Affinage

NUCB2

Nucleobindin-2 · UniProt P80303

Length
420 aa
Mass
50.2 kDa
Annotated
2026-06-10
100 papers in source corpus 28 papers cited in narrative 28 extracted findings
Cross-family judge vs UniProt: Affinage preferred faithfulness: 8/8 claims corpus-supported (100%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

NUCB2 (NEFA) is a calcium-binding EF-hand protein that functions both as a luminal Golgi/secretory-pathway resident regulating Ca²⁺ and Gαi signaling and as the precursor of the anorexigenic neuropeptide nesfatin-1 acting in central and peripheral energy homeostasis (PMID:7811391, PMID:10381334, PMID:21653697, PMID:25534851). Biochemically it binds exactly two Ca²⁺ ions (Kd ~0.08–0.2 µM) through its EF-hand pair, and this binding drives a conformational change that increases α-helical content and alters proteolytic susceptibility (PMID:10381334). NUCB2 behaves as an extrinsic, luminal protein retained in the medial Golgi via its N-terminal Leu/Ile-rich region rather than a transmembrane anchor (PMID:11749975, PMID:11893086). Through a conserved GBA motif it binds the inactive conformation of Gαi1/Gαi3 and acts as a guanine nucleotide exchange factor, an activity abolished when Ca²⁺ binding renders the Gα-contacting residues inaccessible, coupling its Ca²⁺ status to G-protein signaling (PMID:21653697). As the nesfatin-1 precursor, NUCB2 is expressed in hypothalamic PVN neurons where it is directly activated by leptin and FGF21 and is required for their suppression of food intake, and it regulates oxytocin/AVP neurons controlling fluid balance, body weight, and blood pressure (PMID:25534851, PMID:27105386, PMID:28374855). Hypothalamic NUCB2/nesfatin-1 also restrains hepatic gluconeogenesis and improves insulin sensitivity via mTOR-STAT3 signaling (PMID:24478398), while β-cell-derived NUCB2 maintains glucose-stimulated insulin secretion in part by suppressing UCP-2 (PMID:31228099). Its expression is post-transcriptionally stabilized through 3'UTR AU-rich elements via ERK1/2 (PMID:20427483) and controlled by an HDAC5-mTORC1(raptor) acetylation axis (PMID:26357899). In cancer, NUCB2 is transcriptionally driven by KLF4 and promotes tumor growth and metastasis (PMID:30055641, PMID:37277807).

Mechanistic history

Synthesis pass · year-by-year structured walk · 13 steps
  1. 1994 High

    Establishing NUCB2 as a distinct multidomain protein defined its core architecture—EF-hand calcium motifs, an acidic region, and a leucine zipper—and placed it in the secretory pathway.

    Evidence cDNA cloning, peptide sequencing, and immunolocalization of the human protein (~55 kDa)

    PMID:7811391

    Open questions at the time
    • Functional roles of individual domains not yet tested
    • Calcium binding stoichiometry not quantified
  2. 1999 High

    Quantitative Ca²⁺-binding analysis showed NUCB2 binds exactly two Ca²⁺ ions through its EF-hands with submicromolar affinity and undergoes a Ca²⁺-driven conformational change, defining it as a genuine calcium sensor/buffer.

    Evidence Recombinant protein with equilibrium dialysis, atomic absorption, CD, and EF-hand deletion mutants

    PMID:10381334 PMID:8752007

    Open questions at the time
    • Downstream effectors of the conformational change unidentified at this stage
    • In vivo Ca²⁺ buffering role not addressed
  3. 2001 High

    Mapping the Golgi retention signal to the N-terminal Leu/Ile-rich region revealed a novel non-transmembrane mechanism for luminal Golgi residence.

    Evidence Systematic deletion mutagenesis with GFP fusions and cycloheximide chase; biochemical extraction and trypsin protection confirming extrinsic luminal medial-Golgi localization

    PMID:11749975 PMID:11893086

    Open questions at the time
    • Binding partner anchoring NUCB2 in the Golgi lumen not identified
    • Relationship between Golgi pool and secreted/processed pools unresolved
  4. 2000 High

    Identification of necdin as a direct EF-hand-domain interactor that enhances cytoplasmic retention and modulates cytosolic Ca²⁺ linked NUCB2 to neuronal Ca²⁺ handling.

    Evidence Yeast two-hybrid, 45Ca²⁺ overlay, GFP fusion localization, and live-cell Ca²⁺ measurement in neuroblastoma cells

    PMID:10915798

    Open questions at the time
    • Physiological consequence of necdin–NUCB2 interaction in vivo unknown
    • Mechanism by which NUCB2 affects caffeine-evoked Ca²⁺ not defined
  5. 2011 High

    Discovery of a conserved GBA motif that binds inactive Gαi and exerts GEF activity, abolished by Ca²⁺ binding, established NUCB2 as a Ca²⁺-gated regulator of heterotrimeric G-protein signaling.

    Evidence In vitro pulldown/competition, structural analysis, point mutagenesis of the GBA motif and Gαi3, and GEF assays with Ca²⁺ manipulation

    PMID:21653697

    Open questions at the time
    • Cellular pathway downstream of NUCB2-Gαi GEF activity not defined
    • Whether Golgi-luminal versus cytosolic NUCB2 mediates this remains open
  6. 2010 High

    Demonstrating ERK1/2-dependent stabilization of NUCB2 mRNA through 3'UTR AU-rich elements identified a post-transcriptional control layer on NUCB2 abundance.

    Evidence Nuclear run-on, mRNA half-life measurement, ERK inhibitor, and ARE reporter assays

    PMID:20427483

    Open questions at the time
    • ARE-binding protein(s) responsible not definitively identified
    • Physiological stimuli engaging this pathway beyond troglitazone unclear
  7. 2008 Medium

    Linking hypothalamic NUCB2 expression to 5-HT2C receptor signaling positioned it within a leptin-independent melanocortin anorexigenic pathway.

    Evidence Pharmacological agonist and 5-HT2C receptor mutant mice with hypothalamic qRT-PCR

    PMID:18477467

    Open questions at the time
    • Whether NUCB2 is causal or merely correlated with feeding output not tested here
    • Direct transcriptional link to 5-HT2C signaling unproven
  8. 2014 High

    Single-neuron Ca²⁺ imaging and PVN-targeted knockdown established PVN NUCB2/nesfatin-1 as a required downstream mediator of leptin's anorexigenic action, and parallel central knockdown showed it restrains hepatic gluconeogenesis via mTOR-STAT3.

    Evidence Ca²⁺ imaging, AAV-shRNA PVN knockdown with feeding assays, and adenoviral RNAi with hyperinsulinemic-euglycemic clamp

    PMID:24478398 PMID:25534851

    Open questions at the time
    • Receptor for secreted nesfatin-1 not identified
    • Molecular link between leptin signaling and NUCB2 transcription incomplete
  9. 2017 High

    Conditional Sim1-Nucb2 knockout established NUCB2/nesfatin-1 neurons as required for FGF21's anorexigenic effect, extending its role as a convergent hub for hormonal satiety signals.

    Evidence ICV FGF21, c-Fos, Ca²⁺ imaging, and PVN-preferential conditional knockout with feeding assays

    PMID:28374855

    Open questions at the time
    • FGF21 receptor coupling to NUCB2 neurons not resolved
    • Glucose-FGF21 cooperativity mechanism undefined
  10. 2016 High

    PVN-specific knockdown tied NUCB2 to oxytocin and AVP neuron function, linking it to blood pressure, fluid balance, and diurnal feeding regulation.

    Evidence AAV-shRNA PVN knockdown with plasma oxytocin/AVP, blood pressure, body weight readouts; immunoneutralization and circadian mRNA analyses

    PMID:23583201 PMID:27105386

    Open questions at the time
    • Mechanism by which NUCB2 supports AVP/oxytocin neurons not defined
    • Cell-autonomous versus circuit-level effects not separated
  11. 2015 High

    Identifying an HDAC5–raptor acetylation axis controlling mTORC1 and gastric NUCB2 expression revealed an epigenetic/PTM-coupled regulator of NUCB2 levels, complementing direct mTOR regulation.

    Evidence Co-IP of HDAC5 and raptor, raptor acetylation-site mutagenesis, HDAC inhibitors, and NUCB2 expression readouts; rapamycin and TSC1/TSC2 overexpression in earlier work

    PMID:22508056 PMID:26357899

    Open questions at the time
    • Direct transcriptional effectors downstream of mTORC1 on NUCB2 not identified
    • Tissue specificity of this axis incompletely mapped
  12. 2019 High

    β-cell-specific knockout demonstrated that β-cell-produced NUCB2 maintains glucose-stimulated insulin secretion, plausibly through suppression of UCP-2, defining a peripheral metabolic role distinct from central feeding control.

    Evidence Conditional β-cell Nucb2 knockout, glucose tolerance test, isolated islet GSIS, and shNUCB2 MIN6 cells with UCP-2 readout

    PMID:31228099

    Open questions at the time
    • Mechanism linking NUCB2 to UCP-2 repression unknown
    • Whether intracellular NUCB2 or secreted nesfatin-1 is responsible unresolved
  13. 2023 Medium

    Studies in melanoma, breast cancer, and osteosarcoma showed NUCB2 is transcriptionally driven by KLF4 and promotes tumor growth, cholesterol-dependent metastasis (mTORC1-SREBP2-HMGCR), and immunosuppression via NUCKS1-CXCL8-PD-L1, extending NUCB2 function into oncogenic signaling.

    Evidence ChIP/luciferase for KLF4, mTORC1 inhibitor and nesfatin-1 rescue, Co-IP with NUCKS1, and in vitro/in vivo metastasis and immune assays

    PMID:30055641 PMID:37277807 PMID:38636892

    Open questions at the time
    • Acetyltransferase modifying NUCB2 not identified
    • Whether secreted nesfatin-1 versus intracellular NUCB2 drives each oncogenic effect not fully separated

Open questions

Synthesis pass · forward-looking unresolved questions
  • The receptor(s) mediating secreted nesfatin-1 signaling and the integration of NUCB2's Golgi/Gαi-GEF biochemistry with its endocrine neuropeptide function remain unresolved.
  • Cognate nesfatin-1 receptor unidentified
  • Link between intracellular Ca²⁺/Gαi roles and extracellular hormone function unestablished
  • Structural basis of nesfatin-1 processing from NUCB2 not characterized

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0048018 receptor ligand activity 3 GO:0098772 molecular function regulator activity 1 GO:0140096 catalytic activity, acting on a protein 1
Localization
GO:0005576 extracellular region 2 GO:0005794 Golgi apparatus 2 GO:0005635 nuclear envelope 1 GO:0005783 endoplasmic reticulum 1 GO:0031410 cytoplasmic vesicle 1
Pathway
R-HSA-112316 Neuronal System 3 R-HSA-1430728 Metabolism 2 R-HSA-162582 Signal Transduction 1
Partners
GNAI1GNAI3NECDINNUCKS1

Evidence

Reading pass · 28 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
1994 NEFA/NUCB2 was molecularly cloned and characterized as a novel human protein with a DNA-binding domain, two EF-hand (helix-loop-helix) calcium-binding motifs, an acidic amino acid-rich region, and a leucine zipper motif. The protein is expressed on the plasma membrane, in the cytosol, and is secreted into culture medium (~55 kDa on SDS-PAGE). cDNA cloning, 5'-RACE, peptide sequencing, immunolocalization, SDS-PAGE Biological chemistry Hoppe-Seyler High 7811391
1996 Recombinant NEFA/NUCB2 binds Ca2+ via its EF-hand domain (circular dichroism confirmed 51% helical content; Ca2+ binding demonstrated). The leucine zipper cannot form homodimers but may allow heterodimer formation with an unknown protein. Phylogenetic analysis indicates the protein is derived from a four-domain EF-hand ancestor. Circular dichroism spectroscopy, recombinant protein expression, peptide synthesis, phylogenetic analysis Molecular biology and evolution Medium 8752007
1999 Recombinant human NEFA/NUCB2 binds exactly 2 mol Ca2+ per mol protein, with two classes of binding sites (Kd = 0.08 µM and 0.2 µM). Calcium binding induces a conformational change (increase in α-helical content from 30% to 43%) and altered susceptibility to proteolysis. EF-hand deletion mutants abolished Ca2+ binding. Recombinant protein expression in Pichia pastoris, equilibrium dialysis with FURA-2, atomic absorption spectroscopy, fluorescence spectroscopy, circular dichroism, limited proteolysis Biochemical and biophysical research communications High 10381334
2000 The postmitotic growth suppressor necdin directly interacts with NEFA/NUCB2 via a domain encompassing NEFA's two EF-hand motifs. Necdin enhanced cytoplasmic retention of NEFA-GFP fusion protein and potentiated NEFA-GFP's effect on caffeine-evoked elevation of cytosolic Ca2+ in neuroblastoma cells. NEFA localizes to the cisternae of the endoplasmic reticulum and nuclear envelope in brain neurons. Yeast two-hybrid screen, 45Ca2+ overlay assay, NEFA-GFP fusion protein expression, immunoelectron microscopy, cytosolic Ca2+ measurement The Journal of biological chemistry High 10915798
2001 NEFA/NUCB2 is retained in the Golgi apparatus, and its Golgi retention is mediated specifically by the N-terminal Leu/Ile-rich region; deletion of this region (ΔN mutant) abolished Golgi retention after cycloheximide chase, while deletions of the basic region, complete EF-hand pair domain, individual EF-hand motifs, or leucine zipper did not affect Golgi localization. Immunofluorescence microscopy, NEFA-GFP fusion protein expression, cycloheximide chase, seven NEFA deletion mutants, immunoblotting FEBS letters High 11749975
2002 NEFA/NUCB2 (identified as p54) is a luminal resident of medial Golgi cisternae behaving as an extrinsic membrane protein (confirmed by Triton X-114 partition, carbonate extraction, and trypsin protection). It co-localizes with the medial Golgi marker mannosidase II but dissociates from it upon brefeldin A treatment and at metaphase, indicating a novel Golgi retention mechanism distinct from integral transmembrane proteins. MALDI-TOF mass spectrometry protein identification, immunofluorescence, immuno-electron microscopy, Triton X-114 partition, carbonate extraction, trypsin protection assay, nocodazole/brefeldin A/caffeine/potassium depletion treatments European journal of cell biology High 11893086
1999 The Drosophila homolog of NEFA/NUCB2 (NUCB1) is expressed maternally and zygotically, localizes to cytoplasmic substructures consistent with the Golgi apparatus, and shows high-level zygotic expression in salivary glands from embryonic stage 11, indicating conserved subcellular localization across species. cDNA cloning, in situ hybridization, immunolocalization in Drosophila embryos Mechanisms of development Medium 10446275
2008 Serotonin 5-HT2C receptor activation upregulates hypothalamic NUCB2/nesfatin-1 mRNA expression; this upregulation was attenuated in 5-HT2C receptor mutant mice. Hypothalamic NUCB2 and POMC expression were decreased in hyperphagic 5-HT2C receptor mutant mice, placing NUCB2 downstream of 5-HT2C receptor signaling in a leptin-independent melanocortin pathway. Pharmacological agonist administration (mCPP) in vivo, 5-HT2C receptor mutant mice, qRT-PCR of hypothalamic NUCB2 and POMC, db/db leptin receptor-mutant mice Biochemical and biophysical research communications Medium 18477467
2010 Troglitazone (a PPARγ ligand) stabilizes NUCB2 mRNA through adenylate/uridylate-rich elements (AREs) in the 3' UTR by activating the ERK1/2 pathway, independently of PPARγ. The NUCB2 mRNA half-life increased from ~6 h to ~27 h with TZ, an effect blocked by the ERK inhibitor PD98059. The human NUCB2 gene spans 55 kb with 14 exons, and a 5889 bp promoter region is active in neuron-derived cells. Nuclear run-on assay, mRNA stability assay (half-life measurement), ERK inhibitor (PD98059) treatment, reporter assay fused with 3'UTR ARE constructs, phospho-ERK1/2 Western blot, genomic cloning, promoter reporter assay Endocrinology High 20427483
2010 Intracerebroventricular administration of nesfatin-1 elevated plasma ACTH and corticosterone in rats, while in vitro stimulation of the pituitary was ineffective, indicating nesfatin-1 acts at a suprapituitary (hypothalamic/brainstem) level to activate the HPA axis. Restraint stress activated nesfatin-1/NUCB2-immunoreactive neurons in the parvocellular PVN, induced NUCB2 mRNA in PVN and A1 catecholamine cell groups, and bilateral adrenalectomy increased NUCB2 mRNA, demonstrating negative feedback by adrenal steroids. ICV injection of nesfatin-1, plasma ACTH/corticosterone measurement, Fos immunostaining, in situ hybridization for NUCB2 mRNA, adrenalectomy, co-localization immunohistochemistry Neurochemistry international Medium 20435076
2011 NUCB2 and its highly homologous paralog Calnuc share a conserved GBA (Gα-binding and -activating) motif that preferentially binds the inactive conformation of Gαi1 and Gαi3 over other Gα subunits, docking onto the α3/switch II cleft. Calcium binding to NUCB2 abolishes interaction with Gαi3 in vitro and in cells, likely by inducing a conformational change that renders the Gα-binding residues inaccessible. Mutagenesis of hydrophobic residues in the GBA motif impaired NUCB2 binding and activation of Gαi3 in vitro. In vitro pulldown assay, competition assay, bioinformatics/structural analysis, point mutagenesis of NUCB2 GBA motif and Gαi3 α3 helix (K248M), Ca2+ manipulation in vitro and in cells, GEF activity assay The Journal of biological chemistry High 21653697
2012 Gastric mTOR signaling directly regulates NUCB2/nesfatin-1 expression: mTOR co-localizes with nesfatin-1 in gastric X/A-like cells, rapamycin treatment reduced NUCB2 mRNA and protein in lean and obese mice, and overexpression of TSC1 or TSC2 (negative regulators of mTOR) in Min-6 cells reduced NUCB2/nesfatin-1 expression. Fasting down-regulated both mTOR activity and gastric NUCB2/nesfatin-1, which returned to baseline with re-feeding. Immunofluorescence co-localization, RT-PCR, Western blot, rapamycin treatment in vivo and in vitro, TSC1/TSC2 overexpression in Min-6 cells, fasting/re-feeding/high-fat diet models Cellular physiology and biochemistry Medium 22508056
2014 Hypothalamic nesfatin-1/NUCB2 knockdown (via adenoviral shRNA) in rats increased food intake, hepatic glucose flux, and decreased peripheral glucose uptake. The effect was accompanied by increased hepatic glucose-6-phosphatase and PEPCK expression, decreased phosphorylation of insulin receptor, IRS-1, and AKT, and decreased phosphorylation of mTOR and STAT3. This places hypothalamic NUCB2/nesfatin-1 upstream of the mTOR-STAT3 signaling pathway in regulating hepatic gluconeogenesis and insulin sensitivity. Adenoviral RNAi knockdown in vivo, hyperinsulinemic-euglycemic clamp, hepatic glucose flux measurement, Western blot for pathway components, RT-PCR Diabetes High 24478398
2014 Leptin directly activates PVN NUCB2/nesfatin-1 neurons (increasing cytosolic Ca2+ predominantly in NUCB2/nesfatin-1-immunoreactive single neurons) and markedly increases NUCB2 mRNA expression in PVN in vitro and in vivo. AAV-mediated shRNA knockdown of NUCB2 in PVN prevented leptin (peripheral and central injection) from inhibiting food intake, establishing PVN NUCB2/nesfatin-1 as a required downstream mediator of leptin's anorexigenic effect. Single-neuron Ca2+ imaging, AAV-NUCB2-shRNA injection into PVN, food intake measurement after leptin injection, NUCB2 mRNA quantification Biochemical and biophysical research communications High 25534851
2016 PVN-specific NUCB2 knockdown via AAV-shRNA increased food intake and decreased plasma oxytocin selectively in the light phase, leading to increased body weight without affecting energy expenditure. High-salt diet-induced increases in systolic blood pressure, plasma arginine vasopressin (AVP), and PVN AVP mRNA were all blunted by PVN-specific NUCB2 knockdown, indicating that NUCB2/nesfatin-1 in PVN supports AVP and oxytocin neurons to regulate fluid balance and energy homeostasis. AAV-shRNA PVN-specific knockdown, food intake measurement, plasma oxytocin/AVP ELISA, blood pressure measurement, AVP mRNA quantification, body weight and energy expenditure monitoring Endocrinology High 27105386
2017 FGF21, assisted by elevated glucose, activates PVN NUCB2/nesfatin-1 neurons (increased [Ca2+]i) and selectively increases NUCB2/nesfatin-1 mRNA in PVN. ICV FGF21 failed to suppress food intake in PVN-preferential Sim1-Nucb2-KO mice, demonstrating that NUCB2/nesfatin-1 neurons are required for FGF21's anorexigenic effect. ICV FGF21 injection, c-Fos immunostaining, mRNA expression analysis, Ca2+ imaging of PVN neurons, Sim1-Nucb2-KO mice, food intake measurement Scientific reports High 28374855
2015 HDAC5 interacts with mTORC1 component raptor (co-immunoprecipitation). HDAC5 inhibition (by VPA, trichostatin A, or siHDAC5) increased acetylation of raptor Lys840 and subsequent phosphorylation of raptor Ser792, suppressing mTORC1 signaling and decreasing nesfatin-1/NUCB2 expression. A raptor mutant lacking Lys840 acetylation site showed decreased Ser792 phosphorylation and increased mTORC1/NUCB2 expression. This identifies HDAC5-mTORC1 as a regulatory axis controlling gastric NUCB2/nesfatin-1. Co-immunoprecipitation of HDAC5 and raptor, siRNA knockdown, pharmacological HDAC inhibitors, raptor acetylation-site mutagenesis, Western blot for acetylation and phosphorylation, NUCB2/nesfatin-1 mRNA and protein quantification in vivo and in vitro Molecular endocrinology High 26357899
2018 KLF4 directly binds to the NUCB2 promoter (confirmed by luciferase reporter assay and ChIP) and facilitates NUCB2 transcription in melanoma cells. KLF4-mediated upregulation of NUCB2 promotes ER stress resistance, tumor growth, and cell metastasis in vitro and in vivo. RNA sequencing, luciferase reporter assay, chromatin immunoprecipitation (ChIP), qRT-PCR, Western blot, transwell and mouse metastasis assays, tissue microarray Journal of experimental & clinical cancer research Medium 30055641
2019 Pancreatic β-cell-specific NUCB2 knockout (βNUCB2 KO) mice showed elevated blood glucose from 12 weeks, reduced insulin secretion at 15 min during glucose tolerance test, and impaired high glucose-stimulated insulin secretion (GSIS) from isolated islets. NUCB2 knockdown in MIN6 cells reduced GSIS and elevated UCP-2 mRNA, suggesting β-cell-produced NUCB2/nesfatin-1 maintains GSIS potentially by suppressing UCP-2. β-cell-specific conditional Nucb2 knockout mice, glucose tolerance test, isolated islet GSIS assay, shNUCB2 MIN6 β-cell line, UCP-2 mRNA expression The journal of physiological sciences High 31228099
2023 NUCB2/nesfatin-1 promotes breast cancer metastasis by upregulating cholesterol synthesis via the mTORC1-SREBP2-HMGCR axis. NUCB2 was found to be potentially acetylated in breast cancer cells (confirmed by acetyltransferase inhibitor treatment). Nesfatin-1 treatment rescued impaired cell metastasis induced by NUCB2 depletion, confirming the processed peptide mediates the metastatic effect. Gene expression chip/IPA analysis, mTORC1 inhibitor experiments, rescue experiments with recombinant nesfatin-1, transwell migration/invasion assays, nude mouse lung metastasis model, ELISA (serum nesfatin-1), acetyltransferase inhibitor treatment, Western blot Journal of translational medicine Medium 37277807
2009 NUCB2 protein is phosphorylated in gastric mucosa (detected by Western blot in normal tissue). A distinct 55 kDa isoform generated by an unidentified post-translational modification was detected in gastric tumors and AGS gastric cancer cells but absent in normal gastric mucosa. NUCB2 was localized to secretory granules of chief cells and cytoplasm of parietal cells in normal functioning gastric glands. Western blot, immunohistochemistry of stomach tissue microarray, mRNA expression analysis European journal of histochemistry Low 19351608
2024 NUCB2 interacts with NUCKS1 protein and inhibits its degradation; this interaction is required for NUCKS1-mediated transcriptional upregulation of CXCL8, which in turn increases PD-L1 expression to promote immunosuppression in osteosarcoma. NUCB2 depletion reduced CXCL8 and PD-L1 expression and enhanced anti-tumor T-cell immunity. NUCB2 expression was elevated under glucose deprivation-induced metabolic stress. Co-immunoprecipitation of NUCB2 and NUCKS1, protein degradation assay, NUCB2 knockdown in vitro and in vivo, CXCL8/PD-L1 expression analysis, anti-PD-L1 combination treatment, T-cell cytotoxicity assay Cancer letters Medium 38636892
2013 Gastric distension activates NTS NUCB2/nesfatin-1-expressing neurons (demonstrated by Fos immunoreactivity). Several NTS NUCB2/nesfatin-1 neurons were identified as GABAergic. Fluorogold retrograde labeling from the stomach identified DMNX neurons that also express NUCB2/nesfatin-1, establishing a brainstem nesfatin-1 circuit sensitive to gastric mechanosensory input. Fos immunostaining after gastric distension, fluorogold retrograde tracing from stomach, double-immunolabeling for NUCB2/nesfatin-1 and GABAergic markers Regulatory peptides Medium 24120633
2016 Nesfatin-1 injected into the amygdala increased AWR scores, EMG activity (visceral hypersensitivity), and corticosterone in normal rats. Nesfatin-1-induced visceral hypersensitivity was abolished by glucocorticoid receptor (GR) and mineralocorticoid receptor (MR) antagonists, indicating nesfatin-1 acts via GR and MR signaling pathways in the amygdala to modulate visceral sensitivity. Intra-amygdala injection of nesfatin-1, AWR scoring, EMG measurement during colorectal distension, GR/MR antagonist pharmacology, NUCB2 mRNA/protein expression in maternal separation model Neurogastroenterology and motility Medium 27380730
2011 In rats, LPS injection increased plasma NUCB2/nesfatin-1 concentrations by 43–78% at 2–7 h post-injection, associated with increased gastric NUCB2 mRNA and protein, while gastric ghrelin decreased—establishing that an immune challenge differentially and oppositely regulates NUCB2/nesfatin-1 and ghrelin from the same gastric X/A-like cells. Intraperitoneal LPS injection, radioimmunoassay (plasma nesfatin-1), RT-qPCR (gastric NUCB2 mRNA), Western blot (gastric NUCB2 protein), white blood cell NUCB2 mRNA assessment Peptides Medium 21782869
2013 NUCB2 mRNA expression in the PVN shows a diurnal rhythm, rising during early light phase in parallel with suppression of food intake. Immunoneutralization of PVN NUCB2/nesfatin-1 with anti-nesfatin-1 IgG during light phase (but not dark phase) increased food intake. PVN-selective shRNA knockdown of NUCB2 elevated food intake. This diurnal rhythm was blunted in obese Zucker-fatty rats exhibiting light-phase hyperphagia. NUCB2 mRNA quantification at multiple circadian time points, anti-nesfatin-1 IgG immunoneutralization in PVN, PVN-selective shRNA knockdown, Zucker-fatty rat model, ICV nesfatin-1 injection Biochemical and biophysical research communications Medium 23583201
2012 NUCB2/nesfatin-1 is expressed in rat, mouse, and human testes, specifically in mature Leydig cells (and in Sertoli cells upon Leydig cell elimination). Testicular NUCB2/nesfatin-1 expression is upregulated by LH/hCG (enhanced by hCG replacement after hypophysectomy, reduced by hypophysectomy). Nesfatin-1 increased hCG-stimulated testosterone secretion by rat testicular explants ex vivo, establishing a direct role for nesfatin-1 in Leydig cell steroidogenesis. Immunohistochemistry, RT-PCR, Western blot in rat/mouse/human testis; hypophysectomy and hCG replacement in vivo; ex vivo testicular explant testosterone secretion assay Endocrinology Medium 22334726
2022 Nesfatin-1 treatment of LPS-stimulated 3T3-L1 preadipocytes significantly reduced the expression and secretion of pro-inflammatory cytokines (TNFα, IL-6, IL-1β, MCP1) and HMGB1. NUCB2 knockout mice fed an obesogenic diet showed significantly increased pro-inflammatory mediators (Tnfα, Il-6, Il-1β, Adgre1, Mcp1, TLR4, HMGB1, NF-κB) and decreased adiponectin and Nrf2 in subcutaneous WAT, involving HMGB1, NRF2, and NF-κB pathways. NUCB2 KO mouse model, obesogenic diet feeding, qPCR, Western blot, Bioplex cytokine measurement, ELISA, immunofluorescence, nesfatin-1 treatment in LPS-stimulated 3T3-L1 cells Nutrients Medium 35406022

Source papers

Stage 0 corpus · 100 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2010 Expanding roles of NUCB2/nesfatin-1 in neuroendocrine regulation. Journal of molecular endocrinology 112 20682642
2010 Expression of nesfatin-1/NUCB2 in rodent digestive system. World journal of gastroenterology 101 20380005
2012 Cellular distribution, regulated expression, and functional role of the anorexigenic peptide, NUCB2/nesfatin-1, in the testis. Endocrinology 97 22334726
2006 Delayed secretory pathway contributions to VLDL-triglycerides from plasma NEFA, diet, and de novo lipogenesis in humans. Journal of lipid research 96 16929033
1994 Human protein NEFA, a novel DNA binding/EF-hand/leucine zipper protein. Molecular cloning and sequence analysis of the cDNA, isolation and characterization of the protein. Biological chemistry Hoppe-Seyler 92 7811391
2010 Nesfatin-1/NUCB2 may participate in the activation of the hypothalamic-pituitary-adrenal axis in rats. Neurochemistry international 87 20435076
2007 Oral taurine but not N-acetylcysteine ameliorates NEFA-induced impairment in insulin sensitivity and beta cell function in obese and overweight, non-diabetic men. Diabetologia 81 18026714
2000 The postmitotic growth suppressor necdin interacts with a calcium-binding protein (NEFA) in neuronal cytoplasm. The Journal of biological chemistry 79 10915798
2018 NEFA-induced ROS impaired insulin signalling through the JNK and p38MAPK pathways in non-alcoholic steatohepatitis. Journal of cellular and molecular medicine 74 29602237
2011 Nesfatin-1 stimulates glucagon and insulin secretion and beta cell NUCB2 is reduced in human type 2 diabetic subjects. Cell and tissue research 71 22108805
2005 The in vivo effects of the Pro12Ala PPARgamma2 polymorphism on adipose tissue NEFA metabolism: the first use of the Oxford Biobank. Diabetologia 71 16362285
2016 An association between the level of oxidative stress and the concentrations of NEFA and BHBA in the plasma of ketotic dairy cows. Journal of animal physiology and animal nutrition 70 27079290
2013 Central and peripheral expression and distribution of NUCB2/nesfatin-1. Current pharmaceutical design 68 23537079
2013 Ghrelin and NUCB2/nesfatin-1 are expressed in the same gastric cell and differentially correlated with body mass index in obese subjects. Histochemistry and cell biology 65 23515787
2004 Physiological regulation of NEFA availability: lipolysis pathway. The Proceedings of the Nutrition Society 65 15294057
2017 Mulberry leaf alleviates streptozotocin-induced diabetic rats by attenuating NEFA signaling and modulating intestinal microflora. Scientific reports 60 28935866
2016 Impaired adipose tissue lipid storage, but not altered lipolysis, contributes to elevated levels of NEFA in type 2 diabetes. Degree of hyperglycemia and adiposity are important factors. Metabolism: clinical and experimental 58 27832864
2013 Clinical significance of NUCB2 mRNA expression in prostate cancer. Journal of experimental & clinical cancer research : CR 55 23958433
2012 Pharmacological reduction of NEFA restores the efficacy of incretin-based therapies through GLP-1 receptor signalling in the beta cell in mouse models of diabetes. Diabetologia 51 23188390
2014 Hypothalamic nesfatin-1/NUCB2 knockdown augments hepatic gluconeogenesis that is correlated with inhibition of mTOR-STAT3 signaling pathway in rats. Diabetes 49 24478398
2015 Acute, but not chronic, stress increased the plasma concentration and hypothalamic mRNA expression of NUCB2/nesfatin-1 in rats. Neuropeptides 47 26297350
2008 Serotonin systems upregulate the expression of hypothalamic NUCB2 via 5-HT2C receptors and induce anorexia via a leptin-independent pathway in mice. Biochemical and biophysical research communications 46 18477467
2013 Nesfatin-1/NUCB2 as a potential new element of sleep regulation in rats. PloS one 45 23560056
2012 mTOR-dependent modulation of gastric nesfatin-1/NUCB2. Cellular physiology and biochemistry : international journal of experimental cellular physiology, biochemistry, and pharmacology 44 22508056
2011 G Protein binding sites on Calnuc (nucleobindin 1) and NUCB2 (nucleobindin 2) define a new class of G(alpha)i-regulatory motifs. The Journal of biological chemistry 44 21653697
2013 Multi-functional peptide hormone NUCB2/nesfatin-1. Endocrine 43 23526235
2017 Association of NEFA composition with insulin sensitivity and beta cell function in the Prospective Metabolism and Islet Cell Evaluation (PROMISE) cohort. Diabetologia 42 29275428
2011 Association between polymorphisms of the Nesfatin gene, NUCB2, and obesity in men. Molecular genetics and metabolism 41 21459029
2014 NUCB2/nesfatin-1: a new adipokine expressed in human and murine chondrocytes with pro-inflammatory properties, an in vitro study. Journal of orthopaedic research : official publication of the Orthopaedic Research Society 39 24464950
2014 The Tissue Distribution of Nesfatin-1/NUCB2 in Mouse. Development & reproduction 38 25949201
2008 Plasma NEFA storage in adipose tissue in the postprandial state: sex-related and regional differences. Diabetologia 38 18712345
2007 Animal and human tissue Na,K-ATPase in normal and insulin-resistant states: regulation, behaviour and interpretative hypothesis on NEFA effects. Obesity reviews : an official journal of the International Association for the Study of Obesity 37 17444965
2017 Fibroblast growth factor 21, assisted by elevated glucose, activates paraventricular nucleus NUCB2/Nesfatin-1 neurons to produce satiety under fed states. Scientific reports 36 28374855
2016 Paraventricular NUCB2/Nesfatin-1 Supports Oxytocin and Vasopressin Neurons to Control Feeding Behavior and Fluid Balance in Male Mice. Endocrinology 35 27105386
2013 A sustained increase in plasma NEFA upregulates the Toll-like receptor network in human muscle. Diabetologia 34 24337154
2002 The calcium-binding protein p54/NEFA is a novel luminal resident of medial Golgi cisternae that traffics independently of mannosidase II. European journal of cell biology 34 11893086
2017 NUCB2/nesfatin-1: Expression and functions in the regulation of emotion and stress. Progress in neuro-psychopharmacology & biological psychiatry 33 28963067
2011 Lipopolysaccharide increases gastric and circulating NUCB2/nesfatin-1 concentrations in rats. Peptides 33 21782869
2013 Emerging roles of NUCB2/nesfatin-1 in the metabolic control of reproduction. Current pharmaceutical design 31 23537080
2021 Elucidation of the mechanism of NEFA-induced PERK-eIF2α signaling pathway regulation of lipid metabolism in bovine hepatocytes. The Journal of steroid biochemistry and molecular biology 30 33819629
2018 Regulation of the adaptation to ER stress by KLF4 facilitates melanoma cell metastasis via upregulating NUCB2 expression. Journal of experimental & clinical cancer research : CR 30 30055641
2015 Influence of endogenous NEFA on beta cell function in humans. Diabetologia 30 26160433
2008 Energy balance, leptin, NEFA and IGF-I plasma concentrations and resumption of post partum ovarian activity in Swedish Red and White breed cows. Acta veterinaria Scandinavica 29 18184427
2020 FTX contributes to cell proliferation and migration in lung adenocarcinoma via targeting miR-335-5p/NUCB2 axis. Cancer cell international 27 32226311
2014 Paraventricular NUCB2/nesfatin-1 is directly targeted by leptin and mediates its anorexigenic effect. Biochemical and biophysical research communications 27 25534851
1996 The divergent domains of the NEFA and nucleobindin proteins are derived from an EF-hand ancestor. Molecular biology and evolution 27 8752007
2006 To be or NUCB2, is nesfatin the answer? Cell metabolism 26 17141625
2014 Long-term intake of soyabean phytosterols lowers serum TAG and NEFA concentrations, increases bile acid synthesis and protects against fatty liver development in dyslipidaemic hamsters. The British journal of nutrition 25 24932972
2013 Paraventricular NUCB2/nesfatin-1 rises in synchrony with feeding suppression during early light phase in rats. Biochemical and biophysical research communications 25 23583201
2012 Identification of mutations in the NUCB2/nesfatin gene in children with severe obesity. Molecular genetics and metabolism 25 23141462
2010 Troglitazone, a ligand of peroxisome proliferator-activated receptor-{gamma}, stabilizes NUCB2 (Nesfatin) mRNA by activating the ERK1/2 pathway: isolation and characterization of the human NUCB2 gene. Endocrinology 25 20427483
2014 Progesterone and 17β-estradiol regulate expression of nesfatin-1/NUCB2 in mouse pituitary gland. Peptides 24 25451467
2013 Role of brain NUCB2/nesfatin-1 in the regulation of food intake. Current pharmaceutical design 23 23537088
2013 Gastric distension activates NUCB2/nesfatin-1-expressing neurons in the nucleus of the solitary tract. Regulatory peptides 23 24120633
2008 Twenty-four hour insulin secretion and beta cell NEFA oxidation in type 2 diabetic, morbidly obese patients before and after bariatric surgery. Diabetologia 23 18458872
2018 Berberine Protects against NEFA-Induced Impairment of Mitochondrial Respiratory Chain Function and Insulin Signaling in Bovine Hepatocytes. International journal of molecular sciences 22 29882814
2013 Effects of nesfatin-1 on food intake and LH secretion in prepubertal gilts and genomic association of the porcine NUCB2 gene with growth traits. Domestic animal endocrinology 22 23820242
2022 Transcriptome Analysis Reveals That NEFA and β-Hydroxybutyrate Induce Oxidative Stress and Inflammatory Response in Bovine Mammary Epithelial Cells. Metabolites 21 36355143
2017 Glucose, amino acids and fatty acids directly regulate ghrelin and NUCB2/nesfatin-1 in the intestine and hepatopancreas of goldfish (Carassius auratus) in vitro. Comparative biochemistry and physiology. Part A, Molecular & integrative physiology 21 28089858
2017 A novel function of NUCB2 in promoting the development and invasion of renal cell carcinoma. Oncology letters 21 29434954
2001 Golgi retention of human protein NEFA is mediated by its N-terminal Leu/Ile-rich region. FEBS letters 21 11749975
2023 NUCB2/Nesfatin-1 drives breast cancer metastasis through the up-regulation of cholesterol synthesis via the mTORC1 pathway. Journal of translational medicine 20 37277807
2022 Glucolipotoxicity promotes the capacity of the glycerolipid/NEFA cycle supporting the secretory response of pancreatic beta cells. Diabetologia 20 35018486
2016 Expression and regulation of peripheral NUCB2/nesfatin-1. Current opinion in pharmacology 20 27589697
2015 Regulation of NUCB2/nesfatin-1 production in rat's stomach and adipose tissue is dependent on age, testosterone levels and lactating status. Molecular and cellular endocrinology 20 25916958
2010 Novel SNPs of the bovine NUCB2 gene and their association with growth traits in three native Chinese cattle breeds. Molecular biology reports 20 19728157
2003 Chronic leptin administration increases serum NEFA in the pig and differentially regulates PPAR expression in adipose tissue. The Journal of nutritional biochemistry 20 14559108
2016 Tissue-specific expression of ghrelinergic and NUCB2/nesfatin-1 systems in goldfish (Carassius auratus) is modulated by macronutrient composition of diets. Comparative biochemistry and physiology. Part A, Molecular & integrative physiology 19 26805937
2015 Elevated nocturnal NEFA are an early signal for hyperinsulinaemic compensation during diet-induced insulin resistance in dogs. Diabetologia 19 26254577
2015 Developmental expression and distribution of nesfatin-1/NUCB2 in the canine digestive system. Acta histochemica 19 26643216
2009 Molecular characterisation and expression analysis of SEREX-defined antigen NUCB2 in gastric epithelium, gastritis and gastric cancer. European journal of histochemistry : EJH 19 19351608
2013 Role of NUCB2/nesfatin-1 in glucose control: diverse functions in islets, adipocytes and brain. Current pharmaceutical design 18 23537085
2007 PPARGC1A coding variation may initiate impaired NEFA clearance during glucose challenge. Diabetologia 18 17216277
2006 Sustained elevations in NEFA induce cyclooxygenase-2 activity and potentiate THP-1 macrophage foam cell formation. Atherosclerosis 18 16870193
1999 Heterologous overexpression of human NEFA and studies on the two EF-hand calcium-binding sites. Biochemical and biophysical research communications 18 10381334
2019 Gonadotropin regulates NUCB2/nesfatin-1 expression in the mouse ovary and uterus. Biochemical and biophysical research communications 17 30981497
2019 Islet β-cell-produced NUCB2/nesfatin-1 maintains insulin secretion and glycemia along with suppressing UCP-2 in β-cells. The journal of physiological sciences : JPS 17 31228099
2016 Estradiol and testosterone modulate the tissue-specific expression of ghrelin, ghs-r, goat and nucb2 in goldfish. General and comparative endocrinology 17 26773340
2014 Regulation of NucB2/Nesfatin-1 throughout rat pregnancy. Physiology & behavior 17 24905431
2022 NUCB2/Nesfatin-1 Reduces Obesogenic Diet Induced Inflammation in Mice Subcutaneous White Adipose Tissue. Nutrients 16 35406022
2018 Effects of acute NEFA manipulation on incretin-induced insulin secretion in participants with and without type 2 diabetes. Diabetologia 16 29732475
2016 Role of Brain NUCB2/nesfatin-1 in the Stress-induced Modulation of Gastrointestinal Functions. Current neuropharmacology 16 27281021
2015 GSK256073 acutely regulates NEFA levels via HCA2 agonism but does not achieve durable glycaemic control in type 2 diabetes. A randomised trial. European journal of pharmacology 16 25773496
2015 HDAC5-mTORC1 Interaction in Differential Regulation of Ghrelin and Nucleobindin 2 (NUCB2)/Nesfatin-1. Molecular endocrinology (Baltimore, Md.) 16 26357899
2013 Colestilan decreases weight gain by enhanced NEFA incorporation in biliary lipids and fecal lipid excretion. Journal of lipid research 16 23434610
2002 Glycerol and NEFA kinetics in long-term fasting king penguins: phase II versus phase III. The Journal of experimental biology 16 12151380
1999 NUCB1, the Drosophila melanogaster homolog of the mammalian EF-hand proteins NEFA and nucleobindin. Mechanisms of development 16 10446275
2017 Testosterone Regulates NUCB2 mRNA Expression in Male Mouse Hypothalamus and Pituitary Gland. Development & reproduction 15 28484746
2014 A role of nesfatin-1/NucB2 in dehydration-induced anorexia. American journal of physiology. Regulatory, integrative and comparative physiology 15 24829503
2013 Increased nucleobindin-2 (NUCB2) transcriptional activity links the regulation of insulin sensitivity in Type 2 diabetes mellitus. Journal of endocrinological investigation 15 23765387
2013 Expression of Nesfatin-1/NUCB2 in Fetal, Neonatal and Adult Mice. Development & reproduction 15 25949163
2010 Effect of NEFA and glucose levels on CPT-I mRNA expression and translation in cultured bovine hepatocytes. The Journal of veterinary medical science 15 20716862
2012 The association of a nucleobindin 2 gene (NUCB2) variant with childhood adiposity. Gene 14 23266808
2009 Molecular characterisation and expression analysis of SEREX-defined antigen NUCB2 in gastric epithelium, gastritis and gastric cancer. European journal of histochemistry : EJH 14 30256860
2019 High expression of NUCB2 promotes papillary thyroid cancer cells proliferation and invasion. OncoTargets and therapy 13 30863097
2018 Tissue-Specific Localization NUCB2/nesfatin-1 in the Liver and Heart of Mouse Fetus. Development & reproduction 13 30680332
2016 Nesfatin-1/NUCB2 in the amygdala influences visceral sensitivity via glucocorticoid and mineralocorticoid receptors in male maternal separation rats. Neurogastroenterology and motility 13 27380730
2013 Possible role of NUCB2/nesfatin-1 in adipogenesis. Current pharmaceutical design 13 23537078
2024 NUCB2 inhibition antagonizes osteosarcoma progression and promotes anti-tumor immunity through inactivating NUCKS1/CXCL8 axis. Cancer letters 12 38636892
2015 NUCB2 gene polymorphism and its relationship with nesfatin-1 levels in polycystic ovary syndrome. Gynecological endocrinology : the official journal of the International Society of Gynecological Endocrinology 12 26369257

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