{"gene":"C1QTNF3","run_date":"2026-06-09T22:02:45","timeline":{"discoveries":[{"year":2010,"finding":"CTRP3 lowers blood glucose in normal and ob/ob mice by activating the Akt signaling pathway in liver and suppressing hepatic gluconeogenic gene expression; it acts directly and independently of insulin to reduce glucose output in cultured hepatocytes by suppressing gluconeogenic enzyme expression.","method":"Recombinant protein administration in vivo (mouse), Akt pathway analysis by Western blot, gluconeogenic gene expression in primary hepatocytes","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 2 / Strong — in vivo recombinant protein administration with pathway (Akt) and gene expression readouts replicated in primary hepatocyte cell culture; multiple orthogonal methods in a single rigorous study","pmids":["20952387"],"is_preprint":false},{"year":2010,"finding":"In humans, alternative splicing generates two circulating CTRP3 isoforms that form hetero-oligomers; this association does not require interdisulfide bond formation and protects the longer isoform from proteolytic cleavage.","method":"Biochemical characterization of recombinant human CTRP3 isoforms; hetero-oligomer formation assay; protease protection experiments","journal":"The Journal of biological chemistry","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct biochemical characterization of isoform oligomerization and proteolytic protection, single study, two orthogonal methods","pmids":["20952387"],"is_preprint":false},{"year":2005,"finding":"Baculovirus-produced CTRP3 (CORS-26) forms stable trimers in insect cell supernatants and reduces IL-6 and TNF-α secretion from LPS-treated monocytic cells, likely through suppression of NF-κB signaling.","method":"Baculovirus expression system, SDS-PAGE/immunoblot for trimer characterization; ELISA for cytokine measurement; NF-κB reporter assay","journal":"FEBS letters","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct biochemical demonstration of trimer formation plus functional anti-inflammatory assay, single lab, two orthogonal methods","pmids":["16213490"],"is_preprint":false},{"year":2013,"finding":"Transgenic CTRP3 overexpression protects mice from high-fat diet-induced hepatic steatosis by reducing hepatic triglyceride content through decreased expression of triglyceride synthesis enzymes (GPAT, AGPAT, DGAT); recombinant CTRP3 treatment also directly reduces fatty acid synthesis and neutral lipid accumulation in cultured hepatocytes.","method":"Transgenic mouse model, hepatic triglyceride measurement, qPCR for lipogenic enzymes, recombinant protein treatment of H4IIE hepatocytes","journal":"American journal of physiology. Gastrointestinal and liver physiology","confidence":"High","confidence_rationale":"Tier 2 / Strong — genetic overexpression model validated with acute recombinant protein administration and cell culture; multiple orthogonal methods","pmids":["23744740"],"is_preprint":false},{"year":2007,"finding":"CTRP3/cartducin promotes proliferation and migration of endothelial cells in a dose-dependent manner through activation of ERK1/2 and p38 MAPK; MEK1/2 inhibitor (U0126) blocks both proliferation and migration, while p38 inhibitor (SB203580) blocks only proliferation.","method":"Recombinant CTRP3 treatment of MSS31 endothelial cells; cell proliferation and migration assays; kinase inhibitor studies; Western blot for ERK1/2 and p38 phosphorylation","journal":"Molecular and cellular biochemistry","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — pharmacological pathway dissection with two inhibitors and functional readouts (proliferation and migration), single lab","pmids":["17534697"],"is_preprint":false},{"year":2010,"finding":"TGF-β1 (but not bFGF or PDGF-BB) induces CTRP3/cartducin expression in vascular smooth muscle cells; exogenous CTRP3/cartducin promotes VSMC proliferation (but not migration) via ERK1/2 and p38 MAPK signaling pathways.","method":"Recombinant CTRP3 treatment of p53LMAC01 VSMCs; TGF-β1 stimulation; cell proliferation and migration assays; kinase inhibitor studies","journal":"Cell biology international","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — defined upstream inducer (TGF-β1), pathway inhibitor studies in cell culture, single lab, two orthogonal readouts","pmids":["19947921"],"is_preprint":false},{"year":2009,"finding":"Recombinant CTRP3 promotes osteosarcoma cell (NHOS and LM8) proliferation (but not migration) through activation of the ERK1/2 signaling pathway; MEK1/2 inhibitor U0126 blocks this effect.","method":"Recombinant CTRP3 treatment of osteosarcoma cell lines; proliferation and migration assays; Western blot for ERK1/2 phosphorylation; MEK inhibitor U0126","journal":"Oncology reports","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — pharmacological pathway validation, multiple cell lines, single lab","pmids":["19424626"],"is_preprint":false},{"year":2012,"finding":"CTRP3 stimulates testosterone production in TM3 mouse Leydig cells in a dose-dependent manner by upregulating StAR protein and P450scc expression through the cAMP/PKA signaling pathway; PKA inhibitor H89 blocks this effect.","method":"Recombinant CTRP3 treatment of TM3 cells; testosterone ELISA; cAMP measurement; CREB phosphorylation by Western blot; PKA inhibitor H89","journal":"Cytokine","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — pharmacological pathway dissection with PKA inhibitor plus cAMP/CREB readouts, single lab","pmids":["22342437"],"is_preprint":false},{"year":2013,"finding":"C1qtnf3 knockout mice show increased incidence and severity of collagen-induced arthritis, higher anti-type II collagen antibody levels, and elevated pro-inflammatory cytokine mRNA, establishing CTRP3 as a negative regulator of autoimmune arthritis.","method":"C1qtnf3 knockout mouse model; collagen-induced arthritis; histopathology; ELISA; qPCR for cytokines","journal":"Biochemical and biophysical research communications","confidence":"High","confidence_rationale":"Tier 2 / Strong — genetic loss-of-function with defined disease phenotype and molecular readouts, multiple orthogonal assessments","pmids":["24269820"],"is_preprint":false},{"year":2015,"finding":"CTRP3 attenuates cardiac fibrosis post-myocardial infarction by inhibiting myofibroblast differentiation and ECM production; mechanistically, CTRP3 activates AMPK and Akt in cardiac fibroblasts and inhibits TGF-β1-induced Smad3 phosphorylation, nuclear translocation, and interaction with p300; AMPK inhibitor AraA abolishes the anti-fibrotic effect.","method":"Adenovirus-mediated CTRP3 overexpression in rat post-MI model; adult rat cardiac fibroblast culture; AMPK inhibitor AraA; Western blot for Smad3 phosphorylation; Co-IP for Smad3-p300 interaction; siRNA knockdown","journal":"Journal of molecular medicine (Berlin, Germany)","confidence":"High","confidence_rationale":"Tier 2 / Strong — in vivo and in vitro models with genetic gain/loss-of-function, pharmacological inhibition, and biochemical pathway dissection (Smad3 phosphorylation, Co-IP)","pmids":["26138247"],"is_preprint":false},{"year":2017,"finding":"CTRP3 protects against diabetic cardiomyopathy by activating AMPKα via the cAMP-EPAC-MEK pathway; AMPKα deficiency abolishes CTRP3's protective effects against high-glucose-induced oxidative stress, inflammation, and apoptosis.","method":"Adeno-associated virus CTRP3 overexpression in STZ-diabetic rats; H9c2 cell culture; AMPKα knockout/inhibition; pathway inhibitors for cAMP/EPAC/MEK; Western blot; TUNEL assay","journal":"Diabetologia","confidence":"High","confidence_rationale":"Tier 2 / Strong — in vivo (AAV overexpression) and in vitro models with genetic and pharmacological dissection of upstream signaling (cAMP-EPAC-MEK-AMPKα)","pmids":["28258411"],"is_preprint":false},{"year":2017,"finding":"CTRP3 protects against doxorubicin-induced cardiac injury via activation of Sirt1; specific Sirt1 inhibition or siRNA silencing abolishes CTRP3's protective effects against DOX-induced inflammation and apoptosis.","method":"AAV CTRP3 cardiac overexpression in DOX-treated mice; H9C2 cell culture; Sirt1 inhibitor; Sirt1 siRNA; Western blot; TUNEL assay","journal":"Journal of molecular and cellular cardiology","confidence":"High","confidence_rationale":"Tier 2 / Strong — in vivo and in vitro models with genetic (siRNA) and pharmacological (inhibitor) Sirt1 pathway validation","pmids":["29061338"],"is_preprint":false},{"year":2016,"finding":"Globular CTRP3 promotes mitochondrial biogenesis in cardiomyocytes via the AMPK/PGC-1α pathway; CTRP3 increases AMPK phosphorylation, Sirtuin1 expression and activity, and downstream PGC-1α/NRF-1/TFAM/complex III/V; AMPK inhibitor AraA and Sirt1 inhibitor EX-527 attenuate these effects; PGC-1α siRNA blocks CTRP3-induced mitochondrial biogenesis.","method":"Recombinant globular CTRP3 treatment of neonatal rat ventricular myocytes; AMPK inhibitor AraA; Sirt1 inhibitor EX-527; PGC-1α siRNA; mitochondrial morphology by TEM; ATP measurement; OCR measurement; mtDNA copy number","journal":"Biochimica et biophysica acta. General subjects","confidence":"High","confidence_rationale":"Tier 2 / Strong — multiple pharmacological and genetic (siRNA) pathway validations with orthogonal functional readouts (ATP, OCR, mtDNA, TEM)","pmids":["27793739"],"is_preprint":false},{"year":2015,"finding":"CTRP3 acts as a negative regulator of RANKL-induced osteoclastogenesis through the AMPK-c-Fos-NFATc1 signaling axis; CTRP3 activates AMPK in bone marrow macrophages and inhibits RANKL-induced c-Fos and NFATc1 expression, F-actin formation, and bone resorption; CTRP3 also reduces osteoclast formation and bone destruction in mouse calvarial bone in vivo.","method":"Recombinant CTRP3 treatment of mouse bone marrow macrophages; co-culture osteoclastogenesis assay; Western blot for AMPK, c-Fos, NFATc1; calvarial bone injection model; micro-CT; histology","journal":"Bone","confidence":"High","confidence_rationale":"Tier 2 / Strong — in vitro pathway dissection with multiple signaling targets plus in vivo calvarial model, orthogonal methods","pmids":["26103094"],"is_preprint":false},{"year":2016,"finding":"Identification of LAMP1 (lysosomal-associated membrane protein 1) and LIMP II as putative receptors for CTRP3 on hepatoma cells using ligand-receptor glycocapture (LRC-TriCEPS) technology; Co-IP confirmed LAMP1-CTRP3 association; a polyclonal antibody blocking LAMP1 prevented CTRP3 binding to cells.","method":"LRC-TriCEPS ligand-receptor capture; Co-immunoprecipitation; FACS; antibody-blocking assay in H4IIE cells","journal":"PloS one","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — ligand-receptor capture with confirmatory Co-IP and antibody blocking, single lab, novel technology","pmids":["27727322"],"is_preprint":false},{"year":2004,"finding":"The transcription factors SP-1, PPARγ, and Pit-1 bind specifically to the murine CORS-26 (CTRP3) promoter; SP-1 exerts inhibitory (repressive) effects on CORS-26 transcriptional activation in an SP-3-independent manner.","method":"EMSA with nuclear extracts from 3T3-L1 adipocytes; supershift assay; competition experiments; mutated SP-1 binding site oligonucleotides; luciferase reporter gene assay","journal":"Biochimica et biophysica acta","confidence":"Medium","confidence_rationale":"Tier 1 / Moderate — EMSA with supershift and mutagenesis controls plus luciferase reporter, single lab","pmids":["15157741"],"is_preprint":false},{"year":2014,"finding":"Recombinant CTRP3 attenuates LPS-induced systemic inflammation (serum IL-6 and MIP-2) and suppresses LPS-induced ERK-1/-2 phosphorylation in inguinal adipose tissue when administered intraperitoneally in mice; intravenous CTRP3 administration was not sufficient to produce these effects.","method":"Intraperitoneal and intravenous recombinant CTRP3 administration in C57BL/6N mice challenged with LPS; ELISA for serum cytokines; qPCR for adipose cytokine mRNA; Western blot for ERK-1/-2 phosphorylation","journal":"Biochemical and biophysical research communications","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — in vivo recombinant protein administration with route-dependent pharmacological comparison, single lab","pmids":["24996172"],"is_preprint":false},{"year":2016,"finding":"CTRP3 promotes energy (ATP) production in vascular smooth muscle cells by increasing mitochondrial ROS production and upregulating PGC-1α and oxidative phosphorylation complexes; ROS scavenger N-acetyl-L-cysteine and OXPHOS uncoupler CCCP suppress CTRP3-induced ROS, PGC-1α, and ATP synthesis.","method":"Recombinant CTRP3 treatment of VSMCs; CTRP3 siRNA knockdown; PGC-1α siRNA; ATP assay; mitochondrial ROS measurement; Western blot for OXPHOS complexes; N-acetyl-L-cysteine and CCCP treatment","journal":"Experimental cell research","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — gain and loss-of-function with pharmacological pathway inhibition, single lab, multiple readouts","pmids":["26844631"],"is_preprint":false},{"year":2011,"finding":"CTRP3/cartducin is required for maintenance of the perichondrium and normal chondrocyte proliferation/differentiation in Meckel's cartilage and mandibular condylar cartilage; antisense oligodeoxynucleotide (AS-ODN) abrogation of CTRP3 in organ culture caused curvature deformation, loss of perichondrium, ectopic cartilage formation, reduced BrdU incorporation, and decreased aggrecan/collagen expression; these effects were partially rescued by recombinant CTRP3.","method":"In situ hybridization; antisense ODN organ culture system; BrdU incorporation; immunostaining; recombinant CTRP3 rescue experiment","journal":"Journal of anatomy","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — loss-of-function AS-ODN with rescue experiment in organ culture, in situ expression mapping, single lab","pmids":["21371032"],"is_preprint":false},{"year":2015,"finding":"CTRP3-deficient mice on high-fat diet have markedly reduced liver sizes and decreased profibrotic TGFβ1 levels, but markedly increased circulating IL-6; loss of CTRP3 had minimal impact on whole body glucose metabolism or insulin sensitivity, contrary to expectation from gain-of-function studies.","method":"Genetic knockout mouse model (Ctrp3-KO); HFD feeding; hyperinsulinemic-euglycemic clamp; liver weight and histology; ELISA for TGFβ1 and IL-6; liver gene expression by qPCR","journal":"American journal of physiology. Endocrinology and metabolism","confidence":"High","confidence_rationale":"Tier 2 / Strong — genetic KO with comprehensive metabolic phenotyping and biochemical measurements, multiple orthogonal methods","pmids":["26670485"],"is_preprint":false},{"year":2016,"finding":"In a mouse model of endotoxemia or high-fat diet, genetic CTRP3 deficiency or transgenic overexpression did not significantly affect circulating IL-1β, IL-6, TNF-α, or MIP-2 induction by LPS, contrary to findings from recombinant CTRP3 protein administration; CTRP3 transgenic mice had elevated chemokines (CCL11, CXCL9, CXCL10, etc.) on low-fat diet but lower IL-5 and TNF-α on high-fat diet.","method":"CTRP3 knockout and transgenic mouse models; LPS challenge; multiplex serum cytokine profiling (71 cytokines); HFD metabolic challenge","journal":"Physiological reports","confidence":"High","confidence_rationale":"Tier 2 / Strong — dual genetic model (KO and Tg) with comprehensive multiplex cytokine analysis, revealing context-dependent immunomodulation","pmids":["26997632"],"is_preprint":false},{"year":2021,"finding":"CTRP3 suppresses Th17 cell differentiation but not Th1 differentiation via AdipoR2 (not AdipoR1); this suppression is associated with reduced Rorc and Stat3 expression; CTRP3-deficient mice show augmented Th17 cell populations and enhanced myelin oligodendrocyte glycoprotein-induced experimental autoimmune encephalomyelitis; CTRP3 inhibits IL-17 production from T cells by affecting both T cells and dendritic cells.","method":"C1qtnf3 knockout mice; Th17 and Th1 differentiation assays in vitro; AdipoR1/AdipoR2 receptor antagonist treatment; AdipoRon agonist; EAE mouse model; flow cytometry for Th17 populations; qPCR for Rorc and Stat3","journal":"Frontiers in immunology","confidence":"High","confidence_rationale":"Tier 2 / Strong — genetic KO model combined with pharmacological receptor-specific antagonist dissection and in vivo EAE model, multiple orthogonal methods","pmids":["34925309"],"is_preprint":false},{"year":2019,"finding":"CTRP3 regulates mTOR-dependent axonal local protein translation in motor neurons via a muscle-to-neuron secretion mechanism; CTRP3 levels are reduced in SMA muscle secretome and serum; exogenous CTRP3 enhances axonal outgrowth and protein synthesis (including SMN) via the mTOR pathway.","method":"Quantitative proteomics with metabolic labeling of SMA muscle secretome; CTRP3 measurement in SMA mouse model tissue and serum; mTOR pathway analysis; axonal outgrowth assay; protein synthesis rate measurement in motor neurons","journal":"Acta neuropathologica communications","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — mass spectrometry secretome profiling plus functional validation in neurons with pathway analysis, single lab","pmids":["31615574"],"is_preprint":false},{"year":2021,"finding":"CTRP3 exacerbates tendinopathy by promoting abnormal differentiation of tendon stem/progenitor cells toward chondrogenic lineage (ectopic chondrification) through Akt signaling; CTRP3 knockdown suppresses tendinopathy pathogenesis, and a neutralizing antibody against CTRP3 ameliorates overuse-induced Achilles and rotator cuff tendinopathy in mice.","method":"CTRP3 overexpression and knockdown mouse models; neutralizing antibody treatment; transcriptomic analysis; Akt pathway analysis; histology (proteoglycan/collagen fiber analysis); micro-CT","journal":"Science advances","confidence":"High","confidence_rationale":"Tier 2 / Strong — gain-of-function, loss-of-function, and antibody-blockade models combined with transcriptomics and pathway analysis, published in peer-reviewed journal","pmids":["34797714"],"is_preprint":false},{"year":2022,"finding":"CTRP3 exerts anti-inflammatory effects in endothelial cells by inhibiting LPS-induced expression of IL-6, TNF-α, VCAM-1, and ICAM-1 and blocking monocyte adhesion to endothelial monolayers; CTRP3 mRNA is expressed in primary endothelial cells and aorta, and is transiently upregulated by LPS in murine endothelial cells.","method":"qPCR tissue expression analysis; MyEND cell culture; LPS stimulation; CTRP3 treatment; monocyte adhesion assay; ELISA/qPCR for adhesion molecules and cytokines","journal":"Cells","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — cell-based functional assays with direct treatment, multiple cytokine/adhesion molecule readouts, single lab","pmids":["34440913"],"is_preprint":false},{"year":2022,"finding":"CTRP3 attenuates intestinal inflammation via a SIRT1/NF-κB signaling axis; CTRP3-KO mice develop more severe colitis with decreased SIRT1, increased phosphorylated/acetylated NF-κB p65, and increased TNF-α and IL-6; CTRP3 transgenic mice show opposite effects; SIRT1 activator (resveratrol) rescues KO organoids and SIRT1 inhibitor (Ex-527) attenuates Tg organoid protection.","method":"CTRP3 KO and transgenic mice; DSS-induced colitis model; intestinal organoids; resveratrol and Ex-527 pharmacological modulation; Western blot for SIRT1/NF-κB; cytokine measurement; histology","journal":"Cellular and molecular gastroenterology and hepatology","confidence":"High","confidence_rationale":"Tier 2 / Strong — dual genetic model with organoid mechanistic follow-up and pharmacological SIRT1 pathway dissection, replicated in human IBD tissue","pmids":["36592863"],"is_preprint":false},{"year":2022,"finding":"CTRP3 alleviates pathological cardiac hypertrophy and mitochondrial dysfunction by activating mitochondrial unfolded protein response (UPRmt) through the SIRT1/ATF5 axis; ATF5 knockout prevents CTRP3 cardioprotection; SIRT1 knockout blocks CTRP3's protective effects; ATF5 may be regulated by SIRT1 downstream of CTRP3.","method":"CTRP3 KO and lentivirus-overexpressing mice; TAC cardiac hypertrophy model; neonatal rat cardiomyocytes with siRNA/overexpression; Western blot for UPRmt markers; mitochondrial function assays; cardiac function measurements","journal":"Cell death discovery","confidence":"High","confidence_rationale":"Tier 2 / Strong — genetic KO and overexpression with ATF5 KO epistasis and SIRT1 KO epistasis establishing SIRT1/ATF5 as a defined downstream axis","pmids":["38278820"],"is_preprint":false},{"year":2019,"finding":"CTRP3 attenuates high-fat diet-induced spermatogenic impairment through the SIRT1/ER stress pathway; recombinant globular CTRP3 reduces endoplasmic reticulum stress and activates SIRT1 in testes; germ cell-specific SIRT1 knockout abolishes CTRP3 protection in vivo and in vitro.","method":"HFD mouse model; recombinant globular CTRP3 infusion; germ cell-specific SIRT1 knockout; ER stress markers by Western blot; sperm count/motility/viability assays; SIRT1 inhibitor in human sperm","journal":"Clinical science (London, England : 1979)","confidence":"High","confidence_rationale":"Tier 2 / Strong — genetic loss-of-function (SIRT1 cKO) confirms CTRP3-SIRT1-ER stress axis, replicated in vitro and with human sperm","pmids":["29572383"],"is_preprint":false},{"year":2022,"finding":"CTRP3 physically interacts with LAMP1 and exerts anti-inflammatory effects in psoriatic keratinocytes by blocking STAT3 phosphorylation via LAMP1; Co-IP confirmed the CTRP3-LAMP1 interaction, and LAMP1-mediated STAT3 inhibition was demonstrated in vitro.","method":"Co-immunoprecipitation for CTRP3-LAMP1 interaction; STAT3 phosphorylation assay; imiquimod-induced psoriasis mouse model; GLP-1 receptor agonist (exendin-4) treatment; topical CTRP3 application","journal":"The Journal of investigative dermatology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP for physical interaction plus signaling (STAT3) mechanistic follow-up in cell culture, single lab","pmids":["34687744"],"is_preprint":false},{"year":2022,"finding":"CTRP3 alleviates myocardial ischemia/reperfusion injury through activation of the LAMP1/JIP2/JNK signaling pathway; Co-IP identified physical interactions between CTRP3 and LAMP1, and between LAMP1 and JIP2; LAMP1 silencing worsened I/R injury and suppressed JIP2 and JNK; JNK inhibitor (SP600125) reversed CTRP3 overexpression-mediated protection.","method":"Co-immunoprecipitation (CTRP3-LAMP1-JIP2 interaction); CTRP3 overexpression/knockdown in mouse I/R model; LAMP1 siRNA; JNK inhibitor SP600125; Western blot; TUNEL assay; infarct size measurement","journal":"International immunopharmacology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP for protein-protein interactions plus pharmacological and siRNA pathway dissection, single lab","pmids":["35278832"],"is_preprint":false},{"year":2018,"finding":"CTRP3 overexpression in cardiomyocytes protects against sepsis-induced myocardial dysfunction by activating AMPKα signaling and blunting NF-κB-mediated inflammation; CTRP3 overexpression increases AMPKα phosphorylation and decreases phospho-NF-κB p65 and IκBα.","method":"Intramyocardial CTRP3 injection in LPS-induced sepsis mouse model; Western blot for AMPKα, NF-κB p65, IκBα; TUNEL assay; cardiac function measurement","journal":"Molecular and cellular endocrinology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — in vivo gene delivery with defined signaling readouts, single lab","pmids":["29655602"],"is_preprint":false},{"year":2018,"finding":"CTRP3 overexpression in C1QTNF3 transgenic mice reduces hepatic triglyceride accumulation in response to chronic alcohol consumption (6-week model) by increasing hepatic fatty acid oxidation (increased oxygen consumption in the presence of fatty acids in isolated hepatocytes); this effect was not seen in a short-term NIAAA model.","method":"CTRP3 transgenic mice; chronic and NIAAA ALD models; hepatic triglyceride measurement; oxygen consumption rate in isolated primary hepatocytes","journal":"American journal of physiology. Endocrinology and metabolism","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — transgenic model with primary hepatocyte OCR mechanistic follow-up, single lab","pmids":["29763374"],"is_preprint":false},{"year":2021,"finding":"C1QTNF3 is primarily expressed in fibroblasts (not adipocytes or macrophages) in adipose tissue and promotes macrophage chemotaxis and M1-like polarization via ERK and Akt pathway activation; neutralizing antibody against C1QTNF3 inhibited macrophage accumulation in tumor-associated inguinal adipose tissue in vivo.","method":"C1QTNF3 expression analysis in adipose cell fractions; recombinant C1QTNF3 treatment of M1/M2 macrophages; chemotaxis assay; ERK and Akt Western blot; nitric oxide production; Seahorse metabolic assay; neutralizing antibody in vivo","journal":"Frontiers in immunology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — in vitro macrophage functional assays with signaling readouts and in vivo antibody-blocking experiment, single lab","pmids":["35720277"],"is_preprint":false},{"year":2014,"finding":"GLP-1 receptor agonist Exendin-4 increases CTRP3 mRNA and protein expression in 3T3-L1 adipocytes via the PKA signaling pathway; this effect is blocked by GLP-1 receptor antagonist (Exendin-fragment 9-39) and PKA inhibitor H89.","method":"3T3-L1 adipocyte culture; Exendin-4 treatment; GLP-1 receptor antagonist (Ex-9); PKA inhibitor H89; qPCR and Western blot for CTRP3","journal":"Journal of endocrinological investigation","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — dual pharmacological blockade (receptor antagonist + pathway inhibitor) identifying PKA as the upstream regulator, single lab","pmids":["25149084"],"is_preprint":false},{"year":2018,"finding":"CTRP3 is expressed in ovarian granulosa cells and oocytes, is upregulated by gonadotropin, downregulated by excess androgen, and promotes follicle growth by activating AKT/mTOR/p70S6K/4EBP1 signaling, increasing CCND2 expression, and reducing caspase-3 cleavage; intrabursal administration of CTRP3 antibody delayed gonadotropin-induced antral follicle development in vivo.","method":"qPCR and Western blot for C1qtnf3 in ovary; in vitro follicle/granulosa cell culture with recombinant C1QTNF3; AKT/mTOR/p70S6K/4EBP1 Western blot; CASP3/7 activity assay; intrabursal antibody injection in vivo; ovarian explant culture","journal":"Reproduction (Cambridge, England)","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — in vitro signaling analysis plus in vivo antibody-blocking experiment, single lab","pmids":["29438034"],"is_preprint":false},{"year":2019,"finding":"CTRP3 deficiency delays endochondral fracture healing in mice, resulting in abnormal mineral distribution and a nonunion-like state with decreased osteoclast number; CTRP3 transgenic mice show accelerated callus remodeling; gene expression profiling reveals broad impact on osteoblast/osteoclast lineage commitment.","method":"CTRP3 KO and transgenic mice; femoral fracture model; micro-CT; histology; TRAP staining for osteoclasts; gene expression profiling","journal":"Journal of orthopaedic research","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — dual genetic model (KO and Tg) with histological and molecular phenotyping, single lab","pmids":["31808575"],"is_preprint":false},{"year":2020,"finding":"CTRP3 ameliorates cerulein-induced severe acute pancreatitis by activating SIRT1, which suppresses NF-κB p65 phosphorylation and p53 acetylation; CTRP3 overexpression attenuated pathological lesions, inflammatory mediator release, and acinar cell apoptosis in SAP mice.","method":"Cerulein/LPS-induced SAP mouse model; CTRP3 overexpression; Western blot for SIRT1, phospho-NF-κB p65, acetylated p53; histology; ELISA for inflammatory mediators","journal":"Bioscience reports","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — in vivo overexpression model with defined SIRT1/NF-κB/p53 pathway readouts, single lab","pmids":["32219332"],"is_preprint":false},{"year":2017,"finding":"CTRP3 (cartonectin) is detectable in human cerebrospinal fluid with a mean CSF/serum ratio of ~110 × 10⁻³, demonstrating blood-brain barrier permeability; fatty acids (but not glucose) differentially modulate CTRP3 mRNA expression in 3T3-L1 adipocytes in vitro.","method":"ELISA measurement of paired CSF/serum samples (n=270); oral glucose/lipid tolerance test (n=100 each); 3T3-L1 adipocyte stimulation with glucose, sex hormones, and fatty acids; qPCR for CTRP3 mRNA","journal":"European journal of clinical investigation","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct biochemical measurement of CSF/serum distribution in large cohort plus in vitro regulation experiments, single lab","pmids":["27930815"],"is_preprint":false},{"year":2020,"finding":"CTRP3 activates the AMPK/SIRT1-PGC-1α pathway to protect mitochondrial biogenesis and function in hippocampal neurons; PGC-1α silencing partially abolishes CTRP3's mitochondrial protective function after OGD/R treatment.","method":"OGD/R hippocampal neuronal cell model; CTRP3 overexpression; PGC-1α siRNA; AMPK/SIRT1/PGC-1α pathway Western blot; mitochondrial function assays","journal":"Neurochemical research","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — genetic knockdown of downstream effector (PGC-1α) with multiple pathway readouts, single lab","pmids":["33098065"],"is_preprint":false},{"year":2021,"finding":"CTRP3 promotes TNF-α-induced apoptosis and barrier dysfunction in salivary gland ductal epithelial cells by enhancing TNFR1 expression, suppressing c-FLIP, and increasing recruitment of FADD with RIP1 and caspase-8 (complex II pathway); Co-IP confirmed CTRP3 interaction with these components.","method":"Human SMG tissue culture and SMG-C6 cells; flow cytometry for apoptosis; Co-immunoprecipitation for FADD/RIP1/caspase-8; transepithelial resistance and paracellular tracer flux; Western blot for TNFR1, c-FLIP, cleaved caspase-3","journal":"Cellular signalling","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP for complex formation plus functional apoptosis/permeability readouts, single lab","pmids":["33991612"],"is_preprint":false},{"year":2022,"finding":"FOXO4 directly binds the CTRP3 promoter and transcriptionally represses CTRP3 expression in retinal pericytes under high glucose conditions; FOXO4 upregulation in HG reduces CTRP3, which modulates the Nrf2/NF-κB signaling pathway; FOXO4 re-upregulation reverses CTRP3-mediated protection.","method":"JASPAR bioinformatics; ChIP assay; luciferase reporter assay for FOXO4-CTRP3 promoter interaction; FOXO4 and CTRP3 siRNA in retinal pericytes; Western blot for Nrf2/NF-κB; CCK-8; TUNEL; oxidative stress markers","journal":"Bioengineered","confidence":"Medium","confidence_rationale":"Tier 1 / Moderate — ChIP and luciferase assay confirm direct transcription factor binding to CTRP3 promoter, with functional epistasis, single lab","pmids":["35196182"],"is_preprint":false}],"current_model":"CTRP3 is a secreted adipokine that circulates as trimers and hetero-oligomers, lowers hepatic glucose output by suppressing gluconeogenesis and activating Akt, reduces hepatic lipid accumulation by downregulating triglyceride synthesis enzymes, and exerts anti-inflammatory and cytoprotective effects across multiple tissues by activating AMPK, SIRT1, and Akt/mTOR signaling while suppressing NF-κB and Smad3; it signals through cell-surface LAMP1 (a confirmed binding partner), suppresses Th17 differentiation via AdipoR2, and modulates mitochondrial biogenesis via the AMPK/SIRT1-PGC-1α axis, while also playing context-dependent roles in bone, cartilage, reproductive, and vascular biology."},"narrative":{"mechanistic_narrative":"C1QTNF3 (CTRP3/cartducin/cartonectin) is a secreted adipokine that circulates as trimers and alternatively spliced hetero-oligomers, the latter association protecting the longer isoform from proteolytic cleavage [PMID:20952387, PMID:16213490]. It functions broadly as a metabolic and anti-inflammatory cytoprotective factor: in liver it lowers glucose output by activating Akt and suppressing gluconeogenic gene expression independently of insulin [PMID:20952387], and it limits hepatic steatosis by downregulating triglyceride-synthesis enzymes (GPAT, AGPAT, DGAT) and promoting fatty acid oxidation [PMID:23744740, PMID:29763374]. Across cardiac, intestinal, pancreatic, reproductive, and neuronal tissues, CTRP3 confers protection chiefly through an AMPK/SIRT1–PGC-1α axis that drives mitochondrial biogenesis and the mitochondrial unfolded protein response via SIRT1/ATF5, while SIRT1 also restrains NF-κB inflammatory signaling [PMID:27793739, PMID:36592863, PMID:38278820, PMID:29572383, PMID:33098065]. In fibrotic and hypertrophic settings it activates AMPK and Akt and blocks TGF-β1–driven Smad3 phosphorylation and Smad3–p300 interaction [PMID:26138247]. Genetic loss-of-function establishes CTRP3 as a negative regulator of autoimmune and inflammatory disease, increasing severity of collagen-induced arthritis and colitis and augmenting Th17 differentiation, the latter acting through AdipoR2 to lower Rorc and Stat3 [PMID:24269820, PMID:34925309, PMID:36592863]. CTRP3 binds cell-surface LAMP1, a confirmed receptor identified by ligand-receptor capture and Co-IP, which transduces anti-inflammatory STAT3 suppression in keratinocytes and a LAMP1/JIP2/JNK cardioprotective signal [PMID:27727322, PMID:34687744, PMID:35278832]. Its actions are context-dependent and not uniformly protective: CTRP3 exacerbates tendinopathy by driving chondrogenic differentiation of tendon progenitors via Akt and promotes macrophage chemotaxis and M1 polarization in adipose tissue [PMID:34797714, PMID:35720277]. Notably, genetic deletion has minimal impact on whole-body glucose metabolism, contrasting with gain-of-function studies and revealing route- and model-dependent effects [PMID:26670485, PMID:26997632].","teleology":[{"year":2005,"claim":"Established the first functional readout for the secreted protein by showing it assembles into trimers and acts as an anti-inflammatory factor on monocytes.","evidence":"Baculovirus-expressed CTRP3 trimer characterization with cytokine ELISA and NF-κB reporter in monocytic cells","pmids":["16213490"],"confidence":"Medium","gaps":["No receptor identified","NF-κB suppression inferred from reporter, not endogenous pathway","No in vivo confirmation"]},{"year":2007,"claim":"Defined an early mitogenic role and its MAPK basis, showing CTRP3 drives endothelial proliferation and migration through ERK1/2 and p38.","evidence":"Recombinant CTRP3 on endothelial cells with U0126 and SB203580 inhibitor dissection","pmids":["17534697"],"confidence":"Medium","gaps":["No receptor linking CTRP3 to MAPK activation","Single cell line","Physiological relevance to vasculature untested"]},{"year":2010,"claim":"Identified the metabolic core function — insulin-independent suppression of hepatic gluconeogenesis via Akt — and the isoform biology of circulating CTRP3.","evidence":"In vivo recombinant administration in ob/ob mice with hepatocyte gluconeogenic gene analysis; biochemical isoform hetero-oligomerization and protease protection","pmids":["20952387"],"confidence":"High","gaps":["Receptor mediating hepatic Akt activation unknown","Mechanism linking oligomer state to function unclear"]},{"year":2013,"claim":"Extended the hepatic role from glucose to lipid handling, showing CTRP3 reduces steatosis by suppressing triglyceride-synthesis enzymes.","evidence":"Transgenic overexpression on high-fat diet plus recombinant treatment of H4IIE hepatocytes with lipogenic enzyme qPCR","pmids":["23744740"],"confidence":"High","gaps":["Signaling pathway controlling lipogenic enzyme downregulation not defined","Receptor not addressed"]},{"year":2013,"claim":"Provided genetic loss-of-function proof that CTRP3 is a negative regulator of autoimmune arthritis.","evidence":"C1qtnf3 knockout mice in collagen-induced arthritis with histology, autoantibody, and cytokine readouts","pmids":["24269820"],"confidence":"High","gaps":["Cellular target of the anti-inflammatory effect not identified","No mechanistic pathway in this model"]},{"year":2015,"claim":"Resolved the anti-fibrotic mechanism, placing CTRP3 upstream of TGF-β1/Smad3 signaling via AMPK and Akt.","evidence":"Adenoviral CTRP3 in post-MI rats with cardiac fibroblast Co-IP for Smad3-p300 and AMPK inhibitor AraA","pmids":["26138247"],"confidence":"High","gaps":["How CTRP3 activates AMPK upstream not defined","Receptor not identified"]},{"year":2015,"claim":"Defined CTRP3 as a brake on osteoclastogenesis through the AMPK–c-Fos–NFATc1 axis, linking it to bone homeostasis.","evidence":"Recombinant CTRP3 on bone marrow macrophages with signaling Western blot and calvarial bone in vivo model","pmids":["26103094"],"confidence":"High","gaps":["Receptor coupling to AMPK in osteoclast precursors unknown"]},{"year":2015,"claim":"Challenged the gain-of-function metabolic model by showing genetic deletion has minimal effect on glucose metabolism, revealing model-dependence.","evidence":"Ctrp3-KO mice with hyperinsulinemic-euglycemic clamp and liver phenotyping","pmids":["26670485"],"confidence":"High","gaps":["Reasons for discrepancy with recombinant/transgenic studies unresolved","Possible compensation by paralogs not tested"]},{"year":2016,"claim":"Identified the first candidate cell-surface receptors (LAMP1 and LIMP II) for CTRP3, addressing the long-standing receptor gap.","evidence":"LRC-TriCEPS ligand-receptor capture with confirmatory Co-IP and antibody blocking on hepatoma cells","pmids":["27727322"],"confidence":"Medium","gaps":["LAMP1 as a signaling receptor not demonstrated here","LIMP II association not functionally validated","Single lab, novel technology"]},{"year":2016,"claim":"Established the AMPK/SIRT1–PGC-1α axis as the mechanism by which CTRP3 promotes mitochondrial biogenesis.","evidence":"Globular CTRP3 on ventricular myocytes with AMPK/Sirt1 inhibitors, PGC-1α siRNA, and TEM/OCR/mtDNA readouts","pmids":["27793739"],"confidence":"High","gaps":["Receptor upstream of AMPK not identified","Generalizability across cell types established only later"]},{"year":2017,"claim":"Refined cardioprotective signaling by placing AMPKα downstream of a cAMP-EPAC-MEK cascade and demonstrating SIRT1 dependence against drug-induced injury.","evidence":"AAV CTRP3 in diabetic and doxorubicin-treated rodent hearts with AMPKα and Sirt1 genetic/pharmacological loss-of-function","pmids":["28258411","29061338"],"confidence":"High","gaps":["How CTRP3 engages cAMP generation at the membrane unknown","Receptor link to cAMP-EPAC-MEK not established"]},{"year":2021,"claim":"Identified AdipoR2 as the receptor for CTRP3's suppression of Th17 differentiation, providing a defined receptor-to-transcription-factor pathway.","evidence":"C1qtnf3-KO mice and EAE model with AdipoR1/R2 antagonist dissection and Rorc/Stat3 qPCR","pmids":["34925309"],"confidence":"High","gaps":["Direct AdipoR2-CTRP3 binding not shown biochemically","Relationship between AdipoR2 and LAMP1 signaling unclear"]},{"year":2022,"claim":"Demonstrated LAMP1 functions as a signaling receptor, transducing CTRP3 anti-inflammatory STAT3 suppression and a cardioprotective JIP2/JNK signal.","evidence":"Co-IP of CTRP3-LAMP1 and LAMP1-JIP2 with STAT3 and JNK pathway dissection in keratinocyte and cardiac I/R models","pmids":["34687744","35278832"],"confidence":"Medium","gaps":["LAMP1 as canonical lysosomal protein acting as surface receptor mechanistically unusual and not fully resolved","Single Co-IP-based validation per study"]},{"year":2022,"claim":"Generalized the SIRT1 mechanism across inflammatory tissues and extended it to the mitochondrial UPR via SIRT1/ATF5 in cardiac hypertrophy.","evidence":"Dual KO/transgenic colitis and TAC models with organoid and ATF5/SIRT1 epistasis and pharmacological SIRT1 modulation","pmids":["36592863","38278820"],"confidence":"High","gaps":["Receptor coupling CTRP3 to SIRT1 induction not defined","Tissue-specific selectivity of effects unexplained"]},{"year":2022,"claim":"Revealed context-dependent and detrimental roles, with CTRP3 driving chondrogenic tendon degeneration and adipose macrophage recruitment.","evidence":"Gain/loss-of-function and neutralizing antibody mouse models for tendinopathy and tumor-associated adipose tissue with Akt/ERK pathway analysis","pmids":["34797714","35720277"],"confidence":"High","gaps":["Why CTRP3 is protective in some tissues but pathogenic in others not mechanistically reconciled","Receptor mediating pro-pathogenic Akt activation unknown"]},{"year":2022,"claim":"Mapped transcriptional control of CTRP3, showing FOXO4 directly represses its promoter under high glucose.","evidence":"ChIP and luciferase reporter for FOXO4 binding plus siRNA epistasis on Nrf2/NF-κB in retinal pericytes","pmids":["35196182"],"confidence":"Medium","gaps":["Other transcriptional regulators in non-pericyte tissues not addressed","Single lab"]},{"year":null,"claim":"How CTRP3's distinct receptors (LAMP1, AdipoR2, LIMP II) coordinate to produce its divergent tissue-specific and sometimes opposing outcomes remains unresolved.","evidence":"","pmids":[],"confidence":"Medium","gaps":["No unified receptor-to-effector model integrating LAMP1, AdipoR2, and the AMPK/SIRT1 axis","Structural basis of CTRP3 receptor binding undetermined","Determinants of protective versus pathogenic signaling unknown"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0048018","term_label":"receptor ligand activity","supporting_discovery_ids":[0,14,21,28]},{"term_id":"GO:0098772","term_label":"molecular function regulator activity","supporting_discovery_ids":[9,13,25]}],"localization":[{"term_id":"GO:0005576","term_label":"extracellular region","supporting_discovery_ids":[1,2,22,37]}],"pathway":[{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[0,9,12,25]},{"term_id":"R-HSA-1430728","term_label":"Metabolism","supporting_discovery_ids":[0,3,31]},{"term_id":"R-HSA-168256","term_label":"Immune System","supporting_discovery_ids":[8,21,25]},{"term_id":"R-HSA-1852241","term_label":"Organelle biogenesis and maintenance","supporting_discovery_ids":[12,26,38]}],"complexes":[],"partners":["LAMP1","SCARB2","ADIPOR2","JIP2"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"Q9BXJ4","full_name":"Complement C1q tumor necrosis factor-related protein 3","aliases":["Collagenous repeat-containing sequence 26 kDa protein","CORS26","Secretory protein CORS26"],"length_aa":246,"mass_kda":27.0,"function":"","subcellular_location":"Secreted","url":"https://www.uniprot.org/uniprotkb/Q9BXJ4/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/C1QTNF3","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/C1QTNF3","total_profiled":1310},"omim":[{"mim_id":"621480","title":"OTOLIN 1; OTOL1","url":"https://www.omim.org/entry/621480"},{"mim_id":"612045","title":"C1q- AND TUMOR NECROSIS FACTOR-RELATED PROTEIN 3; C1QTNF3","url":"https://www.omim.org/entry/612045"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Approved","locations":[{"location":"Golgi apparatus","reliability":"Approved"}],"tissue_specificity":"Tissue enhanced","tissue_distribution":"Detected in many","driving_tissues":[{"tissue":"esophagus","ntpm":31.2},{"tissue":"salivary gland","ntpm":49.0}],"url":"https://www.proteinatlas.org/search/C1QTNF3"},"hgnc":{"alias_symbol":["CTRP3","Cors","Corcs","2310005P21Rik","Cors-26"],"prev_symbol":[]},"alphafold":{"accession":"Q9BXJ4","domains":[{"cath_id":"2.60.120.40","chopping":"125-193_211-245","consensus_level":"high","plddt":96.8279,"start":125,"end":245}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q9BXJ4","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q9BXJ4-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q9BXJ4-F1-predicted_aligned_error_v6.png","plddt_mean":79.25},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=C1QTNF3","jax_strain_url":"https://www.jax.org/strain/search?query=C1QTNF3"},"sequence":{"accession":"Q9BXJ4","fasta_url":"https://rest.uniprot.org/uniprotkb/Q9BXJ4.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q9BXJ4/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q9BXJ4"}},"corpus_meta":[{"pmid":"20952387","id":"PMC_20952387","title":"C1q/TNF-related protein-3 (CTRP3), a novel adipokine that regulates hepatic glucose output.","date":"2010","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/20952387","citation_count":219,"is_preprint":false},{"pmid":"28258411","id":"PMC_28258411","title":"CTRP3 attenuates cardiac dysfunction, inflammation, oxidative stress and cell death in diabetic cardiomyopathy in rats.","date":"2017","source":"Diabetologia","url":"https://pubmed.ncbi.nlm.nih.gov/28258411","citation_count":146,"is_preprint":false},{"pmid":"29061338","id":"PMC_29061338","title":"CTRP3 protected against doxorubicin-induced cardiac dysfunction, inflammation and cell death via activation of Sirt1.","date":"2017","source":"Journal of molecular and cellular cardiology","url":"https://pubmed.ncbi.nlm.nih.gov/29061338","citation_count":141,"is_preprint":false},{"pmid":"23744740","id":"PMC_23744740","title":"CTRP3 attenuates diet-induced hepatic steatosis by regulating triglyceride metabolism.","date":"2013","source":"American journal of physiology. Gastrointestinal and liver physiology","url":"https://pubmed.ncbi.nlm.nih.gov/23744740","citation_count":112,"is_preprint":false},{"pmid":"16213490","id":"PMC_16213490","title":"The adiponectin paralog CORS-26 has anti-inflammatory properties and is produced by human monocytic cells.","date":"2005","source":"FEBS letters","url":"https://pubmed.ncbi.nlm.nih.gov/16213490","citation_count":89,"is_preprint":false},{"pmid":"26138247","id":"PMC_26138247","title":"CTRP3 attenuates post-infarct cardiac fibrosis by targeting Smad3 activation and inhibiting myofibroblast differentiation.","date":"2015","source":"Journal of molecular medicine (Berlin, Germany)","url":"https://pubmed.ncbi.nlm.nih.gov/26138247","citation_count":82,"is_preprint":false},{"pmid":"21351204","id":"PMC_21351204","title":"C1q/TNF-related protein-3 (CTRP-3) is secreted by visceral adipose tissue and exerts antiinflammatory and antifibrotic effects in primary human colonic fibroblasts.","date":"2011","source":"Inflammatory bowel diseases","url":"https://pubmed.ncbi.nlm.nih.gov/21351204","citation_count":81,"is_preprint":false},{"pmid":"22837306","id":"PMC_22837306","title":"C1q/TNF-related protein-3 (CTRP-3) and pigment epithelium-derived factor (PEDF) concentrations in patients with type 2 diabetes and metabolic syndrome.","date":"2012","source":"Diabetes","url":"https://pubmed.ncbi.nlm.nih.gov/22837306","citation_count":81,"is_preprint":false},{"pmid":"23409033","id":"PMC_23409033","title":"Implication of progranulin and C1q/TNF-related protein-3 (CTRP3) on inflammation and atherosclerosis in subjects with or without metabolic syndrome.","date":"2013","source":"PloS one","url":"https://pubmed.ncbi.nlm.nih.gov/23409033","citation_count":80,"is_preprint":false},{"pmid":"28640446","id":"PMC_28640446","title":"C1q/TNF-Related Protein 3 (CTRP3) Function and Regulation.","date":"2017","source":"Comprehensive Physiology","url":"https://pubmed.ncbi.nlm.nih.gov/28640446","citation_count":74,"is_preprint":false},{"pmid":"17534697","id":"PMC_17534697","title":"CTRP3/cartducin promotes proliferation and migration of endothelial cells.","date":"2007","source":"Molecular and cellular biochemistry","url":"https://pubmed.ncbi.nlm.nih.gov/17534697","citation_count":66,"is_preprint":false},{"pmid":"26222183","id":"PMC_26222183","title":"Lower Circulating C1q/TNF-Related Protein-3 (CTRP3) Levels Are Associated with Obesity: A Cross-Sectional Study.","date":"2015","source":"PloS one","url":"https://pubmed.ncbi.nlm.nih.gov/26222183","citation_count":64,"is_preprint":false},{"pmid":"24269820","id":"PMC_24269820","title":"CTRP3 plays an important role in the development of collagen-induced arthritis in mice.","date":"2013","source":"Biochemical and biophysical research communications","url":"https://pubmed.ncbi.nlm.nih.gov/24269820","citation_count":60,"is_preprint":false},{"pmid":"33516048","id":"PMC_33516048","title":"Up-regulating lncRNA OIP5-AS1 protects neuron injury against cerebral hypoxia-ischemia induced inflammation and oxidative stress in microglia/macrophage through activating CTRP3 via sponging miR-186-5p.","date":"2021","source":"International immunopharmacology","url":"https://pubmed.ncbi.nlm.nih.gov/33516048","citation_count":60,"is_preprint":false},{"pmid":"25878729","id":"PMC_25878729","title":"Serum C1q/TNF-related protein-3 (CTRP3) levels are decreased in obesity and hypertension and are negatively correlated with parameters of insulin resistance.","date":"2015","source":"Diabetology & metabolic syndrome","url":"https://pubmed.ncbi.nlm.nih.gov/25878729","citation_count":59,"is_preprint":false},{"pmid":"19955001","id":"PMC_19955001","title":"Effects of the new adiponectin paralogous protein CTRP-3 and of LPS on cytokine release from monocytes of patients with type 2 diabetes mellitus.","date":"2009","source":"Cytokine","url":"https://pubmed.ncbi.nlm.nih.gov/19955001","citation_count":59,"is_preprint":false},{"pmid":"21570207","id":"PMC_21570207","title":"Anal canal cancer: management of inguinal nodes and benefit of prophylactic inguinal irradiation (CORS-03 Study).","date":"2011","source":"International journal of radiation oncology, biology, physics","url":"https://pubmed.ncbi.nlm.nih.gov/21570207","citation_count":57,"is_preprint":false},{"pmid":"27743997","id":"PMC_27743997","title":"A brief glimpse at CTRP3 and CTRP9 in lipid metabolism and cardiovascular protection.","date":"2016","source":"Progress in lipid research","url":"https://pubmed.ncbi.nlm.nih.gov/27743997","citation_count":56,"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":56,"is_preprint":false},{"pmid":"24417980","id":"PMC_24417980","title":"Implications of C1q/TNF-related protein-3 (CTRP-3) and progranulin in patients with acute coronary syndrome and stable angina pectoris.","date":"2014","source":"Cardiovascular diabetology","url":"https://pubmed.ncbi.nlm.nih.gov/24417980","citation_count":53,"is_preprint":false},{"pmid":"30887395","id":"PMC_30887395","title":"CTRP3 Alleviates Ox-LDL-Induced Inflammatory Response and Endothelial Dysfunction in Mouse Aortic Endothelial Cells by Activating the PI3K/Akt/eNOS Pathway.","date":"2019","source":"Inflammation","url":"https://pubmed.ncbi.nlm.nih.gov/30887395","citation_count":51,"is_preprint":false},{"pmid":"25409499","id":"PMC_25409499","title":"Low serum cartonectin/CTRP3 concentrations in newly diagnosed type 2 diabetes mellitus: in vivo regulation of cartonectin by glucose.","date":"2014","source":"PloS one","url":"https://pubmed.ncbi.nlm.nih.gov/25409499","citation_count":48,"is_preprint":false},{"pmid":"24996172","id":"PMC_24996172","title":"C1q/TNF-related protein-3 (CTRP-3) attenuates lipopolysaccharide (LPS)-induced systemic inflammation and adipose tissue Erk-1/-2 phosphorylation in mice in vivo.","date":"2014","source":"Biochemical and biophysical research communications","url":"https://pubmed.ncbi.nlm.nih.gov/24996172","citation_count":48,"is_preprint":false},{"pmid":"24152681","id":"PMC_24152681","title":"Metformin increases the novel adipokine cartonectin/CTRP3 in women with polycystic ovary syndrome.","date":"2013","source":"The Journal of clinical endocrinology and metabolism","url":"https://pubmed.ncbi.nlm.nih.gov/24152681","citation_count":47,"is_preprint":false},{"pmid":"26670485","id":"PMC_26670485","title":"CTRP3 deficiency reduces liver size and alters IL-6 and TGFβ levels in obese mice.","date":"2015","source":"American journal of physiology. Endocrinology and metabolism","url":"https://pubmed.ncbi.nlm.nih.gov/26670485","citation_count":45,"is_preprint":false},{"pmid":"33098065","id":"PMC_33098065","title":"CTRP3 Activates the AMPK/SIRT1-PGC-1α Pathway to Protect Mitochondrial Biogenesis and Functions in Cerebral Ischemic Stroke.","date":"2020","source":"Neurochemical research","url":"https://pubmed.ncbi.nlm.nih.gov/33098065","citation_count":45,"is_preprint":false},{"pmid":"27793739","id":"PMC_27793739","title":"Globular CTRP3 promotes mitochondrial biogenesis in cardiomyocytes through AMPK/PGC-1α pathway.","date":"2016","source":"Biochimica et biophysica acta. General subjects","url":"https://pubmed.ncbi.nlm.nih.gov/27793739","citation_count":45,"is_preprint":false},{"pmid":"18421280","id":"PMC_18421280","title":"Effects of the new C1q/TNF-related protein (CTRP-3) \"cartonectin\" on the adipocytic secretion of adipokines.","date":"2008","source":"Obesity (Silver Spring, Md.)","url":"https://pubmed.ncbi.nlm.nih.gov/18421280","citation_count":45,"is_preprint":false},{"pmid":"26997632","id":"PMC_26997632","title":"Immunomodulatory roles of CTRP3 in endotoxemia and metabolic stress.","date":"2016","source":"Physiological reports","url":"https://pubmed.ncbi.nlm.nih.gov/26997632","citation_count":43,"is_preprint":false},{"pmid":"28632765","id":"PMC_28632765","title":"CTRP3 is a novel biomarker for diabetic retinopathy and inhibits HGHL-induced VCAM-1 expression in an AMPK-dependent manner.","date":"2017","source":"PloS one","url":"https://pubmed.ncbi.nlm.nih.gov/28632765","citation_count":43,"is_preprint":false},{"pmid":"29655602","id":"PMC_29655602","title":"Overexpression of CTRP3 protects against sepsis-induced myocardial dysfunction in mice.","date":"2018","source":"Molecular and cellular endocrinology","url":"https://pubmed.ncbi.nlm.nih.gov/29655602","citation_count":41,"is_preprint":false},{"pmid":"17311679","id":"PMC_17311679","title":"Plasma levels of leptin, omentin, collagenous repeat-containing sequence of 26-kDa protein (CORS-26) and adiponectin before and after oral glucose uptake in slim adults.","date":"2007","source":"Cardiovascular diabetology","url":"https://pubmed.ncbi.nlm.nih.gov/17311679","citation_count":41,"is_preprint":false},{"pmid":"23780948","id":"PMC_23780948","title":"Effects of a combined aerobic and resistance exercise program on C1q/TNF-related protein-3 (CTRP-3) and CTRP-5 levels.","date":"2013","source":"Diabetes care","url":"https://pubmed.ncbi.nlm.nih.gov/23780948","citation_count":39,"is_preprint":false},{"pmid":"26103094","id":"PMC_26103094","title":"CTRP3 acts as a negative regulator of osteoclastogenesis through AMPK-c-Fos-NFATc1 signaling in vitro and RANKL-induced calvarial bone destruction in vivo.","date":"2015","source":"Bone","url":"https://pubmed.ncbi.nlm.nih.gov/26103094","citation_count":37,"is_preprint":false},{"pmid":"30186439","id":"PMC_30186439","title":"Impact of weight cycling on CTRP3 expression, adipose tissue inflammation and insulin sensitivity in C57BL/6J mice.","date":"2018","source":"Experimental and therapeutic medicine","url":"https://pubmed.ncbi.nlm.nih.gov/30186439","citation_count":36,"is_preprint":false},{"pmid":"26073386","id":"PMC_26073386","title":"Plasma CTRP-3 concentrations in Chinese patients with obesity and type II diabetes negatively correlate with insulin resistance.","date":"2015","source":"Journal of clinical lipidology","url":"https://pubmed.ncbi.nlm.nih.gov/26073386","citation_count":36,"is_preprint":false},{"pmid":"19424626","id":"PMC_19424626","title":"Elevated expression of CTRP3/cartducin contributes to promotion of osteosarcoma cell proliferation.","date":"2009","source":"Oncology reports","url":"https://pubmed.ncbi.nlm.nih.gov/19424626","citation_count":34,"is_preprint":false},{"pmid":"31182031","id":"PMC_31182031","title":"C1q/TNF-related protein 3 (CTRP3) and 9 (CTRP9) concentrations are decreased in patients with heart failure and are associated with increased morbidity and mortality.","date":"2019","source":"BMC cardiovascular disorders","url":"https://pubmed.ncbi.nlm.nih.gov/31182031","citation_count":34,"is_preprint":false},{"pmid":"31629950","id":"PMC_31629950","title":"CTRP3 acts as a novel regulator in depressive-like behavior associated inflammation and apoptosis by meditating p38 and JNK MAPK signaling.","date":"2019","source":"Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie","url":"https://pubmed.ncbi.nlm.nih.gov/31629950","citation_count":32,"is_preprint":false},{"pmid":"34797714","id":"PMC_34797714","title":"CTRP3 exacerbates tendinopathy by dysregulating tendon stem cell differentiation and altering extracellular matrix composition.","date":"2021","source":"Science advances","url":"https://pubmed.ncbi.nlm.nih.gov/34797714","citation_count":31,"is_preprint":false},{"pmid":"27727322","id":"PMC_27727322","title":"Identification of Putative Receptors for the Novel Adipokine CTRP3 Using Ligand-Receptor Capture Technology.","date":"2016","source":"PloS one","url":"https://pubmed.ncbi.nlm.nih.gov/27727322","citation_count":31,"is_preprint":false},{"pmid":"19947921","id":"PMC_19947921","title":"CTRP3/cartducin is induced by transforming growth factor-beta1 and promotes vascular smooth muscle cell proliferation.","date":"2010","source":"Cell biology international","url":"https://pubmed.ncbi.nlm.nih.gov/19947921","citation_count":31,"is_preprint":false},{"pmid":"20619552","id":"PMC_20619552","title":"High-dose split-course radiation therapy for anal cancer: outcome analysis regarding the boost strategy (CORS-03 study).","date":"2010","source":"International journal of radiation oncology, biology, physics","url":"https://pubmed.ncbi.nlm.nih.gov/20619552","citation_count":31,"is_preprint":false},{"pmid":"31556307","id":"PMC_31556307","title":"CTRP3 inhibits high glucose-induced oxidative stress and apoptosis in retinal pigment epithelial cells.","date":"2019","source":"Artificial cells, nanomedicine, and biotechnology","url":"https://pubmed.ncbi.nlm.nih.gov/31556307","citation_count":30,"is_preprint":false},{"pmid":"22342437","id":"PMC_22342437","title":"The adiponectin paralog C1q/TNF-related protein 3 (CTRP3) stimulates testosterone production through the cAMP/PKA signaling pathway.","date":"2012","source":"Cytokine","url":"https://pubmed.ncbi.nlm.nih.gov/22342437","citation_count":30,"is_preprint":false},{"pmid":"25185846","id":"PMC_25185846","title":"CTRP3 improves the insulin sensitivity of 3T3-L1 adipocytes by inhibiting inflammation and ameliorating insulin signalling transduction.","date":"2014","source":"Endokrynologia Polska","url":"https://pubmed.ncbi.nlm.nih.gov/25185846","citation_count":30,"is_preprint":false},{"pmid":"27781167","id":"PMC_27781167","title":"Divergent relationship of circulating CTRP3 levels between obesity and gender: a cross-sectional study.","date":"2016","source":"PeerJ","url":"https://pubmed.ncbi.nlm.nih.gov/27781167","citation_count":29,"is_preprint":false},{"pmid":"29572383","id":"PMC_29572383","title":"CTRP3 attenuates high-fat diet-induced male reproductive dysfunction in mice.","date":"2018","source":"Clinical science (London, England : 1979)","url":"https://pubmed.ncbi.nlm.nih.gov/29572383","citation_count":28,"is_preprint":false},{"pmid":"14654242","id":"PMC_14654242","title":"Genomic organization, promoter, amino acid sequence, chromosomal localization, and expression of the human gene for CORS-26 (collagenous repeat-containing sequence of 26-kDa protein).","date":"2003","source":"Biochimica et biophysica acta","url":"https://pubmed.ncbi.nlm.nih.gov/14654242","citation_count":28,"is_preprint":false},{"pmid":"33343381","id":"PMC_33343381","title":"New Insights Into Implications of CTRP3 in Obesity, Metabolic Dysfunction, and Cardiovascular Diseases: Potential of Therapeutic Interventions.","date":"2020","source":"Frontiers in physiology","url":"https://pubmed.ncbi.nlm.nih.gov/33343381","citation_count":28,"is_preprint":false},{"pmid":"31009504","id":"PMC_31009504","title":"Serum levels of CTRP3 in diabetic nephropathy and its relationship with insulin resistance and kidney function.","date":"2019","source":"PloS one","url":"https://pubmed.ncbi.nlm.nih.gov/31009504","citation_count":26,"is_preprint":false},{"pmid":"25168658","id":"PMC_25168658","title":"CTRP3 modulates the expression and secretion of adipokines in 3T3-L1 adipocytes.","date":"2014","source":"Endocrine journal","url":"https://pubmed.ncbi.nlm.nih.gov/25168658","citation_count":25,"is_preprint":false},{"pmid":"12850274","id":"PMC_12850274","title":"Genomic organization, chromosomal localization and adipocytic expression of the murine gene for CORS-26 (collagenous repeat-containing sequence of 26 kDa protein).","date":"2003","source":"Biochimica et biophysica acta","url":"https://pubmed.ncbi.nlm.nih.gov/12850274","citation_count":25,"is_preprint":false},{"pmid":"26844631","id":"PMC_26844631","title":"CTRP3 promotes energy production by inducing mitochondrial ROS and up-expression of PGC-1α in vascular smooth muscle cells.","date":"2016","source":"Experimental cell research","url":"https://pubmed.ncbi.nlm.nih.gov/26844631","citation_count":25,"is_preprint":false},{"pmid":"30557342","id":"PMC_30557342","title":"Role of CTRP3, CTRP9 and MCP-1 for the evaluation of T2DM associated coronary artery disease in Egyptian postmenopausal females.","date":"2018","source":"PloS one","url":"https://pubmed.ncbi.nlm.nih.gov/30557342","citation_count":25,"is_preprint":false},{"pmid":"23195780","id":"PMC_23195780","title":"Role of brachytherapy in the boost management of anal carcinoma with node involvement (CORS-03 study).","date":"2012","source":"International journal of radiation oncology, biology, physics","url":"https://pubmed.ncbi.nlm.nih.gov/23195780","citation_count":25,"is_preprint":false},{"pmid":"25177707","id":"PMC_25177707","title":"Expression of CTRP3, a novel adipokine, in rats at different pathogenic stages of type 2 diabetes mellitus and the impacts of GLP-1 receptor agonist on it.","date":"2014","source":"Journal of diabetes research","url":"https://pubmed.ncbi.nlm.nih.gov/25177707","citation_count":24,"is_preprint":false},{"pmid":"32432773","id":"PMC_32432773","title":"Neuroprotective effect of CTRP3 overexpression against sevoflurane anesthesia-induced cognitive dysfunction in aged rats through activating AMPK/SIRT1 and PI3K/AKT signaling pathways.","date":"2020","source":"European review for medical and pharmacological sciences","url":"https://pubmed.ncbi.nlm.nih.gov/32432773","citation_count":24,"is_preprint":false},{"pmid":"26218761","id":"PMC_26218761","title":"CTRP3 Stimulates Proliferation and Anti-Apoptosis of Prostate Cells through PKC Signaling Pathways.","date":"2015","source":"PloS one","url":"https://pubmed.ncbi.nlm.nih.gov/26218761","citation_count":23,"is_preprint":false},{"pmid":"30362596","id":"PMC_30362596","title":"CTRP3 inhibits high glucose-induced human glomerular mesangial cell dysfunction.","date":"2018","source":"Journal of cellular biochemistry","url":"https://pubmed.ncbi.nlm.nih.gov/30362596","citation_count":23,"is_preprint":false},{"pmid":"21371032","id":"PMC_21371032","title":"Functional analysis of CTRP3/cartducin in Meckel's cartilage and developing condylar cartilage in the fetal mouse mandible.","date":"2011","source":"Journal of anatomy","url":"https://pubmed.ncbi.nlm.nih.gov/21371032","citation_count":23,"is_preprint":false},{"pmid":"24966928","id":"PMC_24966928","title":"Effect of CTRP3 on activation of adventitial fibroblasts induced by TGF-β1 from rat aorta in vitro.","date":"2014","source":"International journal of clinical and experimental pathology","url":"https://pubmed.ncbi.nlm.nih.gov/24966928","citation_count":23,"is_preprint":false},{"pmid":"15157741","id":"PMC_15157741","title":"Role of specificity protein-1, PPARgamma, and pituitary protein transcription factor-1 in transcriptional regulation of the murine CORS-26 promoter.","date":"2004","source":"Biochimica et biophysica acta","url":"https://pubmed.ncbi.nlm.nih.gov/15157741","citation_count":22,"is_preprint":false},{"pmid":"33424438","id":"PMC_33424438","title":"Association of Plasma C1q/TNF-Related Protein 3 (CTRP3) in Patients with Atrial Fibrillation.","date":"2020","source":"Mediators of inflammation","url":"https://pubmed.ncbi.nlm.nih.gov/33424438","citation_count":21,"is_preprint":false},{"pmid":"11094272","id":"PMC_11094272","title":"Phosphorylation of CorS and CorR, regulatory proteins that modulate production of the phytotoxin coronatine in Pseudomonas syringae.","date":"2000","source":"FEMS microbiology letters","url":"https://pubmed.ncbi.nlm.nih.gov/11094272","citation_count":21,"is_preprint":false},{"pmid":"31615574","id":"PMC_31615574","title":"Muscle regulates mTOR dependent axonal local translation in motor neurons via CTRP3 secretion: implications for a neuromuscular disorder, spinal muscular atrophy.","date":"2019","source":"Acta neuropathologica communications","url":"https://pubmed.ncbi.nlm.nih.gov/31615574","citation_count":20,"is_preprint":false},{"pmid":"27930815","id":"PMC_27930815","title":"CTRP-3 is permeable to the blood-brain barrier and is not regulated by glucose or lipids in vivo.","date":"2017","source":"European journal of clinical investigation","url":"https://pubmed.ncbi.nlm.nih.gov/27930815","citation_count":20,"is_preprint":false},{"pmid":"32219332","id":"PMC_32219332","title":"CTRP3 ameliorates cerulein-induced severe acute pancreatitis in mice via SIRT1/NF-κB/p53 axis.","date":"2020","source":"Bioscience reports","url":"https://pubmed.ncbi.nlm.nih.gov/32219332","citation_count":19,"is_preprint":false},{"pmid":"25149084","id":"PMC_25149084","title":"GLP-1 receptor agonist increases the expression of CTRP3, a novel adipokine, in 3T3-L1 adipocytes through PKA signal pathway.","date":"2014","source":"Journal of endocrinological investigation","url":"https://pubmed.ncbi.nlm.nih.gov/25149084","citation_count":19,"is_preprint":false},{"pmid":"38278820","id":"PMC_38278820","title":"CTRP3 alleviates mitochondrial dysfunction and oxidative stress injury in pathological cardiac hypertrophy by activating UPRmt via the SIRT1/ATF5 axis.","date":"2024","source":"Cell death discovery","url":"https://pubmed.ncbi.nlm.nih.gov/38278820","citation_count":18,"is_preprint":false},{"pmid":"34925309","id":"PMC_34925309","title":"The CTRP3-AdipoR2 Axis Regulates the Development of Experimental Autoimmune Encephalomyelitis by Suppressing Th17 Cell Differentiation.","date":"2021","source":"Frontiers in immunology","url":"https://pubmed.ncbi.nlm.nih.gov/34925309","citation_count":17,"is_preprint":false},{"pmid":"34516334","id":"PMC_34516334","title":"MicroRNA miR-495 regulates the development of Hepatocellular Carcinoma by targeting C1q/tumor necrosis factor-related protein-3 (CTRP3).","date":"2021","source":"Bioengineered","url":"https://pubmed.ncbi.nlm.nih.gov/34516334","citation_count":17,"is_preprint":false},{"pmid":"35720277","id":"PMC_35720277","title":"C1QTNF3 is Upregulated During Subcutaneous Adipose Tissue Remodeling and Stimulates Macrophage Chemotaxis and M1-Like Polarization.","date":"2022","source":"Frontiers in immunology","url":"https://pubmed.ncbi.nlm.nih.gov/35720277","citation_count":16,"is_preprint":false},{"pmid":"35196182","id":"PMC_35196182","title":"C1q/tumor necrosis factor-related protein-3 (CTRP3) activated by forkhead box O4 (FOXO4) down-regulation protects retinal pericytes against high glucose-induced oxidative damage through nuclear factor erythroid 2-related factor 2 (Nrf2)/Nuclear factor-kappaB (NF-κB) signaling.","date":"2022","source":"Bioengineered","url":"https://pubmed.ncbi.nlm.nih.gov/35196182","citation_count":16,"is_preprint":false},{"pmid":"29113741","id":"PMC_29113741","title":"Low serum CTRP3 levels are associated with nonalcoholic fatty liver disease in patients with type 2 diabetes mellitus.","date":"2017","source":"Cytokine","url":"https://pubmed.ncbi.nlm.nih.gov/29113741","citation_count":16,"is_preprint":false},{"pmid":"36311798","id":"PMC_36311798","title":"African swine fever virus infection activates inflammatory responses through downregulation of the anti-inflammatory molecule C1QTNF3.","date":"2022","source":"Frontiers in immunology","url":"https://pubmed.ncbi.nlm.nih.gov/36311798","citation_count":15,"is_preprint":false},{"pmid":"29763374","id":"PMC_29763374","title":"Transgenic overexpression of CTRP3 prevents alcohol-induced hepatic triglyceride accumulation.","date":"2018","source":"American journal of physiology. Endocrinology and metabolism","url":"https://pubmed.ncbi.nlm.nih.gov/29763374","citation_count":15,"is_preprint":false},{"pmid":"32211094","id":"PMC_32211094","title":"MiR-144 affects proliferation and apoptosis of high glucose-induced AC16 cardiomyocytes by regulating CTRP3/JNK signaling.","date":"2020","source":"International journal of clinical and experimental pathology","url":"https://pubmed.ncbi.nlm.nih.gov/32211094","citation_count":15,"is_preprint":false},{"pmid":"29272006","id":"PMC_29272006","title":"Expression of C1q/TNF-related protein-3 (CTRP3) in serum of patients with gestational diabetes mellitus and its relationship with insulin resistance.","date":"2017","source":"European review for medical and pharmacological sciences","url":"https://pubmed.ncbi.nlm.nih.gov/29272006","citation_count":15,"is_preprint":false},{"pmid":"33336518","id":"PMC_33336518","title":"Plasma miR-409-3p promotes acute cerebral infarction via suppressing CTRP3.","date":"2020","source":"The Kaohsiung journal of medical sciences","url":"https://pubmed.ncbi.nlm.nih.gov/33336518","citation_count":15,"is_preprint":false},{"pmid":"28754090","id":"PMC_28754090","title":"Association of serum C1q/TNF-related protein-3 (CTRP-3) in patients with coronary artery disease.","date":"2017","source":"BMC cardiovascular disorders","url":"https://pubmed.ncbi.nlm.nih.gov/28754090","citation_count":15,"is_preprint":false},{"pmid":"15289568","id":"PMC_15289568","title":"Topological and deletion analysis of CorS, a Pseudomonas syringae sensor kinase.","date":"2004","source":"Microbiology (Reading, England)","url":"https://pubmed.ncbi.nlm.nih.gov/15289568","citation_count":14,"is_preprint":false},{"pmid":"31428552","id":"PMC_31428552","title":"CTRP3 Protects against High Glucose-Induced Cell Injury in Human Umbilical Vein Endothelial Cells.","date":"2019","source":"Analytical cellular pathology (Amsterdam)","url":"https://pubmed.ncbi.nlm.nih.gov/31428552","citation_count":14,"is_preprint":false},{"pmid":"31808575","id":"PMC_31808575","title":"CTRP3 Regulates Endochondral Ossification and Bone Remodeling During Fracture Healing.","date":"2019","source":"Journal of orthopaedic research : official publication of the Orthopaedic Research Society","url":"https://pubmed.ncbi.nlm.nih.gov/31808575","citation_count":13,"is_preprint":false},{"pmid":"34687744","id":"PMC_34687744","title":"Adipocyte-Derived CTRP3 Exhibits Anti-Inflammatory Effects via LAMP1-STAT3 Axis in Psoriasis.","date":"2021","source":"The Journal of investigative dermatology","url":"https://pubmed.ncbi.nlm.nih.gov/34687744","citation_count":13,"is_preprint":false},{"pmid":"36103112","id":"PMC_36103112","title":"Astragaloside IV Regulates Insulin Resistance and Inflammatory Response of Adipocytes via Modulating CTRP3 and PI3K/AKT Signaling.","date":"2022","source":"Diabetes therapy : research, treatment and education of diabetes and related disorders","url":"https://pubmed.ncbi.nlm.nih.gov/36103112","citation_count":13,"is_preprint":false},{"pmid":"29438034","id":"PMC_29438034","title":"C1QTNF3 in the murine ovary and its function in folliculogenesis.","date":"2018","source":"Reproduction (Cambridge, England)","url":"https://pubmed.ncbi.nlm.nih.gov/29438034","citation_count":12,"is_preprint":false},{"pmid":"35278832","id":"PMC_35278832","title":"CTRP3 alleviates myocardial ischemia/reperfusion injury in mice through activating LAMP1/JIP2/JNK pathway.","date":"2022","source":"International immunopharmacology","url":"https://pubmed.ncbi.nlm.nih.gov/35278832","citation_count":12,"is_preprint":false},{"pmid":"33180446","id":"PMC_33180446","title":"Protective Role of CTRP3 and CTRP9 in the Development of Gestational Diabetes Mellitus.","date":"2020","source":"Clinical laboratory","url":"https://pubmed.ncbi.nlm.nih.gov/33180446","citation_count":12,"is_preprint":false},{"pmid":"32949652","id":"PMC_32949652","title":"Circulating levels of CTRP3 in patients with type 2 diabetes mellitus compared to controls: A systematic review and meta-analysis.","date":"2020","source":"Diabetes research and clinical practice","url":"https://pubmed.ncbi.nlm.nih.gov/32949652","citation_count":12,"is_preprint":false},{"pmid":"29305845","id":"PMC_29305845","title":"Serum CTRP3 level is inversely associated with nonalcoholic fatty liver disease: A 3-y longitudinal study.","date":"2018","source":"Clinica chimica acta; international journal of clinical chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/29305845","citation_count":12,"is_preprint":false},{"pmid":"33142914","id":"PMC_33142914","title":"Downregulation of CTRP-3 by Weight Loss In Vivo and by Bile Acids and Incretins in Adipocytes In Vitro.","date":"2020","source":"International journal of molecular sciences","url":"https://pubmed.ncbi.nlm.nih.gov/33142914","citation_count":12,"is_preprint":false},{"pmid":"34601891","id":"PMC_34601891","title":"CTRP3 protects against uric acid-induced endothelial injury by inhibiting inflammation and oxidase stress in rats.","date":"2021","source":"Experimental biology and medicine (Maywood, N.J.)","url":"https://pubmed.ncbi.nlm.nih.gov/34601891","citation_count":11,"is_preprint":false},{"pmid":"32821754","id":"PMC_32821754","title":"Increased mRNA Expression of CTRP3 and CTRP9 in Adipose Tissue from Obese Women: Is it Linked to Obesity-Related Parameters and mRNA Expression of Inflammatory Cytokines?","date":"2020","source":"Reports of biochemistry & molecular biology","url":"https://pubmed.ncbi.nlm.nih.gov/32821754","citation_count":11,"is_preprint":false},{"pmid":"36592863","id":"PMC_36592863","title":"Adipokine C1q/Tumor Necrosis Factor- Related Protein 3 (CTRP3) Attenuates Intestinal Inflammation Via Sirtuin 1/NF-κB Signaling.","date":"2022","source":"Cellular and molecular gastroenterology and hepatology","url":"https://pubmed.ncbi.nlm.nih.gov/36592863","citation_count":10,"is_preprint":false},{"pmid":"33991612","id":"PMC_33991612","title":"CTRP3 promotes TNF-α-induced apoptosis and barrier dysfunction in salivary epithelial cells.","date":"2021","source":"Cellular signalling","url":"https://pubmed.ncbi.nlm.nih.gov/33991612","citation_count":10,"is_preprint":false},{"pmid":"34440913","id":"PMC_34440913","title":"Anti-Inflammatory Effects of C1q/Tumor Necrosis Factor-Related Protein 3 (CTRP3) in Endothelial Cells.","date":"2021","source":"Cells","url":"https://pubmed.ncbi.nlm.nih.gov/34440913","citation_count":10,"is_preprint":false},{"pmid":"33501881","id":"PMC_33501881","title":"CTRP3 protects hippocampal neurons from oxygen-glucose deprivation-induced injury through the AMPK/Nrf2/ARE pathway.","date":"2021","source":"Human & experimental toxicology","url":"https://pubmed.ncbi.nlm.nih.gov/33501881","citation_count":10,"is_preprint":false},{"pmid":"31571966","id":"PMC_31571966","title":"Serum CTRP3 Levels In Obese Children: A Potential Protective Adipokine Of Obesity, Insulin Sensitivity And Pancreatic β Cell Function.","date":"2019","source":"Diabetes, metabolic syndrome and obesity : targets and therapy","url":"https://pubmed.ncbi.nlm.nih.gov/31571966","citation_count":10,"is_preprint":false},{"pmid":"34655390","id":"PMC_34655390","title":"Administration of rTMS Alleviates Stroke-Induced Cognitive Deficits by Modulating miR-409-3p/CTRP3/AMPK/Sirt1 Axis.","date":"2021","source":"Journal of molecular neuroscience : MN","url":"https://pubmed.ncbi.nlm.nih.gov/34655390","citation_count":10,"is_preprint":false}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":58942,"output_tokens":11031,"usd":0.171146,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":21839,"output_tokens":4939,"usd":0.116335,"stage2_stop_reason":"end_turn"},"total_usd":0.287481,"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\": 2010,\n      \"finding\": \"CTRP3 lowers blood glucose in normal and ob/ob mice by activating the Akt signaling pathway in liver and suppressing hepatic gluconeogenic gene expression; it acts directly and independently of insulin to reduce glucose output in cultured hepatocytes by suppressing gluconeogenic enzyme expression.\",\n      \"method\": \"Recombinant protein administration in vivo (mouse), Akt pathway analysis by Western blot, gluconeogenic gene expression in primary hepatocytes\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — in vivo recombinant protein administration with pathway (Akt) and gene expression readouts replicated in primary hepatocyte cell culture; multiple orthogonal methods in a single rigorous study\",\n      \"pmids\": [\"20952387\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"In humans, alternative splicing generates two circulating CTRP3 isoforms that form hetero-oligomers; this association does not require interdisulfide bond formation and protects the longer isoform from proteolytic cleavage.\",\n      \"method\": \"Biochemical characterization of recombinant human CTRP3 isoforms; hetero-oligomer formation assay; protease protection experiments\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct biochemical characterization of isoform oligomerization and proteolytic protection, single study, two orthogonal methods\",\n      \"pmids\": [\"20952387\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2005,\n      \"finding\": \"Baculovirus-produced CTRP3 (CORS-26) forms stable trimers in insect cell supernatants and reduces IL-6 and TNF-α secretion from LPS-treated monocytic cells, likely through suppression of NF-κB signaling.\",\n      \"method\": \"Baculovirus expression system, SDS-PAGE/immunoblot for trimer characterization; ELISA for cytokine measurement; NF-κB reporter assay\",\n      \"journal\": \"FEBS letters\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct biochemical demonstration of trimer formation plus functional anti-inflammatory assay, single lab, two orthogonal methods\",\n      \"pmids\": [\"16213490\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"Transgenic CTRP3 overexpression protects mice from high-fat diet-induced hepatic steatosis by reducing hepatic triglyceride content through decreased expression of triglyceride synthesis enzymes (GPAT, AGPAT, DGAT); recombinant CTRP3 treatment also directly reduces fatty acid synthesis and neutral lipid accumulation in cultured hepatocytes.\",\n      \"method\": \"Transgenic mouse model, hepatic triglyceride measurement, qPCR for lipogenic enzymes, recombinant protein treatment of H4IIE hepatocytes\",\n      \"journal\": \"American journal of physiology. Gastrointestinal and liver physiology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — genetic overexpression model validated with acute recombinant protein administration and cell culture; multiple orthogonal methods\",\n      \"pmids\": [\"23744740\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2007,\n      \"finding\": \"CTRP3/cartducin promotes proliferation and migration of endothelial cells in a dose-dependent manner through activation of ERK1/2 and p38 MAPK; MEK1/2 inhibitor (U0126) blocks both proliferation and migration, while p38 inhibitor (SB203580) blocks only proliferation.\",\n      \"method\": \"Recombinant CTRP3 treatment of MSS31 endothelial cells; cell proliferation and migration assays; kinase inhibitor studies; Western blot for ERK1/2 and p38 phosphorylation\",\n      \"journal\": \"Molecular and cellular biochemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — pharmacological pathway dissection with two inhibitors and functional readouts (proliferation and migration), single lab\",\n      \"pmids\": [\"17534697\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"TGF-β1 (but not bFGF or PDGF-BB) induces CTRP3/cartducin expression in vascular smooth muscle cells; exogenous CTRP3/cartducin promotes VSMC proliferation (but not migration) via ERK1/2 and p38 MAPK signaling pathways.\",\n      \"method\": \"Recombinant CTRP3 treatment of p53LMAC01 VSMCs; TGF-β1 stimulation; cell proliferation and migration assays; kinase inhibitor studies\",\n      \"journal\": \"Cell biology international\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — defined upstream inducer (TGF-β1), pathway inhibitor studies in cell culture, single lab, two orthogonal readouts\",\n      \"pmids\": [\"19947921\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"Recombinant CTRP3 promotes osteosarcoma cell (NHOS and LM8) proliferation (but not migration) through activation of the ERK1/2 signaling pathway; MEK1/2 inhibitor U0126 blocks this effect.\",\n      \"method\": \"Recombinant CTRP3 treatment of osteosarcoma cell lines; proliferation and migration assays; Western blot for ERK1/2 phosphorylation; MEK inhibitor U0126\",\n      \"journal\": \"Oncology reports\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — pharmacological pathway validation, multiple cell lines, single lab\",\n      \"pmids\": [\"19424626\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"CTRP3 stimulates testosterone production in TM3 mouse Leydig cells in a dose-dependent manner by upregulating StAR protein and P450scc expression through the cAMP/PKA signaling pathway; PKA inhibitor H89 blocks this effect.\",\n      \"method\": \"Recombinant CTRP3 treatment of TM3 cells; testosterone ELISA; cAMP measurement; CREB phosphorylation by Western blot; PKA inhibitor H89\",\n      \"journal\": \"Cytokine\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — pharmacological pathway dissection with PKA inhibitor plus cAMP/CREB readouts, single lab\",\n      \"pmids\": [\"22342437\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"C1qtnf3 knockout mice show increased incidence and severity of collagen-induced arthritis, higher anti-type II collagen antibody levels, and elevated pro-inflammatory cytokine mRNA, establishing CTRP3 as a negative regulator of autoimmune arthritis.\",\n      \"method\": \"C1qtnf3 knockout mouse model; collagen-induced arthritis; histopathology; ELISA; qPCR for cytokines\",\n      \"journal\": \"Biochemical and biophysical research communications\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — genetic loss-of-function with defined disease phenotype and molecular readouts, multiple orthogonal assessments\",\n      \"pmids\": [\"24269820\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"CTRP3 attenuates cardiac fibrosis post-myocardial infarction by inhibiting myofibroblast differentiation and ECM production; mechanistically, CTRP3 activates AMPK and Akt in cardiac fibroblasts and inhibits TGF-β1-induced Smad3 phosphorylation, nuclear translocation, and interaction with p300; AMPK inhibitor AraA abolishes the anti-fibrotic effect.\",\n      \"method\": \"Adenovirus-mediated CTRP3 overexpression in rat post-MI model; adult rat cardiac fibroblast culture; AMPK inhibitor AraA; Western blot for Smad3 phosphorylation; Co-IP for Smad3-p300 interaction; siRNA knockdown\",\n      \"journal\": \"Journal of molecular medicine (Berlin, Germany)\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — in vivo and in vitro models with genetic gain/loss-of-function, pharmacological inhibition, and biochemical pathway dissection (Smad3 phosphorylation, Co-IP)\",\n      \"pmids\": [\"26138247\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"CTRP3 protects against diabetic cardiomyopathy by activating AMPKα via the cAMP-EPAC-MEK pathway; AMPKα deficiency abolishes CTRP3's protective effects against high-glucose-induced oxidative stress, inflammation, and apoptosis.\",\n      \"method\": \"Adeno-associated virus CTRP3 overexpression in STZ-diabetic rats; H9c2 cell culture; AMPKα knockout/inhibition; pathway inhibitors for cAMP/EPAC/MEK; Western blot; TUNEL assay\",\n      \"journal\": \"Diabetologia\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — in vivo (AAV overexpression) and in vitro models with genetic and pharmacological dissection of upstream signaling (cAMP-EPAC-MEK-AMPKα)\",\n      \"pmids\": [\"28258411\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"CTRP3 protects against doxorubicin-induced cardiac injury via activation of Sirt1; specific Sirt1 inhibition or siRNA silencing abolishes CTRP3's protective effects against DOX-induced inflammation and apoptosis.\",\n      \"method\": \"AAV CTRP3 cardiac overexpression in DOX-treated mice; H9C2 cell culture; Sirt1 inhibitor; Sirt1 siRNA; Western blot; TUNEL assay\",\n      \"journal\": \"Journal of molecular and cellular cardiology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — in vivo and in vitro models with genetic (siRNA) and pharmacological (inhibitor) Sirt1 pathway validation\",\n      \"pmids\": [\"29061338\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"Globular CTRP3 promotes mitochondrial biogenesis in cardiomyocytes via the AMPK/PGC-1α pathway; CTRP3 increases AMPK phosphorylation, Sirtuin1 expression and activity, and downstream PGC-1α/NRF-1/TFAM/complex III/V; AMPK inhibitor AraA and Sirt1 inhibitor EX-527 attenuate these effects; PGC-1α siRNA blocks CTRP3-induced mitochondrial biogenesis.\",\n      \"method\": \"Recombinant globular CTRP3 treatment of neonatal rat ventricular myocytes; AMPK inhibitor AraA; Sirt1 inhibitor EX-527; PGC-1α siRNA; mitochondrial morphology by TEM; ATP measurement; OCR measurement; mtDNA copy number\",\n      \"journal\": \"Biochimica et biophysica acta. General subjects\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — multiple pharmacological and genetic (siRNA) pathway validations with orthogonal functional readouts (ATP, OCR, mtDNA, TEM)\",\n      \"pmids\": [\"27793739\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"CTRP3 acts as a negative regulator of RANKL-induced osteoclastogenesis through the AMPK-c-Fos-NFATc1 signaling axis; CTRP3 activates AMPK in bone marrow macrophages and inhibits RANKL-induced c-Fos and NFATc1 expression, F-actin formation, and bone resorption; CTRP3 also reduces osteoclast formation and bone destruction in mouse calvarial bone in vivo.\",\n      \"method\": \"Recombinant CTRP3 treatment of mouse bone marrow macrophages; co-culture osteoclastogenesis assay; Western blot for AMPK, c-Fos, NFATc1; calvarial bone injection model; micro-CT; histology\",\n      \"journal\": \"Bone\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — in vitro pathway dissection with multiple signaling targets plus in vivo calvarial model, orthogonal methods\",\n      \"pmids\": [\"26103094\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"Identification of LAMP1 (lysosomal-associated membrane protein 1) and LIMP II as putative receptors for CTRP3 on hepatoma cells using ligand-receptor glycocapture (LRC-TriCEPS) technology; Co-IP confirmed LAMP1-CTRP3 association; a polyclonal antibody blocking LAMP1 prevented CTRP3 binding to cells.\",\n      \"method\": \"LRC-TriCEPS ligand-receptor capture; Co-immunoprecipitation; FACS; antibody-blocking assay in H4IIE cells\",\n      \"journal\": \"PloS one\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — ligand-receptor capture with confirmatory Co-IP and antibody blocking, single lab, novel technology\",\n      \"pmids\": [\"27727322\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2004,\n      \"finding\": \"The transcription factors SP-1, PPARγ, and Pit-1 bind specifically to the murine CORS-26 (CTRP3) promoter; SP-1 exerts inhibitory (repressive) effects on CORS-26 transcriptional activation in an SP-3-independent manner.\",\n      \"method\": \"EMSA with nuclear extracts from 3T3-L1 adipocytes; supershift assay; competition experiments; mutated SP-1 binding site oligonucleotides; luciferase reporter gene assay\",\n      \"journal\": \"Biochimica et biophysica acta\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — EMSA with supershift and mutagenesis controls plus luciferase reporter, single lab\",\n      \"pmids\": [\"15157741\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"Recombinant CTRP3 attenuates LPS-induced systemic inflammation (serum IL-6 and MIP-2) and suppresses LPS-induced ERK-1/-2 phosphorylation in inguinal adipose tissue when administered intraperitoneally in mice; intravenous CTRP3 administration was not sufficient to produce these effects.\",\n      \"method\": \"Intraperitoneal and intravenous recombinant CTRP3 administration in C57BL/6N mice challenged with LPS; ELISA for serum cytokines; qPCR for adipose cytokine mRNA; Western blot for ERK-1/-2 phosphorylation\",\n      \"journal\": \"Biochemical and biophysical research communications\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — in vivo recombinant protein administration with route-dependent pharmacological comparison, single lab\",\n      \"pmids\": [\"24996172\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"CTRP3 promotes energy (ATP) production in vascular smooth muscle cells by increasing mitochondrial ROS production and upregulating PGC-1α and oxidative phosphorylation complexes; ROS scavenger N-acetyl-L-cysteine and OXPHOS uncoupler CCCP suppress CTRP3-induced ROS, PGC-1α, and ATP synthesis.\",\n      \"method\": \"Recombinant CTRP3 treatment of VSMCs; CTRP3 siRNA knockdown; PGC-1α siRNA; ATP assay; mitochondrial ROS measurement; Western blot for OXPHOS complexes; N-acetyl-L-cysteine and CCCP treatment\",\n      \"journal\": \"Experimental cell research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — gain and loss-of-function with pharmacological pathway inhibition, single lab, multiple readouts\",\n      \"pmids\": [\"26844631\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"CTRP3/cartducin is required for maintenance of the perichondrium and normal chondrocyte proliferation/differentiation in Meckel's cartilage and mandibular condylar cartilage; antisense oligodeoxynucleotide (AS-ODN) abrogation of CTRP3 in organ culture caused curvature deformation, loss of perichondrium, ectopic cartilage formation, reduced BrdU incorporation, and decreased aggrecan/collagen expression; these effects were partially rescued by recombinant CTRP3.\",\n      \"method\": \"In situ hybridization; antisense ODN organ culture system; BrdU incorporation; immunostaining; recombinant CTRP3 rescue experiment\",\n      \"journal\": \"Journal of anatomy\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — loss-of-function AS-ODN with rescue experiment in organ culture, in situ expression mapping, single lab\",\n      \"pmids\": [\"21371032\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"CTRP3-deficient mice on high-fat diet have markedly reduced liver sizes and decreased profibrotic TGFβ1 levels, but markedly increased circulating IL-6; loss of CTRP3 had minimal impact on whole body glucose metabolism or insulin sensitivity, contrary to expectation from gain-of-function studies.\",\n      \"method\": \"Genetic knockout mouse model (Ctrp3-KO); HFD feeding; hyperinsulinemic-euglycemic clamp; liver weight and histology; ELISA for TGFβ1 and IL-6; liver gene expression by qPCR\",\n      \"journal\": \"American journal of physiology. Endocrinology and metabolism\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — genetic KO with comprehensive metabolic phenotyping and biochemical measurements, multiple orthogonal methods\",\n      \"pmids\": [\"26670485\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"In a mouse model of endotoxemia or high-fat diet, genetic CTRP3 deficiency or transgenic overexpression did not significantly affect circulating IL-1β, IL-6, TNF-α, or MIP-2 induction by LPS, contrary to findings from recombinant CTRP3 protein administration; CTRP3 transgenic mice had elevated chemokines (CCL11, CXCL9, CXCL10, etc.) on low-fat diet but lower IL-5 and TNF-α on high-fat diet.\",\n      \"method\": \"CTRP3 knockout and transgenic mouse models; LPS challenge; multiplex serum cytokine profiling (71 cytokines); HFD metabolic challenge\",\n      \"journal\": \"Physiological reports\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — dual genetic model (KO and Tg) with comprehensive multiplex cytokine analysis, revealing context-dependent immunomodulation\",\n      \"pmids\": [\"26997632\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"CTRP3 suppresses Th17 cell differentiation but not Th1 differentiation via AdipoR2 (not AdipoR1); this suppression is associated with reduced Rorc and Stat3 expression; CTRP3-deficient mice show augmented Th17 cell populations and enhanced myelin oligodendrocyte glycoprotein-induced experimental autoimmune encephalomyelitis; CTRP3 inhibits IL-17 production from T cells by affecting both T cells and dendritic cells.\",\n      \"method\": \"C1qtnf3 knockout mice; Th17 and Th1 differentiation assays in vitro; AdipoR1/AdipoR2 receptor antagonist treatment; AdipoRon agonist; EAE mouse model; flow cytometry for Th17 populations; qPCR for Rorc and Stat3\",\n      \"journal\": \"Frontiers in immunology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — genetic KO model combined with pharmacological receptor-specific antagonist dissection and in vivo EAE model, multiple orthogonal methods\",\n      \"pmids\": [\"34925309\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"CTRP3 regulates mTOR-dependent axonal local protein translation in motor neurons via a muscle-to-neuron secretion mechanism; CTRP3 levels are reduced in SMA muscle secretome and serum; exogenous CTRP3 enhances axonal outgrowth and protein synthesis (including SMN) via the mTOR pathway.\",\n      \"method\": \"Quantitative proteomics with metabolic labeling of SMA muscle secretome; CTRP3 measurement in SMA mouse model tissue and serum; mTOR pathway analysis; axonal outgrowth assay; protein synthesis rate measurement in motor neurons\",\n      \"journal\": \"Acta neuropathologica communications\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — mass spectrometry secretome profiling plus functional validation in neurons with pathway analysis, single lab\",\n      \"pmids\": [\"31615574\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"CTRP3 exacerbates tendinopathy by promoting abnormal differentiation of tendon stem/progenitor cells toward chondrogenic lineage (ectopic chondrification) through Akt signaling; CTRP3 knockdown suppresses tendinopathy pathogenesis, and a neutralizing antibody against CTRP3 ameliorates overuse-induced Achilles and rotator cuff tendinopathy in mice.\",\n      \"method\": \"CTRP3 overexpression and knockdown mouse models; neutralizing antibody treatment; transcriptomic analysis; Akt pathway analysis; histology (proteoglycan/collagen fiber analysis); micro-CT\",\n      \"journal\": \"Science advances\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — gain-of-function, loss-of-function, and antibody-blockade models combined with transcriptomics and pathway analysis, published in peer-reviewed journal\",\n      \"pmids\": [\"34797714\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"CTRP3 exerts anti-inflammatory effects in endothelial cells by inhibiting LPS-induced expression of IL-6, TNF-α, VCAM-1, and ICAM-1 and blocking monocyte adhesion to endothelial monolayers; CTRP3 mRNA is expressed in primary endothelial cells and aorta, and is transiently upregulated by LPS in murine endothelial cells.\",\n      \"method\": \"qPCR tissue expression analysis; MyEND cell culture; LPS stimulation; CTRP3 treatment; monocyte adhesion assay; ELISA/qPCR for adhesion molecules and cytokines\",\n      \"journal\": \"Cells\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — cell-based functional assays with direct treatment, multiple cytokine/adhesion molecule readouts, single lab\",\n      \"pmids\": [\"34440913\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"CTRP3 attenuates intestinal inflammation via a SIRT1/NF-κB signaling axis; CTRP3-KO mice develop more severe colitis with decreased SIRT1, increased phosphorylated/acetylated NF-κB p65, and increased TNF-α and IL-6; CTRP3 transgenic mice show opposite effects; SIRT1 activator (resveratrol) rescues KO organoids and SIRT1 inhibitor (Ex-527) attenuates Tg organoid protection.\",\n      \"method\": \"CTRP3 KO and transgenic mice; DSS-induced colitis model; intestinal organoids; resveratrol and Ex-527 pharmacological modulation; Western blot for SIRT1/NF-κB; cytokine measurement; histology\",\n      \"journal\": \"Cellular and molecular gastroenterology and hepatology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — dual genetic model with organoid mechanistic follow-up and pharmacological SIRT1 pathway dissection, replicated in human IBD tissue\",\n      \"pmids\": [\"36592863\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"CTRP3 alleviates pathological cardiac hypertrophy and mitochondrial dysfunction by activating mitochondrial unfolded protein response (UPRmt) through the SIRT1/ATF5 axis; ATF5 knockout prevents CTRP3 cardioprotection; SIRT1 knockout blocks CTRP3's protective effects; ATF5 may be regulated by SIRT1 downstream of CTRP3.\",\n      \"method\": \"CTRP3 KO and lentivirus-overexpressing mice; TAC cardiac hypertrophy model; neonatal rat cardiomyocytes with siRNA/overexpression; Western blot for UPRmt markers; mitochondrial function assays; cardiac function measurements\",\n      \"journal\": \"Cell death discovery\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — genetic KO and overexpression with ATF5 KO epistasis and SIRT1 KO epistasis establishing SIRT1/ATF5 as a defined downstream axis\",\n      \"pmids\": [\"38278820\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"CTRP3 attenuates high-fat diet-induced spermatogenic impairment through the SIRT1/ER stress pathway; recombinant globular CTRP3 reduces endoplasmic reticulum stress and activates SIRT1 in testes; germ cell-specific SIRT1 knockout abolishes CTRP3 protection in vivo and in vitro.\",\n      \"method\": \"HFD mouse model; recombinant globular CTRP3 infusion; germ cell-specific SIRT1 knockout; ER stress markers by Western blot; sperm count/motility/viability assays; SIRT1 inhibitor in human sperm\",\n      \"journal\": \"Clinical science (London, England : 1979)\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — genetic loss-of-function (SIRT1 cKO) confirms CTRP3-SIRT1-ER stress axis, replicated in vitro and with human sperm\",\n      \"pmids\": [\"29572383\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"CTRP3 physically interacts with LAMP1 and exerts anti-inflammatory effects in psoriatic keratinocytes by blocking STAT3 phosphorylation via LAMP1; Co-IP confirmed the CTRP3-LAMP1 interaction, and LAMP1-mediated STAT3 inhibition was demonstrated in vitro.\",\n      \"method\": \"Co-immunoprecipitation for CTRP3-LAMP1 interaction; STAT3 phosphorylation assay; imiquimod-induced psoriasis mouse model; GLP-1 receptor agonist (exendin-4) treatment; topical CTRP3 application\",\n      \"journal\": \"The Journal of investigative dermatology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP for physical interaction plus signaling (STAT3) mechanistic follow-up in cell culture, single lab\",\n      \"pmids\": [\"34687744\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"CTRP3 alleviates myocardial ischemia/reperfusion injury through activation of the LAMP1/JIP2/JNK signaling pathway; Co-IP identified physical interactions between CTRP3 and LAMP1, and between LAMP1 and JIP2; LAMP1 silencing worsened I/R injury and suppressed JIP2 and JNK; JNK inhibitor (SP600125) reversed CTRP3 overexpression-mediated protection.\",\n      \"method\": \"Co-immunoprecipitation (CTRP3-LAMP1-JIP2 interaction); CTRP3 overexpression/knockdown in mouse I/R model; LAMP1 siRNA; JNK inhibitor SP600125; Western blot; TUNEL assay; infarct size measurement\",\n      \"journal\": \"International immunopharmacology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP for protein-protein interactions plus pharmacological and siRNA pathway dissection, single lab\",\n      \"pmids\": [\"35278832\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"CTRP3 overexpression in cardiomyocytes protects against sepsis-induced myocardial dysfunction by activating AMPKα signaling and blunting NF-κB-mediated inflammation; CTRP3 overexpression increases AMPKα phosphorylation and decreases phospho-NF-κB p65 and IκBα.\",\n      \"method\": \"Intramyocardial CTRP3 injection in LPS-induced sepsis mouse model; Western blot for AMPKα, NF-κB p65, IκBα; TUNEL assay; cardiac function measurement\",\n      \"journal\": \"Molecular and cellular endocrinology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — in vivo gene delivery with defined signaling readouts, single lab\",\n      \"pmids\": [\"29655602\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"CTRP3 overexpression in C1QTNF3 transgenic mice reduces hepatic triglyceride accumulation in response to chronic alcohol consumption (6-week model) by increasing hepatic fatty acid oxidation (increased oxygen consumption in the presence of fatty acids in isolated hepatocytes); this effect was not seen in a short-term NIAAA model.\",\n      \"method\": \"CTRP3 transgenic mice; chronic and NIAAA ALD models; hepatic triglyceride measurement; oxygen consumption rate in isolated primary hepatocytes\",\n      \"journal\": \"American journal of physiology. Endocrinology and metabolism\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — transgenic model with primary hepatocyte OCR mechanistic follow-up, single lab\",\n      \"pmids\": [\"29763374\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"C1QTNF3 is primarily expressed in fibroblasts (not adipocytes or macrophages) in adipose tissue and promotes macrophage chemotaxis and M1-like polarization via ERK and Akt pathway activation; neutralizing antibody against C1QTNF3 inhibited macrophage accumulation in tumor-associated inguinal adipose tissue in vivo.\",\n      \"method\": \"C1QTNF3 expression analysis in adipose cell fractions; recombinant C1QTNF3 treatment of M1/M2 macrophages; chemotaxis assay; ERK and Akt Western blot; nitric oxide production; Seahorse metabolic assay; neutralizing antibody in vivo\",\n      \"journal\": \"Frontiers in immunology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — in vitro macrophage functional assays with signaling readouts and in vivo antibody-blocking experiment, single lab\",\n      \"pmids\": [\"35720277\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"GLP-1 receptor agonist Exendin-4 increases CTRP3 mRNA and protein expression in 3T3-L1 adipocytes via the PKA signaling pathway; this effect is blocked by GLP-1 receptor antagonist (Exendin-fragment 9-39) and PKA inhibitor H89.\",\n      \"method\": \"3T3-L1 adipocyte culture; Exendin-4 treatment; GLP-1 receptor antagonist (Ex-9); PKA inhibitor H89; qPCR and Western blot for CTRP3\",\n      \"journal\": \"Journal of endocrinological investigation\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — dual pharmacological blockade (receptor antagonist + pathway inhibitor) identifying PKA as the upstream regulator, single lab\",\n      \"pmids\": [\"25149084\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"CTRP3 is expressed in ovarian granulosa cells and oocytes, is upregulated by gonadotropin, downregulated by excess androgen, and promotes follicle growth by activating AKT/mTOR/p70S6K/4EBP1 signaling, increasing CCND2 expression, and reducing caspase-3 cleavage; intrabursal administration of CTRP3 antibody delayed gonadotropin-induced antral follicle development in vivo.\",\n      \"method\": \"qPCR and Western blot for C1qtnf3 in ovary; in vitro follicle/granulosa cell culture with recombinant C1QTNF3; AKT/mTOR/p70S6K/4EBP1 Western blot; CASP3/7 activity assay; intrabursal antibody injection in vivo; ovarian explant culture\",\n      \"journal\": \"Reproduction (Cambridge, England)\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — in vitro signaling analysis plus in vivo antibody-blocking experiment, single lab\",\n      \"pmids\": [\"29438034\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"CTRP3 deficiency delays endochondral fracture healing in mice, resulting in abnormal mineral distribution and a nonunion-like state with decreased osteoclast number; CTRP3 transgenic mice show accelerated callus remodeling; gene expression profiling reveals broad impact on osteoblast/osteoclast lineage commitment.\",\n      \"method\": \"CTRP3 KO and transgenic mice; femoral fracture model; micro-CT; histology; TRAP staining for osteoclasts; gene expression profiling\",\n      \"journal\": \"Journal of orthopaedic research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — dual genetic model (KO and Tg) with histological and molecular phenotyping, single lab\",\n      \"pmids\": [\"31808575\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"CTRP3 ameliorates cerulein-induced severe acute pancreatitis by activating SIRT1, which suppresses NF-κB p65 phosphorylation and p53 acetylation; CTRP3 overexpression attenuated pathological lesions, inflammatory mediator release, and acinar cell apoptosis in SAP mice.\",\n      \"method\": \"Cerulein/LPS-induced SAP mouse model; CTRP3 overexpression; Western blot for SIRT1, phospho-NF-κB p65, acetylated p53; histology; ELISA for inflammatory mediators\",\n      \"journal\": \"Bioscience reports\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — in vivo overexpression model with defined SIRT1/NF-κB/p53 pathway readouts, single lab\",\n      \"pmids\": [\"32219332\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"CTRP3 (cartonectin) is detectable in human cerebrospinal fluid with a mean CSF/serum ratio of ~110 × 10⁻³, demonstrating blood-brain barrier permeability; fatty acids (but not glucose) differentially modulate CTRP3 mRNA expression in 3T3-L1 adipocytes in vitro.\",\n      \"method\": \"ELISA measurement of paired CSF/serum samples (n=270); oral glucose/lipid tolerance test (n=100 each); 3T3-L1 adipocyte stimulation with glucose, sex hormones, and fatty acids; qPCR for CTRP3 mRNA\",\n      \"journal\": \"European journal of clinical investigation\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct biochemical measurement of CSF/serum distribution in large cohort plus in vitro regulation experiments, single lab\",\n      \"pmids\": [\"27930815\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"CTRP3 activates the AMPK/SIRT1-PGC-1α pathway to protect mitochondrial biogenesis and function in hippocampal neurons; PGC-1α silencing partially abolishes CTRP3's mitochondrial protective function after OGD/R treatment.\",\n      \"method\": \"OGD/R hippocampal neuronal cell model; CTRP3 overexpression; PGC-1α siRNA; AMPK/SIRT1/PGC-1α pathway Western blot; mitochondrial function assays\",\n      \"journal\": \"Neurochemical research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — genetic knockdown of downstream effector (PGC-1α) with multiple pathway readouts, single lab\",\n      \"pmids\": [\"33098065\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"CTRP3 promotes TNF-α-induced apoptosis and barrier dysfunction in salivary gland ductal epithelial cells by enhancing TNFR1 expression, suppressing c-FLIP, and increasing recruitment of FADD with RIP1 and caspase-8 (complex II pathway); Co-IP confirmed CTRP3 interaction with these components.\",\n      \"method\": \"Human SMG tissue culture and SMG-C6 cells; flow cytometry for apoptosis; Co-immunoprecipitation for FADD/RIP1/caspase-8; transepithelial resistance and paracellular tracer flux; Western blot for TNFR1, c-FLIP, cleaved caspase-3\",\n      \"journal\": \"Cellular signalling\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP for complex formation plus functional apoptosis/permeability readouts, single lab\",\n      \"pmids\": [\"33991612\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"FOXO4 directly binds the CTRP3 promoter and transcriptionally represses CTRP3 expression in retinal pericytes under high glucose conditions; FOXO4 upregulation in HG reduces CTRP3, which modulates the Nrf2/NF-κB signaling pathway; FOXO4 re-upregulation reverses CTRP3-mediated protection.\",\n      \"method\": \"JASPAR bioinformatics; ChIP assay; luciferase reporter assay for FOXO4-CTRP3 promoter interaction; FOXO4 and CTRP3 siRNA in retinal pericytes; Western blot for Nrf2/NF-κB; CCK-8; TUNEL; oxidative stress markers\",\n      \"journal\": \"Bioengineered\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — ChIP and luciferase assay confirm direct transcription factor binding to CTRP3 promoter, with functional epistasis, single lab\",\n      \"pmids\": [\"35196182\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"CTRP3 is a secreted adipokine that circulates as trimers and hetero-oligomers, lowers hepatic glucose output by suppressing gluconeogenesis and activating Akt, reduces hepatic lipid accumulation by downregulating triglyceride synthesis enzymes, and exerts anti-inflammatory and cytoprotective effects across multiple tissues by activating AMPK, SIRT1, and Akt/mTOR signaling while suppressing NF-κB and Smad3; it signals through cell-surface LAMP1 (a confirmed binding partner), suppresses Th17 differentiation via AdipoR2, and modulates mitochondrial biogenesis via the AMPK/SIRT1-PGC-1α axis, while also playing context-dependent roles in bone, cartilage, reproductive, and vascular biology.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"C1QTNF3 (CTRP3/cartducin/cartonectin) is a secreted adipokine that circulates as trimers and alternatively spliced hetero-oligomers, the latter association protecting the longer isoform from proteolytic cleavage [#1, #2]. It functions broadly as a metabolic and anti-inflammatory cytoprotective factor: in liver it lowers glucose output by activating Akt and suppressing gluconeogenic gene expression independently of insulin [#0], and it limits hepatic steatosis by downregulating triglyceride-synthesis enzymes (GPAT, AGPAT, DGAT) and promoting fatty acid oxidation [#3, #31]. Across cardiac, intestinal, pancreatic, reproductive, and neuronal tissues, CTRP3 confers protection chiefly through an AMPK/SIRT1–PGC-1\\u03b1 axis that drives mitochondrial biogenesis and the mitochondrial unfolded protein response via SIRT1/ATF5, while SIRT1 also restrains NF-\\u03baB inflammatory signaling [#12, #25, #26, #27, #38]. In fibrotic and hypertrophic settings it activates AMPK and Akt and blocks TGF-\\u03b21\\u2013driven Smad3 phosphorylation and Smad3\\u2013p300 interaction [#9]. Genetic loss-of-function establishes CTRP3 as a negative regulator of autoimmune and inflammatory disease, increasing severity of collagen-induced arthritis and colitis and augmenting Th17 differentiation, the latter acting through AdipoR2 to lower Rorc and Stat3 [#8, #21, #25]. CTRP3 binds cell-surface LAMP1, a confirmed receptor identified by ligand-receptor capture and Co-IP, which transduces anti-inflammatory STAT3 suppression in keratinocytes and a LAMP1/JIP2/JNK cardioprotective signal [#14, #28, #29]. Its actions are context-dependent and not uniformly protective: CTRP3 exacerbates tendinopathy by driving chondrogenic differentiation of tendon progenitors via Akt and promotes macrophage chemotaxis and M1 polarization in adipose tissue [#23, #32]. Notably, genetic deletion has minimal impact on whole-body glucose metabolism, contrasting with gain-of-function studies and revealing route- and model-dependent effects [#19, #20].\",\n  \"teleology\": [\n    {\n      \"year\": 2005,\n      \"claim\": \"Established the first functional readout for the secreted protein by showing it assembles into trimers and acts as an anti-inflammatory factor on monocytes.\",\n      \"evidence\": \"Baculovirus-expressed CTRP3 trimer characterization with cytokine ELISA and NF-\\u03baB reporter in monocytic cells\",\n      \"pmids\": [\"16213490\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No receptor identified\", \"NF-\\u03baB suppression inferred from reporter, not endogenous pathway\", \"No in vivo confirmation\"]\n    },\n    {\n      \"year\": 2007,\n      \"claim\": \"Defined an early mitogenic role and its MAPK basis, showing CTRP3 drives endothelial proliferation and migration through ERK1/2 and p38.\",\n      \"evidence\": \"Recombinant CTRP3 on endothelial cells with U0126 and SB203580 inhibitor dissection\",\n      \"pmids\": [\"17534697\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No receptor linking CTRP3 to MAPK activation\", \"Single cell line\", \"Physiological relevance to vasculature untested\"]\n    },\n    {\n      \"year\": 2010,\n      \"claim\": \"Identified the metabolic core function — insulin-independent suppression of hepatic gluconeogenesis via Akt — and the isoform biology of circulating CTRP3.\",\n      \"evidence\": \"In vivo recombinant administration in ob/ob mice with hepatocyte gluconeogenic gene analysis; biochemical isoform hetero-oligomerization and protease protection\",\n      \"pmids\": [\"20952387\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Receptor mediating hepatic Akt activation unknown\", \"Mechanism linking oligomer state to function unclear\"]\n    },\n    {\n      \"year\": 2013,\n      \"claim\": \"Extended the hepatic role from glucose to lipid handling, showing CTRP3 reduces steatosis by suppressing triglyceride-synthesis enzymes.\",\n      \"evidence\": \"Transgenic overexpression on high-fat diet plus recombinant treatment of H4IIE hepatocytes with lipogenic enzyme qPCR\",\n      \"pmids\": [\"23744740\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Signaling pathway controlling lipogenic enzyme downregulation not defined\", \"Receptor not addressed\"]\n    },\n    {\n      \"year\": 2013,\n      \"claim\": \"Provided genetic loss-of-function proof that CTRP3 is a negative regulator of autoimmune arthritis.\",\n      \"evidence\": \"C1qtnf3 knockout mice in collagen-induced arthritis with histology, autoantibody, and cytokine readouts\",\n      \"pmids\": [\"24269820\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Cellular target of the anti-inflammatory effect not identified\", \"No mechanistic pathway in this model\"]\n    },\n    {\n      \"year\": 2015,\n      \"claim\": \"Resolved the anti-fibrotic mechanism, placing CTRP3 upstream of TGF-\\u03b21/Smad3 signaling via AMPK and Akt.\",\n      \"evidence\": \"Adenoviral CTRP3 in post-MI rats with cardiac fibroblast Co-IP for Smad3-p300 and AMPK inhibitor AraA\",\n      \"pmids\": [\"26138247\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"How CTRP3 activates AMPK upstream not defined\", \"Receptor not identified\"]\n    },\n    {\n      \"year\": 2015,\n      \"claim\": \"Defined CTRP3 as a brake on osteoclastogenesis through the AMPK–c-Fos–NFATc1 axis, linking it to bone homeostasis.\",\n      \"evidence\": \"Recombinant CTRP3 on bone marrow macrophages with signaling Western blot and calvarial bone in vivo model\",\n      \"pmids\": [\"26103094\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Receptor coupling to AMPK in osteoclast precursors unknown\"]\n    },\n    {\n      \"year\": 2015,\n      \"claim\": \"Challenged the gain-of-function metabolic model by showing genetic deletion has minimal effect on glucose metabolism, revealing model-dependence.\",\n      \"evidence\": \"Ctrp3-KO mice with hyperinsulinemic-euglycemic clamp and liver phenotyping\",\n      \"pmids\": [\"26670485\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Reasons for discrepancy with recombinant/transgenic studies unresolved\", \"Possible compensation by paralogs not tested\"]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"Identified the first candidate cell-surface receptors (LAMP1 and LIMP II) for CTRP3, addressing the long-standing receptor gap.\",\n      \"evidence\": \"LRC-TriCEPS ligand-receptor capture with confirmatory Co-IP and antibody blocking on hepatoma cells\",\n      \"pmids\": [\"27727322\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"LAMP1 as a signaling receptor not demonstrated here\", \"LIMP II association not functionally validated\", \"Single lab, novel technology\"]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"Established the AMPK/SIRT1–PGC-1\\u03b1 axis as the mechanism by which CTRP3 promotes mitochondrial biogenesis.\",\n      \"evidence\": \"Globular CTRP3 on ventricular myocytes with AMPK/Sirt1 inhibitors, PGC-1\\u03b1 siRNA, and TEM/OCR/mtDNA readouts\",\n      \"pmids\": [\"27793739\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Receptor upstream of AMPK not identified\", \"Generalizability across cell types established only later\"]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"Refined cardioprotective signaling by placing AMPK\\u03b1 downstream of a cAMP-EPAC-MEK cascade and demonstrating SIRT1 dependence against drug-induced injury.\",\n      \"evidence\": \"AAV CTRP3 in diabetic and doxorubicin-treated rodent hearts with AMPK\\u03b1 and Sirt1 genetic/pharmacological loss-of-function\",\n      \"pmids\": [\"28258411\", \"29061338\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"How CTRP3 engages cAMP generation at the membrane unknown\", \"Receptor link to cAMP-EPAC-MEK not established\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Identified AdipoR2 as the receptor for CTRP3's suppression of Th17 differentiation, providing a defined receptor-to-transcription-factor pathway.\",\n      \"evidence\": \"C1qtnf3-KO mice and EAE model with AdipoR1/R2 antagonist dissection and Rorc/Stat3 qPCR\",\n      \"pmids\": [\"34925309\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Direct AdipoR2-CTRP3 binding not shown biochemically\", \"Relationship between AdipoR2 and LAMP1 signaling unclear\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Demonstrated LAMP1 functions as a signaling receptor, transducing CTRP3 anti-inflammatory STAT3 suppression and a cardioprotective JIP2/JNK signal.\",\n      \"evidence\": \"Co-IP of CTRP3-LAMP1 and LAMP1-JIP2 with STAT3 and JNK pathway dissection in keratinocyte and cardiac I/R models\",\n      \"pmids\": [\"34687744\", \"35278832\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"LAMP1 as canonical lysosomal protein acting as surface receptor mechanistically unusual and not fully resolved\", \"Single Co-IP-based validation per study\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Generalized the SIRT1 mechanism across inflammatory tissues and extended it to the mitochondrial UPR via SIRT1/ATF5 in cardiac hypertrophy.\",\n      \"evidence\": \"Dual KO/transgenic colitis and TAC models with organoid and ATF5/SIRT1 epistasis and pharmacological SIRT1 modulation\",\n      \"pmids\": [\"36592863\", \"38278820\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Receptor coupling CTRP3 to SIRT1 induction not defined\", \"Tissue-specific selectivity of effects unexplained\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Revealed context-dependent and detrimental roles, with CTRP3 driving chondrogenic tendon degeneration and adipose macrophage recruitment.\",\n      \"evidence\": \"Gain/loss-of-function and neutralizing antibody mouse models for tendinopathy and tumor-associated adipose tissue with Akt/ERK pathway analysis\",\n      \"pmids\": [\"34797714\", \"35720277\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Why CTRP3 is protective in some tissues but pathogenic in others not mechanistically reconciled\", \"Receptor mediating pro-pathogenic Akt activation unknown\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Mapped transcriptional control of CTRP3, showing FOXO4 directly represses its promoter under high glucose.\",\n      \"evidence\": \"ChIP and luciferase reporter for FOXO4 binding plus siRNA epistasis on Nrf2/NF-\\u03baB in retinal pericytes\",\n      \"pmids\": [\"35196182\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Other transcriptional regulators in non-pericyte tissues not addressed\", \"Single lab\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How CTRP3's distinct receptors (LAMP1, AdipoR2, LIMP II) coordinate to produce its divergent tissue-specific and sometimes opposing outcomes remains unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No unified receptor-to-effector model integrating LAMP1, AdipoR2, and the AMPK/SIRT1 axis\", \"Structural basis of CTRP3 receptor binding undetermined\", \"Determinants of protective versus pathogenic signaling unknown\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0048018\", \"supporting_discovery_ids\": [0, 14, 21, 28]},\n      {\"term_id\": \"GO:0098772\", \"supporting_discovery_ids\": [9, 13, 25]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005576\", \"supporting_discovery_ids\": [1, 2, 22, 37]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [0, 9, 12, 25]},\n      {\"term_id\": \"R-HSA-1430728\", \"supporting_discovery_ids\": [0, 3, 31]},\n      {\"term_id\": \"R-HSA-168256\", \"supporting_discovery_ids\": [8, 21, 25]},\n      {\"term_id\": \"R-HSA-1852241\", \"supporting_discovery_ids\": [12, 26, 38]}\n    ],\n    \"complexes\": [],\n    \"partners\": [\"LAMP1\", \"SCARB2\", \"ADIPOR2\", \"JIP2\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"faith_supported":8,"faith_total":8,"faith_pct":100.0}}