Details for: AGRP

Gene ID: 181

Gene Type:  Protein-coding  - A gene that serves as a template for producing a messenger RNA (mRNA) molecule, which is then translated into a functional protein.

Symbol: AGRP

Ensembl ID: ENSG00000159723

Description: agouti related neuropeptide

Selected Context(s):  Overall

Cell Significance Landscape

Contexts:

Associated with

Significant Cells

Cell Significance Index (CSI) scores for the chosen context(s)

  • elicited macrophage CL0000861
    CSI 17.59
    rCSI 16.15%
    PRS 100
  • alveolar macrophage CL0000583
    CSI 4.06
    rCSI 6.68%
    PRS 99.96
  • lung macrophage CL1001603
    CSI 2.48
    rCSI 5.53%
    PRS 100

Cell ID: Standard Cell Ontology term used for mapping and comparing cells across experiments. Ensures consistency in analyzing cellular functions across tissues.
Fold Change: Represents the ratio of the current Cell Significance Index to the Cell Significance Index Threshold, indicating how much the gene expression has changed compared to a baseline.
Cell Significance Index: Reflects how strongly a gene is expressed in this specific cell.

Cell ID: Standard Cell Ontology term used for mapping and comparing cells across experiments. Ensures consistency in analyzing cellular functions across tissues.
Fold Change: Represents the ratio of the current Cell Significance Index to the Cell Significance Index Threshold, indicating how much the gene expression has changed compared to a baseline.
Cell Significance Index: Reflects how strongly a gene is expressed in this cell type. Calculated using techniques like effect size estimation and bootstrapping for reliability.

Cell ID: Standard Cell Ontology term used for mapping and comparing cells across experiments. Ensures consistency in analyzing cellular functions across tissues.
Fold Change: Represents the ratio of the current Cell Significance Index to the Cell Significance Index Threshold, indicating how much the gene expression has changed compared to a baseline.
Cell Significance Index: Reflects how strongly a gene is expressed in this cell type. Calculated using techniques like effect size estimation and bootstrapping for reliability.
Network Configuration

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Other Information

This section provides additional information about the gene, including a description generated by an AI language model and details about associated proteins.

## Summary [AGRP](/details-gene/181) (Agouti-related neuropeptide) is a protein-coding gene located on chromosome 16q22.1. It encodes a neuropeptide that is a potent and long-lasting antagonist of the melanocortin-3 and -4 receptors, playing a critical role in regulating energy homeostasis and increasing food intake ([Link](https://doi.org/10.1126/science.278.5335.135)). While classically studied for its function in hypothalamic neurons, expression data indicates a significant role in specific immune cell populations. **Overall**, [AGRP](/details-gene/181) shows its highest significance as a marker for [elicited macrophage](/details-cell/CL0000861) (CSI: 17.59), and is also notably expressed in [alveolar macrophage](/details-cell/CL0000583) and [lung macrophage](/details-cell/CL1001603). This suggests a potential dual function for [AGRP](/details-gene/181) in both central metabolic control and peripheral immune modulation. Dysregulation of [AGRP](/details-gene/181) is associated with metabolic disorders, including obesity ([Link](https://doi.org/10.1210/jc.2002-011834)) and anorexia nervosa ([Link](https://doi.org/10.1038/sj.mp.4000854)), as referenced in OMIM ([602311](https://omim.org/entry/602311)). ## Cellular Roles and Expression Landscape The expression profile of [AGRP](/details-gene/181) highlights a prominent role in macrophage biology. **Overall**, the gene demonstrates exceptionally high significance in [elicited macrophage](/details-cell/CL0000861), positioning it as a key marker for this cell type. Its significant, albeit lower, CSI scores in [alveolar macrophage](/details-cell/CL0000583) and [lung macrophage](/details-cell/CL1001603) further establish a strong connection to tissue-resident macrophages, particularly within the pulmonary system. This macrophage-centric expression pattern is intriguing when contrasted with its well-established function as a neuropeptide synthesized in the arcuate nucleus of the hypothalamus. There, it is co-expressed with Neuropeptide Y and acts as a powerful orexigenic (appetite-stimulating) signal. The GO annotation for localization in the [neuronal cell body](/details-cell/GO:0043025) and its secretion into the [extracellular space](/details-cell/GO:0005615) are consistent with its function as a signaling molecule in both the central nervous system and potentially within peripheral tissues. The strong expression signature in macrophages suggests that these cells may be a significant peripheral source of [AGRP](/details-gene/181), potentially contributing to local tissue signaling or systemic metabolic regulation. ## Pathways and Molecular Function The primary function of [AGRP](/details-gene/181) is centered on the regulation of energy balance and feeding behavior. This is strongly supported by its annotation in multiple related biological processes, including [feeding behavior](/details-cell/GO:0007631), [positive regulation of feeding behavior](/details-cell/GO:2000253), and the overarching [neuropeptide signaling pathway](/details-cell/GO:0007218). At the molecular level, it functions via [neuropeptide hormone activity](/details-cell/GO:0005184) and acts as an antagonist through [signaling receptor binding](/details-cell/GO:0005102), specifically [type 1 melanocortin receptor binding](/details-cell/GO:0070996) ([Link](https://doi.org/10.1210/mend.13.1.0223)). By inhibiting melanocortin receptors, [AGRP](/details-gene/181) promotes feeding and reduces energy expenditure. The associated Reactome pathways, such as [Foxo-mediated transcription](/details-cell/R-HSA-9614085) and [Rna polymerase ii transcription](/details-cell/R-HSA-73857), likely reflect the transcriptional regulation of the [AGRP](/details-gene/181) gene itself, which is known to be responsive to metabolic cues like insulin and leptin, rather than the direct function of the secreted protein. This transcriptional control is a key mechanism for integrating peripheral energy status signals within the brain and possibly within peripheral cells like macrophages. ## Research Directions The most compelling research direction for [AGRP](/details-gene/181) is to reconcile its canonical role in central appetite control with its newly identified strong expression signature in peripheral macrophages. This discrepancy suggests a potential link between immunometabolism and systemic energy homeostasis that is mediated by macrophage-derived [AGRP](/details-gene/181). Based on this, several testable hypotheses can be proposed: 1. [AGRP](/details-gene/181) expression in tissue-resident macrophages, such as [alveolar macrophage](/details-cell/CL0000583), is dynamically regulated by local inflammatory or metabolic cues (e.g., pathogens, metabolites, cytokines), and it functions as a paracrine modulator of other immune or structural cells within the tissue microenvironment. 2. Macrophage-secreted [AGRP](/details-gene/181) contributes to the systemic pool of the neuropeptide, creating a feed-forward loop where peripheral inflammation and metabolic stress can directly influence central appetite-regulating pathways. 3. In disease states like obesity-associated inflammation, elevated [AGRP](/details-gene/181) from macrophages may exacerbate metabolic dysfunction by locally antagonizing melanocortin receptors on immune cells, which are known to have anti-inflammatory roles. To test the first hypothesis, a key experiment would be to isolate primary human [alveolar macrophage](/details-cell/CL0000583) and expose them *in vitro* to a panel of stimuli, including bacterial components (LPS), inflammatory cytokines (TNF-alpha, IL-4), and metabolic stressors (high glucose, free fatty acids). The expression and secretion of [AGRP](/details-gene/181) could be quantified using qPCR and ELISA. Subsequently, conditioned media from these stimulated macrophages could be applied to co-cultured epithelial cells or T-cells to assess changes in their function, such as barrier integrity or activation state, thereby testing the paracrine signaling potential of macrophage-derived [AGRP](/details-gene/181). Given its function as a potent orexigenic peptide, [AGRP](/details-gene/181) or its downstream receptors are significant therapeutic targets. The primary strategy would be **inhibition** of [AGRP](/details-gene/181) activity or antagonism of its interaction with melanocortin receptors for the treatment of obesity and metabolic syndrome. However, its high expression in macrophages introduces a layer of complexity; systemic inhibition might have unintended immunological consequences. Conversely, this also opens a novel therapeutic avenue for targeting metabolic inflammation ("meta-inflammation") by modulating [AGRP](/details-gene/181) signaling specifically within immune cell compartments.

Genular Protein ID: 3087704506

Symbol: AGRP_HUMAN

Name: Agouti-related protein

UniProtKB Accession Codes:

O00253 O15459 Q2TBD9

Database IDs:

AGR 1 AlphaFoldDB 1 Antibodypedia 1 Bgee 1 BioGRID 1 BioGRID-ORCS 1 BioMuta 1 CCDS 1 CTD 1 DNASU 1 DisGeNET 1 EMBL 6 Ensembl 1 EvolutionaryTrace 1 ExpressionAtlas 1 GO 17 Gene3D 1 GeneCards 1 GeneTree 1 GeneWiki 1 GenomeRNAi 1 HGNC 1 HOGENOM 1 HPA 1 InParanoid 1 IntAct 1 InterPro 3 KEGG 1 MANE-Select 1 MIM 3 MalaCards 1 MassIVE 1 NCBI Taxonomy 1 OMA 1 OpenTargets 1 OrthoDB 1 PANTHER 2 PDB 2 PDBsum 2 PRO 1 PROSITE 2 PathwayCommons 1 PaxDb 1 PeptideAtlas 1 Pfam 1 PharmGKB 1 Pharos 1 PhylomeDB 1 Proteomes 1 ProteomicsDB 1 RNAct 1 Reactome 1 RefSeq 1 SIGNOR 1 SMART 1 SMR 1 STRING 1 SUPFAM 1 SignaLink 1 TreeFam 1 UCSC 1 VEuPathDB 1 eggNOG 1 neXtProt 1

Citations:

PubMed ID: 9119224

Title: Hypothalamic expression of ART, a novel gene related to agouti, is up-regulated in obese and diabetic mutant mice.

PubMed ID: 9119224

DOI: 10.1101/gad.11.5.593

PubMed ID: 9311920

Title: Antagonism of central melanocortin receptors in vitro and in vivo by agouti-related protein.

PubMed ID: 9311920

DOI: 10.1126/science.278.5335.135

PubMed ID: 11602360

Title: The gene structure and minimal promoter of the human agouti related protein.

PubMed ID: 11602360

DOI: 10.1016/s0378-1119(01)00705-3

PubMed ID: 11326303

Title: Association between an agouti-related protein gene polymorphism and anorexia nervosa.

PubMed ID: 11326303

DOI: 10.1038/sj.mp.4000854

PubMed ID: 15489334

Title: The status, quality, and expansion of the NIH full-length cDNA project: the Mammalian Gene Collection (MGC).

PubMed ID: 15489334

DOI: 10.1101/gr.2596504

PubMed ID: 9724530

Title: Determination of disulfide structure in agouti-related protein (AGRP) by stepwise reduction and alkylation.

PubMed ID: 9724530

DOI: 10.1021/bi981082v

PubMed ID: 9892020

Title: Characterization of Agouti-related protein binding to melanocortin receptors.

PubMed ID: 9892020

DOI: 10.1210/mend.13.1.0223

PubMed ID: 11145747

Title: AgRP(83-132) acts as an inverse agonist on the human-melanocortin-4 receptor.

PubMed ID: 11145747

DOI: 10.1210/mend.15.1.0578

PubMed ID: 17185225

Title: Structural and molecular evolutionary analysis of Agouti and Agouti-related proteins.

PubMed ID: 17185225

DOI: 10.1016/j.chembiol.2006.10.006

PubMed ID: 16384863

Title: Agouti-related protein is posttranslationally cleaved by proprotein convertase 1 to generate agouti-related protein (AGRP)83-132: interaction between AGRP83-132 and melanocortin receptors cannot be influenced by syndecan-3.

PubMed ID: 16384863

DOI: 10.1210/en.2005-1373

PubMed ID: 17041250

Title: The natural inverse agonist agouti-related protein induces arrestin-mediated endocytosis of melanocortin-3 and -4 receptors.

PubMed ID: 17041250

DOI: 10.1074/jbc.m605982200

PubMed ID: 10371151

Title: NMR structure of a minimized human agouti related protein prepared by total chemical synthesis.

PubMed ID: 10371151

DOI: 10.1016/s0014-5793(99)00553-0

PubMed ID: 11747427

Title: High-resolution NMR structure of the chemically-synthesized melanocortin receptor binding domain AGRP(87-132) of the agouti-related protein.

PubMed ID: 11747427

DOI: 10.1021/bi0117192

PubMed ID: 12056887

Title: Design, pharmacology, and NMR structure of a minimized cystine knot with agouti-related protein activity.

PubMed ID: 12056887

DOI: 10.1021/bi012000x

PubMed ID: 12213871

Title: A polymorphism in the human agouti-related protein is associated with late-onset obesity.

PubMed ID: 12213871

DOI: 10.1210/jc.2002-011834

PubMed ID: 15927146

Title: Functional analysis of the Ala67Thr polymorphism in agouti related protein associated with anorexia nervosa and leanness.

PubMed ID: 15927146

DOI: 10.1016/j.bcp.2005.04.033

Sequence Information:

  • Length: 132
  • Mass: 14440
  • Checksum: 1CCBE112C3EB10F5
  • Sequence:
    • MLTAAVLSCA LLLALPATRG AQMGLAPMEG IRRPDQALLP ELPGLGLRAP LKKTTAEQAE 
EDLLQEAQAL AEVLDLQDRE PRSSRRCVRL HESCLGQQVP CCDPCATCYC RFFNAFCYCR 
KLGTAMNPCS RT