Cited by 137Adipose Tissue and MetabolismMitochondrial Function and PathologyGenetic Associations and Epidemiology

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The polymorphisms of UCP2 and UCP3 genes associated with fat metabolism, obesity and diabetes

Jia, J.‐J., Zhang, X., Ge, C.‐R., Jois, M.·2009·Obesity Reviews

DOI 10.1111/j.1467-789x.2009.00569.x

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Abstract

Uncoupling proteins (UCPs) belong to the family of mitochondrial transporter proteins that may uncouple the transport of protons across the inner mitochondrial membrane from electron transport and the synthesis of ATP from ADP, hence generating heat rather than energy. In mammals, more than five family members have been identified, including UCP1, UCP2, UCP3, UCP4 (or BMCP1/UCP5) and UCP5. The UCPs may play an important role in energy homeostasis and have become prominent in the fields of thermogenesis, obesity, diabetes and free-radical biology and have been considered candidate genes for obesity and insulin resistance. They have been as important potential targets for treatment of aging, degenerative diseases, diabetes and obesity. Recently, a series of studies showed the polymorphisms of UCPs gene association with the fat metabolism, obesity and diabetes. This review summarizes data supporting the roles of UCP2 and UCP3 in energy dissipation, as well as the genetic variety association with fat metabolism, obesity and diabetes in humans.

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Background
A 45-bp insertion/deletion polymorphism of UCP2 gene is associated with metabolic syndrome
Hashemi, M. M., Rezaei, H., Kaykhaei, M. A., & Taheri, M. (2014) · Journal of Diabetes & Metabolic Disorders · doi:10.1186/2251-6581-13-12 · Cited by 25
“In humans, the gene for UCP2 is located on chromosome 11q13 and contains 8 exons which exons 1 and 2 of UCP2 are untranslated [7].”
Background
Uncoupling Protein-2 45-Base Pair Insertion/Deletion Polymorphism: Is There an Association with Severe Obesity and Weight Loss in Morbidly Obese Subjects?
Papazoglou, D., Papathanasiou, P., Παπάνας, Ν., Papatheodorou, K., Chatziangeli, E., Nikitidis, I., Kotsiou, S., & Maltezos, E. S. (2012) · Metabolic Syndrome and Related Disorders · doi:10.1089/met.2012.0003 · Cited by 23
Molecular cloning and tissue expression of uncoupling protein 1, 2 and 3 genes in Chinese perch (Siniperca chuatsi)
Wen, Z., Liang, X., He, S., Li, L., Shen, D., & Tao, Y. (2015) · Comparative Biochemistry and Physiology Part B Biochemistry and Molecular Biology · doi:10.1016/j.cbpb.2015.03.005 · Cited by 22
“With approximately 60% homology with UCP1, the orthologs UCP2 (Affourtit et al., 2007) and UCP3 (Echtay, 2007; Jastroch et al., 2010) are more closely related to UCP1 than to UCP4 (Azzu et al., 2010) or UCP5 (also named BMCP1) (Jia et al., 2009).”
Background
Lycium barbarum Polysaccharides Promotes Mitochondrial Biogenesis and Energy Balance in a NAFLD Cell Model
Zhang, Y., Guo, Y.-Q., Fan, Y., Tao, X., Gao, Q., & Yang, J. (2021) · Chinese Journal of Integrative Medicine · doi:10.1007/s11655-021-3309-6 · Cited by 23
“The gene for UCP2, one of UCPs, is expressed in many tissues, for example skeletal muscle, white adipose tissue, and pancreatic islets.((30)) Previous study has indicated that UCP2 plays a major role in mitochondrial bioenergetics, and in oxidative stress, lipid metabolism, apoptosis, and even carcinogenesis.”
Integrative system biology and mathematical modeling of genetic networks identifies shared biomarkers for obesity and diabetes
Bima, A. I. H., Elsamanoudy, A. Z., Albaqami, W. F., Khan, Z., Snijesh, V. P., Alrayes, N. M., Kaipa, P. R., Elango, R., Banaganapalli, B., & Shaik, N. A. (2022) · Mathematical Biosciences & Engineering · doi:10.3934/mbe.2022107 · Cited by 22
Polymorphisms in the autosomal genes for mitochondrial function TFAM and UCP2 are associated with performance and longevity in dairy cows
Clempson, A. M., Pollott, G. E., Brickell, J. S., Bourne, N., Munce, N., & Wathes, D. C. (2011) · animal · doi:10.1017/s1751731111000346 · Cited by 22
“UCP2 is expressed in many tissues including skeletal muscle, white adipose tissue, pancreatic islet cells and the nervous system (Jia et al., 2009).”
Background
The -866G/A polymorphism in the promoter of the UCP2 gene is associated with risk for type 2 diabetes and with decreased insulin levels
Gomathi, P., Samarth, A. P., Raj, N. B. A. J., Sasikumar, S., Murugan, P. S., Nallaperumal, S., & Selvam, G. S. (2019) · Gene · doi:10.1016/j.gene.2019.03.041 · Cited by 20
Yerba Mate Stimulates Mitochondrial Biogenesis and Thermogenesis in High‐Fat‐Diet‐Induced Obese Mice
dos Santos, T. W., Miranda, J., Teixeira, L., Aiastui, A., Matheu, A., Gambero, A., Portillo, M. P., & Ribeiro, M. L. (2018) · Molecular Nutrition & Food Research · doi:10.1002/mnfr.201800142 · Cited by 20
The presence of the −866A/55Val/Ins haplotype in the uncoupling protein 2 (UCP2) gene is associated with decreased UCP2 gene expression in human retina
de Souza, B. M., Assmann, T. S., Kliemann, L. M., Marcon, A. S., Gross, J. L., Canani, L. H. S., & Crispim, D. (2011) · Experimental Eye Research · doi:10.1016/j.exer.2011.11.004 · Cited by 16
“However, data on human tissues have been conflicting, reporting either increased (Cassell et al., 1999; Esterbauer et al., 2001; Jia et al., 2009; Walder et al., 1998) or decreased (Oberkofler et al.”
BackgroundInfluential
Effects of breeds and dietary protein levels on the growth performance, energy expenditure and expression of avUCP mRNA in chickens
Li, Q., Xu, Z., Liu, L., Yu, H., Hua, R., Tao, L., Zhang, X., Chen, X., Gu, D., Fan, Y., et al. (2013) · Molecular Biology Reports · doi:10.1007/s11033-012-2030-0 · Cited by 17
UCP3 Ablation Exacerbates High-Salt Induced Cardiac Hypertrophy and Cardiac Dysfunction
Lang, H., Yang, X., Ai, Z., You, Z., Jin, X., Wan, Y., & Yang, Y. (2018) · Cellular Physiology and Biochemistry · doi:10.1159/000489244 · Cited by 16
UCP2 I/D Modulated Change in BMI During a Lifestyle Modification Intervention Study in Japanese Subjects
Mutombo, P. B. W. B., Yamasaki, M., & Shiwaku, K. (2012) · Genetic Testing and Molecular Biomarkers · doi:10.1089/gtmb.2012.0229 · Cited by 15
“…(rs1800592) (Nakano et al., 2006; Jia et al., 2010), UCP2 - 55 A/V (rs660339), a 45bp insertion–deletion polymorphism in the UCP2 gene (UCP2 I/D) (rs1800795), and UCP3 - 55C/T (rs1800849) (Shiinoki et al., 1999; Hamada et al., 2008; Kosuge et al., 2008; Jia et al., 2009; Matsunaga et al., 2009).”
Response of skeletal muscle UCP2-expression during metabolic adaptation to caloric restriction
Heinitz, S., Piaggi, P., Yang, S., Bonfiglio, S. M., Steel, J., Krakoff, J. A., & Votruba, S. B. (2018) · International Journal of Obesity · doi:10.1038/s41366-018-0085-2 · Cited by 16
sfkit: a web-based toolkit for secure and federated genomic analysis
Mendelsohn, S., Froelicher, D., Loginov, D., Bernick, D. L., Berger, B., & Cho, H. (2023) · Nucleic Acids Res. · doi:10.1093/nar/gkad464 · Cited by 12
Association of uncoupling protein gene polymorphisms with essential hypertension in a northeastern Han Chinese population
Sun, H., Zhang, J., Xie, X.-R., Li, T., Li, X., Wang, N., Li, J., Deng, Z.-H., & Qiu, C. (2018) · Journal of Human Hypertension · doi:10.1038/s41371-018-0141-3 · Cited by 13
Association between UCP1, UCP2, and UCP3 gene polymorphisms with markers of adiposity in European adolescents: The HELENA study
Pascual-Gamarra, J. M., Salazar‐Tortosa, D. F., Martínez‐Téllez, B., Labayen, I., Rupérez, A. I., Censi, L., Μanios, Y., Nova, E., Gesteiro, E., Moreno, L. A., et al. (2019) · Pediatric Obesity · doi:10.1111/ijpo.12504 · Cited by 14
“Less clear is, however, the role of UCP2 and UCP3 genetic variants, which have been related with obesity phenotypes through the potential influence on muscle metabolism due to the high expression of these genes in skeletal muscle,(10) diabetes mellitus, and lipid/lipoprotein‐related diseases.(11) UCP2 seems to be invo…”
Background
Uncoupling protein 2 modulates polarization and metabolism of human primary macrophages via glycolysis and the NF‑κB pathway
Lang, L., Zheng, D., Jiang, Q., Meng, T., Ma, X., & Yang, Y. (2023) · Experimental and Therapeutic Medicine · doi:10.3892/etm.2023.12282 · Cited by 12
“UCP2 allows protons to leak back across the membrane without passing through ATP synthase, thereby reducing the efficiency of ATP production (30).”
Background
Mitochondrial uncoupling protein 2: a central player in pancreatic disease pathophysiology
Wang, K., Zhang, L., Deng, B., Zhao, K., Chen, C., & Wang, W. (2024) · Molecular Medicine · doi:10.1186/s10020-024-01027-y · Cited by 12
The UCP2 -866G/A, Ala55Val and UCP3 -55C/T polymorphisms are associated with premature coronary artery disease and cardiovascular risk factors in Mexican population
Gamboa, R., Huesca‐Gómez, C., López-Pérez, V., Posadas‐Sánchez, R., Cardoso-Saldaña, G. C., Medina-Urrutia, A. X., Juárez-Rojas, J. G., Soto, M. E., Posadas‐Romero, C., & Vargas‐Alarcón, G. (2018) · Genetics and Molecular Biology · doi:10.1590/1678-4685-gmb-2017-0008 · Cited by 12
“However, the results of these studies are controversial with positive and negative associations (Jia et al., 2009, Jia et al., 2010; De Souza et al., 2011; Brondani et al., 2012).”
Result
Berberine induces lipolysis in porcine adipocytes by activating the AMP‑activated protein kinase pathway
Yang, Y., Lu, R., Gao, F., Zhang, J., & Liu, F. (2020) · Molecular Medicine Reports · doi:10.3892/mmr.2020.11070 · Cited by 12
UCP2–866G/A Polymorphism is Associated with Prediabetes and Type 2 Diabetes
Hou, G., Jin, Y., Liu, M., Wang, C., & Song, G. (2020) · Archives of Medical Research · doi:10.1016/j.arcmed.2020.06.001 · Cited by 12
Germinated Waxy Black Rice Suppresses Weight Gain in High-Fat Diet-Induced Obese Mice
Lim, W., Ho, J., Lee, H.-S., & Cho, H. (2016) · Journal of Medicinal Food · doi:10.1089/jmf.2015.3590 · Cited by 11
“26,27 GWBR signiﬁcantly increased CPT-1 and UCP2 mRNA expressions in adipose tissue, suggesting that GWBR promotes energy metabolism.”
Vitamin D–vitamin D receptor system down-regulates expression of uncoupling proteins in brown adipocyte through interaction with Hairless protein
Wang, P.-Q., Pan, D.-X., Hu, C., Zhu, Y., & Liu, X.-J. (2020) · Bioscience Reports · doi:10.1042/bsr20194294 · Cited by 10
Network-Based Association Study of Obesity and Type 2 Diabetes with Gene Expression Profiles
Zhang, S., Wang, B., Shi, J., & Li, J. (2015) · BioMed Research International · doi:10.1155/2015/619730 · Cited by 9
“But so far only three genes (ENPP1, PPARG, and UCP3) are common in 26 obesity genes and 34 T2D genes annotated in the OMIM database.”
Background
Maya gene variants related to the risk of type 2 diabetes in a family-based association study
Domínguez-Cruz, M. G., Muñoz, M. D. L., Totomoch-Serra, A., García‐Escalante, M. G., Burgueño, J. A., Valadéz-González, N., Pinto-Escalante, D. D. C., & Díaz-Badillo, Á. (2019) · Gene · doi:10.1016/j.gene.2019.144259 · Cited by 9
The impact of solute carrier proteins on disrupting substance regulation in metabolic disorders: insights and clinical applications
Du, J., Shen, M., Chen, J., Yan, H., Xu, Z., Yang, X., Yang, B., Luo, P., Ding, K., Hu, Y., et al. (2025) · Frontiers in Pharmacology · doi:10.3389/fphar.2024.1510080 · Cited by 9
Uncoupling Protein 2 as genetic risk factor for systemic lupus erythematosus: association with malondialdehyde levels and intima media thickness
Gambino, C. M., Accardi, G., Aiello, A., Caruso, C., Carru, C., Gioia, B. G., Guggino, G., Rizzo, S., Zinellu, A., Ciaccio, M., et al. (2020) · Minerva Cardioangiologica · doi:10.23736/s0026-4725.20.05225-1 · Cited by 8
Frequency of UCP2 45-bp Ins/Del polymorphism in Saudi population from Jazan area and its association with autoimmune hypothyroidism UCP2 45-bp Ins/Del frequency in hypothyroidism.
Kaabi, Y. A., Mansor, A. S., Alfagih, A. S., Hakami, A. M., Summ, M. A., Mjery, Y. A., Alzughbi, M. N., & Habibullah, M. M. (2020) · PubMed Central · Cited by 8
Uncoupling Protein 2 and Peroxisome Proliferator-Activated Receptor γ Gene Polymorphisms in Association with Diabetes Susceptibility in Chinese Han Population with Variant Glucose Tolerance
Zhou, M., He, S., Ping, F., Li, W., Zhu, L., Cui, X., Feng, L., Zhao, X., Zhang, H., Li, Y., et al. (2018) · International Journal of Endocrinology · doi:10.1155/2018/4636783 · Cited by 8
“The -866AA genotype carriers have decreased glucose-stimulated insulin secretion and have increased risk of diabetes than those GG genotype carriers [7].”
Background
The energy intake modulates the association of the –55CT polymorphism of UCP3 with body weight in type 2 diabetic patients
Lapice, E., Monticelli, A., Cocozza, S., Pinelli, M., Giacco, A., Rivellese, A. A., Cocozza, S., Riccardi, G., & Vaccaro, O. (2013) · International Journal of Obesity · doi:10.1038/ijo.2013.174 · Cited by 7
Polymorphisms in the uncoupling protein 3 gene and their associations with feed efficiency in chickens
Jin, S., Yang, L., He, T., Fan, X., Wang, Y., Ge, K., & Geng, Z. (2018) · Asian-Australasian Journal of Animal Sciences · doi:10.5713/ajas.18.0217 · Cited by 7
“Previous studies demonstrated that the UCP3 gene had crucial effects on energy expenditure and homeostasis, and their polymorphisms were significantly associated with fat metabolism, obesity and diabetes in humans and mice [16,23].”
Loss of Uncoupling Protein 3 Attenuates Western Diet–Induced Obesity, Systemic Inflammation, and Insulin Resistance in Rats
Lomax, T. M., Ashraf, S., Yilmaz, G., & Harmancey, R. (2020) · Obesity · doi:10.1002/oby.22879 · Cited by 7
Protein Uncoupling as an Innovative Practice in Diabetes Mellitus Treatment: A Metabolic Disorder
Chaudhary, R., Gupta, S., & Chauhan, S. (2022) · Endocrine Metabolic & Immune Disorders - Drug Targets · doi:10.2174/1871530322666220902143401 · Cited by 7
The roles of orexins on sleep/wakefulness, energy homeostasis and intestinal secretion
Mäkelä, K. A. (2010) · Cited by 7
Role of UCP2 polymorphisms on dietary intake of obese patients who underwent bariatric surgery
Nicoletti, C. F., Kimura, B. M., de Oliveira, B. A. P., Pinhel, M. A. S., Salgado, W., Marchini, J. S., & Nonino, C. B. (2016) · Clinical Obesity · doi:10.1111/cob.12148 · Cited by 6
“The association between the UCP2 gene and BMI and obesity has been explained through the role of uncoupling proteins in energy metabolism (23,24).”
Background
The A allele of the UCP2 -866G/A polymorphism changes UCP2 promoter activity in HUVECs treated with high glucose
Crispim, D., Rodrigues, M. A., da Silva, L. P. A., Bouças, A. P., Canani, L. H. S., Carlessi, R., & de Souza, B. M. (2019) · Molecular Biology Reports · doi:10.1007/s11033-019-04918-0 · Cited by 5
The effect of cranberry consumption on lipid metabolism and inflammation in human apo A-I transgenic mice fed a high-fat and high-cholesterol diet
Caceres, C., Kim, M., Bae, M., Pham, T. X., Lee, Y., Hu, S., O’Neill, E. N., Kim, B., Park, Y., & Lee, J. (2020) · British Journal Of Nutrition · doi:10.1017/s0007114520004080 · Cited by 5
“Uncoupling proteins disrupt the coupling of electron transport and oxidative phosphorylation and therefore stimulate substrate oxidation with energy dissipated as heat rather than supporting ATP synthesis(31).”
Background
Dynamic transcriptome profiles of skeletal muscle growth and development in Shaziling and Yorkshire pigs using RNA‐sequencing
Zheng, C., Zhong, Y., Zhang, P., Guo, Q., Li, F., & Duan, Y. (2024) · Journal of the Science of Food and Agriculture · doi:10.1002/jsfa.13551 · Cited by 5
Potential protective effect of leptin and uncoupling protein-2 genes polymorphism in Egyptian patients with chronic kidney disease
Ghazaly, E. A., EL-Saeed, A. M., Abdelsalam, M., & Seoudi, D. M. (2020) · International Urology and Nephrology · doi:10.1007/s11255-020-02567-y · Cited by 5
Lack of association between 11 gene polymorphisms on weight loss 1 year after Roux‐en‐y gastric bypass surgery in woman
Novais, P. F. S., Crisp, A. H., Leandro‐Merhi, V. A., Verlengia, R., Rasera, I., & de Oliveira, M. R. M. (2022) · Journal of Human Nutrition and Dietetics · doi:10.1111/jhn.13000 · Cited by 5
Genetic etiology and clinical features of non-syndromic pediatric obesity in the Chinese population: a large cohort study
Huang, H., Yang, Y., Yiwei, L., Li, Y., Liling, X., & Dongguang, Z. (2025) · BMC Pediatrics · doi:10.1186/s12887-025-05702-9 · Cited by 4
“Uncoupling protein 3 (UCP3) is a protein-coding gene [19, 20], and research suggests that upregulation of UCP3 expression is associated with physical activity, fasting, and high-fat diets.”
Relationship of short tandem repeats flanking leptin-melanocortin pathway genes with anthropometric profile and leptinemia in Brazilian individuals
Hinuy, H. M., Arazi, S. S., Hirata, M. H., Sampaio, M. F., Armaganijan, D., Cavalli, S. A., & Hirata, R. D. C. (2012) · Arquivos Brasileiros de Endocrinologia & Metabologia · doi:10.1590/s0004-27302012000100008 · Cited by 4
“Polymorphisms in the UCP2/UCP3 cluster have been considered candidate markers for fat metabolism, obesity, and diabetes in humans (16).”
Background
Variante en CAPN10 y factores ambientales muestran evidencia de asociación con exceso de peso en jóvenes de Medellín, Colombia
Orozco, A. C., Contreras, A. M. M., Uscátegui, R. M., Parra, M. V., Villada, F. A. P., Correa, L. M. M., Parra, B. E., Estrada, A., Agudelo, G. M., & Velásquez, C. (2014) · Biomédica · doi:10.7705/biomedica.v34i4.2246 · Cited by 4
-866G/A and Ins/Del polymorphisms in the UCP2 gene and diabetic kidney disease: case-control study and meta-analysis
Dieter, C., Assmann, T. S., Lemos, N. E., Massignam, E. T., de Souza, B. M., Bauer, A. C., & Crispim, D. (2019) · Genetics and Molecular Biology · doi:10.1590/1678-4685-gmb-2018-0374 · Cited by 6
“, 2012) and with the development of DM and its chronic complications (Jia et al., 2009; Crispim et al., 2010; de Souza et al., 2012, 2013, 2015).”
Background

Authors: Jia, J. ‐., Zhang, X., Ge, C. ‐., & Jois, M.
Affiliations: Yunnan Agricultural University (CN)
La Trobe University (AU)
ORCID: Jia, J.‐J.
Jois, M.
Venue: Obesity Reviews
Publisher: Wiley
Published: 2009-08-26
Volume: 10
Issue: 5
Pages: 519-526
ISSN: 1467-7881 (ISSN-L)
1467-789X
DOI: 10.1111/j.1467-789x.2009.00569.x
OpenAlex: W2159844679
Cited by: 137
References: 67
Citations by year: 2026: 1 · 2025: 7 · 2024: 4 · 2023: 9 · 2022: 8 · 2021: 6 · 2020: 10 · 2019: 9 · 2018: 12 · 2017: 5 · 2016: 4 · 2015: 12 · 2014: 14 · 2013: 10 · 2012: 7
FWCI: 0.95
Type: journal article
Language: en
Open access: closed
Licence: onlinelibrary.wiley.com/termsAndConditions#vor (vor)
Locations: Obesity Reviews (publishedVersion)
PubMed (publishedVersion)
Topics: Health Sciences › Medicine › Physiology (medical) › Adipose Tissue and Metabolism
Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Mitochondrial Function and Pathology
Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetic Associations and Epidemiology
Keywords: uncoupling proteins, UCP2, UCP3, genetic polymorphism, fat metabolism, obesity, diabetes mellitus, insulin resistance, energy homeostasis, thermogenesis, mitochondrial uncoupling, genetic association
MeSH terms: Uncoupling Protein 2, Uncoupling Protein 3, Diabetes Mellitus, Exons, Haplotypes, Humans, Ion Channels, Obesity, Promoter Regions, Genetic, 3' Untranslated Regions, Polymorphism, Single Nucleotide, Mitochondrial Proteins, Lipid Metabolism, INDEL Mutation

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The polymorphisms of UCP2 and UCP3 genes associated with fat metabolism, obesity and diabetes

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