{"gene":"C1QL3","run_date":"2026-06-09T22:02:45","timeline":{"discoveries":[{"year":2011,"finding":"CTRP13 is secreted as a disulfide-linked oligomeric protein, and when co-expressed with CTRP10 forms heteromeric complexes via a mechanism that does not involve conserved N-terminal Cys residues.","method":"Heterologous expression system, co-expression, biochemical characterization of secreted protein","journal":"The Journal of biological chemistry","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct biochemical characterization with mutagenesis inference (N-terminal Cys not required), single lab, multiple orthogonal observations","pmids":["21378161"],"is_preprint":false},{"year":2011,"finding":"CTRP13 (CTRP13/C1QL3) promotes glucose uptake in adipocytes, myotubes, and hepatocytes via activation of the AMPK signaling pathway, as demonstrated using purified recombinant protein.","method":"In vitro glucose uptake assay with purified recombinant protein in primary adipocytes, myotubes, and hepatocytes; AMPK activation measured","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1 / Moderate — reconstituted with purified recombinant protein, multiple cell types tested, single lab but multiple orthogonal readouts","pmids":["21378161"],"is_preprint":false},{"year":2011,"finding":"CTRP13 ameliorates lipid-induced insulin resistance in hepatocytes by suppressing SAPK/JNK stress signaling, and reduces hepatocyte glucose output by inhibiting mRNA expression of gluconeogenic enzymes glucose-6-phosphatase and cytosolic phosphoenolpyruvate carboxykinase.","method":"In vitro hepatocyte assay with purified recombinant CTRP13; mRNA expression analysis of gluconeogenic enzymes","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1 / Moderate — recombinant protein in primary hepatocytes, JNK pathway suppression and gluconeogenic gene expression measured, single lab with multiple orthogonal readouts","pmids":["21378161"],"is_preprint":false},{"year":2013,"finding":"Central (intracerebroventricular) administration of recombinant CTRP13 suppressed food intake and reduced body weight in mice, establishing C1QL3 as an anorexigenic factor in the brain.","method":"Central administration of recombinant protein in mice; food intake and body weight measured","journal":"PloS one","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — in vivo loss/gain of function with direct behavioral readout, single lab, multiple experimental conditions","pmids":["23638159"],"is_preprint":false},{"year":2013,"finding":"CTRP13 and the orexigenic neuropeptide AgRP reciprocally regulate each other's expression in the hypothalamus: central CTRP13 delivery suppressed Agrp expression, while AgRP delivery increased Ctrp13 expression, suggesting a hypothalamic feedback loop.","method":"Central delivery of recombinant proteins in mice; qPCR measurement of neuropeptide gene expression in hypothalamus","journal":"PloS one","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — in vivo central administration with molecular readout, single lab, bidirectional relationship demonstrated","pmids":["23638159"],"is_preprint":false},{"year":2016,"finding":"C1QL3 expression in neurons is activity-dependent and supports excitatory synapse density in cultured neurons; C1QL3-deficient mice have fewer excitatory synapses and exhibit impaired fear memories and other behavioral abnormalities.","method":"Conditional and constitutive C1ql3 knockout mice; synapse density quantification in cultured neurons and in vivo; behavioral testing including fear memory assays","journal":"Neuron","confidence":"High","confidence_rationale":"Tier 2 / Strong — conditional and constitutive KO mice, in vitro and in vivo synapse density measurements, behavioral phenotyping, circuit-specific conditional ablation, multiple orthogonal methods replicated across conditions","pmids":["27478018"],"is_preprint":false},{"year":2016,"finding":"C1QL3 is a secreted neuronal protein that binds to BAI3 (ADGRB3), an adhesion-class GPCR, and C1QL3 expression in basolateral amygdala neurons projecting to the medial prefrontal cortex is required for formation/maintenance of those efferent synapses.","method":"Circuit-tracing tools, conditional ablation targeted to specific brain regions, synapse density analysis","journal":"Neuron","confidence":"High","confidence_rationale":"Tier 2 / Strong — multiple conditional KO models, circuit tracing, behavioral and anatomical readouts, replicated across labs (Südhof group)","pmids":["27478018"],"is_preprint":false},{"year":2017,"finding":"C1QL3 is robustly expressed in the suprachiasmatic nucleus (SCN); C1ql3 knockout mice have reduced density of excitatory synapses in the SCN and exhibit disrupted circadian behavior including less consolidated activity and period lengthening after a phase-delaying light pulse.","method":"C1ql3 knockout mice; immunohistochemistry for synapse density; circadian behavioral assays","journal":"Journal of biological rhythms","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — constitutive KO with synaptic and behavioral phenotype, single lab, two orthogonal readouts (anatomy + behavior)","pmids":["28553739"],"is_preprint":false},{"year":2018,"finding":"CTRP13 reduces CD36 protein levels in macrophages through autophagy-lysosome-dependent degradation at the post-transcriptional level, thereby reducing oxidized LDL uptake and foam-cell formation.","method":"Primary peritoneal macrophages treated with recombinant CTRP13; autophagy-lysosome pathway blocking experiments; CD36 protein and mRNA analysis; foam cell formation assays","journal":"FASEB journal","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — recombinant protein with pathway inhibition rescue experiments, in vitro and in vivo (ApoE-/- mice), single lab","pmids":["30222079"],"is_preprint":false},{"year":2019,"finding":"CTRP13 preserves endothelial function in diabetes by increasing GTP cyclohydrolase 1 (GCH1) expression and tetrahydrobiopterin (BH4) levels to ameliorate eNOS coupling; mechanistically, CTRP13 rescues high-glucose-induced inhibition of PKA activity, and increased PKA activity enhances phosphorylation of PPARα and its recruitment to the GCH1 promoter, activating GCH1 transcription.","method":"Ex vivo aortic relaxation assays in diabetic mice; in vitro HUVEC experiments; PKA activity assay; ChIP for PPARα at GCH1 promoter; recombinant CTRP13 treatment","journal":"Diabetes","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — multiple mechanistic steps validated in vitro and in vivo, single lab, ChIP and functional assays","pmids":["31676569"],"is_preprint":false},{"year":2019,"finding":"CTRP13 attenuates vascular calcification by repressing phosphorylation of tristetraprolin (TTP), thereby activating TTP, which binds the 3'UTR of Runx2 mRNA and accelerates Runx2 mRNA destabilization and degradation in vascular smooth muscle cells.","method":"In vitro VSMC calcification assay; Runx2 overexpression rescue; TTP binding assay; mRNA stability analysis; recombinant CTRP13 treatment in CRF rat model","journal":"FASEB journal","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — multiple mechanistic steps (TTP phosphorylation, 3'UTR binding, mRNA degradation) with rescue experiments, single lab","pmids":["31145871"],"is_preprint":false},{"year":2020,"finding":"CTRP13 protects rat liver sinusoidal endothelial cells from high-glucose-induced injury by activating the CaMKKβ/AMPK pathway, reducing laminin and caveolin-1 expression; inhibition of CaMKKβ or AMPK abolished the protective effects.","method":"Lentiviral CTRP13 overexpression in rLSECs; CaMKKβ/AMPK inhibitors (STO-609, Compound C); Western blot and qRT-PCR","journal":"Aging","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — pathway inhibition rescue experiments with two independent inhibitors, single lab","pmids":["32554851"],"is_preprint":false},{"year":2020,"finding":"CTRP13 mitigates abdominal aortic aneurysm formation; mechanistically, CTRP13 stabilizes NAMPT1 protein by reducing its ubiquitination-proteasome-dependent degradation, and NAMPT1 knockdown blocks the beneficial effects of CTRP13 on vascular inflammation and smooth muscle cell apoptosis.","method":"Two murine AAA models (AngII in ApoE-/- and CaCl2 in C57BL/6J); recombinant CTRP13 infusion; NAMPT1 knockdown; ubiquitination assays","journal":"Molecular therapy","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — two independent in vivo models, NAMPT1 knockdown epistasis, ubiquitination mechanism, single lab","pmids":["32966772"],"is_preprint":false},{"year":2021,"finding":"C1QL3 mediates a novel cell-cell adhesion complex involving ADGRB3 (BAI3) and two neuronal pentraxins, NPTX1 and NPTXR, as identified by an in vivo interactome study; C1ql3, Nptx1, and Nptxr are highly co-expressed in the same excitatory neurons.","method":"In vivo interactome study (pulldown/co-IP); single-cell RNA-seq data analysis for co-expression","journal":"FASEB journal","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — in vivo interactome pulldown identifying new binding partners, supported by single-cell RNA-seq co-expression, single lab","pmids":["33337553"],"is_preprint":false},{"year":2021,"finding":"CTRP13 protects cardiomyocytes from hypoxia/reoxygenation injury via the AMPK/Nrf2/ARE signaling pathway; AMPK inhibition reversed CTRP13-mediated Nrf2/ARE activation, and Nrf2 silencing reversed CTRP13's protective effects against oxidative stress and apoptosis.","method":"H9c2 cell H/R model; CTRP13 overexpression and silencing; AMPK inhibitor (Compound C); Nrf2 siRNA; recombinant CTRP13 in rat I/R model","journal":"Cell transplantation","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — epistasis via AMPK inhibition and Nrf2 silencing, gain/loss-of-function, in vivo validation, single lab","pmids":["34338573"],"is_preprint":false},{"year":2023,"finding":"Loss of CTRP13 in mice improves systemic metabolism (reduced body weight, improved glucose tolerance, insulin sensitivity, and triglyceride clearance), reduced hepatic glucose output, lower inflammatory profile in visceral fat and liver, and suppressed lipid synthesis with enhanced lipid catabolism gene expression, suggesting CTRP13 is a negative metabolic regulator.","method":"Ctrp13 knockout mice on chow and high-fat diet; comprehensive metabolic phenotyping; transcriptomic analyses of multiple tissues; mediation analyses with human METSIM cohort data","journal":"Molecular metabolism","confidence":"High","confidence_rationale":"Tier 2 / Strong — constitutive KO mice with comprehensive metabolic phenotyping across sexes and diets, transcriptomic analyses, human cohort integration, multiple orthogonal readouts","pmids":["37844630"],"is_preprint":false},{"year":2024,"finding":"C1QL3 is required for formation of chronic morphine withdrawal memories in the basolateral amygdala (BLA); C1QL3 colocalizes with BAI3 in the BLA, and downregulation of C1QL3 in the BLA reduces conditioned place aversion scores; C1QL3 modulates ubiquitination-mediated degradation of PSD95, resulting in decreased PSD95 protein levels as a downstream effector.","method":"Immunofluorescence colocalization of C1QL3 and BAI3; lentiviral downregulation of C1QL3 in BLA; conditioned place aversion behavioral assay; chemogenetic BLA inhibition; ubiquitination/PSD95 protein analysis","journal":"Biochemical and biophysical research communications","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — in vivo KD with behavioral readout, colocalization, and ubiquitination mechanism, single lab, multiple methods","pmids":["38772224"],"is_preprint":false},{"year":2024,"finding":"C1ql3 knockout in rats disrupts neuronal integrity (reduced dendritic arbors and spine density), alters microglial activation (increased ramified microglia, decreased hypertrophic microglia, increased amoeboid microglia and Arg-1 expression after LPS), and impairs short working memory with hyperactive behavior.","method":"CRISPR/Cas9 C1ql3 KO rats; Golgi staining for dendritic morphology; immunohistochemistry for microglia; MRI; behavioral tests (open field, Morris water maze, Y maze)","journal":"Animal models and experimental medicine","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — constitutive KO with multiple cellular and behavioral phenotypes, single lab, orthogonal methods","pmids":["38379452"],"is_preprint":false},{"year":2024,"finding":"CTRP13 inhibits ferroptosis of endothelial cells via the GCH1/BH4 signaling pathway, upregulating GPX4 and downregulating ACSL4; silencing GCH1 or inhibiting BH4 abolished the protective effects of CTRP13.","method":"ApoE-/- mice with C1ql3 overexpression AAV; ox-LDL-treated mouse aortic endothelial cells; GCH1 siRNA knockdown; BH4 inhibition; GPX4 and ACSL4 protein detection","journal":"International immunopharmacology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — GCH1/BH4 epistasis with rescue experiments in vitro and in vivo, single lab","pmids":["39541845"],"is_preprint":false},{"year":2024,"finding":"CTRP13 prevents HUVEC ferroptosis induced by ox-LDL via the AMPK/KLF4 pathway, reducing ROS overproduction and mitochondrial dysfunction; CTRP13 increased p-AMPK/AMPK and decreased KLF4 expression.","method":"HUVEC ox-LDL model; CTRP13 recombinant protein treatment; Western blot for p-AMPK, KLF4, GPX4, ACSL4; mitochondrial function assays","journal":"Medical science monitor","confidence":"Low","confidence_rationale":"Tier 3 / Weak — single lab, single method (Western blot correlation), no formal AMPK inhibition rescue reported","pmids":["38273650"],"is_preprint":false},{"year":2024,"finding":"CTRP13 reduces endothelial cell proliferation via AMPK (specifically alpha-2 AMPK), reduces cell cycle progression, increases p53 phosphorylation and p21 expression, and reduces Rb phosphorylation; these effects depended on alpha-2 AMPK as shown by adenoviral dominant-negative and wild-type AMPK overexpression.","method":"HUVEC culture; recombinant CTRP13 treatment; adenoviral DN/WT alpha-1/alpha-2 AMPK overexpression; cell cycle analysis; Western blot","journal":"Cells","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — dominant-negative and WT AMPK isoform-specific rescue identifies alpha-2 AMPK, single lab, multiple cell cycle markers","pmids":["39120321"],"is_preprint":false},{"year":2025,"finding":"Brain-wide light-sheet microscopy using a novel C1ql3-2HA epitope-tagged knock-in mouse revealed an expanded neuroanatomical map of endogenous C1QL3 expression in cortical and subcortical regions and the retina; super-resolution STED microscopy localized C1QL3-2HA to hippocampal mossy fiber synapses positioned between pre- and post-synaptic markers; native PAGE determined the endogenous oligomeric state of C1QL3.","method":"Epitope-tagged knock-in mouse (C1ql3-2HA); native PAGE for oligomeric state; brain-wide light-sheet microscopy; dual immunohistochemistry; super-resolution STED microscopy","journal":"bioRxiv","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — endogenous epitope-tag knock-in with multiple orthogonal imaging methods, preprint not yet peer-reviewed, single lab","pmids":["41959109"],"is_preprint":true},{"year":2025,"finding":"Conditional deletion of C1ql3 from neurons specifically in the prefrontal cortex of adult mice was not sufficient to impair attentional set-shifting behavior, indicating C1ql3's role in cognitive flexibility requires expression in other brain circuits and/or neurodevelopmental processes.","method":"Conditional C1ql3 deletion in PFC neurons of adult mice; attentional set-shifting behavioral assay","journal":"Neuroscience letters","confidence":"Medium","confidence_rationale":"Tier 2 / Weak — conditional KO with specific behavioral readout, single lab, result is a negative finding for PFC-specific deletion","pmids":["40541605"],"is_preprint":false}],"current_model":"C1QL3 (CTRP13) is a secreted, oligomeric gC1q-domain protein expressed in adipose tissue, brain, and vasculature that acts as an adipokine/synaptic organizer: in peripheral tissues it activates AMPK (via CaMKKβ) to promote glucose uptake, suppress JNK-mediated insulin resistance, stabilize NAMPT1 via the ubiquitin-proteasome system, degrade CD36 via autophagy-lysosomes, and preserve endothelial function by activating the PKA–PPARα–GCH1/BH4–eNOS coupling axis; in the CNS it binds to the adhesion GPCR BAI3/ADGRB3 and—together with neuronal pentraxins NPTX1/NPTXR—forms a trans-synaptic adhesion complex that maintains excitatory synapse density in multiple circuits (amygdala–prefrontal, SCN, hippocampus), regulates fear and circadian behaviors, and modulates PSD95 stability via ubiquitination to control synaptic memory processes, while paradoxically its global loss in mice improves systemic metabolic homeostasis, suggesting CTRP13 is a context-dependent negative metabolic regulator."},"narrative":{"mechanistic_narrative":"C1QL3 (CTRP13) is a secreted, disulfide-linked oligomeric gC1q-domain protein with two distinct functional arenas: a synaptic organizer in the CNS and a metabolic/vascular regulator in peripheral tissues [PMID:21378161, PMID:27478018]. In neurons, C1QL3 is secreted and binds the adhesion-class GPCR BAI3/ADGRB3, and acts in an activity-dependent manner to support excitatory synapse density; its loss reduces synapse number and produces fear-memory and other behavioral deficits [PMID:27478018]. C1QL3 additionally forms a trans-synaptic adhesion complex with the neuronal pentraxins NPTX1 and NPTXR in co-expressing excitatory neurons, and localizes between pre- and postsynaptic markers at hippocampal mossy fiber synapses [PMID:33337553, PMID:41959109]. This synaptic function extends across circuits, maintaining excitatory synapses in the suprachiasmatic nucleus to support circadian behavior and in the basolateral amygdala, where C1QL3 controls morphine-withdrawal aversion memories through ubiquitination-mediated turnover of PSD95 [PMID:28553739, PMID:38772224]. In peripheral tissues, recombinant CTRP13 promotes glucose uptake in adipocytes, myotubes, and hepatocytes by activating AMPK signaling and ameliorates lipid-induced insulin resistance by suppressing JNK stress signaling and repressing gluconeogenic gene expression [PMID:21378161]. CTRP13 confers broad vasoprotection through several effector axes: activation of CaMKKβ/AMPK, AMPK/Nrf2/ARE, and PKA–PPARα–GCH1/BH4–eNOS signaling, protein-level stabilization of NAMPT1 and autophagy-lysosomal degradation of CD36, and suppression of ferroptosis via GCH1/BH4 and AMPK/KLF4 pathways [PMID:32554851, PMID:34338573, PMID:31676569, PMID:32966772, PMID:30222079, PMID:39541845]. Paradoxically, constitutive loss of CTRP13 in mice improves systemic metabolism, identifying it as a context-dependent negative metabolic regulator [PMID:37844630].","teleology":[{"year":2011,"claim":"Established that C1QL3/CTRP13 is a secreted oligomeric protein and a functional metabolic effector, answering whether this gC1q-domain protein has hormone-like activity on glucose handling.","evidence":"Heterologous expression and biochemical characterization of secreted protein; in vitro glucose uptake and AMPK assays with purified recombinant protein across adipocytes, myotubes, and hepatocytes","pmids":["21378161"],"confidence":"High","gaps":["No receptor identified for the metabolic effects","Mechanism linking C1QL3 binding to AMPK activation not resolved"]},{"year":2013,"claim":"Showed C1QL3 acts centrally as an anorexigenic factor embedded in a hypothalamic feedback loop, extending its biology from peripheral metabolism to CNS energy balance control.","evidence":"Intracerebroventricular recombinant protein administration in mice with food intake/body weight readouts and reciprocal AgRP/Ctrp13 qPCR","pmids":["23638159"],"confidence":"Medium","gaps":["Neurons mediating the anorexigenic effect not defined","Receptor in hypothalamus unknown"]},{"year":2016,"claim":"Defined C1QL3 as an activity-dependent synaptic organizer that binds the adhesion GPCR BAI3 and is required cell-autonomously to maintain specific excitatory circuits, identifying its receptor and a core CNS function.","evidence":"Conditional and constitutive knockout mice, circuit tracing, synapse density quantification, and fear-memory behavioral testing (Südhof group)","pmids":["27478018"],"confidence":"High","gaps":["Signaling downstream of BAI3 engagement not resolved","Whether the same receptor mediates metabolic actions unknown"]},{"year":2017,"claim":"Generalized the synaptic role to circadian circuitry, showing C1QL3 maintains excitatory synapses in the SCN and is needed for normal circadian behavior.","evidence":"Constitutive Ctrp13 KO mice with SCN synapse density immunohistochemistry and circadian behavioral assays","pmids":["28553739"],"confidence":"Medium","gaps":["Molecular link between synapse loss and circadian phenotype not established","Receptor partner in SCN not confirmed"]},{"year":2018,"claim":"Demonstrated a post-transcriptional anti-atherogenic mechanism whereby CTRP13 lowers CD36 via autophagy-lysosomal degradation, reducing foam-cell formation.","evidence":"Recombinant CTRP13 in primary macrophages with autophagy-lysosome pathway blockade and CD36 protein/mRNA and foam-cell assays; ApoE-/- mice","pmids":["30222079"],"confidence":"Medium","gaps":["How CTRP13 triggers autophagic targeting of CD36 unknown","Receptor mediating macrophage response not identified"]},{"year":2019,"claim":"Defined two distinct vasoprotective signaling axes: PKA–PPARα–GCH1/BH4–eNOS coupling preserving endothelial function, and TTP-mediated Runx2 mRNA destabilization limiting vascular calcification.","evidence":"Ex vivo aortic relaxation and HUVEC assays with PKA activity and PPARα ChIP at GCH1 promoter; VSMC calcification assays with TTP binding and mRNA stability analysis in CRF rat model","pmids":["31676569","31145871"],"confidence":"Medium","gaps":["Upstream receptor coupling to PKA not identified","How CTRP13 represses TTP phosphorylation unresolved"]},{"year":2020,"claim":"Extended vasoprotection to two additional mechanisms: CaMKKβ/AMPK protection of liver sinusoidal endothelium, and ubiquitin-proteasome stabilization of NAMPT1 mitigating aortic aneurysm.","evidence":"Lentiviral overexpression in rLSECs with CaMKKβ/AMPK inhibitor rescue; two murine AAA models with NAMPT1 knockdown epistasis and ubiquitination assays","pmids":["32554851","32966772"],"confidence":"Medium","gaps":["How CTRP13 reduces NAMPT1 ubiquitination mechanistically unknown","Receptor upstream of CaMKKβ not defined"]},{"year":2021,"claim":"Identified C1QL3 as part of a tripartite trans-synaptic adhesion complex with BAI3 and neuronal pentraxins NPTX1/NPTXR, refining the molecular architecture of its synaptic action; in parallel showed cardioprotection through AMPK/Nrf2/ARE signaling.","evidence":"In vivo interactome pulldown with single-cell RNA-seq co-expression; H9c2 H/R model with AMPK inhibition and Nrf2 silencing epistasis and rat I/R validation","pmids":["33337553","34338573"],"confidence":"Medium","gaps":["Stoichiometry and assembly order of the BAI3/NPTX1/NPTXR complex unknown","Whether the complex transduces signal bidirectionally not tested"]},{"year":2023,"claim":"Revealed a paradox by showing that constitutive loss of CTRP13 improves systemic metabolism, reframing the protein as a context-dependent negative metabolic regulator rather than a uniformly beneficial adipokine.","evidence":"Ctrp13 KO mice on chow and high-fat diets with comprehensive metabolic and transcriptomic phenotyping and human METSIM cohort mediation analyses","pmids":["37844630"],"confidence":"High","gaps":["Reconciliation of loss-of-function benefit with gain-of-function recombinant effects unresolved","Tissue source driving the systemic phenotype not pinpointed"]},{"year":2024,"claim":"Linked C1QL3 to addiction-related memory and broader neuronal/glial integrity, and showed PFC-specific adult deletion is insufficient for cognitive-flexibility deficits, mapping circuit and developmental dependencies.","evidence":"Lentiviral C1QL3 knockdown in BLA with conditioned place aversion and PSD95 ubiquitination analysis; CRISPR KO rats with Golgi, microglia, and behavioral assays; conditional adult PFC deletion with attentional set-shifting","pmids":["38772224","38379452","40541605"],"confidence":"Medium","gaps":["How C1QL3 controls PSD95 ubiquitination mechanistically unknown","Direct effect of C1QL3 on microglia versus secondary to synapse loss unresolved"]},{"year":2024,"claim":"Resolved additional vascular effector pathways: suppression of endothelial ferroptosis via GCH1/BH4 and AMPK/KLF4, and AMPK-alpha2-dependent restraint of endothelial proliferation through p53/p21/Rb.","evidence":"ox-LDL endothelial and ApoE-/- AAV models with GCH1/BH4 and Nrf2 epistasis; HUVEC cell-cycle analysis with isoform-specific dominant-negative/WT AMPK rescue","pmids":["39541845","38273650","39120321"],"confidence":"Medium","gaps":["Receptor coupling CTRP13 to AMPK in endothelium not identified","AMPK/KLF4 ferroptosis link rests on correlative Western blot without inhibitor rescue"]},{"year":2025,"claim":"Provided the first endogenous mapping of C1QL3 protein, localizing it to specific synaptic clefts and defining its native oligomeric state with a knock-in reporter.","evidence":"C1ql3-2HA epitope-tagged knock-in mouse with native PAGE, brain-wide light-sheet microscopy, and super-resolution STED at mossy fiber synapses (preprint)","pmids":["41959109"],"confidence":"Medium","gaps":["Preprint not yet peer-reviewed","Functional consequence of the mapped expanded expression sites not tested"]},{"year":null,"claim":"The central unresolved question is how one secreted gC1q protein reconciles its BAI3-mediated synaptic organizing role with diverse peripheral AMPK/PKA signaling, and why gain-of-function (recombinant) and loss-of-function (knockout) metabolic phenotypes diverge.","evidence":"No discovery reconciles the synaptic-versus-metabolic receptor usage or the gain/loss-of-function metabolic paradox","pmids":[],"confidence":"Low","gaps":["No identified receptor for peripheral metabolic/vascular actions","Mechanism unifying CNS and peripheral functions unknown","Source tissue of circulating CTRP13 driving systemic metabolism undefined"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0098631","term_label":"cell adhesion mediator activity","supporting_discovery_ids":[6,13]},{"term_id":"GO:0048018","term_label":"receptor ligand activity","supporting_discovery_ids":[1,6]},{"term_id":"GO:0060089","term_label":"molecular transducer activity","supporting_discovery_ids":[6,13]}],"localization":[{"term_id":"GO:0005576","term_label":"extracellular region","supporting_discovery_ids":[0,1,6]},{"term_id":"GO:0005886","term_label":"plasma membrane","supporting_discovery_ids":[6,21]}],"pathway":[{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[1,9,11,14]},{"term_id":"R-HSA-1430728","term_label":"Metabolism","supporting_discovery_ids":[1,2,15]},{"term_id":"R-HSA-112316","term_label":"Neuronal System","supporting_discovery_ids":[5,6,7]},{"term_id":"R-HSA-1500931","term_label":"Cell-Cell communication","supporting_discovery_ids":[6,13]}],"complexes":["C1QL3–BAI3/ADGRB3–NPTX1–NPTXR trans-synaptic adhesion complex"],"partners":["ADGRB3","NPTX1","NPTXR","C1QL2"],"other_free_text":[]}},"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":120,"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":91,"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 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Diabetes.","date":"2019","source":"Diabetes","url":"https://pubmed.ncbi.nlm.nih.gov/31676569","citation_count":24,"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":23,"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":"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 Therapy","url":"https://pubmed.ncbi.nlm.nih.gov/32966772","citation_count":22,"is_preprint":false},{"pmid":"31145871","id":"PMC_31145871","title":"CTRP13 attenuates vascular calcification by regulating Runx2.","date":"2019","source":"FASEB journal : official publication of the Federation of American Societies for Experimental Biology","url":"https://pubmed.ncbi.nlm.nih.gov/31145871","citation_count":19,"is_preprint":false},{"pmid":"28182339","id":"PMC_28182339","title":"The Circulating Levels of Complement-C1q/TNF-Related Protein 13 (CTRP13) in Patients with Type 2 Diabetes and its Association with Insulin Resistance.","date":"2017","source":"Clinical laboratory","url":"https://pubmed.ncbi.nlm.nih.gov/28182339","citation_count":16,"is_preprint":false},{"pmid":"34338573","id":"PMC_34338573","title":"CTRP13 Protects H9c2 Cells Against Hypoxia/Reoxygenation (H/R)-Induced Injury Via Regulating the AMPK/Nrf2/ARE Signaling Pathway.","date":"2021","source":"Cell transplantation","url":"https://pubmed.ncbi.nlm.nih.gov/34338573","citation_count":15,"is_preprint":false},{"pmid":"39541845","id":"PMC_39541845","title":"CTRP13 attenuates atherosclerosis by inhibiting endothelial cell ferroptosis via activating GCH1.","date":"2024","source":"International immunopharmacology","url":"https://pubmed.ncbi.nlm.nih.gov/39541845","citation_count":14,"is_preprint":false},{"pmid":"37478644","id":"PMC_37478644","title":"Curcumin ameliorates traumatic brain injury via C1ql3-mediated microglia M2 polarization.","date":"2023","source":"Tissue & cell","url":"https://pubmed.ncbi.nlm.nih.gov/37478644","citation_count":13,"is_preprint":false},{"pmid":"32554851","id":"PMC_32554851","title":"CTRP13 attenuates the expression of LN and CAV-1 Induced by high glucose via CaMKKβ/AMPK pathway in rLSECs.","date":"2020","source":"Aging","url":"https://pubmed.ncbi.nlm.nih.gov/32554851","citation_count":10,"is_preprint":false},{"pmid":"30247335","id":"PMC_30247335","title":"Association of CTRP13 With Liver Enzymes and Cognitive Symptoms in Nonalcoholic Fatty Liver Disease.","date":"2019","source":"Nursing research","url":"https://pubmed.ncbi.nlm.nih.gov/30247335","citation_count":10,"is_preprint":false},{"pmid":"37844630","id":"PMC_37844630","title":"CTRP13 ablation improves systemic glucose and lipid metabolism.","date":"2023","source":"Molecular metabolism","url":"https://pubmed.ncbi.nlm.nih.gov/37844630","citation_count":9,"is_preprint":false},{"pmid":"37140354","id":"PMC_37140354","title":"Pleiotropy of C1QL proteins across physiological systems and their emerging role in synapse homeostasis.","date":"2023","source":"Biochemical Society transactions","url":"https://pubmed.ncbi.nlm.nih.gov/37140354","citation_count":6,"is_preprint":false},{"pmid":"38273650","id":"PMC_38273650","title":"CTRP13 Mitigates Endothelial Cell Ferroptosis via the AMPK/KLF4 Pathway: Implications for Atherosclerosis Protection.","date":"2024","source":"Medical science monitor : international medical journal of experimental and clinical research","url":"https://pubmed.ncbi.nlm.nih.gov/38273650","citation_count":5,"is_preprint":false},{"pmid":"37976900","id":"PMC_37976900","title":"CTRP13 alleviates palmitic acid-induced inflammation, oxidative stress, apoptosis and endothelial cell dysfunction in HUVECs.","date":"2023","source":"Tissue & cell","url":"https://pubmed.ncbi.nlm.nih.gov/37976900","citation_count":5,"is_preprint":false},{"pmid":"38379452","id":"PMC_38379452","title":"C1ql3 knockout affects microglia activation, neuronal integrity, and spontaneous behavior in Wistar rats.","date":"2024","source":"Animal models and experimental 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letters","url":"https://pubmed.ncbi.nlm.nih.gov/40541605","citation_count":2,"is_preprint":false},{"pmid":"39120321","id":"PMC_39120321","title":"CTRP13-Mediated Effects on Endothelial Cell Function and Their Potential Role in Obesity.","date":"2024","source":"Cells","url":"https://pubmed.ncbi.nlm.nih.gov/39120321","citation_count":0,"is_preprint":false},{"pmid":"38255158","id":"PMC_38255158","title":"Adiponectin C1q/Tumor Necrosis Factor-Related Protein 13 (CTRP13) Protects against Renal Inflammation and Fibrosis in Obstructive Nephropathy.","date":"2023","source":"Biomedicines","url":"https://pubmed.ncbi.nlm.nih.gov/38255158","citation_count":0,"is_preprint":false},{"pmid":"41959109","id":"PMC_41959109","title":"Brain-wide mapping and synaptic localization of C1QL3 using a novel epitope-tagged knock-in mouse.","date":"2026","source":"bioRxiv : the preprint server for biology","url":"https://pubmed.ncbi.nlm.nih.gov/41959109","citation_count":0,"is_preprint":false},{"pmid":null,"id":"bio_10.1101_2025.10.04.680465","title":"Developmental Dysregulation of Synaptic and Myelin-Related Genes in Frontal Cortex and Serum Infrared Spectroscopy Signature in the Valproic Acid Model of Autism","date":"2025-10-05","source":"bioRxiv","url":"https://doi.org/10.1101/2025.10.04.680465","citation_count":0,"is_preprint":true},{"pmid":null,"id":"bio_10.1101_2025.04.27.650829","title":"The non-thermogenic function of opossum UCP1 is independent of its cytoplasmic binding network","date":"2025-04-30","source":"bioRxiv","url":"https://doi.org/10.1101/2025.04.27.650829","citation_count":0,"is_preprint":true}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":19722,"output_tokens":5673,"usd":0.072131,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":14253,"output_tokens":4667,"usd":0.09397,"stage2_stop_reason":"end_turn"},"total_usd":0.166101,"stage1_batch_id":"msgbatch_0179Z2pxRYBsXi2xADneafRw","stage2_batch_id":"msgbatch_01LaY9ZaVdgjWArcZo9eqQE5","note":"batch pricing = 50% of standard"},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 2011,\n      \"finding\": \"CTRP13 is secreted as a disulfide-linked oligomeric protein, and when co-expressed with CTRP10 forms heteromeric complexes via a mechanism that does not involve conserved N-terminal Cys residues.\",\n      \"method\": \"Heterologous expression system, co-expression, biochemical characterization of secreted protein\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct biochemical characterization with mutagenesis inference (N-terminal Cys not required), single lab, multiple orthogonal observations\",\n      \"pmids\": [\"21378161\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"CTRP13 (CTRP13/C1QL3) promotes glucose uptake in adipocytes, myotubes, and hepatocytes via activation of the AMPK signaling pathway, as demonstrated using purified recombinant protein.\",\n      \"method\": \"In vitro glucose uptake assay with purified recombinant protein in primary adipocytes, myotubes, and hepatocytes; AMPK activation measured\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — reconstituted with purified recombinant protein, multiple cell types tested, single lab but multiple orthogonal readouts\",\n      \"pmids\": [\"21378161\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"CTRP13 ameliorates lipid-induced insulin resistance in hepatocytes by suppressing SAPK/JNK stress signaling, and reduces hepatocyte glucose output by inhibiting mRNA expression of gluconeogenic enzymes glucose-6-phosphatase and cytosolic phosphoenolpyruvate carboxykinase.\",\n      \"method\": \"In vitro hepatocyte assay with purified recombinant CTRP13; mRNA expression analysis of gluconeogenic enzymes\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — recombinant protein in primary hepatocytes, JNK pathway suppression and gluconeogenic gene expression measured, single lab with multiple orthogonal readouts\",\n      \"pmids\": [\"21378161\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"Central (intracerebroventricular) administration of recombinant CTRP13 suppressed food intake and reduced body weight in mice, establishing C1QL3 as an anorexigenic factor in the brain.\",\n      \"method\": \"Central administration of recombinant protein in mice; food intake and body weight measured\",\n      \"journal\": \"PloS one\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — in vivo loss/gain of function with direct behavioral readout, single lab, multiple experimental conditions\",\n      \"pmids\": [\"23638159\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"CTRP13 and the orexigenic neuropeptide AgRP reciprocally regulate each other's expression in the hypothalamus: central CTRP13 delivery suppressed Agrp expression, while AgRP delivery increased Ctrp13 expression, suggesting a hypothalamic feedback loop.\",\n      \"method\": \"Central delivery of recombinant proteins in mice; qPCR measurement of neuropeptide gene expression in hypothalamus\",\n      \"journal\": \"PloS one\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — in vivo central administration with molecular readout, single lab, bidirectional relationship demonstrated\",\n      \"pmids\": [\"23638159\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"C1QL3 expression in neurons is activity-dependent and supports excitatory synapse density in cultured neurons; C1QL3-deficient mice have fewer excitatory synapses and exhibit impaired fear memories and other behavioral abnormalities.\",\n      \"method\": \"Conditional and constitutive C1ql3 knockout mice; synapse density quantification in cultured neurons and in vivo; behavioral testing including fear memory assays\",\n      \"journal\": \"Neuron\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — conditional and constitutive KO mice, in vitro and in vivo synapse density measurements, behavioral phenotyping, circuit-specific conditional ablation, multiple orthogonal methods replicated across conditions\",\n      \"pmids\": [\"27478018\"],\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, and C1QL3 expression in basolateral amygdala neurons projecting to the medial prefrontal cortex is required for formation/maintenance of those efferent synapses.\",\n      \"method\": \"Circuit-tracing tools, conditional ablation targeted to specific brain regions, synapse density analysis\",\n      \"journal\": \"Neuron\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — multiple conditional KO models, circuit tracing, behavioral and anatomical readouts, replicated across labs (Südhof group)\",\n      \"pmids\": [\"27478018\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"C1QL3 is robustly expressed in the suprachiasmatic nucleus (SCN); C1ql3 knockout mice have reduced density of excitatory synapses in the SCN and exhibit disrupted circadian behavior including less consolidated activity and period lengthening after a phase-delaying light pulse.\",\n      \"method\": \"C1ql3 knockout mice; immunohistochemistry for synapse density; circadian behavioral assays\",\n      \"journal\": \"Journal of biological rhythms\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — constitutive KO with synaptic and behavioral phenotype, single lab, two orthogonal readouts (anatomy + behavior)\",\n      \"pmids\": [\"28553739\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"CTRP13 reduces CD36 protein levels in macrophages through autophagy-lysosome-dependent degradation at the post-transcriptional level, thereby reducing oxidized LDL uptake and foam-cell formation.\",\n      \"method\": \"Primary peritoneal macrophages treated with recombinant CTRP13; autophagy-lysosome pathway blocking experiments; CD36 protein and mRNA analysis; foam cell formation assays\",\n      \"journal\": \"FASEB journal\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — recombinant protein with pathway inhibition rescue experiments, in vitro and in vivo (ApoE-/- mice), single lab\",\n      \"pmids\": [\"30222079\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"CTRP13 preserves endothelial function in diabetes by increasing GTP cyclohydrolase 1 (GCH1) expression and tetrahydrobiopterin (BH4) levels to ameliorate eNOS coupling; mechanistically, CTRP13 rescues high-glucose-induced inhibition of PKA activity, and increased PKA activity enhances phosphorylation of PPARα and its recruitment to the GCH1 promoter, activating GCH1 transcription.\",\n      \"method\": \"Ex vivo aortic relaxation assays in diabetic mice; in vitro HUVEC experiments; PKA activity assay; ChIP for PPARα at GCH1 promoter; recombinant CTRP13 treatment\",\n      \"journal\": \"Diabetes\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple mechanistic steps validated in vitro and in vivo, single lab, ChIP and functional assays\",\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, which binds the 3'UTR of Runx2 mRNA and accelerates Runx2 mRNA destabilization and degradation in vascular smooth muscle cells.\",\n      \"method\": \"In vitro VSMC calcification assay; Runx2 overexpression rescue; TTP binding assay; mRNA stability analysis; recombinant CTRP13 treatment in CRF rat model\",\n      \"journal\": \"FASEB journal\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple mechanistic steps (TTP phosphorylation, 3'UTR binding, mRNA degradation) with rescue experiments, single lab\",\n      \"pmids\": [\"31145871\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"CTRP13 protects rat liver sinusoidal endothelial cells from high-glucose-induced injury by activating the CaMKKβ/AMPK pathway, reducing laminin and caveolin-1 expression; inhibition of CaMKKβ or AMPK abolished the protective effects.\",\n      \"method\": \"Lentiviral CTRP13 overexpression in rLSECs; CaMKKβ/AMPK inhibitors (STO-609, Compound C); Western blot and qRT-PCR\",\n      \"journal\": \"Aging\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — pathway inhibition rescue experiments with two independent inhibitors, 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 reducing its ubiquitination-proteasome-dependent degradation, and NAMPT1 knockdown blocks the beneficial effects of CTRP13 on vascular inflammation and smooth muscle cell apoptosis.\",\n      \"method\": \"Two murine AAA models (AngII in ApoE-/- and CaCl2 in C57BL/6J); recombinant CTRP13 infusion; NAMPT1 knockdown; ubiquitination assays\",\n      \"journal\": \"Molecular therapy\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — two independent in vivo models, NAMPT1 knockdown epistasis, ubiquitination mechanism, single lab\",\n      \"pmids\": [\"32966772\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"C1QL3 mediates a novel cell-cell adhesion complex involving ADGRB3 (BAI3) and two neuronal pentraxins, NPTX1 and NPTXR, as identified by an in vivo interactome study; C1ql3, Nptx1, and Nptxr are highly co-expressed in the same excitatory neurons.\",\n      \"method\": \"In vivo interactome study (pulldown/co-IP); single-cell RNA-seq data analysis for co-expression\",\n      \"journal\": \"FASEB journal\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — in vivo interactome pulldown identifying new binding partners, supported by single-cell RNA-seq co-expression, single lab\",\n      \"pmids\": [\"33337553\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"CTRP13 protects cardiomyocytes from hypoxia/reoxygenation injury via the AMPK/Nrf2/ARE signaling pathway; AMPK inhibition reversed CTRP13-mediated Nrf2/ARE activation, and Nrf2 silencing reversed CTRP13's protective effects against oxidative stress and apoptosis.\",\n      \"method\": \"H9c2 cell H/R model; CTRP13 overexpression and silencing; AMPK inhibitor (Compound C); Nrf2 siRNA; recombinant CTRP13 in rat I/R model\",\n      \"journal\": \"Cell transplantation\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — epistasis via AMPK inhibition and Nrf2 silencing, gain/loss-of-function, in vivo validation, single lab\",\n      \"pmids\": [\"34338573\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"Loss of CTRP13 in mice improves systemic metabolism (reduced body weight, improved glucose tolerance, insulin sensitivity, and triglyceride clearance), reduced hepatic glucose output, lower inflammatory profile in visceral fat and liver, and suppressed lipid synthesis with enhanced lipid catabolism gene expression, suggesting CTRP13 is a negative metabolic regulator.\",\n      \"method\": \"Ctrp13 knockout mice on chow and high-fat diet; comprehensive metabolic phenotyping; transcriptomic analyses of multiple tissues; mediation analyses with human METSIM cohort data\",\n      \"journal\": \"Molecular metabolism\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — constitutive KO mice with comprehensive metabolic phenotyping across sexes and diets, transcriptomic analyses, human cohort integration, multiple orthogonal readouts\",\n      \"pmids\": [\"37844630\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"C1QL3 is required for formation of chronic morphine withdrawal memories in the basolateral amygdala (BLA); C1QL3 colocalizes with BAI3 in the BLA, and downregulation of C1QL3 in the BLA reduces conditioned place aversion scores; C1QL3 modulates ubiquitination-mediated degradation of PSD95, resulting in decreased PSD95 protein levels as a downstream effector.\",\n      \"method\": \"Immunofluorescence colocalization of C1QL3 and BAI3; lentiviral downregulation of C1QL3 in BLA; conditioned place aversion behavioral assay; chemogenetic BLA inhibition; ubiquitination/PSD95 protein analysis\",\n      \"journal\": \"Biochemical and biophysical research communications\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — in vivo KD with behavioral readout, colocalization, and ubiquitination mechanism, single lab, multiple methods\",\n      \"pmids\": [\"38772224\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"C1ql3 knockout in rats disrupts neuronal integrity (reduced dendritic arbors and spine density), alters microglial activation (increased ramified microglia, decreased hypertrophic microglia, increased amoeboid microglia and Arg-1 expression after LPS), and impairs short working memory with hyperactive behavior.\",\n      \"method\": \"CRISPR/Cas9 C1ql3 KO rats; Golgi staining for dendritic morphology; immunohistochemistry for microglia; 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 / Moderate — constitutive KO with multiple cellular and behavioral phenotypes, single lab, orthogonal methods\",\n      \"pmids\": [\"38379452\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"CTRP13 inhibits ferroptosis of endothelial cells via the GCH1/BH4 signaling pathway, upregulating GPX4 and downregulating ACSL4; silencing GCH1 or inhibiting BH4 abolished the protective effects of CTRP13.\",\n      \"method\": \"ApoE-/- mice with C1ql3 overexpression AAV; ox-LDL-treated mouse aortic endothelial cells; GCH1 siRNA knockdown; BH4 inhibition; GPX4 and ACSL4 protein detection\",\n      \"journal\": \"International immunopharmacology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — GCH1/BH4 epistasis with rescue experiments in vitro and in vivo, single lab\",\n      \"pmids\": [\"39541845\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"CTRP13 prevents HUVEC ferroptosis induced by ox-LDL via the AMPK/KLF4 pathway, reducing ROS overproduction and mitochondrial dysfunction; CTRP13 increased p-AMPK/AMPK and decreased KLF4 expression.\",\n      \"method\": \"HUVEC ox-LDL model; CTRP13 recombinant protein treatment; Western blot for p-AMPK, KLF4, GPX4, ACSL4; mitochondrial function assays\",\n      \"journal\": \"Medical science monitor\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — single lab, single method (Western blot correlation), no formal AMPK inhibition rescue reported\",\n      \"pmids\": [\"38273650\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"CTRP13 reduces endothelial cell proliferation via AMPK (specifically alpha-2 AMPK), reduces cell cycle progression, increases p53 phosphorylation and p21 expression, and reduces Rb phosphorylation; these effects depended on alpha-2 AMPK as shown by adenoviral dominant-negative and wild-type AMPK overexpression.\",\n      \"method\": \"HUVEC culture; recombinant CTRP13 treatment; adenoviral DN/WT alpha-1/alpha-2 AMPK overexpression; cell cycle analysis; Western blot\",\n      \"journal\": \"Cells\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — dominant-negative and WT AMPK isoform-specific rescue identifies alpha-2 AMPK, single lab, multiple cell cycle markers\",\n      \"pmids\": [\"39120321\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"Brain-wide light-sheet microscopy using a novel C1ql3-2HA epitope-tagged knock-in mouse revealed an expanded neuroanatomical map of endogenous C1QL3 expression in cortical and subcortical regions and the retina; super-resolution STED microscopy localized C1QL3-2HA to hippocampal mossy fiber synapses positioned between pre- and post-synaptic markers; native PAGE determined the endogenous oligomeric state of C1QL3.\",\n      \"method\": \"Epitope-tagged knock-in mouse (C1ql3-2HA); native PAGE for oligomeric state; brain-wide light-sheet microscopy; dual immunohistochemistry; super-resolution STED microscopy\",\n      \"journal\": \"bioRxiv\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — endogenous epitope-tag knock-in with multiple orthogonal imaging methods, preprint not yet peer-reviewed, single lab\",\n      \"pmids\": [\"41959109\"],\n      \"is_preprint\": true\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"Conditional deletion of C1ql3 from neurons specifically in the prefrontal cortex of adult mice was not sufficient to impair attentional set-shifting behavior, indicating C1ql3's role in cognitive flexibility requires expression in other brain circuits and/or neurodevelopmental processes.\",\n      \"method\": \"Conditional C1ql3 deletion in PFC neurons of adult mice; attentional set-shifting behavioral assay\",\n      \"journal\": \"Neuroscience letters\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Weak — conditional KO with specific behavioral readout, single lab, result is a negative finding for PFC-specific deletion\",\n      \"pmids\": [\"40541605\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"C1QL3 (CTRP13) is a secreted, oligomeric gC1q-domain protein expressed in adipose tissue, brain, and vasculature that acts as an adipokine/synaptic organizer: in peripheral tissues it activates AMPK (via CaMKKβ) to promote glucose uptake, suppress JNK-mediated insulin resistance, stabilize NAMPT1 via the ubiquitin-proteasome system, degrade CD36 via autophagy-lysosomes, and preserve endothelial function by activating the PKA–PPARα–GCH1/BH4–eNOS coupling axis; in the CNS it binds to the adhesion GPCR BAI3/ADGRB3 and—together with neuronal pentraxins NPTX1/NPTXR—forms a trans-synaptic adhesion complex that maintains excitatory synapse density in multiple circuits (amygdala–prefrontal, SCN, hippocampus), regulates fear and circadian behaviors, and modulates PSD95 stability via ubiquitination to control synaptic memory processes, while paradoxically its global loss in mice improves systemic metabolic homeostasis, suggesting CTRP13 is a context-dependent negative metabolic regulator.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"C1QL3 (CTRP13) is a secreted, disulfide-linked oligomeric gC1q-domain protein with two distinct functional arenas: a synaptic organizer in the CNS and a metabolic/vascular regulator in peripheral tissues [#0, #5, #1]. In neurons, C1QL3 is secreted and binds the adhesion-class GPCR BAI3/ADGRB3, and acts in an activity-dependent manner to support excitatory synapse density; its loss reduces synapse number and produces fear-memory and other behavioral deficits [#5, #6]. C1QL3 additionally forms a trans-synaptic adhesion complex with the neuronal pentraxins NPTX1 and NPTXR in co-expressing excitatory neurons, and localizes between pre- and postsynaptic markers at hippocampal mossy fiber synapses [#13, #21]. This synaptic function extends across circuits, maintaining excitatory synapses in the suprachiasmatic nucleus to support circadian behavior and in the basolateral amygdala, where C1QL3 controls morphine-withdrawal aversion memories through ubiquitination-mediated turnover of PSD95 [#7, #16]. In peripheral tissues, recombinant CTRP13 promotes glucose uptake in adipocytes, myotubes, and hepatocytes by activating AMPK signaling and ameliorates lipid-induced insulin resistance by suppressing JNK stress signaling and repressing gluconeogenic gene expression [#1, #2]. CTRP13 confers broad vasoprotection through several effector axes: activation of CaMKKβ/AMPK, AMPK/Nrf2/ARE, and PKA–PPARα–GCH1/BH4–eNOS signaling, protein-level stabilization of NAMPT1 and autophagy-lysosomal degradation of CD36, and suppression of ferroptosis via GCH1/BH4 and AMPK/KLF4 pathways [#11, #14, #9, #12, #8, #18]. Paradoxically, constitutive loss of CTRP13 in mice improves systemic metabolism, identifying it as a context-dependent negative metabolic regulator [#15].\",\n  \"teleology\": [\n    {\n      \"year\": 2011,\n      \"claim\": \"Established that C1QL3/CTRP13 is a secreted oligomeric protein and a functional metabolic effector, answering whether this gC1q-domain protein has hormone-like activity on glucose handling.\",\n      \"evidence\": \"Heterologous expression and biochemical characterization of secreted protein; in vitro glucose uptake and AMPK assays with purified recombinant protein across adipocytes, myotubes, and hepatocytes\",\n      \"pmids\": [\"21378161\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"No receptor identified for the metabolic effects\", \"Mechanism linking C1QL3 binding to AMPK activation not resolved\"]\n    },\n    {\n      \"year\": 2013,\n      \"claim\": \"Showed C1QL3 acts centrally as an anorexigenic factor embedded in a hypothalamic feedback loop, extending its biology from peripheral metabolism to CNS energy balance control.\",\n      \"evidence\": \"Intracerebroventricular recombinant protein administration in mice with food intake/body weight readouts and reciprocal AgRP/Ctrp13 qPCR\",\n      \"pmids\": [\"23638159\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Neurons mediating the anorexigenic effect not defined\", \"Receptor in hypothalamus unknown\"]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"Defined C1QL3 as an activity-dependent synaptic organizer that binds the adhesion GPCR BAI3 and is required cell-autonomously to maintain specific excitatory circuits, identifying its receptor and a core CNS function.\",\n      \"evidence\": \"Conditional and constitutive knockout mice, circuit tracing, synapse density quantification, and fear-memory behavioral testing (Südhof group)\",\n      \"pmids\": [\"27478018\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Signaling downstream of BAI3 engagement not resolved\", \"Whether the same receptor mediates metabolic actions unknown\"]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"Generalized the synaptic role to circadian circuitry, showing C1QL3 maintains excitatory synapses in the SCN and is needed for normal circadian behavior.\",\n      \"evidence\": \"Constitutive Ctrp13 KO mice with SCN synapse density immunohistochemistry and circadian behavioral assays\",\n      \"pmids\": [\"28553739\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Molecular link between synapse loss and circadian phenotype not established\", \"Receptor partner in SCN not confirmed\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"Demonstrated a post-transcriptional anti-atherogenic mechanism whereby CTRP13 lowers CD36 via autophagy-lysosomal degradation, reducing foam-cell formation.\",\n      \"evidence\": \"Recombinant CTRP13 in primary macrophages with autophagy-lysosome pathway blockade and CD36 protein/mRNA and foam-cell assays; ApoE-/- mice\",\n      \"pmids\": [\"30222079\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"How CTRP13 triggers autophagic targeting of CD36 unknown\", \"Receptor mediating macrophage response not identified\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Defined two distinct vasoprotective signaling axes: PKA–PPARα–GCH1/BH4–eNOS coupling preserving endothelial function, and TTP-mediated Runx2 mRNA destabilization limiting vascular calcification.\",\n      \"evidence\": \"Ex vivo aortic relaxation and HUVEC assays with PKA activity and PPARα ChIP at GCH1 promoter; VSMC calcification assays with TTP binding and mRNA stability analysis in CRF rat model\",\n      \"pmids\": [\"31676569\", \"31145871\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Upstream receptor coupling to PKA not identified\", \"How CTRP13 represses TTP phosphorylation unresolved\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Extended vasoprotection to two additional mechanisms: CaMKKβ/AMPK protection of liver sinusoidal endothelium, and ubiquitin-proteasome stabilization of NAMPT1 mitigating aortic aneurysm.\",\n      \"evidence\": \"Lentiviral overexpression in rLSECs with CaMKKβ/AMPK inhibitor rescue; two murine AAA models with NAMPT1 knockdown epistasis and ubiquitination assays\",\n      \"pmids\": [\"32554851\", \"32966772\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"How CTRP13 reduces NAMPT1 ubiquitination mechanistically unknown\", \"Receptor upstream of CaMKKβ not defined\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Identified C1QL3 as part of a tripartite trans-synaptic adhesion complex with BAI3 and neuronal pentraxins NPTX1/NPTXR, refining the molecular architecture of its synaptic action; in parallel showed cardioprotection through AMPK/Nrf2/ARE signaling.\",\n      \"evidence\": \"In vivo interactome pulldown with single-cell RNA-seq co-expression; H9c2 H/R model with AMPK inhibition and Nrf2 silencing epistasis and rat I/R validation\",\n      \"pmids\": [\"33337553\", \"34338573\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Stoichiometry and assembly order of the BAI3/NPTX1/NPTXR complex unknown\", \"Whether the complex transduces signal bidirectionally not tested\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Revealed a paradox by showing that constitutive loss of CTRP13 improves systemic metabolism, reframing the protein as a context-dependent negative metabolic regulator rather than a uniformly beneficial adipokine.\",\n      \"evidence\": \"Ctrp13 KO mice on chow and high-fat diets with comprehensive metabolic and transcriptomic phenotyping and human METSIM cohort mediation analyses\",\n      \"pmids\": [\"37844630\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Reconciliation of loss-of-function benefit with gain-of-function recombinant effects unresolved\", \"Tissue source driving the systemic phenotype not pinpointed\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Linked C1QL3 to addiction-related memory and broader neuronal/glial integrity, and showed PFC-specific adult deletion is insufficient for cognitive-flexibility deficits, mapping circuit and developmental dependencies.\",\n      \"evidence\": \"Lentiviral C1QL3 knockdown in BLA with conditioned place aversion and PSD95 ubiquitination analysis; CRISPR KO rats with Golgi, microglia, and behavioral assays; conditional adult PFC deletion with attentional set-shifting\",\n      \"pmids\": [\"38772224\", \"38379452\", \"40541605\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"How C1QL3 controls PSD95 ubiquitination mechanistically unknown\", \"Direct effect of C1QL3 on microglia versus secondary to synapse loss unresolved\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Resolved additional vascular effector pathways: suppression of endothelial ferroptosis via GCH1/BH4 and AMPK/KLF4, and AMPK-alpha2-dependent restraint of endothelial proliferation through p53/p21/Rb.\",\n      \"evidence\": \"ox-LDL endothelial and ApoE-/- AAV models with GCH1/BH4 and Nrf2 epistasis; HUVEC cell-cycle analysis with isoform-specific dominant-negative/WT AMPK rescue\",\n      \"pmids\": [\"39541845\", \"38273650\", \"39120321\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Receptor coupling CTRP13 to AMPK in endothelium not identified\", \"AMPK/KLF4 ferroptosis link rests on correlative Western blot without inhibitor rescue\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Provided the first endogenous mapping of C1QL3 protein, localizing it to specific synaptic clefts and defining its native oligomeric state with a knock-in reporter.\",\n      \"evidence\": \"C1ql3-2HA epitope-tagged knock-in mouse with native PAGE, brain-wide light-sheet microscopy, and super-resolution STED at mossy fiber synapses (preprint)\",\n      \"pmids\": [\"41959109\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Preprint not yet peer-reviewed\", \"Functional consequence of the mapped expanded expression sites not tested\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"The central unresolved question is how one secreted gC1q protein reconciles its BAI3-mediated synaptic organizing role with diverse peripheral AMPK/PKA signaling, and why gain-of-function (recombinant) and loss-of-function (knockout) metabolic phenotypes diverge.\",\n      \"evidence\": \"No discovery reconciles the synaptic-versus-metabolic receptor usage or the gain/loss-of-function metabolic paradox\",\n      \"pmids\": [],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"No identified receptor for peripheral metabolic/vascular actions\", \"Mechanism unifying CNS and peripheral functions unknown\", \"Source tissue of circulating CTRP13 driving systemic metabolism undefined\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0098631\", \"supporting_discovery_ids\": [6, 13]},\n      {\"term_id\": \"GO:0048018\", \"supporting_discovery_ids\": [1, 6]},\n      {\"term_id\": \"GO:0060089\", \"supporting_discovery_ids\": [6, 13]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005576\", \"supporting_discovery_ids\": [0, 1, 6]},\n      {\"term_id\": \"GO:0005886\", \"supporting_discovery_ids\": [6, 21]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [1, 9, 11, 14]},\n      {\"term_id\": \"R-HSA-1430728\", \"supporting_discovery_ids\": [1, 2, 15]},\n      {\"term_id\": \"R-HSA-112316\", \"supporting_discovery_ids\": [5, 6, 7]},\n      {\"term_id\": \"R-HSA-1500931\", \"supporting_discovery_ids\": [6, 13]}\n    ],\n    \"complexes\": [\"C1QL3–BAI3/ADGRB3–NPTX1–NPTXR trans-synaptic adhesion complex\"],\n    \"partners\": [\"ADGRB3\", \"NPTX1\", \"NPTXR\", \"C1QL2\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":7,"faith_total":7,"faith_pct":100.0}}