Details for: INSL5

Gene ID: 10022

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: INSL5

Ensembl ID: ENSG00000172410

Description: insulin like 5

Cell Significance Landscape

Associated with

Significant Cells

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

  • enteroendocrine cell CL0000164
    CSI 5.23
    rCSI 7.15%
    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 [INSL5](/details-gene/10022) (Insulin Like 5) is a protein-coding gene located on chromosome 1 that encodes a member of the insulin superfamily of peptide hormones [Link](https://doi.org/10.1006/geno.1999.5899). Functionally, [INSL5](/details-gene/10022) operates as a secreted hormone, engaging in [G protein-coupled receptor binding](/details-cell/GO:0001664) to mediate signal transduction, particularly through [G alpha (i) signalling events](/details-cell/R-HSA-418594). Its expression is remarkably specific, serving as a defining marker for [enteroendocrine cells](/details-cell/CL0000164) in the gastrointestinal tract. This localization, combined with its annotated role in the [positive regulation of feeding behavior](/details-cell/GO:2000253), suggests that [INSL5](/details-gene/10022) is a key hormonal regulator involved in metabolism and appetite control. ## Cellular Roles and Expression Landscape The expression profile of [INSL5](/details-gene/10022) demonstrates a highly specialized cellular role. **Overall**, the gene exhibits its most significant expression and defining characteristic in [enteroendocrine cells](/details-cell/CL0000164) (CSI: 5.23). These cells are hormone-secreting cells dispersed throughout the gastrointestinal epithelium, responsible for sensing nutrients and releasing peptides that regulate digestion, metabolism, and food intake. The high significance score for [INSL5](/details-gene/10022) in this cell type indicates it is a crucial and specific product of these cells, likely playing a primary role in their physiological function. The lack of significant expression in other cell types underscores its specialized function as a gut-derived hormone. ## Pathways and Molecular Function The molecular function of [INSL5](/details-gene/10022) is centered on its activity as a signaling ligand. As an extracellular peptide ([GO:0005576](https://www.ebi.ac.uk/QuickGO/term/GO:0005576)), it functions through [hormone activity](/details-cell/GO:0005179) by binding to and activating specific receptors. Research has identified it as a high-affinity agonist for the G-protein coupled receptor GPCR142 (also known as RXFP4) [Link](https://doi.org/10.1074/jbc.m409916200). This interaction initiates downstream signaling cascades, as reflected in its association with Reactome pathways such as [GPCR ligand binding](/details-cell/R-HSA-500792) and broader [Signaling by GPCR](/details-cell/R-HSA-372790). Specifically, its involvement in [G alpha (i) signalling events](/details-cell/R-HSA-418594) suggests its receptor coupling leads to the inhibition of adenylyl cyclase, a common mechanism for metabolic hormones. This entire signaling axis is consistent with its expression in [enteroendocrine cells](/details-cell/CL0000164) and its proposed role in systemic metabolic regulation. ## Research Directions The highly specific expression of [INSL5](/details-gene/10022) in gut [enteroendocrine cells](/details-cell/CL0000164) and its function as a GPCR ligand position it as a critical component of the gut-brain and gut-liver axes. However, its precise physiological role remains an active area of investigation. ### Proposed Hypotheses 1. **[INSL5](/details-gene/10022) acts as a post-prandial satiety or hunger signal.** Given its location in the colon and its involvement in regulating feeding behavior, it is hypothesized that the secretion of [INSL5](/details-gene/10022) in response to specific gut luminal contents (e.g., short-chain fatty acids) sends signals to the brain to modulate appetite and energy expenditure. 2. **Dysregulation of the [INSL5](/details-gene/10022)-RXFP4 signaling axis contributes to metabolic diseases.** It is hypothesized that altered levels of circulating [INSL5](/details-gene/10022) or impaired receptor function are associated with the pathophysiology of conditions like obesity, type 2 diabetes, or inflammatory bowel disease, potentially by disrupting glucose homeostasis or gut hormone balance. ### Key Experimental Approach To test the hypothesis that [INSL5](/details-gene/10022) is a key regulator of appetite and metabolism, a critical experiment would be the use of a conditional knockout mouse model. Specifically, one could generate mice with a floxed [INSL5](/details-gene/10022) allele and cross them with a line expressing Cre recombinase under the control of a promoter specific for [enteroendocrine cells](/details-cell/CL0000164) (e.g., *Gcg*-Cre or *Neurog3*-Cre). The resulting knockout mice would be subjected to a comprehensive metabolic phenotyping protocol, including analysis of food intake, body weight changes on normal and high-fat diets, glucose and insulin tolerance tests, and energy expenditure via indirect calorimetry. This would directly assess the physiological necessity of gut-derived [INSL5](/details-gene/10022) in systemic energy balance. ### Therapeutic Potential The [INSL5](/details-gene/10022) pathway presents a promising therapeutic target for metabolic disorders. Its receptor, RXFP4, is a GPCR, which is a highly druggable class of proteins. Given the specificity of the ligand-receptor pair, developing small-molecule or peptide-based agonists or antagonists could allow for precise modulation of this signaling pathway with potentially minimal off-target effects. If [INSL5](/details-gene/10022) is confirmed to be an anorexigenic (appetite-suppressing) hormone, RXFP4 agonists could be developed as anti-obesity therapeutics. Conversely, if it is orexigenic (appetite-stimulating), RXFP4 antagonists could serve the same purpose, while agonists might be useful for treating cachexia and anorexia.

Genular Protein ID: 3231065245

Symbol: INSL5_HUMAN

Name: Insulin-like peptide INSL5

UniProtKB Accession Codes:

Q9Y5Q6 Q3MIY4 Q5VYD8

Database IDs:

AGR 1 AlphaFoldDB 1 Antibodypedia 1 Bgee 1 BioGRID 1 BioGRID-ORCS 1 BioMuta 1 CCDS 1 CDD 1 CTD 1 DMDM 1 DNASU 1 DisGeNET 1 EMBL 5 EMDB 1 Ensembl 1 EvolutionaryTrace 1 GO 4 Gene3D 1 GeneCards 1 GeneTree 1 GeneWiki 1 GenomeRNAi 1 HGNC 1 HOGENOM 1 HPA 1 InParanoid 1 IntAct 1 InterPro 4 KEGG 1 MANE-Select 1 MIM 1 MassIVE 1 NCBI Taxonomy 1 OMA 1 OpenTargets 1 OrthoDB 1 PANTHER 2 PDB 3 PDBsum 3 PRO 1 PROSITE 1 PathwayCommons 1 PaxDb 1 PeptideAtlas 1 Pfam 1 PharmGKB 1 Pharos 1 PhylomeDB 1 Proteomes 1 ProteomicsDB 1 RNAct 1 Reactome 2 RefSeq 1 SMART 1 SMR 1 STRING 1 SUPFAM 1 SignaLink 1 TreeFam 1 UCSC 1 VEuPathDB 1 eggNOG 1 neXtProt 1

Citations:

PubMed ID: 10458910

Title: Identification of INSL5, a new member of the insulin superfamily.

PubMed ID: 10458910

DOI: 10.1006/geno.1999.5899

PubMed ID: 12975309

Title: The secreted protein discovery initiative (SPDI), a large-scale effort to identify novel human secreted and transmembrane proteins: a bioinformatics assessment.

PubMed ID: 12975309

DOI: 10.1101/gr.1293003

PubMed ID: 16710414

Title: The DNA sequence and biological annotation of human chromosome 1.

PubMed ID: 16710414

DOI: 10.1038/nature04727

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: 15340161

Title: Signal peptide prediction based on analysis of experimentally verified cleavage sites.

PubMed ID: 15340161

DOI: 10.1110/ps.04682504

PubMed ID: 15525639

Title: INSL5 is a high affinity specific agonist for GPCR142 (GPR100).

PubMed ID: 15525639

DOI: 10.1074/jbc.m409916200

PubMed ID: 18576448

Title: Synthesis, conformation, and activity of human insulin-like peptide 5 (INSL5).

PubMed ID: 18576448

DOI: 10.1002/cbic.200800113

PubMed ID: 19178384

Title: Structure of human insulin-like peptide 5 and characterization of conserved hydrogen bonds and electrostatic interactions within the relaxin framework.

PubMed ID: 19178384

DOI: 10.1042/bj20082353

Sequence Information:

  • Length: 135
  • Mass: 15333
  • Checksum: A932D7EDE9D173F5
  • Sequence:
    • MKGSIFTLFL FSVLFAISEV RSKESVRLCG LEYIRTVIYI CASSRWRRHQ EGIPQAQQAE 
TGNSFQLPHK REFSEENPAQ NLPKVDASGE DRLWGGQMPT EELWKSKKHS VMSRQDLQTL 
CCTDGCSMTD LSALC