{"gene":"ADRB3","run_date":"2026-06-09T22:02:42","timeline":{"discoveries":[{"year":2007,"finding":"ADRB3 is present and functional in human myometrium, where ADRB3 agonists inhibit spontaneous contractions via a cAMP-mediated pathway. ADRB3 is the predominant beta-adrenergic subtype over ADRB2 in human myometrium, its expression is increased in near-term myometrium compared to non-pregnant myometrium, and unlike ADRB2, myometrial ADRB3 is resistant to long-term agonist-induced desensitization.","method":"Myometrial strip contractility assay, cAMP measurement, receptor subtype pharmacology, gene expression analysis","journal":"BMC pregnancy and childbirth","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — functional assay in human tissue with pharmacological dissection and expression analysis, single lab, multiple orthogonal methods","pmids":["17570158"],"is_preprint":false},{"year":2007,"finding":"ADRB3 activation in human myometrium prevents LPS-induced apoptosis (via caspase-3/BAX/BCL2 pathway) and suppresses proinflammatory cytokine production (IL-6, IL-8) in a chorioamnionitis model. The ADRB3 agonist SAR150640 blocked these effects in a concentration-dependent manner; neutralization of TNF also antagonized LPS-induced apoptosis, placing ADRB3 upstream of TNF-mediated apoptotic signaling.","method":"Western blot (CASP3, BAX, BCL2), immunostaining, RT-PCR, cytokine ELISA, in vitro LPS stimulation of human myometrial strips, pharmacological rescue with ADRB3 agonist SAR150640","journal":"Biology of reproduction","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — multiple orthogonal in vitro methods in human tissue, single lab, pharmacological dissection with selective agonist","pmids":["17989355"],"is_preprint":false},{"year":2005,"finding":"ADRB3 is expressed and functional in human placental arteries; selective ADRB3 agonism induces concentration-dependent relaxation and cAMP production that is insensitive to low-dose propranolol (ADRB1/2 blocker) but blocked by high-dose propranolol. In preeclampsia, ADRB3 protein expression is decreased and ADRB3-mediated relaxation and cAMP production are impaired, without changes in ADRB3 transcript levels, indicating post-transcriptional/translational regulation.","method":"Pharmacological organ bath (arterial ring relaxation), cAMP ELISA, Western blot, RT-PCR, selective antagonist/agonist pharmacology","journal":"Biology of reproduction","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — functional pharmacology plus protein/mRNA quantification in human tissue, single lab, multiple orthogonal methods","pmids":["16177222"],"is_preprint":false},{"year":2009,"finding":"Genetic deletion of beta3-adrenoceptor (Adrb3 knockout mice) abolishes the antidepressant-like effects of the ADRB3 agonist amibegron in the chronic mild stress model, establishing ADRB3 as necessary for mediating the antidepressant-like actions of this compound.","method":"Adrb3 knockout mice (Adrb3tm1Lowl), chronic mild stress behavioral paradigm, pharmacological challenge with amibegron","journal":"Behavioural brain research","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — genetic loss-of-function with specific behavioral phenotype, single lab, clean KO model","pmids":["19744528"],"is_preprint":false},{"year":2013,"finding":"Two novel ADRB3 missense polymorphisms (Ser165Pro and Ser257Pro) impair ADRB3 function by reducing cAMP accumulation in stably transfected cell lines without affecting ADRB3 mRNA/protein expression levels or receptor trafficking, establishing a functional signaling defect as the molecular mechanism underlying their association with type 2 diabetes.","method":"Site-directed mutagenesis, stable transfection (HEK293 and CHO-K1 cells), real-time PCR, Western blot, confocal microscopy (receptor trafficking), cAMP accumulation assay","journal":"The Journal of clinical endocrinology and metabolism","confidence":"High","confidence_rationale":"Tier 1 / Moderate — in vitro reconstitution with mutagenesis, multiple orthogonal methods (expression, trafficking, function), single lab but rigorous mechanistic characterization","pmids":["23640967"],"is_preprint":false},{"year":2014,"finding":"Norepinephrine inhibits SDF-1-induced migration of bone marrow mesenchymal stem cells (MSCs) and suppresses their osteogenic differentiation via adrb3; siRNA knockdown of adrb3 in MSCs abolishes both the anti-migratory effect (including suppression of MMP-2 and upregulation of TIMP-3) and the inhibition of osteogenic marker genes (ALP, OCN, RUNX2), placing ADRB3 as the essential receptor mediating sympathetic nervous system suppression of MSC function.","method":"Transwell migration assay, siRNA knockdown of adrb3, in vitro osteogenic differentiation (bone nodule formation), gene expression analysis, rat mandibular distraction osteogenesis model with cervical sympathetic trunk transection","journal":"PloS one","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — siRNA loss-of-function with defined cellular phenotypes and pathway placement, in vivo sympathetic denervation model, single lab","pmids":["25144690"],"is_preprint":false},{"year":2021,"finding":"HDAC3 represses miR-18a expression in cardiomyocytes, and miR-18a directly targets ADRB3 (validated by dual luciferase reporter assay); ADRB3 is upregulated in heart failure, and its downregulation (along with HDAC3 silencing or miR-18a overexpression) reduces cardiac fibrosis, hypertrophy, and apoptosis in HF mouse models.","method":"Dual luciferase reporter assay (miR-18a targeting ADRB3), RT-qPCR, Western blot, mouse coronary artery ligation HF model, ectopic expression and silencing experiments, flow cytometry (apoptosis), TUNEL staining, echocardiography","journal":"Cell & bioscience","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — luciferase reporter validates miRNA-target relationship, supported by in vivo and in vitro loss-of-function, single lab","pmids":["33549119"],"is_preprint":false},{"year":2022,"finding":"Brown adipocyte-specific ADRB3 knockout (BKO) mice exhibit accelerated cardiac hypertrophy and fibrosis in response to angiotensin II. Mechanistically, ADRB3 activation in brown adipocytes suppresses iNOS loading into secreted exosomes; loss of ADRB3 or pharmacological antagonism increases exosomal iNOS, which drives cardiac fibroblast dysfunction. Knockdown of iNOS in brown adipocytes reverses the pro-fibrotic effect of ADRB3-deficient exosomes, establishing a brown adipocyte ADRB3 → exosomal iNOS → cardiac fibrosis signaling axis.","method":"Brown adipocyte-specific ADRB3 knockout mice, angiotensin II infusion model, exosome isolation and intravenous injection, exosome inhibitor treatment, iNOS siRNA knockdown, in vitro co-culture of brown adipocytes with cardiac fibroblasts, gene expression analysis","journal":"Circulation research","confidence":"High","confidence_rationale":"Tier 2 / Strong — cell-type-specific KO with defined cardiac phenotype, mechanistic rescue by iNOS knockdown, multiple orthogonal methods across in vivo and in vitro systems, single lab with rigorous controls","pmids":["35652349"],"is_preprint":false},{"year":2022,"finding":"ADRB3 promotes breast cancer cell proliferation and inhibits their transdifferentiation into adipocyte-like cells by activating the mTOR pathway. ADRB3 also expands myeloid-derived suppressor cells (MDSCs) by stimulating bone marrow mobilization and inhibiting differentiation of immature myeloid cells. ADRB3-knockout PyMT mice show an MDSC-deficient phenotype associated with impaired mammary tumorigenesis and reduced pulmonary metastasis.","method":"ADRB3 knockout mice (PyMT model), immunohistochemistry, MCF-7 cell proliferation and differentiation assays, mTOR pathway analysis, MDSC quantification, in vivo tumor and metastasis assessment","journal":"Cell death & disease","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — in vivo KO model with defined tumor phenotype, pathway placement via mTOR, multiple cell type analyses, single lab","pmids":["35145073"],"is_preprint":false},{"year":2025,"finding":"WWP1 (a HECT-type E3 ubiquitin ligase) suppresses Adrb3 mRNA expression in white adipose tissue of obese mice independently of noradrenaline metabolism; Wwp1 knockout increases Adrb3 expression and phosphorylated hormone-sensitive lipase levels, enhancing lipolysis, establishing WWP1 as a negative regulator of the ADRB3-lipolysis axis.","method":"Wwp1 knockout mice on high-fat diet, mRNA quantification, phospho-HSL Western blot, noradrenaline measurement in WAT","journal":"International journal of molecular sciences","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — clean genetic KO with defined molecular phenotype (Adrb3 expression, HSL phosphorylation), single lab, mechanistic pathway placement","pmids":["40362456"],"is_preprint":false},{"year":2024,"finding":"Swertiamarin (STM) directly interacts with ADRB3 and activates ADRB3/UCP1 thermogenic signaling in adipocytes, increasing glucose uptake, glycerol release, p-HSL expression, mitochondrial content, and oxidative phosphorylation complex expression; all these effects are reversed upon ADRB3 inhibition, establishing ADRB3 as the necessary receptor mediating STM's thermogenic and lipolytic actions in adipose tissue.","method":"Molecular docking (STM-ADRB3 interaction), 3T3-L1 adipocyte differentiation model, ADRB3 inhibitor rescue experiments, cAMP/UCP1/p-HSL assays, mitochondrial membrane potential measurement, in vivo T2DM mouse model (HFD/STZ), bioinformatics","journal":"Phytomedicine","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — pharmacological loss-of-function rescue in vitro with multiple readouts, single lab; molecular docking provides supporting but not definitive structural evidence","pmids":["39515102"],"is_preprint":false},{"year":2025,"finding":"The suprachiasmatic nucleus (SCN) restrains ADRB3 signaling in brown adipose tissue; SCN lesioning leads to sustained ADRB3 activity accompanied by upregulation of S100B in BAT, which promotes thermogenesis by stimulating brown adipocyte proliferation and suppressing senescence. S100B is both necessary and sufficient for sustaining BAT thermogenesis downstream of ADRB3, defining a SCN→ADRB3→S100B signaling axis governing thermogenic output.","method":"SCN lesioning (NMDA excitotoxicity, Caspase-3 ablation, light-induced arrhythmia), β3-agonist CL 316,243 treatment, S100B gain- and loss-of-function, brown adipocyte proliferation and senescence assays, indirect calorimetry, gene expression analysis","journal":"PLoS biology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — multiple SCN disruption models converge on same phenotype, S100B necessity and sufficiency tested, single lab with multiple orthogonal approaches","pmids":["41343575"],"is_preprint":false},{"year":2026,"finding":"Stress activates ADRB3 in brown adipocytes to induce IL-6 production via cAMP-PKA-CREB signaling, which transcriptionally upregulates KLF7, and KLF7 in turn drives IL-6 expression; Klf7 adipocyte-specific knockout abolishes ADRB3-induced IL-6 production, placing KLF7 as an essential effector downstream of the ADRB3-cAMP-PKA-CREB axis for stress-induced IL-6 secretion.","method":"Klf7 adipocyte-specific knockout mice, ADRB3 agonist administration in vivo and in vitro, cAMP-PKA-CREB pathway inhibition, CREB ChIP at KLF7 promoter, IL-6 ELISA, brown adipocyte primary culture","journal":"Journal of lipid research","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — adipocyte-specific KO with defined IL-6 phenotype, CREB-KLF7 promoter binding, in vivo and in vitro validation, single lab","pmids":["41565113"],"is_preprint":false},{"year":2024,"finding":"Fat tissue-specific deletion of Adrb3 in adipocytes protects mice from acute alcohol binge-induced adipose tissue lipolysis, hepatic fat accumulation, and liver injury; systemic and local sympathetic nerve ablation phenocopies adipocyte Adrb3 deletion, establishing the sympathetic nerve→ADRB3→WAT lipolysis→liver steatosis pathway.","method":"Adipocyte-specific Adrb3 knockout mice (Adrb3 FKO), 6-OHDA sympathetic denervation (systemic and local), acute alcohol binge model, plasma FFA measurement, hepatic fat quantification, liver injury markers, WAT norepinephrine measurement","journal":"bioRxiv","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — adipocyte-specific KO with defined metabolic phenotype, convergent sympathetic denervation evidence, single lab; preprint status lowers certainty","pmids":[],"is_preprint":true},{"year":2026,"finding":"In C3H/HeJ mice, Adrb3 expression is minimal in BAT and WAT and is unaffected by cold exposure; β3-agonist CL 316,243 fails to increase energy expenditure in C3H mice (though it does in C57BL/6J mice), while norepinephrine increases EE in both strains and propranolol (β1/β2 antagonist) abolishes strain differences—demonstrating that C3H mice achieve cold-induced thermogenesis via ADRB3-independent (β1/β2 or non-canonical) mechanisms.","method":"Indirect calorimetry (Promethion), β3-agonist CL 316,243 challenge, norepinephrine challenge, propranolol pretreatment, BAT/WAT gene expression analysis, comparative strain study (C57BL/6J vs C3H/HeJ)","journal":"Scientific reports","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — pharmacological dissection with multiple adrenergic agents, two-strain comparison, negative result for ADRB3 in C3H explicitly tested and confirmed, single lab","pmids":["41663555"],"is_preprint":false}],"current_model":"ADRB3 is a G-protein-coupled β3-adrenergic receptor that couples to cAMP-PKA signaling in adipose tissue and other cell types to regulate lipolysis, thermogenesis (via UCP1), and energy metabolism; in brown adipocytes it controls an exosomal iNOS pathway that protects the heart from remodeling and a cAMP-PKA-CREB-KLF7 axis that drives stress-induced IL-6 secretion; in white adipose tissue it mediates sympathetic nerve-stimulated lipolysis (regulated negatively by the E3 ubiquitin ligase WWP1); in human myometrium it signals through cAMP to suppress contractions and inflammation while resisting desensitization; and loss-of-function variants that impair cAMP accumulation are mechanistically linked to metabolic disorders including type 2 diabetes."},"narrative":{"mechanistic_narrative":"ADRB3 is a G-protein-coupled β3-adrenergic receptor that transduces sympathetic and pharmacological catecholamine signals into cAMP-dependent responses governing adipose energy metabolism, smooth muscle relaxation, and tissue protection [PMID:17570158, PMID:23640967, PMID:39515102]. In adipocytes it activates ADRB3/UCP1 thermogenic signaling and PKA-dependent lipolysis, raising cAMP, phosphorylating hormone-sensitive lipase, and increasing mitochondrial oxidative capacity [PMID:39515102]; this lipolytic axis is restrained by the HECT-type E3 ubiquitin ligase WWP1, which suppresses Adrb3 mRNA in white adipose tissue independently of noradrenaline metabolism [PMID:40362456]. Sympathetic input through adipocyte ADRB3 drives white adipose lipolysis that feeds hepatic fat accumulation and liver injury during alcohol challenge, while in brown adipose tissue the receptor's thermogenic output is tuned by the suprachiasmatic nucleus via an S100B-dependent program [PMID:41343575]. Beyond metabolism, brown adipocyte ADRB3 acts as a cardioprotective node: it suppresses iNOS loading into secreted exosomes, and its loss raises exosomal iNOS that drives cardiac fibroblast dysfunction and remodeling [PMID:35652349], and the receptor also signals through cAMP-PKA-CREB to transcriptionally induce KLF7 and stress-evoked IL-6 secretion [PMID:41565113]. In human myometrium and placental arteries ADRB3 is the predominant β-adrenergic subtype, signaling through cAMP to inhibit contractions, relax vasculature, and suppress LPS-induced apoptosis and proinflammatory cytokines, while resisting agonist-induced desensitization [PMID:17570158, PMID:17989355, PMID:16177222]. Loss-of-function missense variants (Ser165Pro, Ser257Pro) that reduce cAMP accumulation without altering expression or trafficking mechanistically link impaired ADRB3 signaling to type 2 diabetes [PMID:23640967].","teleology":[{"year":2007,"claim":"Established that ADRB3 is the dominant functional β-adrenergic subtype in human reproductive smooth muscle, answering whether a peripheral receptor could control myometrial tone via cAMP and resist the desensitization that limits ADRB2-targeted tocolytics.","evidence":"Myometrial strip contractility, cAMP measurement, subtype pharmacology, and arterial ring relaxation in human tissue","pmids":["17570158","16177222"],"confidence":"Medium","gaps":["Molecular basis of desensitization resistance not defined","Downstream effectors linking cAMP to contractile suppression not mapped","Preeclampsia decrease shown post-transcriptionally but regulatory mechanism unidentified"]},{"year":2007,"claim":"Showed ADRB3 activation is anti-inflammatory and anti-apoptotic in myometrium, placing the receptor upstream of TNF-mediated apoptotic signaling in a chorioamnionitis model.","evidence":"LPS stimulation of human myometrial strips with selective agonist SAR150640, caspase-3/BAX/BCL2 Western blot, cytokine ELISA, TNF neutralization","pmids":["17989355"],"confidence":"Medium","gaps":["Signaling intermediates between ADRB3 and caspase/cytokine outputs not resolved","In vivo relevance to preterm labor untested"]},{"year":2009,"claim":"Genetic deletion demonstrated ADRB3 is necessary for an antidepressant-like behavioral response, extending its functional reach beyond peripheral tissues.","evidence":"Adrb3 knockout mice in a chronic mild stress paradigm with amibegron challenge","pmids":["19744528"],"confidence":"Medium","gaps":["Site and circuit of action not localized","Downstream signaling in this context uncharacterized"]},{"year":2013,"claim":"Defined the molecular lesion behind disease-associated ADRB3 variants, showing that impaired cAMP accumulation—not altered expression or trafficking—links the receptor to type 2 diabetes.","evidence":"Site-directed mutagenesis, stable HEK293/CHO-K1 expression, confocal trafficking analysis, and cAMP accumulation assays","pmids":["23640967"],"confidence":"High","gaps":["Conformational/coupling defect causing reduced cAMP not structurally explained","In vivo metabolic consequence of these specific variants not modeled"]},{"year":2014,"claim":"Placed ADRB3 as the essential receptor by which sympathetic norepinephrine suppresses mesenchymal stem cell migration and osteogenic differentiation.","evidence":"siRNA knockdown in MSCs, transwell migration, osteogenic differentiation assays, and a rat sympathetic denervation model","pmids":["25144690"],"confidence":"Medium","gaps":["Intracellular signaling from ADRB3 to MMP-2/TIMP-3 and osteogenic genes not delineated"]},{"year":2021,"claim":"Identified ADRB3 as a direct miR-18a target under HDAC3 control in the heart, connecting its upregulation to cardiac fibrosis, hypertrophy, and apoptosis in heart failure.","evidence":"Dual luciferase reporter, RT-qPCR/Western blot, coronary artery ligation HF model, and gain/loss-of-function with echocardiography","pmids":["33549119"],"confidence":"Medium","gaps":["Cardiomyocyte-autonomous vs systemic contribution of ADRB3 not separated","Signaling downstream of cardiac ADRB3 in HF not detailed"]},{"year":2022,"claim":"Defined a tissue-crosstalk mechanism whereby brown adipocyte ADRB3 protects the heart by restraining iNOS loading into secreted exosomes.","evidence":"Brown adipocyte-specific Adrb3 knockout, angiotensin II model, exosome isolation/injection, iNOS siRNA rescue, and adipocyte–fibroblast co-culture","pmids":["35652349"],"confidence":"High","gaps":["How ADRB3-cAMP signaling controls iNOS exosomal sorting not mechanistically resolved","Receptor(s) on cardiac fibroblasts receiving exosomal iNOS not identified"]},{"year":2022,"claim":"Revealed a pro-tumor role for ADRB3 in driving breast cancer proliferation via mTOR and expanding myeloid-derived suppressor cells.","evidence":"ADRB3 knockout PyMT mice, MCF-7 proliferation/transdifferentiation assays, mTOR pathway analysis, and MDSC quantification","pmids":["35145073"],"confidence":"Medium","gaps":["Direct coupling between ADRB3 and mTOR not biochemically established","Cell-of-origin for MDSC effect not defined"]},{"year":2024,"claim":"Demonstrated that pharmacological ADRB3 agonism (swertiamarin) is necessary to activate ADRB3/UCP1 thermogenic and lipolytic signaling, reinforcing the receptor's metabolic effector role.","evidence":"Molecular docking, 3T3-L1 adipocytes with ADRB3 inhibitor rescue, cAMP/UCP1/p-HSL and mitochondrial assays, and a T2DM mouse model","pmids":["39515102"],"confidence":"Medium","gaps":["Docking does not establish a defined binding site or direct agonism in cells","Selectivity over other adrenergic receptors not exhaustively tested"]},{"year":2024,"claim":"Established a sympathetic-nerve→adipocyte ADRB3→WAT lipolysis→liver steatosis pathway driving alcohol-induced liver injury.","evidence":"Adipocyte-specific Adrb3 knockout and 6-OHDA sympathetic denervation in an acute alcohol binge model (preprint)","pmids":[],"confidence":"Medium","gaps":["Preprint, not peer-reviewed","Mediators carrying lipolytic FFA signal to liver not specified"]},{"year":2025,"claim":"Identified WWP1 as a transcriptional/expression-level negative regulator of the ADRB3-lipolysis axis in obese white adipose tissue.","evidence":"Wwp1 knockout mice on high-fat diet, Adrb3 mRNA quantification, phospho-HSL Western blot, and WAT noradrenaline measurement","pmids":["40362456"],"confidence":"Medium","gaps":["Mechanism by which the WWP1 E3 ligase suppresses Adrb3 mRNA not defined","Direct substrate linking WWP1 to Adrb3 expression unknown"]},{"year":2025,"claim":"Showed the suprachiasmatic nucleus restrains brown adipose ADRB3 signaling and that S100B is necessary and sufficient to sustain thermogenesis downstream, defining a central clock→ADRB3→S100B thermogenic axis.","evidence":"Multiple SCN disruption models, β3-agonist CL 316,243, S100B gain/loss-of-function, and indirect calorimetry","pmids":["41343575"],"confidence":"Medium","gaps":["Signaling linking ADRB3 activity to S100B induction not detailed","How SCN output reaches BAT to limit ADRB3 not mapped"]},{"year":2026,"claim":"Defined a stress-responsive cAMP-PKA-CREB-KLF7 transcriptional cascade by which brown adipocyte ADRB3 drives IL-6 secretion.","evidence":"Klf7 adipocyte-specific knockout, ADRB3 agonist in vivo/in vitro, pathway inhibition, CREB ChIP at the KLF7 promoter, and IL-6 ELISA","pmids":["41565113"],"confidence":"Medium","gaps":["Physiological consequences of ADRB3-driven IL-6 not established","KLF7-IL6 promoter regulation not fully mapped"]},{"year":2026,"claim":"Demonstrated genetic-background dependence of ADRB3's thermogenic role, with C3H/HeJ mice achieving cold-induced thermogenesis through ADRB3-independent β1/β2 or non-canonical routes.","evidence":"Indirect calorimetry with CL 316,243, norepinephrine, and propranolol challenge in a C57BL/6J vs C3H/HeJ comparison","pmids":["41663555"],"confidence":"Medium","gaps":["Cause of minimal Adrb3 expression in C3H not determined","Identity of compensating non-canonical thermogenic mechanism unresolved"]},{"year":null,"claim":"How a single cAMP-coupled receptor selects among divergent outputs—lipolysis, thermogenesis, exosomal cargo sorting, transcriptional IL-6 induction, contractile relaxation—across tissues remains unresolved.","evidence":"","pmids":[],"confidence":"Medium","gaps":["No structural model of ADRB3 ligand binding or G-protein coupling in the corpus","Tissue-specific effector selection mechanism unknown","Direct physical partners of the receptor not characterized"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0060089","term_label":"molecular transducer activity","supporting_discovery_ids":[0,2,4,10]}],"localization":[{"term_id":"GO:0005886","term_label":"plasma membrane","supporting_discovery_ids":[4]}],"pathway":[{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[4,10,12]},{"term_id":"R-HSA-1430728","term_label":"Metabolism","supporting_discovery_ids":[9,10,11,13]}],"complexes":[],"partners":[],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"P13945","full_name":"Beta-3 adrenergic receptor","aliases":["Beta-3 adrenoreceptor","Beta-3 adrenoceptor"],"length_aa":408,"mass_kda":43.5,"function":"G protein-coupled receptor for catecholamines that couples to both G(s) and G(i) proteins, leading to either activation or inhibition of adenylate cyclase and cAMP-dependent pathway, respectively (PubMed:10188996, PubMed:2570461, PubMed:8641219). The rank order of potency for physiological agonists is norepinephrine > epinephrine (PubMed:10188996, PubMed:2570461, PubMed:8641219). Involved in the regulation of thermogenesis and lipolysis in brown and white adipose tissue, after coupling to G(s) proteins and stimulation of the cAMP-PKA axis (By similarity). Also activates lipolytic process by coupling to G(i) proteins and consequent initiation of the ERK1/2 MAP kinase cascade (PubMed:10207024). Participates in relaxation of the blood vessels and the urinary bladder (PubMed:10188996). Also mediates negative inotropic effects in cardiomyocytes through activation of an NO synthase pathway and subsequent increase in cGMP levels, possibly involving G(i/o) protein-mediated coupling (PubMed:9769330)","subcellular_location":"Cell membrane","url":"https://www.uniprot.org/uniprotkb/P13945/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/ADRB3","classification":"Not Classified","n_dependent_lines":1,"n_total_lines":1208,"dependency_fraction":0.0008278145695364238},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[],"url":"https://opencell.sf.czbiohub.org/search/ADRB3","total_profiled":1310},"omim":[{"mim_id":"620373","title":"ADIPOSE-SECRETED SIGNALING PROTEIN; ADISSP","url":"https://www.omim.org/entry/620373"},{"mim_id":"617851","title":"SERTA DOMAIN-CONTAINING PROTEIN 2; SERTAD2","url":"https://www.omim.org/entry/617851"},{"mim_id":"602186","title":"VGF, NERVE GROWTH FACTOR-INDUCIBLE; VGF","url":"https://www.omim.org/entry/602186"},{"mim_id":"601665","title":"OBESITY","url":"https://www.omim.org/entry/601665"},{"mim_id":"600835","title":"CHEMOKINE, CXC MOTIF, LIGAND 12; CXCL12","url":"https://www.omim.org/entry/600835"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Uncertain","locations":[{"location":"Vesicles","reliability":"Uncertain"},{"location":"Basal body","reliability":"Uncertain"}],"tissue_specificity":"Tissue enhanced","tissue_distribution":"Detected in some","driving_tissues":[{"tissue":"fallopian tube","ntpm":5.3},{"tissue":"ovary","ntpm":12.8},{"tissue":"urinary bladder","ntpm":5.2}],"url":"https://www.proteinatlas.org/search/ADRB3"},"hgnc":{"alias_symbol":[],"prev_symbol":[]},"alphafold":{"accession":"P13945","domains":[{"cath_id":"1.20.1070.10","chopping":"35-244_283-362","consensus_level":"medium","plddt":92.775,"start":35,"end":362}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/P13945","model_url":"https://alphafold.ebi.ac.uk/files/AF-P13945-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-P13945-F1-predicted_aligned_error_v6.png","plddt_mean":78.94},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=ADRB3","jax_strain_url":"https://www.jax.org/strain/search?query=ADRB3"},"sequence":{"accession":"P13945","fasta_url":"https://rest.uniprot.org/uniprotkb/P13945.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/P13945/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/P13945"}},"corpus_meta":[{"pmid":"18574485","id":"PMC_18574485","title":"The ADRB3 Trp64Arg variant and BMI: a meta-analysis of 44 833 individuals.","date":"2008","source":"International journal of obesity (2005)","url":"https://pubmed.ncbi.nlm.nih.gov/18574485","citation_count":67,"is_preprint":false},{"pmid":"18611262","id":"PMC_18611262","title":"Genetic variation in candidate obesity genes ADRB2, ADRB3, GHRL, HSD11B1, IRS1, IRS2, and SHC1 and risk for breast cancer in the Cancer Prevention Study II.","date":"2008","source":"Breast cancer research : BCR","url":"https://pubmed.ncbi.nlm.nih.gov/18611262","citation_count":43,"is_preprint":false},{"pmid":"35652349","id":"PMC_35652349","title":"Brown Adipocyte ADRB3 Mediates Cardioprotection via Suppressing Exosomal iNOS.","date":"2022","source":"Circulation research","url":"https://pubmed.ncbi.nlm.nih.gov/35652349","citation_count":40,"is_preprint":false},{"pmid":"24579945","id":"PMC_24579945","title":"ADRB3 gene promoter DNA methylation in blood and visceral adipose tissue is associated with metabolic disturbances in men.","date":"2014","source":"Epigenomics","url":"https://pubmed.ncbi.nlm.nih.gov/24579945","citation_count":40,"is_preprint":false},{"pmid":"25144690","id":"PMC_25144690","title":"Sympathetic denervation-induced MSC mobilization in distraction osteogenesis associates with inhibition of MSC migration and osteogenesis by norepinephrine/adrb3.","date":"2014","source":"PloS one","url":"https://pubmed.ncbi.nlm.nih.gov/25144690","citation_count":33,"is_preprint":false},{"pmid":"22937051","id":"PMC_22937051","title":"Human-specific SNP in obesity genes, adrenergic receptor beta2 (ADRB2), Beta3 (ADRB3), and PPAR γ2 (PPARG), during primate evolution.","date":"2012","source":"PloS one","url":"https://pubmed.ncbi.nlm.nih.gov/22937051","citation_count":28,"is_preprint":false},{"pmid":"19553224","id":"PMC_19553224","title":"Trp64Arg polymorphism in ADRB3 gene is associated with elite endurance performance.","date":"2009","source":"British journal of sports medicine","url":"https://pubmed.ncbi.nlm.nih.gov/19553224","citation_count":27,"is_preprint":false},{"pmid":"17570158","id":"PMC_17570158","title":"Is the beta3-adrenoceptor (ADRB3) a potential target for uterorelaxant drugs?","date":"2007","source":"BMC pregnancy and childbirth","url":"https://pubmed.ncbi.nlm.nih.gov/17570158","citation_count":25,"is_preprint":false},{"pmid":"17989355","id":"PMC_17989355","title":"ADRB3 adrenergic receptor is a key regulator of human myometrial apoptosis and inflammation during chorioamnionitis.","date":"2007","source":"Biology of reproduction","url":"https://pubmed.ncbi.nlm.nih.gov/17989355","citation_count":24,"is_preprint":false},{"pmid":"19744528","id":"PMC_19744528","title":"Implication of beta3-adrenoceptors in the antidepressant-like effects of amibegron using Adrb3 knockout mice in the chronic mild stress.","date":"2009","source":"Behavioural brain research","url":"https://pubmed.ncbi.nlm.nih.gov/19744528","citation_count":24,"is_preprint":false},{"pmid":"33549119","id":"PMC_33549119","title":"The crosstalk of HDAC3, microRNA-18a and ADRB3 in the progression of heart failure.","date":"2021","source":"Cell & bioscience","url":"https://pubmed.ncbi.nlm.nih.gov/33549119","citation_count":22,"is_preprint":false},{"pmid":"29587766","id":"PMC_29587766","title":"ADRB3 polymorphism rs4994 (Trp64Arg) associates significantly with bodyweight elevation and dyslipidaemias in Saudis but not rs1801253 (Arg389Gly) polymorphism in ARDB1.","date":"2018","source":"Lipids in health and disease","url":"https://pubmed.ncbi.nlm.nih.gov/29587766","citation_count":22,"is_preprint":false},{"pmid":"22391136","id":"PMC_22391136","title":"The absence of polymorphisms in ADRB3, UCP1, PPARγ, and ADIPOQ genes protects morbid obese patients toward insulin resistance.","date":"2012","source":"Journal of endocrinological investigation","url":"https://pubmed.ncbi.nlm.nih.gov/22391136","citation_count":22,"is_preprint":false},{"pmid":"17644783","id":"PMC_17644783","title":"Polymorphism at the ovine beta3-adrenergic receptor locus (ADRB3) and its association with lamb mortality.","date":"2007","source":"Journal of animal science","url":"https://pubmed.ncbi.nlm.nih.gov/17644783","citation_count":21,"is_preprint":false},{"pmid":"29046732","id":"PMC_29046732","title":"Effect of a diet containing folate and hazelnut oil capsule on the methylation level of the ADRB3 gene, lipid profile and oxidative stress in overweight or obese women.","date":"2017","source":"Clinical epigenetics","url":"https://pubmed.ncbi.nlm.nih.gov/29046732","citation_count":21,"is_preprint":false},{"pmid":"18088254","id":"PMC_18088254","title":"T64A polymorphism in beta3-adrenergic receptor gene (ADRB3) and coronary heart disease: a case-cohort study and meta-analysis.","date":"2008","source":"Journal of internal medicine","url":"https://pubmed.ncbi.nlm.nih.gov/18088254","citation_count":19,"is_preprint":false},{"pmid":"24688286","id":"PMC_24688286","title":"Obesity-related gene ADRB2, ADRB3 and GHRL polymorphisms and the response to a weight loss diet intervention in adult women.","date":"2013","source":"Genetics and molecular biology","url":"https://pubmed.ncbi.nlm.nih.gov/24688286","citation_count":19,"is_preprint":false},{"pmid":"16493638","id":"PMC_16493638","title":"Impact of variation in ADRB2, ADRB3, and GNB3 genes on body mass index and waist circumference in a Brazilian population.","date":"2006","source":"American journal of human biology : the official journal of the Human Biology Council","url":"https://pubmed.ncbi.nlm.nih.gov/16493638","citation_count":18,"is_preprint":false},{"pmid":"32008426","id":"PMC_32008426","title":"The ADRB3 rs4994 polymorphism increases risk of childhood and adolescent overweight/obesity for East Asia's population: an evidence-based meta-analysis.","date":"2020","source":"Adipocyte","url":"https://pubmed.ncbi.nlm.nih.gov/32008426","citation_count":17,"is_preprint":false},{"pmid":"16177222","id":"PMC_16177222","title":"Stimulation of the ADRB3 adrenergic receptor induces relaxation of human placental arteries: influence of preeclampsia.","date":"2005","source":"Biology of reproduction","url":"https://pubmed.ncbi.nlm.nih.gov/16177222","citation_count":17,"is_preprint":false},{"pmid":"24138564","id":"PMC_24138564","title":"The presence of at least three alleles of the ADRB3 Trp64Arg (C/T) and UCP1 -3826A/G polymorphisms is associated with protection to overweight/obesity and with higher high-density lipoprotein cholesterol levels in Caucasian-Brazilian patients with type 2 diabetes.","date":"2013","source":"Metabolic syndrome and related disorders","url":"https://pubmed.ncbi.nlm.nih.gov/24138564","citation_count":17,"is_preprint":false},{"pmid":"22550477","id":"PMC_22550477","title":"ADRB3 polymorphism associated with BMI gain in Japanese men.","date":"2012","source":"Experimental diabetes research","url":"https://pubmed.ncbi.nlm.nih.gov/22550477","citation_count":16,"is_preprint":false},{"pmid":"35145073","id":"PMC_35145073","title":"ADRB3 induces mobilization and inhibits differentiation of both breast cancer cells and myeloid-derived suppressor cells.","date":"2022","source":"Cell death & disease","url":"https://pubmed.ncbi.nlm.nih.gov/35145073","citation_count":15,"is_preprint":false},{"pmid":"29670643","id":"PMC_29670643","title":"ADRB3 Gene Trp64Arg Polymorphism and Essential Hypertension: A Meta-Analysis Including 9,555 Subjects.","date":"2018","source":"Frontiers in genetics","url":"https://pubmed.ncbi.nlm.nih.gov/29670643","citation_count":15,"is_preprint":false},{"pmid":"17299491","id":"PMC_17299491","title":"Metabolic syndrome and ADRB3 gene polymorphism in severely obese patients from South Italy.","date":"2007","source":"European journal of clinical nutrition","url":"https://pubmed.ncbi.nlm.nih.gov/17299491","citation_count":15,"is_preprint":false},{"pmid":"26290728","id":"PMC_26290728","title":"Effect of dietary supplementation with Spirulina on the expressions of AANAT, ADRB3, BTG2 and FASN genes in the subcutaneous adipose and Longissimus dorsi muscle tissues of purebred and crossbred Australian sheep.","date":"2015","source":"Journal of animal science and technology","url":"https://pubmed.ncbi.nlm.nih.gov/26290728","citation_count":15,"is_preprint":false},{"pmid":"20401689","id":"PMC_20401689","title":"Lifestyle modifies the relationship between body composition and adrenergic receptor genetic polymorphisms, ADRB2, ADRB3 and ADRA2B: a secondary analysis of a randomized controlled trial of physical activity among postmenopausal women.","date":"2010","source":"Behavior genetics","url":"https://pubmed.ncbi.nlm.nih.gov/20401689","citation_count":15,"is_preprint":false},{"pmid":"16978175","id":"PMC_16978175","title":"Polymorphism at the beta-adrenergic receptor (ADRB3) locus of Merino sheep and its association with lamb mortality.","date":"2006","source":"Animal genetics","url":"https://pubmed.ncbi.nlm.nih.gov/16978175","citation_count":14,"is_preprint":false},{"pmid":"17727676","id":"PMC_17727676","title":"Effect of the combination of the variants -75G/A APOA1 and Trp64Arg ADRB3 on the risk of type 2 diabetes (DM2).","date":"2007","source":"Clinical endocrinology","url":"https://pubmed.ncbi.nlm.nih.gov/17727676","citation_count":14,"is_preprint":false},{"pmid":"30580338","id":"PMC_30580338","title":"Adipocyte ADRB3 Down-Regulated in Chinese Overweight Individuals Adipocyte ADRB3 in Overweight.","date":"2018","source":"Obesity facts","url":"https://pubmed.ncbi.nlm.nih.gov/30580338","citation_count":13,"is_preprint":false},{"pmid":"32430022","id":"PMC_32430022","title":"The Trp64Arg polymorphism in β3 adrenergic receptor (ADRB3) gene is associated with adipokines and plasma lipids: a systematic review, meta-analysis, and meta-regression.","date":"2020","source":"Lipids in health and disease","url":"https://pubmed.ncbi.nlm.nih.gov/32430022","citation_count":13,"is_preprint":false},{"pmid":"26888112","id":"PMC_26888112","title":"Influence of ADRB2 Gln27Glu and ADRB3 Trp64Arg polymorphisms on body weight and body composition changes after a controlled weight-loss intervention.","date":"2015","source":"Applied physiology, nutrition, and metabolism = Physiologie appliquee, nutrition et metabolisme","url":"https://pubmed.ncbi.nlm.nih.gov/26888112","citation_count":13,"is_preprint":false},{"pmid":"20416661","id":"PMC_20416661","title":"Association studies on the porcine RETN, UCP1, UCP3 and ADRB3 genes polymorphism with fatness traits.","date":"2009","source":"Meat science","url":"https://pubmed.ncbi.nlm.nih.gov/20416661","citation_count":13,"is_preprint":false},{"pmid":"24201118","id":"PMC_24201118","title":"Significant role of ADRB3 rs4994 towards the development of coronary artery disease.","date":"2014","source":"Coronary artery disease","url":"https://pubmed.ncbi.nlm.nih.gov/24201118","citation_count":12,"is_preprint":false},{"pmid":"28941386","id":"PMC_28941386","title":"Trp64Arg polymorphism of the ADRB3 gene associated with maximal fat oxidation and LDL-C levels in non-obese adolescents.","date":"2017","source":"Jornal de pediatria","url":"https://pubmed.ncbi.nlm.nih.gov/28941386","citation_count":12,"is_preprint":false},{"pmid":"23640967","id":"PMC_23640967","title":"Two novel functional single nucleotide polymorphisms of ADRB3 are associated with type 2 diabetes in the Chinese population.","date":"2013","source":"The Journal of clinical endocrinology and metabolism","url":"https://pubmed.ncbi.nlm.nih.gov/23640967","citation_count":12,"is_preprint":false},{"pmid":"21619577","id":"PMC_21619577","title":"Association of beta3-adrenergic receptor (ADRB3) Trp64Arg gene polymorphism with obesity and metabolic syndrome in the Balinese: a pilot study.","date":"2011","source":"BMC research notes","url":"https://pubmed.ncbi.nlm.nih.gov/21619577","citation_count":11,"is_preprint":false},{"pmid":"30954083","id":"PMC_30954083","title":"Methylation profile of the ADRB3 gene and its association with lipid profile and nutritional status in adults.","date":"2019","source":"Biological research","url":"https://pubmed.ncbi.nlm.nih.gov/30954083","citation_count":10,"is_preprint":false},{"pmid":"23113754","id":"PMC_23113754","title":"ADRB3 and PPARγ2 gene polymorphisms and their association with cardiovascular disease risk in postmenopausal women.","date":"2012","source":"Climacteric : the journal of the International Menopause Society","url":"https://pubmed.ncbi.nlm.nih.gov/23113754","citation_count":10,"is_preprint":false},{"pmid":"33326437","id":"PMC_33326437","title":"The direct correlation between oxidative stress and LDL-C levels in adults is maintained by the Friedewald and Martin equations, but the methylation levels in the MTHFR and ADRB3 genes differ.","date":"2020","source":"PloS one","url":"https://pubmed.ncbi.nlm.nih.gov/33326437","citation_count":10,"is_preprint":false},{"pmid":"16444766","id":"PMC_16444766","title":"A novel missense mutation in ADRB3 increases risk for type 2 diabetes in a Mexican American family.","date":"2006","source":"Diabetes/metabolism research and reviews","url":"https://pubmed.ncbi.nlm.nih.gov/16444766","citation_count":10,"is_preprint":false},{"pmid":"20008926","id":"PMC_20008926","title":"Trp64Arg polymorphism of the ADRB3 gene predicts hyperuricemia risk in a population from southern Spain.","date":"2009","source":"The Journal of rheumatology","url":"https://pubmed.ncbi.nlm.nih.gov/20008926","citation_count":10,"is_preprint":false},{"pmid":"21285172","id":"PMC_21285172","title":"Positive correlation between Beta-3-Adrenergic Receptor (ADRB3) gene and gout in a Chinese male population.","date":"2011","source":"The Journal of rheumatology","url":"https://pubmed.ncbi.nlm.nih.gov/21285172","citation_count":9,"is_preprint":false},{"pmid":"24827746","id":"PMC_24827746","title":"Impact of GNB3-C825T, ADRB3-Trp64Arg, UCP2-3'UTR 45 bp del/ins, and PPARγ-Pro12Ala polymorphisms on Bofutsushosan response in obese subjects: a randomized, double-blind, placebo-controlled trial.","date":"2014","source":"Journal of medicinal food","url":"https://pubmed.ncbi.nlm.nih.gov/24827746","citation_count":9,"is_preprint":false},{"pmid":"31802204","id":"PMC_31802204","title":"Relation of ADRB3, GEF, ROCK2 gene polymorphisms to clinical findings in overactive bladder.","date":"2019","source":"World journal of urology","url":"https://pubmed.ncbi.nlm.nih.gov/31802204","citation_count":8,"is_preprint":false},{"pmid":"32340905","id":"PMC_32340905","title":"Can study of the ADRB3 gene help improve weight loss programs in obese individuals?","date":"2020","source":"Endocrinologia, diabetes y nutricion","url":"https://pubmed.ncbi.nlm.nih.gov/32340905","citation_count":8,"is_preprint":false},{"pmid":"22711302","id":"PMC_22711302","title":"SNP variation in ADRB3 gene reflects the breed difference of sheep populations.","date":"2012","source":"Molecular biology reports","url":"https://pubmed.ncbi.nlm.nih.gov/22711302","citation_count":8,"is_preprint":false},{"pmid":"29866117","id":"PMC_29866117","title":"Decrease of the DNA methylation levels of the ADRB3 gene in leukocytes is related with serum folate in eutrophic adults.","date":"2018","source":"Journal of translational medicine","url":"https://pubmed.ncbi.nlm.nih.gov/29866117","citation_count":8,"is_preprint":false},{"pmid":"19531115","id":"PMC_19531115","title":"Polymorphism of the ovine beta3-adrenergic receptor gene (ADRB3) and its association with wool mean staple strength and yield.","date":"2009","source":"Animal genetics","url":"https://pubmed.ncbi.nlm.nih.gov/19531115","citation_count":8,"is_preprint":false},{"pmid":"20091127","id":"PMC_20091127","title":"Polymorphism of the bovine ADRB3 gene.","date":"2009","source":"Molecular biology reports","url":"https://pubmed.ncbi.nlm.nih.gov/20091127","citation_count":8,"is_preprint":false},{"pmid":"39515102","id":"PMC_39515102","title":"Swertiamarin ameliorates type 2 diabetes by activating ADRB3/UCP1 thermogenic signals in adipose tissue.","date":"2024","source":"Phytomedicine : international journal of phytotherapy and phytopharmacology","url":"https://pubmed.ncbi.nlm.nih.gov/39515102","citation_count":7,"is_preprint":false},{"pmid":"34260097","id":"PMC_34260097","title":"Association between the Trp64Arg polymorphism of the ADRB3 gene and overactive bladder.","date":"2021","source":"Neurourology and urodynamics","url":"https://pubmed.ncbi.nlm.nih.gov/34260097","citation_count":7,"is_preprint":false},{"pmid":"24658877","id":"PMC_24658877","title":"Higher cardiorespiratory fitness attenuates the risk of atherosclerosis associated with ADRB3 Trp64Arg polymorphism.","date":"2014","source":"European journal of applied physiology","url":"https://pubmed.ncbi.nlm.nih.gov/24658877","citation_count":7,"is_preprint":false},{"pmid":"22609474","id":"PMC_22609474","title":"Possible impact of ADRB3 Trp64Arg polymorphism on BMI in patients with schizophrenia.","date":"2012","source":"Progress in neuro-psychopharmacology & biological psychiatry","url":"https://pubmed.ncbi.nlm.nih.gov/22609474","citation_count":7,"is_preprint":false},{"pmid":"25059067","id":"PMC_25059067","title":"[Regional features of obesity-associated gene polymorphism (rs9939609 FTO gene and gene Trp64Arg ADRB3) in Russian population].","date":"2014","source":"Voprosy pitaniia","url":"https://pubmed.ncbi.nlm.nih.gov/25059067","citation_count":7,"is_preprint":false},{"pmid":"31977906","id":"PMC_31977906","title":"Stratified meta-analysis by ethnicity revealed that ADRB3 Trp64Arg polymorphism was associated with coronary artery disease in Asians, but not in Caucasians.","date":"2020","source":"Medicine","url":"https://pubmed.ncbi.nlm.nih.gov/31977906","citation_count":6,"is_preprint":false},{"pmid":"17264845","id":"PMC_17264845","title":"The ADRB3 Trp64Arg variant and obesity in African-American breast cancer cases.","date":"2007","source":"International journal of obesity (2005)","url":"https://pubmed.ncbi.nlm.nih.gov/17264845","citation_count":6,"is_preprint":false},{"pmid":"26602921","id":"PMC_26602921","title":"A Multiple Interaction Analysis Reveals ADRB3 as a Potential Candidate for Gallbladder Cancer Predisposition via a Complex Interaction with Other Candidate Gene Variations.","date":"2015","source":"International journal of molecular sciences","url":"https://pubmed.ncbi.nlm.nih.gov/26602921","citation_count":6,"is_preprint":false},{"pmid":"23968135","id":"PMC_23968135","title":"Trp homozygotes at codon 64 of ADRB3 gene are protected against the risk of type 2 diabetes in the Kashmiri population.","date":"2013","source":"Genetic testing and molecular biomarkers","url":"https://pubmed.ncbi.nlm.nih.gov/23968135","citation_count":5,"is_preprint":false},{"pmid":"29606859","id":"PMC_29606859","title":"PPARgamma-2 and ADRB3 polymorphisms in connective tissue diseases and lipid disorders.","date":"2018","source":"Clinical interventions in aging","url":"https://pubmed.ncbi.nlm.nih.gov/29606859","citation_count":4,"is_preprint":false},{"pmid":"37628593","id":"PMC_37628593","title":"Effects of the Trp64Arg Polymorphism in the ADRB3 Gene on Body Composition, Cardiorespiratory Fitness, and Physical Activity in Healthy Adults.","date":"2023","source":"Genes","url":"https://pubmed.ncbi.nlm.nih.gov/37628593","citation_count":4,"is_preprint":false},{"pmid":"26410938","id":"PMC_26410938","title":"[Genetic Association of ADRA2A and ADRB3 Genes with Metabolic Syndrome among the Tatars].","date":"2015","source":"Genetika","url":"https://pubmed.ncbi.nlm.nih.gov/26410938","citation_count":4,"is_preprint":false},{"pmid":"32452228","id":"PMC_32452228","title":"The relationship between PNP, GSTO-1, AS3MT and ADRB3 gene polymorphisms and urinary arsenic concentration among copper smelter and refinery employers.","date":"2020","source":"Human & experimental toxicology","url":"https://pubmed.ncbi.nlm.nih.gov/32452228","citation_count":3,"is_preprint":false},{"pmid":"19507019","id":"PMC_19507019","title":"Extensive diversity of the ADRB3 gene in Chinese sheep identified by PCR-SSCP.","date":"2009","source":"Biochemical genetics","url":"https://pubmed.ncbi.nlm.nih.gov/19507019","citation_count":3,"is_preprint":false},{"pmid":"21348572","id":"PMC_21348572","title":"Extended haplotype analysis of ovine ADRB3 using polymerase chain reaction single strand conformational polymorphism on two regions of the gene.","date":"2011","source":"DNA and cell biology","url":"https://pubmed.ncbi.nlm.nih.gov/21348572","citation_count":3,"is_preprint":false},{"pmid":"35236048","id":"PMC_35236048","title":"ADRB3, ROCK2, and GEF Levels in Overactive Bladder Patients.","date":"2022","source":"International neurourology journal","url":"https://pubmed.ncbi.nlm.nih.gov/35236048","citation_count":2,"is_preprint":false},{"pmid":"23653006","id":"PMC_23653006","title":"Halplotypes of the ovine ADRB3 gene (ADRB3) and their association with post-weaning growth in New Zealand Suffolk sheep.","date":"2013","source":"Molecular biology reports","url":"https://pubmed.ncbi.nlm.nih.gov/23653006","citation_count":2,"is_preprint":false},{"pmid":"34775903","id":"PMC_34775903","title":"Identification of polymorphisms in the MSTN and ADRB3 genes associated with growth and ultrasound carcass traits in Kajli sheep.","date":"2021","source":"Animal biotechnology","url":"https://pubmed.ncbi.nlm.nih.gov/34775903","citation_count":2,"is_preprint":false},{"pmid":"41663555","id":"PMC_41663555","title":"Thermoregulatory adaptations to cold in C3H/HeJ mice are independent of ADRB3 signaling.","date":"2026","source":"Scientific reports","url":"https://pubmed.ncbi.nlm.nih.gov/41663555","citation_count":2,"is_preprint":false},{"pmid":"40362456","id":"PMC_40362456","title":"Depletion of WWP1 Increases Adrb3 Expression and Lipolysis in White Adipose Tissue of Obese Mice.","date":"2025","source":"International journal of molecular sciences","url":"https://pubmed.ncbi.nlm.nih.gov/40362456","citation_count":1,"is_preprint":false},{"pmid":"41343575","id":"PMC_41343575","title":"The suprachiasmatic nucleus regulates brown fat thermogenesis in male mice through an adrenergic receptor ADRB3-S100B signaling pathway.","date":"2025","source":"PLoS biology","url":"https://pubmed.ncbi.nlm.nih.gov/41343575","citation_count":1,"is_preprint":false},{"pmid":"36556105","id":"PMC_36556105","title":"Functional Polymorphism in the ADRB3 Gene, Encoding the Beta-3 Adrenergic Receptor, and Response to Intra-Detrusor Injection of Botulinum Toxin-A in Women with Overactive Bladder.","date":"2022","source":"Journal of clinical medicine","url":"https://pubmed.ncbi.nlm.nih.gov/36556105","citation_count":1,"is_preprint":false},{"pmid":"36989522","id":"PMC_36989522","title":"Association of an ADRB3 Variant with Coronary Artery Disease Within the Chinese Han Population: Construction of a Predictive Nomogram Model.","date":"2023","source":"Genetic testing and molecular biomarkers","url":"https://pubmed.ncbi.nlm.nih.gov/36989522","citation_count":1,"is_preprint":false},{"pmid":"41272565","id":"PMC_41272565","title":"GLIS3 rs7034200 and ADRB3 rs4994 genetic variants associated with an increased risk of gestational diabetes mellitus in Chinese women: a case-control study.","date":"2025","source":"BMC pregnancy and childbirth","url":"https://pubmed.ncbi.nlm.nih.gov/41272565","citation_count":1,"is_preprint":false},{"pmid":"29381017","id":"PMC_29381017","title":"[The investigation the combined effect of SNP rs9939609 (gene FTO) and rs4994 (gene ADRB3) polymorphisms on risk of obesity].","date":"2016","source":"Voprosy pitaniia","url":"https://pubmed.ncbi.nlm.nih.gov/29381017","citation_count":1,"is_preprint":false},{"pmid":"40441323","id":"PMC_40441323","title":"Investigating ADRB1 and ADRB3 polymorphisms as risk factors for type 2 diabetes: A retrospective study.","date":"2025","source":"Gene","url":"https://pubmed.ncbi.nlm.nih.gov/40441323","citation_count":0,"is_preprint":false},{"pmid":"41565113","id":"PMC_41565113","title":"KLF7 induced ADRB3-dependent IL-6 production in brown adipocytes during stress.","date":"2026","source":"Journal of lipid research","url":"https://pubmed.ncbi.nlm.nih.gov/41565113","citation_count":0,"is_preprint":false},{"pmid":"39259490","id":"PMC_39259490","title":"Association analysis of ADRB3:rs4994 with urodynamic outcome, six months after a single intra-detrusor injection of botulinum toxin, in women with overactive bladder.","date":"2024","source":"Pharmacological reports : PR","url":"https://pubmed.ncbi.nlm.nih.gov/39259490","citation_count":0,"is_preprint":false},{"pmid":"41917258","id":"PMC_41917258","title":"The epigenetic role of ADRB3 DNA methylation in post-bariatric energy expenditure for women with obesity: a longitudinal observational study.","date":"2026","source":"Scientific reports","url":"https://pubmed.ncbi.nlm.nih.gov/41917258","citation_count":0,"is_preprint":false},{"pmid":null,"id":"bio_10.1101_2025.10.04.25337310","title":"Obesity-Associated Genetic Variants and AMPK Signaling in Cardiovascular Disease: A Systematic Review of Mechanisms and Clinical Implications","date":"2025-10-07","source":"bioRxiv","url":"https://doi.org/10.1101/2025.10.04.25337310","citation_count":0,"is_preprint":true},{"pmid":null,"id":"bio_10.1101_2024.12.08.627372","title":"Ablation of sympathetic nerve-β3 adrenergic receptor-mediated adipose tissue lipolysis attenuates alcohol-induced liver injury in mice","date":"2024-12-10","source":"bioRxiv","url":"https://doi.org/10.1101/2024.12.08.627372","citation_count":0,"is_preprint":true},{"pmid":null,"id":"bio_10.1101_2025.06.20.660779","title":"A pre-menopausal single-cell atlas for ovarian drug discovery","date":"2025-06-25","source":"bioRxiv","url":"https://doi.org/10.1101/2025.06.20.660779","citation_count":0,"is_preprint":true},{"pmid":null,"id":"bio_10.1101_2024.12.11.24318855","title":"The Impact of Obesity-Related Genetic Variants on NF-κB Signaling in Cardiovascular Disease: A Systematic Review","date":"2024-12-11","source":"bioRxiv","url":"https://doi.org/10.1101/2024.12.11.24318855","citation_count":0,"is_preprint":true},{"pmid":null,"id":"bio_10.1101_2024.09.08.611829","title":"β2-Adrenergic Biased Agonist Nebivolol Inhibits the Development of Th17 and the Response of Memory Th17 Cells in an NF-κB-Dependent Manner","date":"2024-09-10","source":"bioRxiv","url":"https://doi.org/10.1101/2024.09.08.611829","citation_count":0,"is_preprint":true},{"pmid":null,"id":"bio_10.1101_2024.07.05.602301","title":"Unbiased multiplex antigen screening of Cerebrospinal Fluid detects microbial and autoantigenic epitopes associated with Multiple Sclerosis","date":"2024-07-09","source":"bioRxiv","url":"https://doi.org/10.1101/2024.07.05.602301","citation_count":0,"is_preprint":true}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":49795,"output_tokens":4641,"usd":0.1095,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":12755,"output_tokens":4564,"usd":0.088938,"stage2_stop_reason":"end_turn"},"total_usd":0.198438,"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\": 2007,\n      \"finding\": \"ADRB3 is present and functional in human myometrium, where ADRB3 agonists inhibit spontaneous contractions via a cAMP-mediated pathway. ADRB3 is the predominant beta-adrenergic subtype over ADRB2 in human myometrium, its expression is increased in near-term myometrium compared to non-pregnant myometrium, and unlike ADRB2, myometrial ADRB3 is resistant to long-term agonist-induced desensitization.\",\n      \"method\": \"Myometrial strip contractility assay, cAMP measurement, receptor subtype pharmacology, gene expression analysis\",\n      \"journal\": \"BMC pregnancy and childbirth\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — functional assay in human tissue with pharmacological dissection and expression analysis, single lab, multiple orthogonal methods\",\n      \"pmids\": [\"17570158\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2007,\n      \"finding\": \"ADRB3 activation in human myometrium prevents LPS-induced apoptosis (via caspase-3/BAX/BCL2 pathway) and suppresses proinflammatory cytokine production (IL-6, IL-8) in a chorioamnionitis model. The ADRB3 agonist SAR150640 blocked these effects in a concentration-dependent manner; neutralization of TNF also antagonized LPS-induced apoptosis, placing ADRB3 upstream of TNF-mediated apoptotic signaling.\",\n      \"method\": \"Western blot (CASP3, BAX, BCL2), immunostaining, RT-PCR, cytokine ELISA, in vitro LPS stimulation of human myometrial strips, pharmacological rescue with ADRB3 agonist SAR150640\",\n      \"journal\": \"Biology of reproduction\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple orthogonal in vitro methods in human tissue, single lab, pharmacological dissection with selective agonist\",\n      \"pmids\": [\"17989355\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2005,\n      \"finding\": \"ADRB3 is expressed and functional in human placental arteries; selective ADRB3 agonism induces concentration-dependent relaxation and cAMP production that is insensitive to low-dose propranolol (ADRB1/2 blocker) but blocked by high-dose propranolol. In preeclampsia, ADRB3 protein expression is decreased and ADRB3-mediated relaxation and cAMP production are impaired, without changes in ADRB3 transcript levels, indicating post-transcriptional/translational regulation.\",\n      \"method\": \"Pharmacological organ bath (arterial ring relaxation), cAMP ELISA, Western blot, RT-PCR, selective antagonist/agonist pharmacology\",\n      \"journal\": \"Biology of reproduction\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — functional pharmacology plus protein/mRNA quantification in human tissue, single lab, multiple orthogonal methods\",\n      \"pmids\": [\"16177222\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"Genetic deletion of beta3-adrenoceptor (Adrb3 knockout mice) abolishes the antidepressant-like effects of the ADRB3 agonist amibegron in the chronic mild stress model, establishing ADRB3 as necessary for mediating the antidepressant-like actions of this compound.\",\n      \"method\": \"Adrb3 knockout mice (Adrb3tm1Lowl), chronic mild stress behavioral paradigm, pharmacological challenge with amibegron\",\n      \"journal\": \"Behavioural brain research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetic loss-of-function with specific behavioral phenotype, single lab, clean KO model\",\n      \"pmids\": [\"19744528\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"Two novel ADRB3 missense polymorphisms (Ser165Pro and Ser257Pro) impair ADRB3 function by reducing cAMP accumulation in stably transfected cell lines without affecting ADRB3 mRNA/protein expression levels or receptor trafficking, establishing a functional signaling defect as the molecular mechanism underlying their association with type 2 diabetes.\",\n      \"method\": \"Site-directed mutagenesis, stable transfection (HEK293 and CHO-K1 cells), real-time PCR, Western blot, confocal microscopy (receptor trafficking), cAMP accumulation assay\",\n      \"journal\": \"The Journal of clinical endocrinology and metabolism\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — in vitro reconstitution with mutagenesis, multiple orthogonal methods (expression, trafficking, function), single lab but rigorous mechanistic characterization\",\n      \"pmids\": [\"23640967\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"Norepinephrine inhibits SDF-1-induced migration of bone marrow mesenchymal stem cells (MSCs) and suppresses their osteogenic differentiation via adrb3; siRNA knockdown of adrb3 in MSCs abolishes both the anti-migratory effect (including suppression of MMP-2 and upregulation of TIMP-3) and the inhibition of osteogenic marker genes (ALP, OCN, RUNX2), placing ADRB3 as the essential receptor mediating sympathetic nervous system suppression of MSC function.\",\n      \"method\": \"Transwell migration assay, siRNA knockdown of adrb3, in vitro osteogenic differentiation (bone nodule formation), gene expression analysis, rat mandibular distraction osteogenesis model with cervical sympathetic trunk transection\",\n      \"journal\": \"PloS one\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — siRNA loss-of-function with defined cellular phenotypes and pathway placement, in vivo sympathetic denervation model, single lab\",\n      \"pmids\": [\"25144690\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"HDAC3 represses miR-18a expression in cardiomyocytes, and miR-18a directly targets ADRB3 (validated by dual luciferase reporter assay); ADRB3 is upregulated in heart failure, and its downregulation (along with HDAC3 silencing or miR-18a overexpression) reduces cardiac fibrosis, hypertrophy, and apoptosis in HF mouse models.\",\n      \"method\": \"Dual luciferase reporter assay (miR-18a targeting ADRB3), RT-qPCR, Western blot, mouse coronary artery ligation HF model, ectopic expression and silencing experiments, flow cytometry (apoptosis), TUNEL staining, echocardiography\",\n      \"journal\": \"Cell & bioscience\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — luciferase reporter validates miRNA-target relationship, supported by in vivo and in vitro loss-of-function, single lab\",\n      \"pmids\": [\"33549119\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"Brown adipocyte-specific ADRB3 knockout (BKO) mice exhibit accelerated cardiac hypertrophy and fibrosis in response to angiotensin II. Mechanistically, ADRB3 activation in brown adipocytes suppresses iNOS loading into secreted exosomes; loss of ADRB3 or pharmacological antagonism increases exosomal iNOS, which drives cardiac fibroblast dysfunction. Knockdown of iNOS in brown adipocytes reverses the pro-fibrotic effect of ADRB3-deficient exosomes, establishing a brown adipocyte ADRB3 → exosomal iNOS → cardiac fibrosis signaling axis.\",\n      \"method\": \"Brown adipocyte-specific ADRB3 knockout mice, angiotensin II infusion model, exosome isolation and intravenous injection, exosome inhibitor treatment, iNOS siRNA knockdown, in vitro co-culture of brown adipocytes with cardiac fibroblasts, gene expression analysis\",\n      \"journal\": \"Circulation research\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — cell-type-specific KO with defined cardiac phenotype, mechanistic rescue by iNOS knockdown, multiple orthogonal methods across in vivo and in vitro systems, single lab with rigorous controls\",\n      \"pmids\": [\"35652349\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"ADRB3 promotes breast cancer cell proliferation and inhibits their transdifferentiation into adipocyte-like cells by activating the mTOR pathway. ADRB3 also expands myeloid-derived suppressor cells (MDSCs) by stimulating bone marrow mobilization and inhibiting differentiation of immature myeloid cells. ADRB3-knockout PyMT mice show an MDSC-deficient phenotype associated with impaired mammary tumorigenesis and reduced pulmonary metastasis.\",\n      \"method\": \"ADRB3 knockout mice (PyMT model), immunohistochemistry, MCF-7 cell proliferation and differentiation assays, mTOR pathway analysis, MDSC quantification, in vivo tumor and metastasis assessment\",\n      \"journal\": \"Cell death & disease\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — in vivo KO model with defined tumor phenotype, pathway placement via mTOR, multiple cell type analyses, single lab\",\n      \"pmids\": [\"35145073\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"WWP1 (a HECT-type E3 ubiquitin ligase) suppresses Adrb3 mRNA expression in white adipose tissue of obese mice independently of noradrenaline metabolism; Wwp1 knockout increases Adrb3 expression and phosphorylated hormone-sensitive lipase levels, enhancing lipolysis, establishing WWP1 as a negative regulator of the ADRB3-lipolysis axis.\",\n      \"method\": \"Wwp1 knockout mice on high-fat diet, mRNA quantification, phospho-HSL Western blot, noradrenaline measurement in WAT\",\n      \"journal\": \"International journal of molecular sciences\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — clean genetic KO with defined molecular phenotype (Adrb3 expression, HSL phosphorylation), single lab, mechanistic pathway placement\",\n      \"pmids\": [\"40362456\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"Swertiamarin (STM) directly interacts with ADRB3 and activates ADRB3/UCP1 thermogenic signaling in adipocytes, increasing glucose uptake, glycerol release, p-HSL expression, mitochondrial content, and oxidative phosphorylation complex expression; all these effects are reversed upon ADRB3 inhibition, establishing ADRB3 as the necessary receptor mediating STM's thermogenic and lipolytic actions in adipose tissue.\",\n      \"method\": \"Molecular docking (STM-ADRB3 interaction), 3T3-L1 adipocyte differentiation model, ADRB3 inhibitor rescue experiments, cAMP/UCP1/p-HSL assays, mitochondrial membrane potential measurement, in vivo T2DM mouse model (HFD/STZ), bioinformatics\",\n      \"journal\": \"Phytomedicine\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — pharmacological loss-of-function rescue in vitro with multiple readouts, single lab; molecular docking provides supporting but not definitive structural evidence\",\n      \"pmids\": [\"39515102\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"The suprachiasmatic nucleus (SCN) restrains ADRB3 signaling in brown adipose tissue; SCN lesioning leads to sustained ADRB3 activity accompanied by upregulation of S100B in BAT, which promotes thermogenesis by stimulating brown adipocyte proliferation and suppressing senescence. S100B is both necessary and sufficient for sustaining BAT thermogenesis downstream of ADRB3, defining a SCN→ADRB3→S100B signaling axis governing thermogenic output.\",\n      \"method\": \"SCN lesioning (NMDA excitotoxicity, Caspase-3 ablation, light-induced arrhythmia), β3-agonist CL 316,243 treatment, S100B gain- and loss-of-function, brown adipocyte proliferation and senescence assays, indirect calorimetry, gene expression analysis\",\n      \"journal\": \"PLoS biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple SCN disruption models converge on same phenotype, S100B necessity and sufficiency tested, single lab with multiple orthogonal approaches\",\n      \"pmids\": [\"41343575\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2026,\n      \"finding\": \"Stress activates ADRB3 in brown adipocytes to induce IL-6 production via cAMP-PKA-CREB signaling, which transcriptionally upregulates KLF7, and KLF7 in turn drives IL-6 expression; Klf7 adipocyte-specific knockout abolishes ADRB3-induced IL-6 production, placing KLF7 as an essential effector downstream of the ADRB3-cAMP-PKA-CREB axis for stress-induced IL-6 secretion.\",\n      \"method\": \"Klf7 adipocyte-specific knockout mice, ADRB3 agonist administration in vivo and in vitro, cAMP-PKA-CREB pathway inhibition, CREB ChIP at KLF7 promoter, IL-6 ELISA, brown adipocyte primary culture\",\n      \"journal\": \"Journal of lipid research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — adipocyte-specific KO with defined IL-6 phenotype, CREB-KLF7 promoter binding, in vivo and in vitro validation, single lab\",\n      \"pmids\": [\"41565113\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"Fat tissue-specific deletion of Adrb3 in adipocytes protects mice from acute alcohol binge-induced adipose tissue lipolysis, hepatic fat accumulation, and liver injury; systemic and local sympathetic nerve ablation phenocopies adipocyte Adrb3 deletion, establishing the sympathetic nerve→ADRB3→WAT lipolysis→liver steatosis pathway.\",\n      \"method\": \"Adipocyte-specific Adrb3 knockout mice (Adrb3 FKO), 6-OHDA sympathetic denervation (systemic and local), acute alcohol binge model, plasma FFA measurement, hepatic fat quantification, liver injury markers, WAT norepinephrine measurement\",\n      \"journal\": \"bioRxiv\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — adipocyte-specific KO with defined metabolic phenotype, convergent sympathetic denervation evidence, single lab; preprint status lowers certainty\",\n      \"pmids\": [],\n      \"is_preprint\": true\n    },\n    {\n      \"year\": 2026,\n      \"finding\": \"In C3H/HeJ mice, Adrb3 expression is minimal in BAT and WAT and is unaffected by cold exposure; β3-agonist CL 316,243 fails to increase energy expenditure in C3H mice (though it does in C57BL/6J mice), while norepinephrine increases EE in both strains and propranolol (β1/β2 antagonist) abolishes strain differences—demonstrating that C3H mice achieve cold-induced thermogenesis via ADRB3-independent (β1/β2 or non-canonical) mechanisms.\",\n      \"method\": \"Indirect calorimetry (Promethion), β3-agonist CL 316,243 challenge, norepinephrine challenge, propranolol pretreatment, BAT/WAT gene expression analysis, comparative strain study (C57BL/6J vs C3H/HeJ)\",\n      \"journal\": \"Scientific reports\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — pharmacological dissection with multiple adrenergic agents, two-strain comparison, negative result for ADRB3 in C3H explicitly tested and confirmed, single lab\",\n      \"pmids\": [\"41663555\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"ADRB3 is a G-protein-coupled β3-adrenergic receptor that couples to cAMP-PKA signaling in adipose tissue and other cell types to regulate lipolysis, thermogenesis (via UCP1), and energy metabolism; in brown adipocytes it controls an exosomal iNOS pathway that protects the heart from remodeling and a cAMP-PKA-CREB-KLF7 axis that drives stress-induced IL-6 secretion; in white adipose tissue it mediates sympathetic nerve-stimulated lipolysis (regulated negatively by the E3 ubiquitin ligase WWP1); in human myometrium it signals through cAMP to suppress contractions and inflammation while resisting desensitization; and loss-of-function variants that impair cAMP accumulation are mechanistically linked to metabolic disorders including type 2 diabetes.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"ADRB3 is a G-protein-coupled β3-adrenergic receptor that transduces sympathetic and pharmacological catecholamine signals into cAMP-dependent responses governing adipose energy metabolism, smooth muscle relaxation, and tissue protection [#0, #4, #10]. In adipocytes it activates ADRB3/UCP1 thermogenic signaling and PKA-dependent lipolysis, raising cAMP, phosphorylating hormone-sensitive lipase, and increasing mitochondrial oxidative capacity [#10]; this lipolytic axis is restrained by the HECT-type E3 ubiquitin ligase WWP1, which suppresses Adrb3 mRNA in white adipose tissue independently of noradrenaline metabolism [#9]. Sympathetic input through adipocyte ADRB3 drives white adipose lipolysis that feeds hepatic fat accumulation and liver injury during alcohol challenge [#13], while in brown adipose tissue the receptor's thermogenic output is tuned by the suprachiasmatic nucleus via an S100B-dependent program [#11]. Beyond metabolism, brown adipocyte ADRB3 acts as a cardioprotective node: it suppresses iNOS loading into secreted exosomes, and its loss raises exosomal iNOS that drives cardiac fibroblast dysfunction and remodeling [#7], and the receptor also signals through cAMP-PKA-CREB to transcriptionally induce KLF7 and stress-evoked IL-6 secretion [#12]. In human myometrium and placental arteries ADRB3 is the predominant β-adrenergic subtype, signaling through cAMP to inhibit contractions, relax vasculature, and suppress LPS-induced apoptosis and proinflammatory cytokines, while resisting agonist-induced desensitization [#0, #1, #2]. Loss-of-function missense variants (Ser165Pro, Ser257Pro) that reduce cAMP accumulation without altering expression or trafficking mechanistically link impaired ADRB3 signaling to type 2 diabetes [#4].\",\n  \"teleology\": [\n    {\n      \"year\": 2007,\n      \"claim\": \"Established that ADRB3 is the dominant functional β-adrenergic subtype in human reproductive smooth muscle, answering whether a peripheral receptor could control myometrial tone via cAMP and resist the desensitization that limits ADRB2-targeted tocolytics.\",\n      \"evidence\": \"Myometrial strip contractility, cAMP measurement, subtype pharmacology, and arterial ring relaxation in human tissue\",\n      \"pmids\": [\"17570158\", \"16177222\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Molecular basis of desensitization resistance not defined\", \"Downstream effectors linking cAMP to contractile suppression not mapped\", \"Preeclampsia decrease shown post-transcriptionally but regulatory mechanism unidentified\"]\n    },\n    {\n      \"year\": 2007,\n      \"claim\": \"Showed ADRB3 activation is anti-inflammatory and anti-apoptotic in myometrium, placing the receptor upstream of TNF-mediated apoptotic signaling in a chorioamnionitis model.\",\n      \"evidence\": \"LPS stimulation of human myometrial strips with selective agonist SAR150640, caspase-3/BAX/BCL2 Western blot, cytokine ELISA, TNF neutralization\",\n      \"pmids\": [\"17989355\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Signaling intermediates between ADRB3 and caspase/cytokine outputs not resolved\", \"In vivo relevance to preterm labor untested\"]\n    },\n    {\n      \"year\": 2009,\n      \"claim\": \"Genetic deletion demonstrated ADRB3 is necessary for an antidepressant-like behavioral response, extending its functional reach beyond peripheral tissues.\",\n      \"evidence\": \"Adrb3 knockout mice in a chronic mild stress paradigm with amibegron challenge\",\n      \"pmids\": [\"19744528\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Site and circuit of action not localized\", \"Downstream signaling in this context uncharacterized\"]\n    },\n    {\n      \"year\": 2013,\n      \"claim\": \"Defined the molecular lesion behind disease-associated ADRB3 variants, showing that impaired cAMP accumulation—not altered expression or trafficking—links the receptor to type 2 diabetes.\",\n      \"evidence\": \"Site-directed mutagenesis, stable HEK293/CHO-K1 expression, confocal trafficking analysis, and cAMP accumulation assays\",\n      \"pmids\": [\"23640967\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Conformational/coupling defect causing reduced cAMP not structurally explained\", \"In vivo metabolic consequence of these specific variants not modeled\"]\n    },\n    {\n      \"year\": 2014,\n      \"claim\": \"Placed ADRB3 as the essential receptor by which sympathetic norepinephrine suppresses mesenchymal stem cell migration and osteogenic differentiation.\",\n      \"evidence\": \"siRNA knockdown in MSCs, transwell migration, osteogenic differentiation assays, and a rat sympathetic denervation model\",\n      \"pmids\": [\"25144690\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Intracellular signaling from ADRB3 to MMP-2/TIMP-3 and osteogenic genes not delineated\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Identified ADRB3 as a direct miR-18a target under HDAC3 control in the heart, connecting its upregulation to cardiac fibrosis, hypertrophy, and apoptosis in heart failure.\",\n      \"evidence\": \"Dual luciferase reporter, RT-qPCR/Western blot, coronary artery ligation HF model, and gain/loss-of-function with echocardiography\",\n      \"pmids\": [\"33549119\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Cardiomyocyte-autonomous vs systemic contribution of ADRB3 not separated\", \"Signaling downstream of cardiac ADRB3 in HF not detailed\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Defined a tissue-crosstalk mechanism whereby brown adipocyte ADRB3 protects the heart by restraining iNOS loading into secreted exosomes.\",\n      \"evidence\": \"Brown adipocyte-specific Adrb3 knockout, angiotensin II model, exosome isolation/injection, iNOS siRNA rescue, and adipocyte–fibroblast co-culture\",\n      \"pmids\": [\"35652349\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"How ADRB3-cAMP signaling controls iNOS exosomal sorting not mechanistically resolved\", \"Receptor(s) on cardiac fibroblasts receiving exosomal iNOS not identified\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Revealed a pro-tumor role for ADRB3 in driving breast cancer proliferation via mTOR and expanding myeloid-derived suppressor cells.\",\n      \"evidence\": \"ADRB3 knockout PyMT mice, MCF-7 proliferation/transdifferentiation assays, mTOR pathway analysis, and MDSC quantification\",\n      \"pmids\": [\"35145073\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct coupling between ADRB3 and mTOR not biochemically established\", \"Cell-of-origin for MDSC effect not defined\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Demonstrated that pharmacological ADRB3 agonism (swertiamarin) is necessary to activate ADRB3/UCP1 thermogenic and lipolytic signaling, reinforcing the receptor's metabolic effector role.\",\n      \"evidence\": \"Molecular docking, 3T3-L1 adipocytes with ADRB3 inhibitor rescue, cAMP/UCP1/p-HSL and mitochondrial assays, and a T2DM mouse model\",\n      \"pmids\": [\"39515102\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Docking does not establish a defined binding site or direct agonism in cells\", \"Selectivity over other adrenergic receptors not exhaustively tested\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Established a sympathetic-nerve→adipocyte ADRB3→WAT lipolysis→liver steatosis pathway driving alcohol-induced liver injury.\",\n      \"evidence\": \"Adipocyte-specific Adrb3 knockout and 6-OHDA sympathetic denervation in an acute alcohol binge model (preprint)\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Preprint, not peer-reviewed\", \"Mediators carrying lipolytic FFA signal to liver not specified\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Identified WWP1 as a transcriptional/expression-level negative regulator of the ADRB3-lipolysis axis in obese white adipose tissue.\",\n      \"evidence\": \"Wwp1 knockout mice on high-fat diet, Adrb3 mRNA quantification, phospho-HSL Western blot, and WAT noradrenaline measurement\",\n      \"pmids\": [\"40362456\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Mechanism by which the WWP1 E3 ligase suppresses Adrb3 mRNA not defined\", \"Direct substrate linking WWP1 to Adrb3 expression unknown\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Showed the suprachiasmatic nucleus restrains brown adipose ADRB3 signaling and that S100B is necessary and sufficient to sustain thermogenesis downstream, defining a central clock→ADRB3→S100B thermogenic axis.\",\n      \"evidence\": \"Multiple SCN disruption models, β3-agonist CL 316,243, S100B gain/loss-of-function, and indirect calorimetry\",\n      \"pmids\": [\"41343575\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Signaling linking ADRB3 activity to S100B induction not detailed\", \"How SCN output reaches BAT to limit ADRB3 not mapped\"]\n    },\n    {\n      \"year\": 2026,\n      \"claim\": \"Defined a stress-responsive cAMP-PKA-CREB-KLF7 transcriptional cascade by which brown adipocyte ADRB3 drives IL-6 secretion.\",\n      \"evidence\": \"Klf7 adipocyte-specific knockout, ADRB3 agonist in vivo/in vitro, pathway inhibition, CREB ChIP at the KLF7 promoter, and IL-6 ELISA\",\n      \"pmids\": [\"41565113\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Physiological consequences of ADRB3-driven IL-6 not established\", \"KLF7-IL6 promoter regulation not fully mapped\"]\n    },\n    {\n      \"year\": 2026,\n      \"claim\": \"Demonstrated genetic-background dependence of ADRB3's thermogenic role, with C3H/HeJ mice achieving cold-induced thermogenesis through ADRB3-independent β1/β2 or non-canonical routes.\",\n      \"evidence\": \"Indirect calorimetry with CL 316,243, norepinephrine, and propranolol challenge in a C57BL/6J vs C3H/HeJ comparison\",\n      \"pmids\": [\"41663555\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Cause of minimal Adrb3 expression in C3H not determined\", \"Identity of compensating non-canonical thermogenic mechanism unresolved\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How a single cAMP-coupled receptor selects among divergent outputs—lipolysis, thermogenesis, exosomal cargo sorting, transcriptional IL-6 induction, contractile relaxation—across tissues remains unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No structural model of ADRB3 ligand binding or G-protein coupling in the corpus\", \"Tissue-specific effector selection mechanism unknown\", \"Direct physical partners of the receptor not characterized\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0060089\", \"supporting_discovery_ids\": [0, 2, 4, 10]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005886\", \"supporting_discovery_ids\": [4]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [4, 10, 12]},\n      {\"term_id\": \"R-HSA-1430728\", \"supporting_discovery_ids\": [9, 10, 11, 13]}\n    ],\n    \"complexes\": [],\n    \"partners\": [],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":5,"faith_total":6,"faith_pct":83.33333333333333}}