw":"```json\n{\n  \"mechanistic_narrative\": \"C1QL3 is a secreted, oligomeric gC1q-domain protein that functions as a trans-synaptic organizer in the brain and as a metabolic regulator (adipokine CTRP13) in peripheral tissues. In excitatory neurons, C1QL3 binds the adhesion GPCR BAI3/ADGRB3 and neuronal pentraxins NPTX1/NPTXR to form trans-synaptic adhesion complexes that maintain excitatory synapse density in the amygdala-prefrontal cortex circuit, suprachiasmatic nucleus, and hippocampal mossy fibers, with knockout animals exhibiting reduced synapse numbers, impaired fear memory, disrupted circadian consolidation, hyperactivity, and working memory deficits [PMID:27478018, PMID:28553739, PMID:38379452, PMID:33337553]. Peripherally, CTRP13 activates CaMKKβ/AMPK signaling to promote glucose uptake and suppress hepatic glucose output, and loss-of-function studies in knockout mice reveal it acts as a negative metabolic regulator whose absence paradoxically improves glucose tolerance, insulin sensitivity, and triglyceride clearance [PMID:21378161, PMID:37844630]. CTRP13 also exerts vascular protective effects by upregulating GCH1/BH4 to preserve eNOS coupling and inhibit endothelial ferroptosis, by promoting autophagy-lysosomal degradation of CD36 to reduce foam cell formation, and by stabilizing NAMPT1 protein to attenuate aortic aneurysm formation [PMID:31676569, PMID:39541845, PMID:30222079, PMID:32966772].\",\n  \"teleology\": [\n    {\n      \"year\": 2011,\n      \"claim\": \"Identification of CTRP13 as a secreted oligomeric adipokine that activates AMPK signaling established C1QL3 as a metabolic hormone capable of promoting glucose uptake and suppressing lipid-induced stress signaling across multiple cell types.\",\n      \"evidence\": \"Recombinant protein functional assays measuring glucose uptake and AMPK/JNK signaling in adipocytes, myotubes, and hepatocytes\",\n      \"pmids\": [\"21378161\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Receptor mediating metabolic signaling unidentified\", \"No in vivo metabolic phenotyping of loss-of-function models\", \"Oligomeric state of native endogenous protein not determined\"]\n    },\n    {\n      \"year\": 2013,\n      \"claim\": \"Central administration of CTRP13 demonstrated that C1QL3 acts in the hypothalamus to suppress food intake and reciprocally regulates AgRP, establishing a central anorexigenic role beyond its peripheral metabolic effects.\",\n      \"evidence\": \"Intracerebroventricular delivery of recombinant protein in mice with qPCR of hypothalamic neuropeptide expression\",\n      \"pmids\": [\"23638159\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Hypothalamic receptor for CTRP13 not identified\", \"No genetic loss-of-function confirmation of feeding phenotype\", \"Single lab finding\"]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"Discovery that C1QL3 binds BAI3/ADGRB3 and is required for excitatory synapse maintenance in the BLA-PFC circuit transformed understanding of C1QL3 from a purely metabolic factor to a trans-synaptic organizer controlling synapse number and fear memory.\",\n      \"evidence\": \"Constitutive and conditional C1QL3 knockout mice, electrophysiology, synapse counting, circuit tracing, and behavioral assays\",\n      \"pmids\": [\"27478018\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Mechanism by which C1QL3–BAI3 interaction promotes synapse formation unknown\", \"Whether C1QL3 signals through BAI3 GPCR activity or purely as adhesion molecule unresolved\"]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"Extension of the synaptic role to the suprachiasmatic nucleus demonstrated that C1QL3's synaptogenic function is not circuit-specific and that synapse loss in the SCN has functional consequences for circadian behavioral consolidation.\",\n      \"evidence\": \"C1QL3 knockout mice with SCN synapse quantification and circadian phase-shift behavioral assays\",\n      \"pmids\": [\"28553739\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Molecular mechanism of C1QL3-dependent synapse maintenance in SCN not dissected\", \"Single lab replication\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"Identification of autophagy-lysosomal degradation of CD36 as a downstream effector of CTRP13 provided the first specific vascular protective mechanism, explaining how CTRP13 reduces foam cell formation and atherosclerosis.\",\n      \"evidence\": \"ApoE−/− mice with CTRP13 infusion, peritoneal macrophage assays, pharmacological autophagy blockade\",\n      \"pmids\": [\"30222079\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct receptor or upstream signal linking CTRP13 to autophagy pathway not identified\", \"Single lab\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Three studies collectively delineated CTRP13's vascular protective mechanisms: preservation of eNOS coupling via PKA-PPARα-GCH1/BH4 transcriptional axis, attenuation of vascular calcification via TTP-mediated Runx2 mRNA destabilization, and regulation of cerebrovascular integrity downstream of miR-124.\",\n      \"evidence\": \"Diabetic mouse aortic relaxation and HUVEC ChIP assays (GCH1); CRF rat VSMC calcification with TTP binding and Runx2 overexpression rescue; APP/PS1 mice with lentiviral miR-124 overexpression and BBB assays\",\n      \"pmids\": [\"31676569\", \"31145871\", \"31499089\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Whether these vascular pathways converge on a common receptor unknown\", \"TTP regulation mechanism (which kinase/phosphatase) not fully resolved\", \"miR-124–C1QL3 link lacks direct target validation by reporter assay\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Discovery that CTRP13 stabilizes NAMPT1 by preventing its ubiquitination and that CTRP13 signals through CaMKKβ/AMPK in liver sinusoidal endothelial cells expanded the catalogue of downstream effectors and confirmed AMPK as a conserved signaling node across tissues.\",\n      \"evidence\": \"ApoE−/− AAA mouse models with NAMPT1 siRNA epistasis and ubiquitination assays; rLSEC overexpression with CaMKKβ/AMPK pharmacological inhibition\",\n      \"pmids\": [\"32966772\", \"32554851\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct CTRP13 receptor on vascular SMCs and LSECs unidentified\", \"Whether NAMPT1 stabilization is AMPK-dependent not tested\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Identification of NPTX1 and NPTXR as C1QL3 binding partners that co-assemble into a trans-synaptic adhesion complex with BAI3 provided a molecular framework for how C1QL3 bridges pre- and post-synaptic compartments at excitatory synapses.\",\n      \"evidence\": \"In vivo co-immunoprecipitation/pulldown, cell–cell adhesion assays, single-cell RNA-seq co-expression analysis\",\n      \"pmids\": [\"33337553\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Stoichiometry and structure of the C1QL3–NPTX–BAI3 complex not determined\", \"Functional necessity of NPTX1/NPTXR for C1QL3 synaptogenic activity not tested by combined loss-of-function\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Comprehensive metabolic phenotyping of Ctrp13 knockout mice revealed that CTRP13 paradoxically acts as a negative metabolic regulator in vivo, resolving the apparent contradiction between gain-of-function studies showing metabolic benefit and the actual physiological role.\",\n      \"evidence\": \"Ctrp13 KO mouse metabolic phenotyping (body composition, glucose/insulin tolerance, triglyceride clearance), RNA-seq, integration with human METSIM cohort\",\n      \"pmids\": [\"37844630\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Tissue-specific contributions (adipose vs. brain vs. liver) to the metabolic phenotype not dissected\", \"Mechanism by which CTRP13 restrains metabolic fitness not identified\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Studies in 2024 extended C1QL3's neural functions: C1QL3 knockout rats showed altered microglial morphology, dendritic damage, and cognitive deficits, while BLA-specific knockdown revealed C1QL3 modulates PSD95 ubiquitination during morphine withdrawal memory, linking synapse remodeling to substance-use-related behavior.\",\n      \"evidence\": \"CRISPR/Cas9 C1ql3 KO rats with Golgi staining, microglial immunohistochemistry, MRI, behavioral tests; BLA viral knockdown with conditioned place aversion, PSD95 ubiquitination assays\",\n      \"pmids\": [\"38379452\", \"38772224\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Whether PSD95 ubiquitination is a direct or indirect effect of C1QL3 unknown\", \"Microglial phenotype could be secondary to synapse loss rather than direct C1QL3 action on microglia\", \"Rat KO findings not yet replicated across species\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Demonstration that CTRP13 inhibits endothelial ferroptosis through GCH1/BH4-dependent upregulation of GPX4 unified the earlier eNOS-coupling mechanism with a new cell-death modality, establishing GCH1/BH4 as a central node in CTRP13's vascular protection.\",\n      \"evidence\": \"ApoE−/− mice with C1ql3 AAV overexpression, MAEC culture with GCH1 siRNA and BH4 inhibitor rescue, ferroptosis marker quantification\",\n      \"pmids\": [\"39541845\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Whether ferroptosis inhibition operates through AMPK or an independent pathway not tested\", \"Single lab\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"The identity of the peripheral receptor(s) mediating CTRP13's metabolic and vascular signaling remains unknown, and the structural basis and stoichiometry of the C1QL3–NPTX–BAI3 trans-synaptic complex have not been determined.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"No receptor identified for CTRP13 in metabolic or vascular tissues\", \"No high-resolution structure of C1QL3 or its complexes\", \"Tissue-specific conditional knockouts needed to decouple neural vs. peripheral phenotypes\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0098631\", \"supporting_discovery_ids\": [1, 10, 16]},\n      {\"term_id\": \"GO:0098772\", \"supporting_discovery_ids\": [0, 12]},\n      {\"term_id\": \"GO:0048018\", \"supporting_discovery_ids\": [0, 2, 5]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005576\", \"supporting_discovery_ids\": [0, 1, 10]},\n      {\"term_id\": \"GO:0005886\", \"supporting_discovery_ids\": [1, 10, 16]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"GO:0005886\", \"supporting_discovery_ids\": []},\n      {\"term_id\": \"R-HSA-112316\", \"supporting_discovery_ids\": [1, 3, 10, 14]},\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [0, 5, 8, 11]},\n      {\"term_id\": \"R-HSA-1430728\", \"supporting_discovery_ids\": [0, 12]},\n      {\"term_id\": \"R-HSA-1500931\", \"supporting_discovery_ids\": [1, 10, 16]},\n      {\"term_id\": \"R-HSA-9612973\", \"supporting_discovery_ids\": [4]}\n    ],\n    \"complexes\": [\n      \"C1QL3–NPTX1–NPTXR–BAI3 trans-synaptic complex\",\n      \"CTRP13–CTRP10 heteromeric complex\"\n    ],\n    \"partners\": [\n      \"ADGRB3\",\n      \"NPTX1\",\n      \"NPTXR\",\n      \"CTRP10\",\n      \"GCH1\",\n      \"NAMPT1\",\n      \"PSD95\"\n    ],\n    \"other_free_text\": []\n  }\n}\n```"}