{"gene":"ADIPOR2","run_date":"2026-04-28T17:12:37","timeline":{"discoveries":[{"year":2007,"finding":"Targeted disruption of AdipoR2 in mice abrogates adiponectin binding and results in decreased PPAR-α signaling activity, increased tissue triglyceride content, inflammation, oxidative stress, insulin resistance, and glucose intolerance; simultaneous disruption of both AdipoR1 and AdipoR2 abolishes all adiponectin binding and actions in vivo.","method":"Targeted gene disruption (knockout mice), adenovirus-mediated receptor re-expression in liver of Lepr(-/-) mice, metabolic phenotyping","journal":"Nature medicine","confidence":"High","confidence_rationale":"Tier 2 — clean KO with defined metabolic phenotypes, replicated with gain-of-function rescue, highly cited foundational study","pmids":["17268472"],"is_preprint":false},{"year":2008,"finding":"Hepatic AdipoR2 signaling promotes PPAR-α activity and catalase expression; knockdown of AdipoR2 diminishes PPAR-α signaling (decreased ACO and catalase), increases lipid peroxidation and ROS accumulation, and worsens NASH pathology; overexpression reverses these effects.","method":"Adenovirus-mediated shRNA knockdown and overexpression in mice on MCD diet; primary hepatocyte culture with TGF-β; gene expression and ROS assays","journal":"Hepatology (Baltimore, Md.)","confidence":"High","confidence_rationale":"Tier 2 — bidirectional manipulation (KD and OE) with clear pathway placement and phenotypic readouts in vivo and in vitro","pmids":["18666257"],"is_preprint":false},{"year":2008,"finding":"AdipoR2 (along with AdipoR1) mediates adiponectin-stimulated ERK1/2 activation through a Src kinase- and Ras-dependent pathway; downregulation of the adapter protein APPL1 impairs this signaling; simultaneous knockdown of both receptors attenuates ERK1/2 activation, while overexpression of either receptor or adiponectin promotes HEK293 cell growth.","method":"RNA interference in HEK293 cells, pharmacological inhibition (PP2, Clostridium difficile toxin B), Ras activation assay, cell growth assay","journal":"Biochemistry","confidence":"High","confidence_rationale":"Tier 2 — multiple orthogonal inhibition methods and functional readout in same study","pmids":["18842004"],"is_preprint":false},{"year":2010,"finding":"AdipoR2 (but not AdipoR1) serves as the dominant receptor for adiponectin in suppression of scavenger receptor A type 1 (SR-AI) and upregulation of IL-1Ra in macrophage foam cells; the adapter protein APPL1 mediates adiponectin-induced inhibition of lipid accumulation and NF-κB, and Akt phosphorylation through both receptors.","method":"Lentiviral-shRNA knockdown of AdipoR1, AdipoR2, and APPL1 in THP-1 monocytes; foam cell transformation with oxLDL; gene expression and protein analysis","journal":"Atherosclerosis","confidence":"High","confidence_rationale":"Tier 2 — receptor-specific KD with defined cytokine signaling differences, APPL1 adapter mechanistically placed","pmids":["22227293"],"is_preprint":false},{"year":2010,"finding":"ERp46 interacts specifically with AdipoR1 (not AdipoR2), mediated by the cytoplasmic N-terminal residues (1–70) of AdipoR1; ERp46 knockdown increases surface levels of both AdipoR1 and AdipoR2 and enhances adiponectin-stimulated AMPK phosphorylation, while reducing p38MAPK phosphorylation.","method":"Co-immunoprecipitation followed by mass spectrometry, GST-fusion protein pulldown with truncated constructs, indirect immunofluorescence, subcellular fractionation, siRNA knockdown, phosphorylation assays","journal":"Biochemical and biophysical research communications","confidence":"High","confidence_rationale":"Tier 2 — reciprocal Co-IP/MS plus domain mapping and functional signaling consequence of KD","pmids":["20074551"],"is_preprint":false},{"year":2010,"finding":"AdipoR2 expression in the anterior cingulate cortex is regulated by alcohol in a K-ras-dependent manner; AdipoR2 null mice show attenuated withdrawal-associated increased drinking; adiponectin increases excitability of ACC neurons through AdipoR2, an effect enhanced during alcohol withdrawal.","method":"Gene expression analysis (ACC), AdipoR2 knockout mice behavioral testing, intracellular electrophysiological recordings in brain slices","journal":"Brain research","confidence":"Medium","confidence_rationale":"Tier 2 — KO mouse with behavioral and electrophysiological phenotypes, single lab","pmids":["20380822"],"is_preprint":false},{"year":2010,"finding":"ATF3, induced by ER stress, transcriptionally represses AdipoR2 by binding a region between nucleotides -94 and -86 of the AdipoR2 promoter, reducing both AdipoR2 mRNA and protein in hepatocytes.","method":"Reporter gene assays with 5'-deleted AdipoR2 promoter constructs, EMSA, chromatin immunoprecipitation, siRNA/overexpression of ATF3 in HepG2 cells","journal":"The FEBS journal","confidence":"High","confidence_rationale":"Tier 1 — in vitro promoter dissection with EMSA and ChIP identifying specific binding site","pmids":["20423458"],"is_preprint":false},{"year":2013,"finding":"C. elegans PAQR-2 (AdipoR2 homolog) regulates fatty acid desaturation and phosphatidylcholine synthesis during cold adaptation to maintain membrane fluidity; genetic suppressors of paqr-2 phenotypes act through fatty acid metabolism genes and Δ9-desaturases.","method":"Suppressor screen in C. elegans, genetic epistasis analysis, fatty acid composition measurements","journal":"PLoS genetics","confidence":"High","confidence_rationale":"Tier 2 — forward genetic suppressor screen with epistasis analysis in ortholog organism, multiple replicated interactions","pmids":["24068966"],"is_preprint":false},{"year":2013,"finding":"The non-conserved N-terminal region of AdipoR2 (residues 1–81) prevents its constitutive cell-surface expression; AdipoR1 and AdipoR2 can form heterodimers, and co-expression with AdipoR1 promotes cell-surface localization of AdipoR2.","method":"Epitope-tagged receptor constructs, indirect immunofluorescence, quantitative plate-based cell-surface expression analysis, chimeric and truncated receptor constructs","journal":"Biochemical and biophysical research communications","confidence":"High","confidence_rationale":"Tier 2 — systematic chimeric/truncation analysis with quantitative surface expression readout, domain responsibility clearly mapped","pmids":["23376713"],"is_preprint":false},{"year":2014,"finding":"In vivo, AdipoR2 (but not AdipoR1) is required for adiponectin-dependent revascularization after hindlimb ischemia; conversely, AdipoR1 (but not AdipoR2) deficiency causes diet-induced metabolic dysfunction, revealing divergent in vivo roles of the two receptors.","method":"AdipoR1- and AdipoR2-deficient mice subjected to hindlimb ischemia surgery and diet-induced obesity models; blood flow recovery measurement; metabolic phenotyping","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 2 — parallel KO studies with two distinct physiological models revealing receptor-specific functions","pmids":["24742672"],"is_preprint":false},{"year":2015,"finding":"The non-conserved N-terminal trunks of AdipoR1 and AdipoR2 define differential temporal signaling profiles: AdipoR1 peaks at 15 min and AdipoR2 at 24 h post-adiponectin stimulation; adiponectin also induces internalization of both receptors from the cell surface.","method":"Transient expression in HEK293 cells, receptor chimera analysis, temporal phosphorylation profiling of downstream effectors, cell-surface expression quantification","journal":"Molecular and cellular endocrinology","confidence":"Medium","confidence_rationale":"Tier 2 — chimeric receptor approach with temporal signaling readout, single lab","pmids":["25892445"],"is_preprint":false},{"year":2015,"finding":"Crystal structures of truncated human AdipoR1 (Δ88) and AdipoR2 (Δ99) were obtained at 2.8 Å and 2.4 Å resolution respectively by lipidic mesophase crystallography with anti-AdipoR1 Fv; both proteins bind lipids and show structural integrity by SPR ligand binding and thermostability assays.","method":"Protein expression in insect cells, affinity purification, lipidic mesophase crystallization, X-ray crystallography, SPR, thermostability assay, TLC of bound lipids","journal":"Journal of structural and functional genomics","confidence":"High","confidence_rationale":"Tier 1 — crystal structures obtained with functional validation by SPR and thermostability","pmids":["25575462"],"is_preprint":false},{"year":2016,"finding":"AdipoR2 deletion in the dentate gyrus (DG) of the hippocampus results in augmented contextual fear expression, reduced extinction, and intrinsic hyperexcitability of DG granule neurons; adiponectin and AdipoRon fail to suppress fear or neuronal excitability in AdipoR2 knockout mice, placing AdipoR2 as the necessary and sufficient receptor for these effects.","method":"DG-specific AdipoR2 knockout mice, contextual fear conditioning/extinction behavioral tests, whole-cell patch-clamp recordings in brain slices, AdipoRon pharmacology","journal":"Molecular psychiatry","confidence":"High","confidence_rationale":"Tier 2 — region-specific KO plus pharmacological rescue attempt, combined behavioral and electrophysiological readouts","pmids":["27137743"],"is_preprint":false},{"year":2016,"finding":"C. elegans PAQR-2 (AdipoR2 homolog) and its partner IGLR-2 physically interact at plasma membranes and together function as a membrane fluidity sensor; paqr-2 or iglr-2 mutants are glucose-intolerant and die in the presence of 20 mM glucose due to membrane rigidification; their function is independent of the insulin/FoxO pathway.","method":"Bimolecular fluorescence complementation (BiFC) for protein interaction, FRAP for membrane fluidity, genetic epistasis with daf-2 and daf-16, glucose intolerance assays","journal":"PLoS genetics","confidence":"High","confidence_rationale":"Tier 2 — direct protein interaction shown by BiFC, functional assays with membrane fluidity measurements, epistasis analysis","pmids":["27082444"],"is_preprint":false},{"year":2017,"finding":"AdipoR2 (and C. elegans PAQR-2) are essential to counter membrane rigidification caused by exogenously provided saturated fatty acids; mammalian cells with AdipoR2 knocked down by siRNA cannot prevent palmitic acid-induced membrane rigidity; this function is evolutionarily conserved.","method":"Dietary supplement experiments in C. elegans paqr-2 mutants, direct membrane fluidity measurement, siRNA KD of AdipoR2 in mammalian cells, lipidomics of phospholipid fatty acid composition","journal":"PLoS genetics","confidence":"High","confidence_rationale":"Tier 1–2 — direct fluidity measurements in both organisms, KD phenotype in mammalian cells, lipidomics","pmids":["28886012"],"is_preprint":false},{"year":2017,"finding":"AdipoR2 (but not AdipoR1) in hepatic stellate cells modulates Col1-α1, α-SMA gene expression, HSC migration, and AMPK activity in response to adiponectin, establishing AdipoR2 as the major anti-fibrotic adiponectin receptor on HSCs.","method":"AdipoR1 and AdipoR2 knockout mice in CCl4 liver fibrosis model; siRNA knockdown in primary hepatic stellate cells with adiponectin treatment; gene expression, migration assays, AMPK activity measurement","journal":"Biochimica et biophysica acta. Molecular basis of disease","confidence":"High","confidence_rationale":"Tier 2 — in vivo KO and in vitro KD with receptor-specific functional phenotypes","pmids":["29237572"],"is_preprint":false},{"year":2018,"finding":"PAQR-2 (AdipoR2 homolog) expression in the hypodermis, gonad sheath cells, or intestine of C. elegans is sufficient to non-cell-autonomously maintain membrane fluidity throughout the organism, including in intestinal cells where PAQR-2 is not expressed; this cell-nonautonomous regulation is conserved in human HEK293 cells where AdipoR2-expressing cells normalize membrane fluidity in neighboring AdipoR2-silenced cells; Δ9 desaturases are essential effectors of this process.","method":"Mosaic analysis, tissue-specific rescue expression constructs in C. elegans, FRAP membrane fluidity assay, SCD siRNA in HEK293 cells","journal":"Genetics","confidence":"High","confidence_rationale":"Tier 2 — mosaic/tissue-specific genetics plus direct fluidity measurements in two organisms","pmids":["29997234"],"is_preprint":false},{"year":2019,"finding":"AdipoR1 and AdipoR2 are essential for sustaining desaturase expression and high levels of unsaturated fatty acids in membrane phospholipids of many human cell types including primary HUVECs, and for preventing membrane rigidification in cells challenged with exogenous palmitate; this function is independent of adiponectin.","method":"AdipoR1/AdipoR2 KD, FRAP, Laurdan dye generalized polarization, mass spectrometry of phospholipid fatty acid composition; experiments performed in absence of adiponectin","journal":"Journal of lipid research","confidence":"High","confidence_rationale":"Tier 1–2 — three independent methods measuring membrane fluidity/composition, multiple cell types including primary cells, adiponectin-independent condition tested","pmids":["30890562"],"is_preprint":false},{"year":2019,"finding":"PAQR-2 (AdipoR2 homolog) senses temperature drop in C. elegans and promotes biosynthesis of γ-linolenic acid and arachidonic acid (ω-6 PUFAs), which initiate autophagy in the epidermis, delaying collagen decline and extending lifespan at low temperature.","method":"C. elegans genetic analysis, fatty acid profiling, autophagy assays, lifespan measurements at low temperature","journal":"Nature communications","confidence":"High","confidence_rationale":"Tier 2 — pathway dissection linking receptor to PUFA synthesis, autophagy, and lifespan in ortholog organism","pmids":["31197136"],"is_preprint":false},{"year":2021,"finding":"AdipoR2-deficient HEK293 cells challenged with saturated fatty acids show extensive transcriptome dysregulation similar to SREBP-deficient cells; AdipoR2 is the most important factor (among AdipoR2, SCD, FADS2, PEMT, ACSL4) for preventing membrane rigidification and excess saturation in cells challenged with exogenous SFAs; AdipoR2 deficiency impairs growth and respiration.","method":"Transcriptomics, lipidomics, growth and respiration assays, membrane property analysis in AdipoR2 KD HEK293 and HUVEC cells; comparative gene KD analysis","journal":"Biochimica et biophysica acta. Molecular and cell biology of lipids","confidence":"High","confidence_rationale":"Tier 1–2 — multi-omic approach with transcriptomics, lipidomics, and functional assays; gene comparison hierarchy established","pmids":["33444759"],"is_preprint":false},{"year":2021,"finding":"PAQR-2/IGLR-2 (AdipoR2 pathway) is the only pathway specifically essential for tolerance to dietary saturated fatty acids in a whole-organism C. elegans forward genetic screen; SFA-rich diet causes membrane rigidification in paqr-2 mutants; FRET analysis shows that the PAQR-2/IGLR-2 interaction is regulated by membrane fluidity, indicating a fluidity-sensing mechanism; the cytoplasmic N-terminal domain of PAQR-2 is dispensable for function but interaction with IGLR-2 is required.","method":"Whole-organism forward genetic screen in C. elegans, fluorescence resonance energy transfer (FRET), phospholipid fatty acid composition by mass spectrometry, FRAP membrane fluidity assay, domain deletion analysis","journal":"Biochimica et biophysica acta. Molecular and cell biology of lipids","confidence":"High","confidence_rationale":"Tier 1–2 — genome-wide forward screen, FRET-based interaction regulation, multiple orthogonal methods","pmids":["33444761"],"is_preprint":false},{"year":2021,"finding":"CTRP3 suppresses Th17 cell differentiation via AdipoR2 (not AdipoR1); suppression of Rorc and Stat3 expression by CTRP3 is blocked by AdipoR2 antagonist but not AdipoR1 antagonist; AdipoRon also suppresses Th17 differentiation via AdipoR2; CTRP3 deficiency enhances EAE development associated with increased Th17 population.","method":"Receptor-specific antagonists, C1qtnf3 knockout mice, Th17 differentiation assays in vitro, EAE model","journal":"Frontiers in immunology","confidence":"Medium","confidence_rationale":"Tier 2 — receptor-specific pharmacological blockade with KO mice and cellular differentiation readouts, single lab","pmids":["34925309"],"is_preprint":false},{"year":2022,"finding":"RNF145, an ER-resident E3 ubiquitin ligase, is a lipid-sensitive regulator that ubiquitinates and degrades AdipoR2 when membranes are enriched in unsaturated fatty acids; when membranes become saturated, RNF145 undergoes auto-ubiquitination and is degraded, stabilizing AdipoR2 whose hydrolase activity restores lipid homeostasis; this defines an autoregulatory loop controlling membrane lipid composition.","method":"Systematic proteomics of cells fed saturated vs unsaturated FAs, RNF145 and AdipoR2 interaction biochemistry, ubiquitination assays, RNF145 KO/KD, membrane fluidity and lipid composition measurements, lipotoxicity assays","journal":"The EMBO journal","confidence":"High","confidence_rationale":"Tier 1–2 — systematic proteomic discovery plus mechanistic ubiquitination assays with functional lipotoxicity readout, comprehensive study","pmids":["35993436"],"is_preprint":false},{"year":2023,"finding":"AdipoR2 promotes elongation of membrane-fluidizing polyunsaturated fatty acids and their incorporation into phospholipids by recruiting protein interactors; co-immunoprecipitation with MS identified HACD3 (dehydratase, third step in long-chain fatty acid elongation) and ACSL4 (activates unsaturated fatty acids for phospholipid channeling) as conserved AdipoR2/PAQR-2 interactors essential for membrane fluidity.","method":"13C-labeled fatty acid tracing, co-immunoprecipitation of tagged AdipoR2/PAQR-2 in HEK293 cells and C. elegans followed by mass spectrometry, functional verification of interactions","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1–2 — 13C-tracer metabolic assay plus co-IP/MS in two organisms, specific interactors functionally validated","pmids":["37164154"],"is_preprint":false},{"year":2024,"finding":"AdipoR2 regulates the meiosis-specific lipidome in mouse testes by promoting ELOVL2 expression (both transcriptionally and post-transcriptionally) to synthesize very-long-chain polyunsaturated fatty acids (VLC-PUFAs); AdipoR2 knockout causes depletion of VLC-PUFAs and palmitic acid accumulation, stiffening the cellular membrane, causing nuclear envelope invagination, impairing meiotic telomere distribution, and disrupting homologous synapsis, recombination, and intercellular bridge formation.","method":"AdipoR2 knockout mice, lipidomics of testes, transcriptional and protein analysis of ELOVL2, membrane fluidity assays, meiosis chromosome spread analysis, electron microscopy of nuclear envelope","journal":"Nature communications","confidence":"High","confidence_rationale":"Tier 2 — KO mouse with multi-level mechanistic analysis linking AdipoR2 to ELOVL2 regulation, lipid composition, membrane properties, and meiotic chromosome dynamics","pmids":["38485951"],"is_preprint":false},{"year":2024,"finding":"SCM-198 binds selectively to AdipoR2, with AdipoR2 R335 critical for binding/signaling and Y274 serving as a molecular switch for Ca2+ influx; SCM-198-AdipoR2 interaction causes Ca2+ influx, elevates phosphorylation of CaMKII and NOS3 in an AdipoR2-CaM-CaMKII-NOS3 complex, rapidly inducing nitric oxide production for liver protection.","method":"Molecular docking, site-directed mutagenesis (R335, Y274), co-immunoprecipitation identifying AdipoR2-CaM-CaMKII-NOS3 complex, Ca2+ influx measurement, NOS3 phosphorylation assay, ALF mouse model","journal":"Nature communications","confidence":"High","confidence_rationale":"Tier 1–2 — mutagenesis of specific residues combined with co-IP identifying a novel protein complex and in vivo functional rescue","pmids":["39681560"],"is_preprint":false},{"year":2018,"finding":"miR-449a targets AdipoR2 (confirmed by luciferase reporter assay) and suppresses its expression; loss of AdipoR2 reduces its interaction with E-cadherin in lipid rafts, promoting endothelial-to-mesenchymal transition (EndMT) and atherosclerosis in endothelial cells.","method":"Luciferase reporter assay, miR-449a mimic/inhibitor transfection, lipid raft isolation, co-immunoprecipitation of AdipoR2 and E-cadherin, ApoE KO diabetic mouse atherosclerosis model","journal":"Biomedicine & pharmacotherapy","confidence":"Medium","confidence_rationale":"Tier 3 — luciferase validation plus Co-IP interaction, single lab","pmids":["30551487"],"is_preprint":false},{"year":2006,"finding":"Adiponectin downregulates AdipoR2 expression (but not AdipoR1) in adipose tissue via a feedback loop; this was shown both in transgenic mice overexpressing adiponectin (which showed decreased AdipoR2 mRNA) and in adipocytes treated with recombinant adiponectin in vitro; conversely, AdipoR2 is upregulated in adipose tissue of adiponectin-null mice.","method":"Transgenic mice with adipose-specific adiponectin overexpression, adiponectin-null mice, 3T3-F442A adipocyte culture with recombinant adiponectin, qPCR","journal":"Biochemical and biophysical research communications","confidence":"High","confidence_rationale":"Tier 2 — bidirectional genetic (OE and KO) combined with cell culture, consistent results across systems","pmids":["16729974"],"is_preprint":false},{"year":2017,"finding":"Muscle-specific overexpression of AdipoR2 (but not AdipoR1) increases PPARα and its target gene acox1 in skeletal muscle, and in obese mice promotes systemic effects including decreased weight gain, reduced epididymal fat inflammation, and increased circulating adiponectin; both AdipoR1 and AdipoR2 overexpression increase AMPK, AKT, ERK phosphorylation and GLUT4 expression.","method":"In vivo electrotransfer-mediated gene overexpression in tibialis anterior muscle of lean and obese mice; phosphorylation assays; metabolic phenotyping","journal":"Scientific reports","confidence":"Medium","confidence_rationale":"Tier 2 — parallel OE of each receptor with signaling and metabolic readouts, single lab","pmids":["28145500"],"is_preprint":false},{"year":2021,"finding":"AdipoR2 silencing in the presence of exogenous palmitic acid causes increased dihydroceramide levels (ceramide precursor in the de novo synthesis pathway); conversely, AdipoR2 overexpression depletes dihydroceramides; the mechanism is consistent with AdipoR2 limiting intracellular palmitic acid supply to the rate-limiting serine palmitoyl transferase step.","method":"siRNA knockdown and overexpression of AdipoR2 in cultured cells, sphingolipid profiling by mass spectrometry","journal":"Lipids in health and disease","confidence":"Medium","confidence_rationale":"Tier 2 — bidirectional manipulation with lipidomics readout, single lab, mechanistic interpretation is model-based","pmids":["34839823"],"is_preprint":false},{"year":2023,"finding":"AdipoR2 activation by ESME (emodin succinate monoethyl ester) in hepatocytes activates CaMKK2 and LKB1 to activate AMPK, reducing lipogenesis; suppression of AdipoR2 expression or AMPK activation completely eliminates the lipid-reducing effect of ESME; AdipoR2 on the cytomembrane of HepG2 cells can be labeled by fluorescent ESME-Cy5.","method":"Molecular docking, fluorescent ligand labeling, AdipoR2 siRNA KD, AMPK inhibition, in vivo hamster/mouse hepatic steatosis models","journal":"Free radical biology & medicine","confidence":"Medium","confidence_rationale":"Tier 2 — receptor KD epistasis plus in vivo model with pathway mapping, single lab","pmids":["37044149"],"is_preprint":false},{"year":2024,"finding":"AdipoR2-knockout mouse brains are enlarged with ~12% excess saturated fatty acids (primarily palmitic acid at the expense of oleic acid) in phosphatidylcholines across cerebrum, cerebellum, and myelin sheaths; aging AdipoR2 KO mice exhibit hyperactivity and anxiety; cell density is lower in the cerebrum of KO mice.","method":"AdipoR2 KO mouse model, lipidomics at multiple ages, histology, electron microscopy, proteomics of cerebellum, behavioral tests","journal":"FASEB journal","confidence":"Medium","confidence_rationale":"Tier 2 — comprehensive KO phenotyping with lipidomics and behavior, single lab","pmids":["38989587"],"is_preprint":false},{"year":2024,"finding":"AdipoR2 mediates adiponectin-induced inhibition of goat luteal steroidogenesis via AMPK; siRNA knockdown of AdipoR2 (but not AdipoR1 or T-cadherin) abolishes APN-induced AMPK phosphorylation, CYP11A1 suppression, and progesterone reduction in luteal steroidogenic cells.","method":"siRNA knockdown of AdipoR1, AdipoR2, and T-cadherin in primary goat luteal steroidogenic cells; P-AMPK measurement; steroidogenic protein and progesterone assays","journal":"Cells","confidence":"Medium","confidence_rationale":"Tier 2 — receptor-specific KD with clear signaling and steroidogenesis phenotype, single lab","pmids":["37408227"],"is_preprint":false},{"year":2025,"finding":"Transmission electron microscopy reveals that AdipoR2 silencing combined with palmitic acid exposure causes disruption of cytoplasmic membrane ultrastructure, mitochondrial cristae damage, and nuclear envelope blebbing; these defects are partially rescued by oleic acid supplementation; ectopic localization of PINK1 and ACSL1 to ER-apposed membranes occurs specifically in palmitate-treated cells.","method":"Transmission electron microscopy of AdipoR2 siRNA-silenced human cells challenged with palmitic acid; immunofluorescence for PINK1 and ACSL1 localization","journal":"Lipids in health and disease","confidence":"Medium","confidence_rationale":"Tier 2 — direct ultrastructural visualization of membrane defects in KD cells, single lab","pmids":["41327238"],"is_preprint":false}],"current_model":"AdipoR2 is an atypical seven-transmembrane receptor that functions primarily as a membrane lipid homeostasis regulator, sensing membrane rigidification caused by saturated fatty acids and responding by promoting fatty acid desaturation (via HACD3 and ACSL4 interactions), elongation (via ELOVL2 upregulation), and incorporation of unsaturated fatty acids into phospholipids to maintain membrane fluidity; it also signals through PPAR-α, AMPK, and a Ca2+-CaM-CaMKII-NOS3 complex in response to its ligand adiponectin, mediating metabolic effects in liver (PPAR-α/fatty acid oxidation), muscle, and dentate gyrus neurons, and its surface expression and degradation are regulated by its non-conserved N-terminal domain and by the ER ubiquitin ligase RNF145 in a lipid-composition-dependent manner."},"narrative":{"teleology":[{"year":2006,"claim":"Establishing that adiponectin selectively downregulates AdipoR2 expression in adipose tissue revealed a ligand-dependent negative-feedback loop that distinguishes AdipoR2 from AdipoR1 at the transcriptional level.","evidence":"Transgenic adiponectin-overexpressing and adiponectin-null mice with qPCR and adipocyte culture","pmids":["16729974"],"confidence":"High","gaps":["Mechanism of selective transcriptional repression not identified","Whether feedback operates in non-adipose tissues unknown"]},{"year":2007,"claim":"Knockout mice demonstrated that AdipoR2 is required for adiponectin-mediated PPARα activation in liver and that loss of both AdipoR1 and AdipoR2 abolishes all adiponectin actions, establishing these as the principal adiponectin receptors in vivo.","evidence":"AdipoR2 single and AdipoR1/R2 double KO mice with adenoviral rescue in Lepr⁻/⁻ liver; metabolic phenotyping","pmids":["17268472"],"confidence":"High","gaps":["Receptor-specific downstream effectors not fully delineated","Relative contribution to non-hepatic tissues unclear"]},{"year":2008,"claim":"Bidirectional manipulation in liver and hepatocytes placed AdipoR2 upstream of PPARα-driven catalase expression and fatty acid oxidation, while parallel work showed AdipoR2 can signal through Src/Ras/ERK1/2 via the adaptor APPL1, broadening the signaling repertoire beyond AMPK/PPARα.","evidence":"Adenoviral KD/OE in MCD-diet mice and TGFβ-treated hepatocytes; siRNA/pharmacological inhibition in HEK293 cells","pmids":["18666257","18842004"],"confidence":"High","gaps":["Direct physical interaction between AdipoR2 and Src not shown","Relative use of ERK vs PPARα pathways in different cell types not resolved"]},{"year":2010,"claim":"Receptor-specific knockdown in macrophages, stellate cells, and ischemia models established that AdipoR2 has non-redundant roles distinct from AdipoR1 — particularly in anti-inflammatory SR-AI suppression, anti-fibrotic signaling, and revascularization — while domain-swapping showed the N-terminal cytoplasmic tail controls surface expression and temporal signaling profiles.","evidence":"Lentiviral shRNA in THP-1 macrophages; chimeric/truncated receptor constructs with quantitative surface expression; AdipoR1/R2 KO mice in hindlimb ischemia","pmids":["22227293","23376713","24742672","20074551"],"confidence":"High","gaps":["Structural basis for N-terminal gating of surface expression unknown","Whether AdipoR1/R2 heterodimers have distinct signaling outputs not tested"]},{"year":2013,"claim":"A forward genetic suppressor screen in C. elegans revealed that the AdipoR2 homolog PAQR-2 controls membrane fluidity by regulating fatty acid desaturation and phospholipid composition, shifting the conceptual framework from pure adiponectin signaling to membrane lipid homeostasis.","evidence":"C. elegans suppressor screen with epistasis analysis and fatty acid composition measurements","pmids":["24068966"],"confidence":"High","gaps":["Whether the mammalian receptor has intrinsic enzymatic activity or acts as a scaffold was unresolved","Mechanism of fluidity sensing not yet identified"]},{"year":2015,"claim":"Crystal structures of AdipoR2 (2.4 Å) and AdipoR1 revealed a novel seven-transmembrane fold with an internal cavity containing bound lipids, providing the first structural framework for the receptor's lipid-related functions.","evidence":"Lipidic mesophase crystallography with anti-AdipoR1 Fv, SPR ligand binding, thermostability assays","pmids":["25575462"],"confidence":"High","gaps":["Identity of bound lipids not fully characterized","No structure with adiponectin or agonist bound"]},{"year":2016,"claim":"BiFC and FRAP experiments in C. elegans established that PAQR-2 physically interacts with IGLR-2 at the plasma membrane to form a fluidity-sensing complex, while DG-specific AdipoR2 KO in mice showed the receptor is required for fear extinction and regulation of granule neuron excitability.","evidence":"BiFC for PAQR-2/IGLR-2 interaction, FRAP in C. elegans; DG-specific KO mice with fear conditioning and patch-clamp","pmids":["27082444","27137743"],"confidence":"High","gaps":["Mammalian homolog of IGLR-2 not identified","Whether neuronal AdipoR2 functions involve membrane fluidity sensing not tested"]},{"year":2017,"claim":"Direct membrane fluidity measurements in both C. elegans and mammalian cells demonstrated that AdipoR2 is essential to counteract palmitate-induced rigidification, confirming evolutionary conservation of the membrane homeostasis function; muscle-specific OE in mice showed AdipoR2 preferentially activates PPARα/acox1 with systemic metabolic benefits.","evidence":"FRAP and Laurdan GP in AdipoR2-KD mammalian cells and paqr-2 mutant worms; electrotransfer OE in mouse tibialis anterior","pmids":["28886012","28145500"],"confidence":"High","gaps":["Signal transduction between fluidity sensing and desaturase transcription not mapped","Whether muscle AdipoR2 acts via fluidity regulation or canonical signaling unclear"]},{"year":2018,"claim":"Tissue-specific rescue and mosaic analysis showed PAQR-2 acts cell-nonautonomously: expression in one tissue restores membrane fluidity organism-wide, a property conserved in human cells where AdipoR2-expressing cells normalize fluidity in neighboring AdipoR2-silenced cells.","evidence":"C. elegans tissue-specific rescue constructs with FRAP; HEK293 co-culture with SCD siRNA","pmids":["29997234"],"confidence":"High","gaps":["Identity of the secreted or transferred lipid signal mediating non-cell-autonomous rescue unknown","Whether this operates in intact mammalian tissues not shown"]},{"year":2019,"claim":"AdipoR2 sustains desaturase expression and unsaturated fatty acid levels in membrane phospholipids even in the absence of adiponectin, establishing that the core membrane homeostasis function is ligand-independent; in C. elegans, PAQR-2 promotes ω-6 PUFA synthesis linked to autophagy and lifespan extension at low temperature.","evidence":"AdipoR1/R2 KD with FRAP, Laurdan GP, and MS lipidomics in adiponectin-free conditions; C. elegans fatty acid profiling and autophagy assays","pmids":["30890562","31197136"],"confidence":"High","gaps":["How AdipoR2 activates desaturase transcription without adiponectin not mechanistically resolved","Whether autophagy link extends to mammalian cells unknown"]},{"year":2021,"claim":"Genome-wide screening in C. elegans confirmed PAQR-2/IGLR-2 as the sole essential pathway for SFA tolerance, FRET showed their interaction is regulated by membrane fluidity itself, and multi-omic analysis in human cells ranked AdipoR2 as the single most important factor for preventing SFA-induced membrane rigidification and transcriptomic collapse.","evidence":"Forward genetic screen, FRET-based interaction monitoring, transcriptomics and lipidomics in AdipoR2-KD HEK293/HUVEC","pmids":["33444761","33444759"],"confidence":"High","gaps":["Direct biophysical mechanism by which membrane fluidity regulates PAQR-2/IGLR-2 interaction not resolved","Downstream transcription factor(s) mediating AdipoR2-dependent desaturase gene activation unidentified"]},{"year":2022,"claim":"Identification of RNF145 as an ER-resident E3 ligase that ubiquitinates and degrades AdipoR2 when membranes are unsaturated-rich — and is itself degraded when membranes become saturated — revealed an autoregulatory feedback loop controlling AdipoR2 protein levels in response to membrane lipid composition.","evidence":"Systematic proteomics of cells fed saturated vs unsaturated FAs, ubiquitination assays, RNF145 KO/KD, lipotoxicity assays","pmids":["35993436"],"confidence":"High","gaps":["RNF145 ubiquitination sites on AdipoR2 not mapped","Whether RNF145 regulation operates in vivo not shown"]},{"year":2023,"claim":"Co-IP/MS in human cells and C. elegans identified HACD3 and ACSL4 as conserved AdipoR2 physical interactors that mediate fatty acid elongation and channeling of unsaturated fatty acids into phospholipids, providing the first direct link between the receptor and the lipid-remodeling enzymatic machinery.","evidence":"13C-labeled fatty acid tracing, co-IP/MS of tagged AdipoR2/PAQR-2 in HEK293 and C. elegans","pmids":["37164154"],"confidence":"High","gaps":["Whether AdipoR2 has intrinsic ceramidase/hydrolase activity that contributes to HACD3/ACSL4 regulation not resolved","Structural basis of AdipoR2–HACD3/ACSL4 interaction unknown"]},{"year":2024,"claim":"AdipoR2 KO in mouse testes demonstrated that AdipoR2 promotes ELOVL2 expression to synthesize VLC-PUFAs essential for meiotic membrane integrity, telomere distribution, and homologous recombination; in brain, KO causes saturated FA excess with enlarged cerebrum and behavioral abnormalities; a novel AdipoR2–CaM–CaMKII–NOS3 signaling complex was identified through which AdipoR2 agonists drive Ca²⁺-dependent NO production for liver protection.","evidence":"AdipoR2 KO mice with testes lipidomics, meiotic spreads, EM; brain lipidomics/behavior; site-directed mutagenesis (R335, Y274), co-IP for complex, Ca²⁺ imaging, ALF model","pmids":["38485951","38989587","39681560"],"confidence":"High","gaps":["How AdipoR2 regulates ELOVL2 transcription mechanistically not defined","Whether Ca²⁺/CaMKII signaling intersects with the membrane fluidity pathway is untested","Brain phenotype not yet linked to specific neuronal membrane composition changes at single-cell resolution"]},{"year":null,"claim":"Major unresolved questions include: (1) the identity of the mammalian IGLR-2 homolog that may partner with AdipoR2 for fluidity sensing; (2) whether AdipoR2 possesses intrinsic ceramidase or hydrolase activity in vivo and how this relates to its scaffold/receptor functions; (3) the transcription factor(s) downstream of AdipoR2 that activate desaturase and elongase gene expression; and (4) the structural basis of adiponectin or agonist binding to AdipoR2 in a full-length context.","evidence":"","pmids":[],"confidence":"Low","gaps":["No full-length AdipoR2 structure with ligand","Mammalian IGLR-2 counterpart unidentified","Intrinsic enzymatic activity debated but not definitively demonstrated in vivo"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0098772","term_label":"molecular function regulator activity","supporting_discovery_ids":[14,17,19,22,23]},{"term_id":"GO:0060089","term_label":"molecular transducer activity","supporting_discovery_ids":[0,2,3,25]},{"term_id":"GO:0008289","term_label":"lipid binding","supporting_discovery_ids":[11,23]},{"term_id":"GO:0140299","term_label":"molecular sensor activity","supporting_discovery_ids":[13,14,20]}],"localization":[{"term_id":"GO:0005886","term_label":"plasma membrane","supporting_discovery_ids":[8,10,13,26]},{"term_id":"GO:0005783","term_label":"endoplasmic reticulum","supporting_discovery_ids":[22]}],"pathway":[{"term_id":"R-HSA-1430728","term_label":"Metabolism","supporting_discovery_ids":[7,14,17,19,23,24,29]},{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[0,1,2,3,25,28]},{"term_id":"R-HSA-168256","term_label":"Immune System","supporting_discovery_ids":[21]},{"term_id":"R-HSA-1474165","term_label":"Reproduction","supporting_discovery_ids":[24]}],"complexes":["AdipoR2-CaM-CaMKII-NOS3"],"partners":["APPL1","HACD3","ACSL4","RNF145","ADIPOQ","ADIPOR1","ELOVL2","IGLR-2"],"other_free_text":[]},"mechanistic_narrative":"ADIPOR2 encodes an evolutionarily conserved seven-transmembrane receptor that functions as a master regulator of membrane lipid homeostasis, sensing membrane rigidification caused by saturated fatty acids and restoring fluidity by promoting fatty acid desaturation, elongation, and incorporation of polyunsaturated fatty acids into phospholipids [PMID:28886012, PMID:33444761, PMID:37164154, PMID:38485951]. This membrane-fluidizing function operates in part through physical recruitment of the fatty acid elongation dehydratase HACD3 and the acyl-CoA synthetase ACSL4, and through transcriptional upregulation of desaturases and ELOVL2, and is subject to autoregulatory feedback via the ER ubiquitin ligase RNF145, which degrades AdipoR2 when membranes are unsaturated-rich and is itself degraded when membranes become saturated [PMID:37164154, PMID:35993436, PMID:38485951]. As a receptor for adiponectin (and other C1q-family ligands), AdipoR2 signals through AMPK, PPARα, ERK1/2, and a Ca²⁺–CaM–CaMKII–NOS3 complex to regulate hepatic fatty acid oxidation, anti-fibrotic responses in stellate cells, revascularization, Th17 suppression, and neuronal excitability in the dentate gyrus [PMID:17268472, PMID:18666257, PMID:29237572, PMID:27137743, PMID:39681560]. Loss of AdipoR2 in mice causes tissue-specific accumulation of saturated fatty acids with consequent membrane stiffening, leading to meiotic failure in testes, brain lipid remodeling with behavioral abnormalities, and exacerbated metabolic and inflammatory pathology [PMID:38485951, PMID:38989587, PMID:17268472]."},"prefetch_data":{"uniprot":{"accession":"Q86V24","full_name":"Adiponectin receptor protein 2","aliases":["Progestin and adipoQ receptor family member 2","Progestin and adipoQ receptor family member II"],"length_aa":386,"mass_kda":43.9,"function":"Receptor for ADIPOQ, an essential hormone secreted by adipocytes that regulates glucose and lipid metabolism (PubMed:12802337, PubMed:25855295). Required for normal body fat and glucose homeostasis. ADIPOQ-binding activates a signaling cascade that leads to increased PPARA activity, and ultimately to increased fatty acid oxidation and glucose uptake. Has intermediate affinity for globular and full-length adiponectin. Required for normal revascularization after chronic ischemia caused by severing of blood vessels (By similarity)","subcellular_location":"Cell membrane","url":"https://www.uniprot.org/uniprotkb/Q86V24/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/ADIPOR2","classification":"Not Classified","n_dependent_lines":14,"n_total_lines":1208,"dependency_fraction":0.011589403973509934},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[],"url":"https://opencell.sf.czbiohub.org/search/ADIPOR2","total_profiled":1310},"omim":[{"mim_id":"620967","title":"TLC DOMAIN-CONTAINING PROTEIN 2; TLCD2","url":"https://www.omim.org/entry/620967"},{"mim_id":"620966","title":"TLC DOMAIN-CONTAINING PROTEIN 1; TLCD1","url":"https://www.omim.org/entry/620966"},{"mim_id":"620640","title":"RING FINGER PROTEIN 145; RNF145","url":"https://www.omim.org/entry/620640"},{"mim_id":"614581","title":"MONOCYTE-TO-MACROPHAGE DIFFERENTIATION-ASSOCIATED PROTEIN 2; MMD2","url":"https://www.omim.org/entry/614581"},{"mim_id":"614580","title":"PROGESTIN AND ADIPOQ RECEPTOR FAMILY, MEMBER 9; PAQR9","url":"https://www.omim.org/entry/614580"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"","locations":[],"tissue_specificity":"Tissue enhanced","tissue_distribution":"Detected in all","driving_tissues":[{"tissue":"brain","ntpm":121.3}],"url":"https://www.proteinatlas.org/search/ADIPOR2"},"hgnc":{"alias_symbol":["PAQR2","ACDCR2"],"prev_symbol":[]},"alphafold":{"accession":"Q86V24","domains":[{"cath_id":"1.20.1070","chopping":"142-371","consensus_level":"high","plddt":97.187,"start":142,"end":371}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q86V24","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q86V24-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q86V24-F1-predicted_aligned_error_v6.png","plddt_mean":82.5},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=ADIPOR2","jax_strain_url":"https://www.jax.org/strain/search?query=ADIPOR2"},"sequence":{"accession":"Q86V24","fasta_url":"https://rest.uniprot.org/uniprotkb/Q86V24.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q86V24/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q86V24"}},"corpus_meta":[{"pmid":"17268472","id":"PMC_17268472","title":"Targeted 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simultaneous disruption of both AdipoR1 and AdipoR2 abolishes all adiponectin binding and actions in vivo.\",\n      \"method\": \"Targeted gene disruption (knockout mice), adenovirus-mediated receptor re-expression in liver of Lepr(-/-) mice, metabolic phenotyping\",\n      \"journal\": \"Nature medicine\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — clean KO with defined metabolic phenotypes, replicated with gain-of-function rescue, highly cited foundational study\",\n      \"pmids\": [\"17268472\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"Hepatic AdipoR2 signaling promotes PPAR-α activity and catalase expression; knockdown of AdipoR2 diminishes PPAR-α signaling (decreased ACO and catalase), increases lipid peroxidation and ROS accumulation, and worsens NASH pathology; overexpression reverses these effects.\",\n      \"method\": \"Adenovirus-mediated shRNA knockdown and overexpression in mice on MCD diet; primary hepatocyte culture with TGF-β; gene expression and ROS assays\",\n      \"journal\": \"Hepatology (Baltimore, Md.)\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — bidirectional manipulation (KD and OE) with clear pathway placement and phenotypic readouts in vivo and in vitro\",\n      \"pmids\": [\"18666257\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"AdipoR2 (along with AdipoR1) mediates adiponectin-stimulated ERK1/2 activation through a Src kinase- and Ras-dependent pathway; downregulation of the adapter protein APPL1 impairs this signaling; simultaneous knockdown of both receptors attenuates ERK1/2 activation, while overexpression of either receptor or adiponectin promotes HEK293 cell growth.\",\n      \"method\": \"RNA interference in HEK293 cells, pharmacological inhibition (PP2, Clostridium difficile toxin B), Ras activation assay, cell growth assay\",\n      \"journal\": \"Biochemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — multiple orthogonal inhibition methods and functional readout in same study\",\n      \"pmids\": [\"18842004\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"AdipoR2 (but not AdipoR1) serves as the dominant receptor for adiponectin in suppression of scavenger receptor A type 1 (SR-AI) and upregulation of IL-1Ra in macrophage foam cells; the adapter protein APPL1 mediates adiponectin-induced inhibition of lipid accumulation and NF-κB, and Akt phosphorylation through both receptors.\",\n      \"method\": \"Lentiviral-shRNA knockdown of AdipoR1, AdipoR2, and APPL1 in THP-1 monocytes; foam cell transformation with oxLDL; gene expression and protein analysis\",\n      \"journal\": \"Atherosclerosis\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — receptor-specific KD with defined cytokine signaling differences, APPL1 adapter mechanistically placed\",\n      \"pmids\": [\"22227293\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"ERp46 interacts specifically with AdipoR1 (not AdipoR2), mediated by the cytoplasmic N-terminal residues (1–70) of AdipoR1; ERp46 knockdown increases surface levels of both AdipoR1 and AdipoR2 and enhances adiponectin-stimulated AMPK phosphorylation, while reducing p38MAPK phosphorylation.\",\n      \"method\": \"Co-immunoprecipitation followed by mass spectrometry, GST-fusion protein pulldown with truncated constructs, indirect immunofluorescence, subcellular fractionation, siRNA knockdown, phosphorylation assays\",\n      \"journal\": \"Biochemical and biophysical research communications\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — reciprocal Co-IP/MS plus domain mapping and functional signaling consequence of KD\",\n      \"pmids\": [\"20074551\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"AdipoR2 expression in the anterior cingulate cortex is regulated by alcohol in a K-ras-dependent manner; AdipoR2 null mice show attenuated withdrawal-associated increased drinking; adiponectin increases excitability of ACC neurons through AdipoR2, an effect enhanced during alcohol withdrawal.\",\n      \"method\": \"Gene expression analysis (ACC), AdipoR2 knockout mice behavioral testing, intracellular electrophysiological recordings in brain slices\",\n      \"journal\": \"Brain research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — KO mouse with behavioral and electrophysiological phenotypes, single lab\",\n      \"pmids\": [\"20380822\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"ATF3, induced by ER stress, transcriptionally represses AdipoR2 by binding a region between nucleotides -94 and -86 of the AdipoR2 promoter, reducing both AdipoR2 mRNA and protein in hepatocytes.\",\n      \"method\": \"Reporter gene assays with 5'-deleted AdipoR2 promoter constructs, EMSA, chromatin immunoprecipitation, siRNA/overexpression of ATF3 in HepG2 cells\",\n      \"journal\": \"The FEBS journal\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — in vitro promoter dissection with EMSA and ChIP identifying specific binding site\",\n      \"pmids\": [\"20423458\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"C. elegans PAQR-2 (AdipoR2 homolog) regulates fatty acid desaturation and phosphatidylcholine synthesis during cold adaptation to maintain membrane fluidity; genetic suppressors of paqr-2 phenotypes act through fatty acid metabolism genes and Δ9-desaturases.\",\n      \"method\": \"Suppressor screen in C. elegans, genetic epistasis analysis, fatty acid composition measurements\",\n      \"journal\": \"PLoS genetics\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — forward genetic suppressor screen with epistasis analysis in ortholog organism, multiple replicated interactions\",\n      \"pmids\": [\"24068966\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"The non-conserved N-terminal region of AdipoR2 (residues 1–81) prevents its constitutive cell-surface expression; AdipoR1 and AdipoR2 can form heterodimers, and co-expression with AdipoR1 promotes cell-surface localization of AdipoR2.\",\n      \"method\": \"Epitope-tagged receptor constructs, indirect immunofluorescence, quantitative plate-based cell-surface expression analysis, chimeric and truncated receptor constructs\",\n      \"journal\": \"Biochemical and biophysical research communications\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — systematic chimeric/truncation analysis with quantitative surface expression readout, domain responsibility clearly mapped\",\n      \"pmids\": [\"23376713\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"In vivo, AdipoR2 (but not AdipoR1) is required for adiponectin-dependent revascularization after hindlimb ischemia; conversely, AdipoR1 (but not AdipoR2) deficiency causes diet-induced metabolic dysfunction, revealing divergent in vivo roles of the two receptors.\",\n      \"method\": \"AdipoR1- and AdipoR2-deficient mice subjected to hindlimb ischemia surgery and diet-induced obesity models; blood flow recovery measurement; metabolic phenotyping\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — parallel KO studies with two distinct physiological models revealing receptor-specific functions\",\n      \"pmids\": [\"24742672\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"The non-conserved N-terminal trunks of AdipoR1 and AdipoR2 define differential temporal signaling profiles: AdipoR1 peaks at 15 min and AdipoR2 at 24 h post-adiponectin stimulation; adiponectin also induces internalization of both receptors from the cell surface.\",\n      \"method\": \"Transient expression in HEK293 cells, receptor chimera analysis, temporal phosphorylation profiling of downstream effectors, cell-surface expression quantification\",\n      \"journal\": \"Molecular and cellular endocrinology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — chimeric receptor approach with temporal signaling readout, single lab\",\n      \"pmids\": [\"25892445\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"Crystal structures of truncated human AdipoR1 (Δ88) and AdipoR2 (Δ99) were obtained at 2.8 Å and 2.4 Å resolution respectively by lipidic mesophase crystallography with anti-AdipoR1 Fv; both proteins bind lipids and show structural integrity by SPR ligand binding and thermostability assays.\",\n      \"method\": \"Protein expression in insect cells, affinity purification, lipidic mesophase crystallization, X-ray crystallography, SPR, thermostability assay, TLC of bound lipids\",\n      \"journal\": \"Journal of structural and functional genomics\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — crystal structures obtained with functional validation by SPR and thermostability\",\n      \"pmids\": [\"25575462\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"AdipoR2 deletion in the dentate gyrus (DG) of the hippocampus results in augmented contextual fear expression, reduced extinction, and intrinsic hyperexcitability of DG granule neurons; adiponectin and AdipoRon fail to suppress fear or neuronal excitability in AdipoR2 knockout mice, placing AdipoR2 as the necessary and sufficient receptor for these effects.\",\n      \"method\": \"DG-specific AdipoR2 knockout mice, contextual fear conditioning/extinction behavioral tests, whole-cell patch-clamp recordings in brain slices, AdipoRon pharmacology\",\n      \"journal\": \"Molecular psychiatry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — region-specific KO plus pharmacological rescue attempt, combined behavioral and electrophysiological readouts\",\n      \"pmids\": [\"27137743\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"C. elegans PAQR-2 (AdipoR2 homolog) and its partner IGLR-2 physically interact at plasma membranes and together function as a membrane fluidity sensor; paqr-2 or iglr-2 mutants are glucose-intolerant and die in the presence of 20 mM glucose due to membrane rigidification; their function is independent of the insulin/FoxO pathway.\",\n      \"method\": \"Bimolecular fluorescence complementation (BiFC) for protein interaction, FRAP for membrane fluidity, genetic epistasis with daf-2 and daf-16, glucose intolerance assays\",\n      \"journal\": \"PLoS genetics\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — direct protein interaction shown by BiFC, functional assays with membrane fluidity measurements, epistasis analysis\",\n      \"pmids\": [\"27082444\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"AdipoR2 (and C. elegans PAQR-2) are essential to counter membrane rigidification caused by exogenously provided saturated fatty acids; mammalian cells with AdipoR2 knocked down by siRNA cannot prevent palmitic acid-induced membrane rigidity; this function is evolutionarily conserved.\",\n      \"method\": \"Dietary supplement experiments in C. elegans paqr-2 mutants, direct membrane fluidity measurement, siRNA KD of AdipoR2 in mammalian cells, lipidomics of phospholipid fatty acid composition\",\n      \"journal\": \"PLoS genetics\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 — direct fluidity measurements in both organisms, KD phenotype in mammalian cells, lipidomics\",\n      \"pmids\": [\"28886012\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"AdipoR2 (but not AdipoR1) in hepatic stellate cells modulates Col1-α1, α-SMA gene expression, HSC migration, and AMPK activity in response to adiponectin, establishing AdipoR2 as the major anti-fibrotic adiponectin receptor on HSCs.\",\n      \"method\": \"AdipoR1 and AdipoR2 knockout mice in CCl4 liver fibrosis model; siRNA knockdown in primary hepatic stellate cells with adiponectin treatment; gene expression, migration assays, AMPK activity measurement\",\n      \"journal\": \"Biochimica et biophysica acta. Molecular basis of disease\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — in vivo KO and in vitro KD with receptor-specific functional phenotypes\",\n      \"pmids\": [\"29237572\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"PAQR-2 (AdipoR2 homolog) expression in the hypodermis, gonad sheath cells, or intestine of C. elegans is sufficient to non-cell-autonomously maintain membrane fluidity throughout the organism, including in intestinal cells where PAQR-2 is not expressed; this cell-nonautonomous regulation is conserved in human HEK293 cells where AdipoR2-expressing cells normalize membrane fluidity in neighboring AdipoR2-silenced cells; Δ9 desaturases are essential effectors of this process.\",\n      \"method\": \"Mosaic analysis, tissue-specific rescue expression constructs in C. elegans, FRAP membrane fluidity assay, SCD siRNA in HEK293 cells\",\n      \"journal\": \"Genetics\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — mosaic/tissue-specific genetics plus direct fluidity measurements in two organisms\",\n      \"pmids\": [\"29997234\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"AdipoR1 and AdipoR2 are essential for sustaining desaturase expression and high levels of unsaturated fatty acids in membrane phospholipids of many human cell types including primary HUVECs, and for preventing membrane rigidification in cells challenged with exogenous palmitate; this function is independent of adiponectin.\",\n      \"method\": \"AdipoR1/AdipoR2 KD, FRAP, Laurdan dye generalized polarization, mass spectrometry of phospholipid fatty acid composition; experiments performed in absence of adiponectin\",\n      \"journal\": \"Journal of lipid research\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 — three independent methods measuring membrane fluidity/composition, multiple cell types including primary cells, adiponectin-independent condition tested\",\n      \"pmids\": [\"30890562\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"PAQR-2 (AdipoR2 homolog) senses temperature drop in C. elegans and promotes biosynthesis of γ-linolenic acid and arachidonic acid (ω-6 PUFAs), which initiate autophagy in the epidermis, delaying collagen decline and extending lifespan at low temperature.\",\n      \"method\": \"C. elegans genetic analysis, fatty acid profiling, autophagy assays, lifespan measurements at low temperature\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — pathway dissection linking receptor to PUFA synthesis, autophagy, and lifespan in ortholog organism\",\n      \"pmids\": [\"31197136\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"AdipoR2-deficient HEK293 cells challenged with saturated fatty acids show extensive transcriptome dysregulation similar to SREBP-deficient cells; AdipoR2 is the most important factor (among AdipoR2, SCD, FADS2, PEMT, ACSL4) for preventing membrane rigidification and excess saturation in cells challenged with exogenous SFAs; AdipoR2 deficiency impairs growth and respiration.\",\n      \"method\": \"Transcriptomics, lipidomics, growth and respiration assays, membrane property analysis in AdipoR2 KD HEK293 and HUVEC cells; comparative gene KD analysis\",\n      \"journal\": \"Biochimica et biophysica acta. Molecular and cell biology of lipids\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 — multi-omic approach with transcriptomics, lipidomics, and functional assays; gene comparison hierarchy established\",\n      \"pmids\": [\"33444759\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"PAQR-2/IGLR-2 (AdipoR2 pathway) is the only pathway specifically essential for tolerance to dietary saturated fatty acids in a whole-organism C. elegans forward genetic screen; SFA-rich diet causes membrane rigidification in paqr-2 mutants; FRET analysis shows that the PAQR-2/IGLR-2 interaction is regulated by membrane fluidity, indicating a fluidity-sensing mechanism; the cytoplasmic N-terminal domain of PAQR-2 is dispensable for function but interaction with IGLR-2 is required.\",\n      \"method\": \"Whole-organism forward genetic screen in C. elegans, fluorescence resonance energy transfer (FRET), phospholipid fatty acid composition by mass spectrometry, FRAP membrane fluidity assay, domain deletion analysis\",\n      \"journal\": \"Biochimica et biophysica acta. Molecular and cell biology of lipids\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 — genome-wide forward screen, FRET-based interaction regulation, multiple orthogonal methods\",\n      \"pmids\": [\"33444761\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"CTRP3 suppresses Th17 cell differentiation via AdipoR2 (not AdipoR1); suppression of Rorc and Stat3 expression by CTRP3 is blocked by AdipoR2 antagonist but not AdipoR1 antagonist; AdipoRon also suppresses Th17 differentiation via AdipoR2; CTRP3 deficiency enhances EAE development associated with increased Th17 population.\",\n      \"method\": \"Receptor-specific antagonists, C1qtnf3 knockout mice, Th17 differentiation assays in vitro, EAE model\",\n      \"journal\": \"Frontiers in immunology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — receptor-specific pharmacological blockade with KO mice and cellular differentiation readouts, single lab\",\n      \"pmids\": [\"34925309\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"RNF145, an ER-resident E3 ubiquitin ligase, is a lipid-sensitive regulator that ubiquitinates and degrades AdipoR2 when membranes are enriched in unsaturated fatty acids; when membranes become saturated, RNF145 undergoes auto-ubiquitination and is degraded, stabilizing AdipoR2 whose hydrolase activity restores lipid homeostasis; this defines an autoregulatory loop controlling membrane lipid composition.\",\n      \"method\": \"Systematic proteomics of cells fed saturated vs unsaturated FAs, RNF145 and AdipoR2 interaction biochemistry, ubiquitination assays, RNF145 KO/KD, membrane fluidity and lipid composition measurements, lipotoxicity assays\",\n      \"journal\": \"The EMBO journal\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 — systematic proteomic discovery plus mechanistic ubiquitination assays with functional lipotoxicity readout, comprehensive study\",\n      \"pmids\": [\"35993436\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"AdipoR2 promotes elongation of membrane-fluidizing polyunsaturated fatty acids and their incorporation into phospholipids by recruiting protein interactors; co-immunoprecipitation with MS identified HACD3 (dehydratase, third step in long-chain fatty acid elongation) and ACSL4 (activates unsaturated fatty acids for phospholipid channeling) as conserved AdipoR2/PAQR-2 interactors essential for membrane fluidity.\",\n      \"method\": \"13C-labeled fatty acid tracing, co-immunoprecipitation of tagged AdipoR2/PAQR-2 in HEK293 cells and C. elegans followed by mass spectrometry, functional verification of interactions\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 — 13C-tracer metabolic assay plus co-IP/MS in two organisms, specific interactors functionally validated\",\n      \"pmids\": [\"37164154\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"AdipoR2 regulates the meiosis-specific lipidome in mouse testes by promoting ELOVL2 expression (both transcriptionally and post-transcriptionally) to synthesize very-long-chain polyunsaturated fatty acids (VLC-PUFAs); AdipoR2 knockout causes depletion of VLC-PUFAs and palmitic acid accumulation, stiffening the cellular membrane, causing nuclear envelope invagination, impairing meiotic telomere distribution, and disrupting homologous synapsis, recombination, and intercellular bridge formation.\",\n      \"method\": \"AdipoR2 knockout mice, lipidomics of testes, transcriptional and protein analysis of ELOVL2, membrane fluidity assays, meiosis chromosome spread analysis, electron microscopy of nuclear envelope\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — KO mouse with multi-level mechanistic analysis linking AdipoR2 to ELOVL2 regulation, lipid composition, membrane properties, and meiotic chromosome dynamics\",\n      \"pmids\": [\"38485951\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"SCM-198 binds selectively to AdipoR2, with AdipoR2 R335 critical for binding/signaling and Y274 serving as a molecular switch for Ca2+ influx; SCM-198-AdipoR2 interaction causes Ca2+ influx, elevates phosphorylation of CaMKII and NOS3 in an AdipoR2-CaM-CaMKII-NOS3 complex, rapidly inducing nitric oxide production for liver protection.\",\n      \"method\": \"Molecular docking, site-directed mutagenesis (R335, Y274), co-immunoprecipitation identifying AdipoR2-CaM-CaMKII-NOS3 complex, Ca2+ influx measurement, NOS3 phosphorylation assay, ALF mouse model\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 — mutagenesis of specific residues combined with co-IP identifying a novel protein complex and in vivo functional rescue\",\n      \"pmids\": [\"39681560\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"miR-449a targets AdipoR2 (confirmed by luciferase reporter assay) and suppresses its expression; loss of AdipoR2 reduces its interaction with E-cadherin in lipid rafts, promoting endothelial-to-mesenchymal transition (EndMT) and atherosclerosis in endothelial cells.\",\n      \"method\": \"Luciferase reporter assay, miR-449a mimic/inhibitor transfection, lipid raft isolation, co-immunoprecipitation of AdipoR2 and E-cadherin, ApoE KO diabetic mouse atherosclerosis model\",\n      \"journal\": \"Biomedicine & pharmacotherapy\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 — luciferase validation plus Co-IP interaction, single lab\",\n      \"pmids\": [\"30551487\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2006,\n      \"finding\": \"Adiponectin downregulates AdipoR2 expression (but not AdipoR1) in adipose tissue via a feedback loop; this was shown both in transgenic mice overexpressing adiponectin (which showed decreased AdipoR2 mRNA) and in adipocytes treated with recombinant adiponectin in vitro; conversely, AdipoR2 is upregulated in adipose tissue of adiponectin-null mice.\",\n      \"method\": \"Transgenic mice with adipose-specific adiponectin overexpression, adiponectin-null mice, 3T3-F442A adipocyte culture with recombinant adiponectin, qPCR\",\n      \"journal\": \"Biochemical and biophysical research communications\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — bidirectional genetic (OE and KO) combined with cell culture, consistent results across systems\",\n      \"pmids\": [\"16729974\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"Muscle-specific overexpression of AdipoR2 (but not AdipoR1) increases PPARα and its target gene acox1 in skeletal muscle, and in obese mice promotes systemic effects including decreased weight gain, reduced epididymal fat inflammation, and increased circulating adiponectin; both AdipoR1 and AdipoR2 overexpression increase AMPK, AKT, ERK phosphorylation and GLUT4 expression.\",\n      \"method\": \"In vivo electrotransfer-mediated gene overexpression in tibialis anterior muscle of lean and obese mice; phosphorylation assays; metabolic phenotyping\",\n      \"journal\": \"Scientific reports\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — parallel OE of each receptor with signaling and metabolic readouts, single lab\",\n      \"pmids\": [\"28145500\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"AdipoR2 silencing in the presence of exogenous palmitic acid causes increased dihydroceramide levels (ceramide precursor in the de novo synthesis pathway); conversely, AdipoR2 overexpression depletes dihydroceramides; the mechanism is consistent with AdipoR2 limiting intracellular palmitic acid supply to the rate-limiting serine palmitoyl transferase step.\",\n      \"method\": \"siRNA knockdown and overexpression of AdipoR2 in cultured cells, sphingolipid profiling by mass spectrometry\",\n      \"journal\": \"Lipids in health and disease\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — bidirectional manipulation with lipidomics readout, single lab, mechanistic interpretation is model-based\",\n      \"pmids\": [\"34839823\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"AdipoR2 activation by ESME (emodin succinate monoethyl ester) in hepatocytes activates CaMKK2 and LKB1 to activate AMPK, reducing lipogenesis; suppression of AdipoR2 expression or AMPK activation completely eliminates the lipid-reducing effect of ESME; AdipoR2 on the cytomembrane of HepG2 cells can be labeled by fluorescent ESME-Cy5.\",\n      \"method\": \"Molecular docking, fluorescent ligand labeling, AdipoR2 siRNA KD, AMPK inhibition, in vivo hamster/mouse hepatic steatosis models\",\n      \"journal\": \"Free radical biology & medicine\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — receptor KD epistasis plus in vivo model with pathway mapping, single lab\",\n      \"pmids\": [\"37044149\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"AdipoR2-knockout mouse brains are enlarged with ~12% excess saturated fatty acids (primarily palmitic acid at the expense of oleic acid) in phosphatidylcholines across cerebrum, cerebellum, and myelin sheaths; aging AdipoR2 KO mice exhibit hyperactivity and anxiety; cell density is lower in the cerebrum of KO mice.\",\n      \"method\": \"AdipoR2 KO mouse model, lipidomics at multiple ages, histology, electron microscopy, proteomics of cerebellum, behavioral tests\",\n      \"journal\": \"FASEB journal\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — comprehensive KO phenotyping with lipidomics and behavior, single lab\",\n      \"pmids\": [\"38989587\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"AdipoR2 mediates adiponectin-induced inhibition of goat luteal steroidogenesis via AMPK; siRNA knockdown of AdipoR2 (but not AdipoR1 or T-cadherin) abolishes APN-induced AMPK phosphorylation, CYP11A1 suppression, and progesterone reduction in luteal steroidogenic cells.\",\n      \"method\": \"siRNA knockdown of AdipoR1, AdipoR2, and T-cadherin in primary goat luteal steroidogenic cells; P-AMPK measurement; steroidogenic protein and progesterone assays\",\n      \"journal\": \"Cells\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — receptor-specific KD with clear signaling and steroidogenesis phenotype, single lab\",\n      \"pmids\": [\"37408227\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"Transmission electron microscopy reveals that AdipoR2 silencing combined with palmitic acid exposure causes disruption of cytoplasmic membrane ultrastructure, mitochondrial cristae damage, and nuclear envelope blebbing; these defects are partially rescued by oleic acid supplementation; ectopic localization of PINK1 and ACSL1 to ER-apposed membranes occurs specifically in palmitate-treated cells.\",\n      \"method\": \"Transmission electron microscopy of AdipoR2 siRNA-silenced human cells challenged with palmitic acid; immunofluorescence for PINK1 and ACSL1 localization\",\n      \"journal\": \"Lipids in health and disease\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — direct ultrastructural visualization of membrane defects in KD cells, single lab\",\n      \"pmids\": [\"41327238\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"AdipoR2 is an atypical seven-transmembrane receptor that functions primarily as a membrane lipid homeostasis regulator, sensing membrane rigidification caused by saturated fatty acids and responding by promoting fatty acid desaturation (via HACD3 and ACSL4 interactions), elongation (via ELOVL2 upregulation), and incorporation of unsaturated fatty acids into phospholipids to maintain membrane fluidity; it also signals through PPAR-α, AMPK, and a Ca2+-CaM-CaMKII-NOS3 complex in response to its ligand adiponectin, mediating metabolic effects in liver (PPAR-α/fatty acid oxidation), muscle, and dentate gyrus neurons, and its surface expression and degradation are regulated by its non-conserved N-terminal domain and by the ER ubiquitin ligase RNF145 in a lipid-composition-dependent manner.\"\n}\n```","stage2_raw":"```json\n{\n  \"mechanistic_narrative\": \"ADIPOR2 encodes an evolutionarily conserved seven-transmembrane receptor that functions as a master regulator of membrane lipid homeostasis, sensing membrane rigidification caused by saturated fatty acids and restoring fluidity by promoting fatty acid desaturation, elongation, and incorporation of polyunsaturated fatty acids into phospholipids [PMID:28886012, PMID:33444761, PMID:37164154, PMID:38485951]. This membrane-fluidizing function operates in part through physical recruitment of the fatty acid elongation dehydratase HACD3 and the acyl-CoA synthetase ACSL4, and through transcriptional upregulation of desaturases and ELOVL2, and is subject to autoregulatory feedback via the ER ubiquitin ligase RNF145, which degrades AdipoR2 when membranes are unsaturated-rich and is itself degraded when membranes become saturated [PMID:37164154, PMID:35993436, PMID:38485951]. As a receptor for adiponectin (and other C1q-family ligands), AdipoR2 signals through AMPK, PPARα, ERK1/2, and a Ca²⁺–CaM–CaMKII–NOS3 complex to regulate hepatic fatty acid oxidation, anti-fibrotic responses in stellate cells, revascularization, Th17 suppression, and neuronal excitability in the dentate gyrus [PMID:17268472, PMID:18666257, PMID:29237572, PMID:27137743, PMID:39681560]. Loss of AdipoR2 in mice causes tissue-specific accumulation of saturated fatty acids with consequent membrane stiffening, leading to meiotic failure in testes, brain lipid remodeling with behavioral abnormalities, and exacerbated metabolic and inflammatory pathology [PMID:38485951, PMID:38989587, PMID:17268472].\",\n  \"teleology\": [\n    {\n      \"year\": 2006,\n      \"claim\": \"Establishing that adiponectin selectively downregulates AdipoR2 expression in adipose tissue revealed a ligand-dependent negative-feedback loop that distinguishes AdipoR2 from AdipoR1 at the transcriptional level.\",\n      \"evidence\": \"Transgenic adiponectin-overexpressing and adiponectin-null mice with qPCR and adipocyte culture\",\n      \"pmids\": [\"16729974\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Mechanism of selective transcriptional repression not identified\", \"Whether feedback operates in non-adipose tissues unknown\"]\n    },\n    {\n      \"year\": 2007,\n      \"claim\": \"Knockout mice demonstrated that AdipoR2 is required for adiponectin-mediated PPARα activation in liver and that loss of both AdipoR1 and AdipoR2 abolishes all adiponectin actions, establishing these as the principal adiponectin receptors in vivo.\",\n      \"evidence\": \"AdipoR2 single and AdipoR1/R2 double KO mice with adenoviral rescue in Lepr⁻/⁻ liver; metabolic phenotyping\",\n      \"pmids\": [\"17268472\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Receptor-specific downstream effectors not fully delineated\", \"Relative contribution to non-hepatic tissues unclear\"]\n    },\n    {\n      \"year\": 2008,\n      \"claim\": \"Bidirectional manipulation in liver and hepatocytes placed AdipoR2 upstream of PPARα-driven catalase expression and fatty acid oxidation, while parallel work showed AdipoR2 can signal through Src/Ras/ERK1/2 via the adaptor APPL1, broadening the signaling repertoire beyond AMPK/PPARα.\",\n      \"evidence\": \"Adenoviral KD/OE in MCD-diet mice and TGFβ-treated hepatocytes; siRNA/pharmacological inhibition in HEK293 cells\",\n      \"pmids\": [\"18666257\", \"18842004\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Direct physical interaction between AdipoR2 and Src not shown\", \"Relative use of ERK vs PPARα pathways in different cell types not resolved\"]\n    },\n    {\n      \"year\": 2010,\n      \"claim\": \"Receptor-specific knockdown in macrophages, stellate cells, and ischemia models established that AdipoR2 has non-redundant roles distinct from AdipoR1 — particularly in anti-inflammatory SR-AI suppression, anti-fibrotic signaling, and revascularization — while domain-swapping showed the N-terminal cytoplasmic tail controls surface expression and temporal signaling profiles.\",\n      \"evidence\": \"Lentiviral shRNA in THP-1 macrophages; chimeric/truncated receptor constructs with quantitative surface expression; AdipoR1/R2 KO mice in hindlimb ischemia\",\n      \"pmids\": [\"22227293\", \"23376713\", \"24742672\", \"20074551\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Structural basis for N-terminal gating of surface expression unknown\", \"Whether AdipoR1/R2 heterodimers have distinct signaling outputs not tested\"]\n    },\n    {\n      \"year\": 2013,\n      \"claim\": \"A forward genetic suppressor screen in C. elegans revealed that the AdipoR2 homolog PAQR-2 controls membrane fluidity by regulating fatty acid desaturation and phospholipid composition, shifting the conceptual framework from pure adiponectin signaling to membrane lipid homeostasis.\",\n      \"evidence\": \"C. elegans suppressor screen with epistasis analysis and fatty acid composition measurements\",\n      \"pmids\": [\"24068966\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether the mammalian receptor has intrinsic enzymatic activity or acts as a scaffold was unresolved\", \"Mechanism of fluidity sensing not yet identified\"]\n    },\n    {\n      \"year\": 2015,\n      \"claim\": \"Crystal structures of AdipoR2 (2.4 Å) and AdipoR1 revealed a novel seven-transmembrane fold with an internal cavity containing bound lipids, providing the first structural framework for the receptor's lipid-related functions.\",\n      \"evidence\": \"Lipidic mesophase crystallography with anti-AdipoR1 Fv, SPR ligand binding, thermostability assays\",\n      \"pmids\": [\"25575462\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Identity of bound lipids not fully characterized\", \"No structure with adiponectin or agonist bound\"]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"BiFC and FRAP experiments in C. elegans established that PAQR-2 physically interacts with IGLR-2 at the plasma membrane to form a fluidity-sensing complex, while DG-specific AdipoR2 KO in mice showed the receptor is required for fear extinction and regulation of granule neuron excitability.\",\n      \"evidence\": \"BiFC for PAQR-2/IGLR-2 interaction, FRAP in C. elegans; DG-specific KO mice with fear conditioning and patch-clamp\",\n      \"pmids\": [\"27082444\", \"27137743\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Mammalian homolog of IGLR-2 not identified\", \"Whether neuronal AdipoR2 functions involve membrane fluidity sensing not tested\"]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"Direct membrane fluidity measurements in both C. elegans and mammalian cells demonstrated that AdipoR2 is essential to counteract palmitate-induced rigidification, confirming evolutionary conservation of the membrane homeostasis function; muscle-specific OE in mice showed AdipoR2 preferentially activates PPARα/acox1 with systemic metabolic benefits.\",\n      \"evidence\": \"FRAP and Laurdan GP in AdipoR2-KD mammalian cells and paqr-2 mutant worms; electrotransfer OE in mouse tibialis anterior\",\n      \"pmids\": [\"28886012\", \"28145500\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Signal transduction between fluidity sensing and desaturase transcription not mapped\", \"Whether muscle AdipoR2 acts via fluidity regulation or canonical signaling unclear\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"Tissue-specific rescue and mosaic analysis showed PAQR-2 acts cell-nonautonomously: expression in one tissue restores membrane fluidity organism-wide, a property conserved in human cells where AdipoR2-expressing cells normalize fluidity in neighboring AdipoR2-silenced cells.\",\n      \"evidence\": \"C. elegans tissue-specific rescue constructs with FRAP; HEK293 co-culture with SCD siRNA\",\n      \"pmids\": [\"29997234\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Identity of the secreted or transferred lipid signal mediating non-cell-autonomous rescue unknown\", \"Whether this operates in intact mammalian tissues not shown\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"AdipoR2 sustains desaturase expression and unsaturated fatty acid levels in membrane phospholipids even in the absence of adiponectin, establishing that the core membrane homeostasis function is ligand-independent; in C. elegans, PAQR-2 promotes ω-6 PUFA synthesis linked to autophagy and lifespan extension at low temperature.\",\n      \"evidence\": \"AdipoR1/R2 KD with FRAP, Laurdan GP, and MS lipidomics in adiponectin-free conditions; C. elegans fatty acid profiling and autophagy assays\",\n      \"pmids\": [\"30890562\", \"31197136\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"How AdipoR2 activates desaturase transcription without adiponectin not mechanistically resolved\", \"Whether autophagy link extends to mammalian cells unknown\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Genome-wide screening in C. elegans confirmed PAQR-2/IGLR-2 as the sole essential pathway for SFA tolerance, FRET showed their interaction is regulated by membrane fluidity itself, and multi-omic analysis in human cells ranked AdipoR2 as the single most important factor for preventing SFA-induced membrane rigidification and transcriptomic collapse.\",\n      \"evidence\": \"Forward genetic screen, FRET-based interaction monitoring, transcriptomics and lipidomics in AdipoR2-KD HEK293/HUVEC\",\n      \"pmids\": [\"33444761\", \"33444759\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Direct biophysical mechanism by which membrane fluidity regulates PAQR-2/IGLR-2 interaction not resolved\", \"Downstream transcription factor(s) mediating AdipoR2-dependent desaturase gene activation unidentified\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Identification of RNF145 as an ER-resident E3 ligase that ubiquitinates and degrades AdipoR2 when membranes are unsaturated-rich — and is itself degraded when membranes become saturated — revealed an autoregulatory feedback loop controlling AdipoR2 protein levels in response to membrane lipid composition.\",\n      \"evidence\": \"Systematic proteomics of cells fed saturated vs unsaturated FAs, ubiquitination assays, RNF145 KO/KD, lipotoxicity assays\",\n      \"pmids\": [\"35993436\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"RNF145 ubiquitination sites on AdipoR2 not mapped\", \"Whether RNF145 regulation operates in vivo not shown\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Co-IP/MS in human cells and C. elegans identified HACD3 and ACSL4 as conserved AdipoR2 physical interactors that mediate fatty acid elongation and channeling of unsaturated fatty acids into phospholipids, providing the first direct link between the receptor and the lipid-remodeling enzymatic machinery.\",\n      \"evidence\": \"13C-labeled fatty acid tracing, co-IP/MS of tagged AdipoR2/PAQR-2 in HEK293 and C. elegans\",\n      \"pmids\": [\"37164154\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether AdipoR2 has intrinsic ceramidase/hydrolase activity that contributes to HACD3/ACSL4 regulation not resolved\", \"Structural basis of AdipoR2–HACD3/ACSL4 interaction unknown\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"AdipoR2 KO in mouse testes demonstrated that AdipoR2 promotes ELOVL2 expression to synthesize VLC-PUFAs essential for meiotic membrane integrity, telomere distribution, and homologous recombination; in brain, KO causes saturated FA excess with enlarged cerebrum and behavioral abnormalities; a novel AdipoR2–CaM–CaMKII–NOS3 signaling complex was identified through which AdipoR2 agonists drive Ca²⁺-dependent NO production for liver protection.\",\n      \"evidence\": \"AdipoR2 KO mice with testes lipidomics, meiotic spreads, EM; brain lipidomics/behavior; site-directed mutagenesis (R335, Y274), co-IP for complex, Ca²⁺ imaging, ALF model\",\n      \"pmids\": [\"38485951\", \"38989587\", \"39681560\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"How AdipoR2 regulates ELOVL2 transcription mechanistically not defined\", \"Whether Ca²⁺/CaMKII signaling intersects with the membrane fluidity pathway is untested\", \"Brain phenotype not yet linked to specific neuronal membrane composition changes at single-cell resolution\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"Major unresolved questions include: (1) the identity of the mammalian IGLR-2 homolog that may partner with AdipoR2 for fluidity sensing; (2) whether AdipoR2 possesses intrinsic ceramidase or hydrolase activity in vivo and how this relates to its scaffold/receptor functions; (3) the transcription factor(s) downstream of AdipoR2 that activate desaturase and elongase gene expression; and (4) the structural basis of adiponectin or agonist binding to AdipoR2 in a full-length context.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"No full-length AdipoR2 structure with ligand\", \"Mammalian IGLR-2 counterpart unidentified\", \"Intrinsic enzymatic activity debated but not definitively demonstrated in vivo\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0098772\", \"supporting_discovery_ids\": [14, 17, 19, 22, 23]},\n      {\"term_id\": \"GO:0060089\", \"supporting_discovery_ids\": [0, 2, 3, 25]},\n      {\"term_id\": \"GO:0008289\", \"supporting_discovery_ids\": [11, 23]},\n      {\"term_id\": \"GO:0140299\", \"supporting_discovery_ids\": [13, 14, 20]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005886\", \"supporting_discovery_ids\": [8, 10, 13, 26]},\n      {\"term_id\": \"GO:0005783\", \"supporting_discovery_ids\": [22]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-1430728\", \"supporting_discovery_ids\": [7, 14, 17, 19, 23, 24, 29]},\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [0, 1, 2, 3, 25, 28]},\n      {\"term_id\": \"R-HSA-168256\", \"supporting_discovery_ids\": [21]},\n      {\"term_id\": \"R-HSA-1474165\", \"supporting_discovery_ids\": [24]}\n    ],\n    \"complexes\": [\n      \"AdipoR2-CaM-CaMKII-NOS3\"\n    ],\n    \"partners\": [\n      \"APPL1\",\n      \"HACD3\",\n      \"ACSL4\",\n      \"RNF145\",\n      \"ADIPOQ\",\n      \"ADIPOR1\",\n      \"ELOVL2\",\n      \"IGLR-2\"\n    ],\n    \"other_free_text\": []\n  }\n}\n```"}