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25 sources retrieved · Most recent: April 2026 · Index updated 14 days ago
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UCP1
uncoupling protein 1
Chromosome 4 · 4q31.1
NCBI Gene: 7350Ensembl: ENSG00000109424.5HGNC: HGNC:12517UniProt: P25874
194PubMed Papers
20Diseases
0Drugs
0Pathogenic Variants
FUNCTIONAL ROLE
Ion ChannelTransporter
DATA QUALITY
✓ Experimental GO Evidence✓ Swiss-Prot Reviewed
proton transmembrane transporter activitytransmembrane transporter activitymitochondrial inner membranemitochondrionulcerative colitisneoplasmobesitytype 2 diabetes mellitus
✦AI Summary

UCP1 (uncoupling protein 1) is a mitochondrial inner membrane protein that mediates adaptive thermogenesis—the production of heat without muscle contractions—primarily in brown and beige adipose tissue 1. UCP1 functions as a long-chain fatty acid/proton symporter, simultaneously transporting one long-chain fatty acid and one proton across the inner mitochondrial membrane [UniProt reference]. By dissipating the mitochondrial proton gradient, UCP1 converts oxidative substrate energy directly into heat rather than ATP synthesis, enabling non-shivering thermogenesis in response to cold and metabolic demand 1. Recent evidence reveals that beige adipocytes—thermogenic cells arising within white fat deposits—exhibit UCP1 expression patterns distinct from classical brown fat and respond dynamically to hormonal signals 1. UCP1 regulation involves multiple transcriptional pathways, including IRF4-mediated control in concert with PGC-1α 2, and PPARγ-dependent beiging mechanisms 3. Critically, UCP1-dependent thermogenesis involves mitochondrial reactive oxygen species (ROS), which sulfenylate UCP1 at Cys253 to enhance uncoupling capacity 4. Beyond classical thermogenesis, UCP1 expression inversely correlates with immune activation and ROS production in epicardial adipose tissue, suggesting tissue-homeostatic functions 5. The existence of alternative futile cycle-dependent thermogenic adipocytes indicates redundant energy dissipation mechanisms 6, positioning UCP1 within a broader thermogenic network relevant to metabolic disease intervention.

Sources cited
1
UCP1 mediates heat generation in brown fat; beige adipocytes are a distinct thermogenic cell type with low basal UCP1 expression that responds to cAMP stimulation
PMID: 22796012
2
IRF4 is a key transcriptional partner of PGC-1α that drives UCP1 expression and thermogenic gene programs in response to cold and cAMP
PMID: 24995979
3
Mitochondrial ROS support thermogenesis by sulfenylating UCP1 at Cys253, enhancing uncoupling-dependent heat production
PMID: 27027295
4
PPARγ mediates beige adipocyte formation and UCP1 expression, while PPARα acts as a negative regulator of beiging
PMID: 39828228
5
High UCP1 expression in epicardial adipose tissue is associated with reduced ROS production and immune responses
PMID: 30996144
6
Beige adipocytes comprise distinct subpopulations including UCP1-beige adipocytes and futile cycle adipocytes that dissipate energy independently
PMID: 39084216
Disease Associationsⓘ20
ulcerative colitisOpen Targets
0.23Weak
neoplasmOpen Targets
0.10Weak
obesityOpen Targets
0.10Weak
type 2 diabetes mellitusOpen Targets
0.10Suggestive
breast cancerOpen Targets
0.10Suggestive
acute kidney injuryOpen Targets
0.09Suggestive
cancerOpen Targets
0.09Suggestive
renal cell carcinomaOpen Targets
0.08Suggestive
hepatocellular carcinomaOpen Targets
0.08Suggestive
triple-negative breast cancerOpen Targets
0.08Suggestive
rheumatoid arthritisOpen Targets
0.07Suggestive
nonpapillary renal cell carcinomaOpen Targets
0.07Suggestive
COVID-19–associated multisystem inflammatory syndrome in adultsOpen Targets
0.07Suggestive
FRAXF syndromeOpen Targets
0.06Suggestive
metabolic syndromeOpen Targets
0.06Suggestive
primary familial polycythemia due to EPO receptor mutationOpen Targets
0.06Suggestive
gastric cancerOpen Targets
0.06Suggestive
mosaic variegated aneuploidy syndrome 4Open Targets
0.06Suggestive
hemolytic anemia due to diphosphoglycerate mutase deficiencyOpen Targets
0.06Suggestive
Familial cold urticariaOpen Targets
0.06Suggestive
Pathogenic Variants
No pathogenic variants reported on ClinVar for this gene.
View on ClinVar ↗
Related Genes
PNPLA2Protein interaction97%ADIPOQProtein interaction86%DIO2Protein interaction85%TMEM26Protein interaction82%PPARAProtein interaction81%ADRB3Protein interaction80%
Tissue Expression6 tissues
Heart
100%
Ovary
33%
Lung
17%
Liver
0%
Brain
0%
Bone Marrow
0%
Gene Interaction Network
Click a node to explore
UCP1PNPLA2ADIPOQDIO2TMEM26PPARAADRB3
PROTEIN STRUCTURE
Preparing viewer…
PDB8HBV · 2.51 Å · EM
View on RCSB ↗
Constraintⓘ
LOEUFⓘ
1.24LoF Tolerant
pLIⓘ
0.00Tolerant
Observed/Expected LoF0.91 [0.68–1.24]
RankingsWhere UCP1 stands among ~20K protein-coding genes
  • #2,210of 20,598
    Most Researched194 · top quartile
  • #13,079of 17,882
    Most Constrained (LOEUF)1.24
Genes detectedUCP1
Sources retrieved25 papers
Response time—
📄 Sources
25▼
1
Beige adipocytes are a distinct type of thermogenic fat cell in mouse and human.
PMID: 22796012
Cell · 2012
1.00
2
Evolution of UCP1.
PMID: 29748882
Handb Exp Pharmacol · 2019
0.90
3
Single-nucleus transcriptomics identifies separate classes of UCP1 and futile cycle adipocytes.
PMID: 39084216
Cell Metab · 2024
0.80
4
A creatine-driven substrate cycle enhances energy expenditure and thermogenesis in beige fat.
PMID: 26496606
Cell · 2015
0.70
5
cAMP driven UCP1 induction in human adipocytes requires ATGL-catalyzed lipolysis.
PMID: 39454826
Mol Metab · 2024
0.64