C1QTNF12

Summary

C1QTNF12 (C1q and TNF related 12, HGNC:32308) is a protein-coding gene on chromosome 1p36.33, encoding Adipolin (Q5T7M4). Insulin-sensitizing adipocyte-secreted protein (adipokine) that regulates glucose metabolism in liver and adipose tissue.

Predicted to enable hormone activity. Predicted to be involved in negative regulation of gluconeogenesis; positive regulation of D-glucose import; and positive regulation of insulin receptor signaling pathway. Predicted to act upstream of or within negative regulation of inflammatory response; positive regulation of cell communication; and regulation of glucose metabolic process. Predicted to be located in extracellular region. Predicted to be active in extracellular space.

Source: NCBI Gene 388581 — RefSeq curated summary.

At a glance

• GWAS associations: 3
• Clinical variants (ClinVar): 109 total
• MANE Select transcript: NM_001014980

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:32308
Approved symbol	C1QTNF12
Name	C1q and TNF related 12
Location	1p36.33
Locus type	gene with protein product
Status	Approved
Aliases	MGC105127, CTRP12, ADIPOLIN
Ensembl gene	ENSG00000184163
Ensembl biotype	protein_coding
OMIM	616593
Entrez	388581

Gene structure

Transcript identifiers

Ensembl transcripts: 5 — 4 retained_intron, 1 protein_coding

ENST00000330388, ENST00000462849, ENST00000468365, ENST00000478606, ENST00000486627

RefSeq mRNA: 1 — MANE Select: NM_001014980 NM_001014980

CCDS: CCDS30554

Canonical transcript exons

ENST00000330388 — 8 exons

Exon	Start	End
ENSE00001299832	1243444	1243552
ENSE00001311835	1243954	1244105
ENSE00001327847	1243062	1243152
ENSE00001330101	1242453	1242646
ENSE00001330968	1246514	1246722
ENSE00001480047	1244191	1244275
ENSE00001480048	1244381	1244497
ENSE00003523654	1242835	1242913

Expression profiles

Bgee: expression breadth ubiquitous, 166 present calls, max score 92.40.

FANTOM5 (CAGE): breadth tissue_specific, TPM avg 0.0448 / max 19.8275, expressed in 12 samples.

FANTOM5 promoters (2 alternative TSS)

Promoter ID	TPM avg	Samples expressed
9741	0.0371	10
9740	0.0077	4

Top tissues by expression

248 total, by Bgee expression score (0-100, higher = more expressed):

Tissue	Anatomy ID	Expression score	Quality
mucosa of transverse colon	UBERON:0004991	92.40	gold quality
ileal mucosa	UBERON:0000331	91.39	gold quality
jejunal mucosa	UBERON:0000399	88.83	gold quality
duodenum	UBERON:0002114	87.09	gold quality
lower esophagus mucosa	UBERON:0035834	84.45	gold quality
small intestine Peyer’s patch	UBERON:0003454	84.13	gold quality
transverse colon	UBERON:0001157	83.93	gold quality
male germ line stem cell (sensu Vertebrata) in testis	CL:0000089 ∩ UBERON:0000473	83.66	gold quality
small intestine	UBERON:0002108	83.35	gold quality
primordial germ cell in gonad	CL:0000670 ∩ UBERON:0000991	81.50	gold quality
kidney epithelium	UBERON:0004819	80.77	gold quality
skin of abdomen	UBERON:0001416	80.32	gold quality
mucosa of stomach	UBERON:0001199	79.77	gold quality
skin of leg	UBERON:0001511	78.64	gold quality
intestine	UBERON:0000160	77.81	gold quality
zone of skin	UBERON:0000014	77.16	gold quality
colon	UBERON:0001155	77.08	gold quality
apex of heart	UBERON:0002098	76.90	gold quality
large intestine	UBERON:0000059	76.79	gold quality
jejunum	UBERON:0002115	76.66	gold quality
cartilage tissue	UBERON:0002418	75.83	gold quality
muscle layer of sigmoid colon	UBERON:0035805	74.69	gold quality
right lobe of liver	UBERON:0001114	74.24	gold quality
omental fat pad	UBERON:0010414	73.91	gold quality
peritoneum	UBERON:0002358	73.87	gold quality
adult mammalian kidney	UBERON:0000082	73.51	gold quality
adipose tissue of abdominal region	UBERON:0007808	72.87	gold quality
cortex of kidney	UBERON:0001225	72.32	gold quality
tibial artery	UBERON:0007610	72.30	gold quality
popliteal artery	UBERON:0002250	72.28	gold quality

Single-cell (SCXA)

Detected in 1 experiment(s), a significant marker in 0.

Experiment	Marker?	Max mean expression
E-ANND-3	no	2.65

Regulation

Is transcription factor: no

Upstream regulators (CollecTRI, top): KLF15, KLF3, KLF9

miRNA regulators (miRDB)

3 targeting C1QTNF12, top 30 by miRDB confidence (max_score; target_count = how many genes the miRNA targets in total — lower means more specific):

miRNA	Max score	Avg score	miRNA target_count
HSA-MIR-6825-5P	99.96	69.81	3431
HSA-MIR-149-3P	99.72	68.22	3963
HSA-MIR-5587-3P	82.90	60.79	138

Literature-anchored findings (GeneRIF, showing 15)

• Reports cloning, expression, regulation and function of mouse adipolin (Fam132a) (PMID:21849507)
• we describe, for the first time, adipolin expression in human chondrocytes as well as the intracellular mechanism involved in its regulation (PMID:22736092)
• Endopeptidase cleavage generates a functionally distinct isoform of C1q/tumor necrosis factor-related protein-12 (CTRP12) with an altered oligomeric state and signaling specificity. (PMID:22942287)
• In subcutaneous adipose tissue explants, insulin significantly increased CTRP12 protein expression and secretion. (PMID:24492466)
• Serum adipolin concentrations were significantly lower in polycystic ovarian syndrome compared with control subjects. (PMID:24612181)
• Coenzyme Q10 reduced HbA1c considerably in overweight and obese patients with diabetes, although interestingly adipolin levels declined simultaneously. In this study, Q10 modulated glucose homeostasis, which was expected to be mediated by increasing adipolin. The similar mechanisms of action of Q10 and adipolin may justify lowering effect of Q10 on adipolin. (PMID:27657997)
• Low serum CTRP12 level is associated with Type 2 diabetes mellitus. (PMID:28207876)
• Adipolin and adiponectin are cytokines that exert substantial impact on obesity, progression of atherosclerosis, insulin resistance, and glucose metabolism. (PMID:29452073)
• The results suggest a possible link between CTRP12 and pathogenic mechanisms of atherosclerosis, such as inflammation and high density lipoprotein-cholesterol metabolism. (PMID:30337217)
• Study results indicated that decreased adiponectin, CTRP12, and CTRP13 levels, regardless of obesity, could independently predict polycystic ovarian syndrome (PCOS). This finding suggested a novel link between adipokines and PCOS. (PMID:30540803)
• High Serum adipolin levels are associated with metabolic syndrome and prediabetes. (PMID:31405651)
• High CTRP12 expression is associated with obesity. (PMID:31405681)
• Potential emerging roles of the novel adipokines adipolin/CTRP12 and meteorin-like/METRNL in obesity-osteoarthritis interplay. (PMID:33248913)
• CTRP12 ameliorates atherosclerosis by promoting cholesterol efflux and inhibiting inflammatory response via the miR-155-5p/LXRalpha pathway. (PMID:33692340)
• Circulating C1q/TNF-related protein-12 levels are associated with the severity of coronary artery disease. (PMID:33965313)

Cross-species orthologs

3 orthologs

Organism	Symbol	Gene ID
danio_rerio	c1qtnf12	ENSDARG00000070681
mus_musculus	C1qtnf12	ENSMUSG00000023571
rattus_norvegicus	C1qtnf12	ENSRNOG00000019864

Paralogs (1): ERFE (ENSG00000178752)

Protein

Protein identifiers

Adipolin — Q5T7M4 (reviewed: Q5T7M4)

Alternative names: Adipose-derived insulin-sensitizing factor, C1q and TNF related protein 12, Complement C1q tumor necrosis factor-related protein 12

All UniProt accessions (1): Q5T7M4

UniProt curated annotations — full annotation on UniProt →

Function. Insulin-sensitizing adipocyte-secreted protein (adipokine) that regulates glucose metabolism in liver and adipose tissue. Promotes glucose uptake in adipocytes and suppresses de novo glucose production in hepatocytes via the PI3K-Akt signaling pathway. Administration lead to reduction of blood glucose. Able to attenuate inflammation in fat tissue.

Subunit / interactions. Homomultimer; disulfide-linked. May interact with ERFE.

Subcellular location. Secreted Secreted.

Tissue specificity. Predominantly expressed by adipose tissues.

Post-translational modifications. Processed into Adipolin fC1QTNF12 and Adipolin gC1QTNF12 by FURIN. Insulin enhances endogenous C1QTNF12 cleavage.

Induction. By insulin in subcutaneous adipose tissue.

Similarity. Belongs to the adipolin/erythroferrone family.

RefSeq proteins (1): NP_001014980* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR001073	C1q_dom	Domain
IPR008983	Tumour_necrosis_fac-like_dom	Homologous_superfamily
IPR052136	Adipolin/Erythroferrone-rel	Family

UniProt features (10 total): chain 2, region of interest 2, signal peptide 1, domain 1, compositionally biased region 1, site 1, glycosylation site 1, sequence variant 1

Structure

Experimental structures (PDB)

0 structures.

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q5T7M4-F1	74.09	0.41

Functional residue map

Curated UniProt residues grouped by drug-discovery relevance — catalytic, ligand-binding, modification, and mutation-validated positions. Source: UniProtKB sequence features.

Catalytic / active sites (1): 97–98 (cleavage; by furin)

Glycosylation sites (1): 43

Function

Pathways and Gene Ontology

Reactome pathways

0 pathways

MSigDB gene sets: 204 (showing top): GOBP_RESPONSE_TO_NITROGEN_COMPOUND, GOBP_CARBOHYDRATE_TRANSPORT, GOBP_INFLAMMATORY_RESPONSE, GOBP_INSULIN_SECRETION, GOBP_CELLULAR_RESPONSE_TO_CARBOHYDRATE_STIMULUS, GRAESSMANN_APOPTOSIS_BY_DOXORUBICIN_DN, GRAESSMANN_RESPONSE_TO_MC_AND_DOXORUBICIN_DN, GOBP_POSITIVE_REGULATION_OF_PROTEIN_LOCALIZATION, IVANOVA_HEMATOPOIESIS_LATE_PROGENITOR, GOBP_REGULATION_OF_HORMONE_LEVELS, GOBP_HORMONE_TRANSPORT, GOBP_CELLULAR_RESPONSE_TO_OXYGEN_CONTAINING_COMPOUND, GOBP_POSITIVE_REGULATION_OF_TRANSMEMBRANE_TRANSPORT, GOBP_CELLULAR_RESPONSE_TO_INSULIN_STIMULUS, GOBP_CELL_CELL_SIGNALING

GO Biological Process (12): gluconeogenesis (GO:0006094), positive regulation of insulin secretion involved in cellular response to glucose stimulus (GO:0035774), phosphatidylinositol 3-kinase/protein kinase B signal transduction (GO:0043491), negative regulation of gluconeogenesis (GO:0045721), obsolete D-glucose import (GO:0046323), regulation of D-glucose import across plasma membrane (GO:0046324), positive regulation of D-glucose import across plasma membrane (GO:0046326), positive regulation of insulin receptor signaling pathway (GO:0046628), negative regulation of inflammatory response (GO:0050728), establishment of localization in cell (GO:0051649), positive regulation of phosphatidylinositol 3-kinase/protein kinase B signal transduction (GO:0051897), regulation of glucose metabolic process (GO:0010906)

GO Molecular Function (2): hormone activity (GO:0005179), protein binding (GO:0005515)

GO Cellular Component (2): extracellular region (GO:0005576), obsolete extracellular space (GO:0005615)

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
glucose metabolic process	2
D-glucose import across plasma membrane	2
hexose biosynthetic process	1
positive regulation of insulin secretion	1
insulin secretion involved in cellular response to glucose stimulus	1
regulation of insulin secretion involved in cellular response to glucose stimulus	1
intracellular signaling cassette	1
gluconeogenesis	1
regulation of gluconeogenesis	1
negative regulation of biosynthetic process	1
negative regulation of carbohydrate metabolic process	1
negative regulation of small molecule metabolic process	1
regulation of D-glucose transmembrane transport	1
positive regulation of D-glucose transmembrane transport	1
regulation of D-glucose import across plasma membrane	1
insulin receptor signaling pathway	1
positive regulation of signal transduction	1
regulation of insulin receptor signaling pathway	1
positive regulation of cellular response to insulin stimulus	1
inflammatory response	1
negative regulation of defense response	1
negative regulation of response to external stimulus	1
regulation of inflammatory response	1
establishment of localization	1
cellular localization	1
phosphatidylinositol 3-kinase/protein kinase B signal transduction	1
regulation of phosphatidylinositol 3-kinase/protein kinase B signal transduction	1
positive regulation of intracellular signal transduction	1
regulation of carbohydrate metabolic process	1
regulation of small molecule metabolic process	1
receptor ligand activity	1
binding	1
cellular anatomical structure	1

Protein interactions and networks

STRING

587 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
C1QTNF12	C1QTNF3	Q9BXJ4	603
C1QTNF12	C1QTNF9	P0C862	600
C1QTNF12	C1QL3	Q5VWW1	584
C1QTNF12	C1QTNF7	Q9BXJ2	547
C1QTNF12	C1QTNF1	Q9BXJ1	541
C1QTNF12	C1QTNF6	Q9BXI9	511
C1QTNF12	CAPRIN2	Q6IMN6	455
C1QTNF12	HCFC1R1	Q9NWW0	448
C1QTNF12	ADIPOQ	Q15848	446
C1QTNF12	C1QTNF2	Q9BXJ5	446
C1QTNF12	C1QL4	Q86Z23	434
C1QTNF12	KLF3	P57682	422
C1QTNF12	CAPN9	O14815	398
C1QTNF12	C1QTNF4	Q9BXJ3	397
C1QTNF12	SAMD4B	Q5PRF9	378

IntAct

0 interactions, top by confidence:

BioGRID (1): FAM132A (Protein-peptide)

ESM2 similar proteins: A0A5F4BST2, A0PJX4, A0RZB4, A1L515, A2A9Q0, A2BDG0, A6QQ85, A6XN32, A9JSM3, B0FP48, D3YZZ2, D4A2Q0, E5RIL1, F1SAM7, P01183, Q1RMK9, Q3UPR0, Q3ZCQ3, Q5BIV7, Q5BIV9, Q5BK01, Q5GH56, Q5GH64, Q5GH72, Q5SNT2, Q5T7M4, Q6IEE6, Q6PRD1, Q6UWJ8, Q70RD5, Q864V4, Q86UD0, Q8BWU1, Q8BX43, Q8CCB5, Q8IVY1, Q8K064, Q8K2Y3, Q8K5A9, Q8N9H8

Diamond homologs: A1A5X5, A4IH36, D4AB34, Q4G0M1, Q5T7M4, Q6PGN1, Q8R2Z0

SIGNOR signaling

0 interactions.

Disease & clinical

Clinical variants and AI predictions

ClinVar

109 variants total. Per-class counts are floors (≥ shown; pagination cap):

Classification	Count (floor)
Pathogenic	0
Likely pathogenic	0
Uncertain significance	88
Likely benign	5
Benign	3

Top pathogenic / likely-pathogenic (0)

SpliceAI

1333 predictions. Top by Δscore:

Variant	Effect	Δscore
1:1242646:CCTG:C	acceptor_loss	1.0000
1:1242831:TCA:T	donor_loss	1.0000
1:1242833:A:T	donor_loss	1.0000
1:1242834:C:CG	donor_loss	1.0000
1:1242927:C:CT	acceptor_gain	1.0000
1:1242927:C:T	acceptor_gain	1.0000
1:1243950:TCA:T	donor_loss	1.0000
1:1243951:CAC:C	donor_loss	1.0000
1:1243952:A:AC	donor_gain	1.0000
1:1243952:ACAGC:A	donor_gain	1.0000
1:1243953:C:CA	donor_gain	1.0000
1:1243953:CAG:C	donor_gain	1.0000
1:1243953:CAGCC:C	donor_gain	1.0000
1:1244271:TCCCG:T	acceptor_gain	1.0000
1:1244272:CCCG:C	acceptor_gain	1.0000
1:1244272:CCCGC:C	acceptor_gain	1.0000
1:1244273:CCG:C	acceptor_gain	1.0000
1:1244273:CCGC:C	acceptor_gain	1.0000
1:1244274:CG:C	acceptor_gain	1.0000
1:1244274:CGC:C	acceptor_gain	1.0000
1:1244276:C:CC	acceptor_gain	1.0000
1:1244380:CCGG:C	donor_gain	1.0000
1:1244410:T:TA	donor_gain	1.0000
1:1246508:GCGTA:G	donor_loss	1.0000
1:1246509:CGTAC:C	donor_loss	1.0000
1:1246510:GTACC:G	donor_loss	1.0000
1:1246511:TACCT:T	donor_loss	1.0000
1:1246513:C:CA	donor_loss	1.0000
1:1242642:CCAGC:C	acceptor_gain	0.9900
1:1242643:CAGC:C	acceptor_gain	0.9900

AlphaMissense

1899 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
1:1244023:A:C	F154L	0.983
1:1244023:A:T	F154L	0.983
1:1244025:A:G	F154L	0.983
1:1243493:G:C	F197L	0.982
1:1243493:G:T	F197L	0.982
1:1243495:A:G	F197L	0.982
1:1243960:G:C	F175L	0.972
1:1243960:G:T	F175L	0.972
1:1243962:A:G	F175L	0.972
1:1242572:G:C	F295L	0.970
1:1242572:G:T	F295L	0.970
1:1242574:A:G	F295L	0.970
1:1243494:A:G	F197S	0.968
1:1243532:G:C	F184L	0.965
1:1243532:G:T	F184L	0.965
1:1243534:A:G	F184L	0.965
1:1243469:G:C	F205L	0.963
1:1243469:G:T	F205L	0.963
1:1243471:A:G	F205L	0.963
1:1243464:A:G	F207S	0.960
1:1243961:A:C	F175C	0.953
1:1244450:C:A	W75C	0.951
1:1244450:C:G	W75C	0.951
1:1243961:A:G	F175S	0.949
1:1244024:A:C	F154C	0.945
1:1243494:A:C	F197C	0.939
1:1244024:A:G	F154S	0.937
1:1242573:A:G	F295S	0.935
1:1242591:A:T	I289N	0.935
1:1244452:A:G	W75R	0.935

dbSNP variants (sampled 300 via entrez): RS1000190648 (1:1242027 G>A), RS1000299631 (1:1246338 C>T), RS1000399684 (1:1246105 A>C), RS1000680997 (1:1244586 C>T), RS1000950429 (1:1244576 C>G), RS1001382776 (1:1245358 C>A,G,T), RS1001527606 (1:1244956 T>C,G), RS1002425028 (1:1247375 C>T), RS1002711135 (1:1247584 G>A,C), RS1002763298 (1:1247412 C>G,T), RS1002988605 (1:1243194 G>A), RS1003252253 (1:1242290 G>A,C), RS1003822106 (1:1246567 G>A,C), RS1004154500 (1:1247769 C>G,T), RS10047044 (1:1243285 A>C,G)

Disease associations

OMIM: gene MIM:616593 | disease phenotypes:

GenCC curated gene-disease

Mondo (0):

Orphanet (0):

HPO phenotypes

0 total (0 of 0 shown, HPO-id order):

GWAS associations

3 associations (top):

Study	Trait	p-value
GCST005752_172	Systemic lupus erythematosus	9.000000e-06
GCST011096_6	Systemic lupus erythematosus	3.000000e-09
GCST90011866_4	Systemic lupus erythematosus	4.000000e-06

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

PharmGKB: 1 entry (VIP=true, CPIC=false)

CTD chemical–gene interactions

12 total (human), top 12 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
Smoke	affects expression, increases abundance, increases expression	2
Valproic Acid	decreases expression, affects cotreatment	2
aristolochic acid I	increases expression	1
triphenyl phosphate	affects expression	1
bisphenol A	decreases methylation	1
4-(5-benzo(1,3)dioxol-5-yl-4-pyridin-2-yl-1H-imidazol-2-yl)benzamide	affects cotreatment, decreases expression	1
dorsomorphin	affects cotreatment, decreases expression	1
bisphenol S	decreases methylation	1
Sunitinib	decreases expression	1
Air Pollutants	increases abundance, increases expression	1
Estradiol	decreases expression	1
Tobacco Smoke Pollution	decreases expression	1

Cellosaurus cell lines

1 cell lines: 1 cancer cell line

First 10 cell lines (id-ordered, not curated):

Cellosaurus	Name	Category	Sex
CVCL_2058	HCC33	Cancer cell line	Male

Clinical trials (associated diseases)

0 trials via MONDO — disease-level, not drug-specific.