Uncoupling Protein 2 as a pathogenic determinant and therapeutic target in cardiovascular and metabolic diseases

: Uncoupling protein 2 (UCP2) is a mitochondrial protein that acts as an anion carrier. It is involved in the regulation of several processes including mitochondrial membrane potential, generation of reactive oxygen species within the inner mitochondrial membrane and calcium homeostasis. UCP2 expression can be regulated at different levels: genetic (gene variants), transcriptional [by peroxisome proliferator-activated receptors (PPARs) and microRNAs], and post-translational. Experimental evidence indicates that activation of UCP2 expression through the AMPK/PPAR-α axis exerts a protective effect toward renal damage and stroke occurrence in an animal model of ischemic stroke (IS) associated with hypertension. UCP2 plays a key role in heart diseases (myocardial infarction and cardiac hypertrophy) and metabolic disorders (obesity and diabetes). In humans, UCP2 genetic variants (-866G/A and Ala55Val) associate with an increased risk of type 2 diabetes mellitus and of IS development. Over the last few years, many agents that modulate UCP2 expression have been identified. Some of them are natural compounds of plant origin such as Brassica oleracea, curcumin, berberine and resveratrol. Other molecules, currently used in clinical practice, include anti-diabetic (gliptin) and chemotherapeutic (doxorubicin and taxol) drugs. This evidence highlights the relevant role of UCP2 for the treatment of a wide range of diseases, which affect the national health systems of the Western countries. We will review current knowledge on the physiological and pathological implications of UCP2 with particular regard to cardiovascular and metabolic disorders and will focus on the available therapeutic approaches affecting UCP2 level for the treatment of human diseases.

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Differential Association of Uncoupling Protein 2 Polymorphisms with Pattern Identification among Korean Stroke Patients: A Diagnostic System in Traditional Korean Medicine

Evidence-based Complementary and Alternative Medicine ◽

10.1155/2012/532078 ◽

2012 ◽

Vol 2012 ◽

pp. 1-9 ◽

Cited By ~ 2

Author(s):

Ji Hye Lim ◽

Mi Mi Ko ◽

Hoyoung Lee ◽

Ho Yeon Go ◽

Tae-Woong Moon ◽

...

Keyword(s):

Uncoupling Protein ◽

Mitochondrial Protein ◽

Diagnostic System ◽

Cell Types ◽

Pattern Identification ◽

Uncoupling Protein 2 ◽

Stroke Patients ◽

Standard Pattern ◽

Yin Deficiency ◽

Predictive Parameters

Uncoupling protein 2 (UCP2), a mitochondrial protein present in many organs and cell types, is known to dissipate the proton gradient formed by the electron transport chain. Its function is correlated with predictive parameters, such as obesity, diabetes, and metabolic syndromes. We analyzed the distribution of UCP2 polymorphisms in stroke patients diagnosed with one of the following four stroke subtypes based on the TKM standard pattern identification (PI): Qi-deficiency (QD), Dampness and Phlegm (D&P), Yin-deficiency (YD), and Fire and Heat (F&D). We studied a total of 1,786 stroke patients (397/QD, 645/D&P, 223/YD, and 522/F&D, 586/normal). Genotyping for the G-1957A, G-866A and A55V UCP2 polymorphisms was performed using the TaqMan. G-866A and A55V were significantly associated with the D&P and H&F subtypes. The frequency of subjects with the A allele of G-866A was significantly lower than the frequency of subjects with the GG type. The A55V polymorphism was also shown similar effect with G-866A in the dominant model. In contrast, no SNPs were shown to be associated with the QD or YD subtypes in this study. These results showed that the G-866A and A55V UCP2 polymorphisms may be genetic factors for specific PI types among Korean stroke patients.

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Association Study of Candidate Gene Uncoupling Protein 2 (UCP2) with Type 2 Diabetes Mellitus in the Different Population Groups of Jammu Region

Biosciences Biotechnology Research Asia ◽

10.13005/bbra/2751 ◽

2019 ◽

Vol 16 (2) ◽

pp. 351-357

Author(s):

Sunil Raina ◽

Roopali Fotra

Keyword(s):

Diabetes Mellitus ◽

Metabolic Disorders ◽

Uncoupling Protein ◽

Molecular Genetic ◽

Promoter Polymorphism ◽

Uncoupling Protein 2 ◽

Population Groups ◽

Allelic Odds Ratio

Diabetes Mellitus is a group of metabolic disorders characterized by hyperglycaemic resulting from the defects of insulin secretion, insulin action or both. The present study was conducted in order to know the molecular genetic cause of the T2DM patients belonging to the Jammu region of J&K State. Many genes have been known to be linked with the onset and progression of the T2DM therefore the present data represents the role of one of the genes Uncoupling protein 2 (UCP2) known to be strongly associated with T2DM was selected. A total of 250 confirmed cases & controls samples belonging to four population groups (Hindu, Muslim, Sikh & Christians) of Jammu region were also screened for UCP2 -866G/A promoter polymorphism (rs659366). The allelic odds ratio (OR) as observed for UCP2 -866G/A polymorphism in the four population groups showed significant association with Muslim & Sikh population groups. The study undertaken supports the findings of the previous investigations and thus is an addition to the existing literatute in support of UCP2 and T2DM.

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The role of uncoupling protein 2 in macrophages and its impact on obesity-induced adipose tissue inflammation and insulin resistance

Journal of Biological Chemistry ◽

10.1074/jbc.ra120.014868 ◽

2020 ◽

Vol 295 (51) ◽

pp. 17535-17548

Author(s):

Xanthe A. M. H. van Dierendonck ◽

Tiphaine Sancerni ◽

Marie-Clotilde Alves-Guerra ◽

Rinke Stienstra

Keyword(s):

Insulin Resistance ◽

Adipose Tissue ◽

Macrophage Activation ◽

Uncoupling Protein ◽

Uncoupling Protein 2 ◽

Adipose Tissue Inflammation ◽

Tissue Inflammation ◽

Obesity And Diabetes ◽

Adipose Tissue Macrophages

The development of a chronic, low-grade inflammation originating from adipose tissue in obese subjects is widely recognized to induce insulin resistance, leading to the development of type 2 diabetes. The adipose tissue microenvironment drives specific metabolic reprogramming of adipose tissue macrophages, contributing to the induction of tissue inflammation. Uncoupling protein 2 (UCP2), a mitochondrial anion carrier, is thought to separately modulate inflammatory and metabolic processes in macrophages and is up-regulated in macrophages in the context of obesity and diabetes. Here, we investigate the role of UCP2 in macrophage activation in the context of obesity-induced adipose tissue inflammation and insulin resistance. Using a myeloid-specific knockout of UCP2 (Ucp2ΔLysM), we found that UCP2 deficiency significantly increases glycolysis and oxidative respiration, both unstimulated and after inflammatory conditions. Strikingly, fatty acid loading abolished the metabolic differences between Ucp2ΔLysM macrophages and their floxed controls. Furthermore, Ucp2ΔLysM macrophages show attenuated pro-inflammatory responses toward Toll-like receptor-2 and -4 stimulation. To test the relevance of macrophage-specific Ucp2 deletion in vivo, Ucp2ΔLysM and Ucp2fl/fl mice were rendered obese and insulin resistant through high-fat feeding. Although no differences in adipose tissue inflammation or insulin resistance was found between the two genotypes, adipose tissue macrophages isolated from diet-induced obese Ucp2ΔLysM mice showed decreased TNFα secretion after ex vivo lipopolysaccharide stimulation compared with their Ucp2fl/fl littermates. Together, these results demonstrate that although UCP2 regulates both metabolism and the inflammatory response of macrophages, its activity is not crucial in shaping macrophage activation in the adipose tissue during obesity-induced insulin resistance.

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Uncoupling Protein 2 Drives Myocardial Dysfunction in Murine Models of Septic Shock

BioMed Research International ◽

10.1155/2019/9786101 ◽

2019 ◽

Vol 2019 ◽

pp. 1-10 ◽

Cited By ~ 1

Author(s):

Rong Tang ◽

Ping-ping Qi ◽

Yan-song Liu ◽

Liu Jia ◽

Rui-jin Liu ◽

...

Keyword(s):

Membrane Potential ◽

Mitochondrial Membrane Potential ◽

Cardiac Dysfunction ◽

Mitochondrial Membrane ◽

Viral Vector ◽

Therapeutic Potential ◽

Uncoupling Protein ◽

Myocardial Dysfunction ◽

Multiorgan Failure ◽

Uncoupling Protein 2

Cardiac dysfunction is a major component of sepsis-induced multiorgan failure in critical care units. Uncoupling protein 2 (UCP2) involves immune response, regulation of oxidative stress, and maintenance of mitochondrial membrane potential as well as energy production. However, whether and how UCP2 plays roles in the development of septic cardiac dysfunction are largely unknown. Here, intraperitoneal injection of LPS significantly activated UCP2 expression accompanied by a significant decrease of cardiac function and caused a significantly lower survival rate in mice. Of note, knockdown of UCP2 through a cardiotropic adenoassociated viral vector carrying a short hairpin RNA (shRNA) specifically targeting the UCP2 evoked resistance to LPS-triggered septic cardiac dysfunction and lethality in vivo. Moreover, UCP2 deficiency ameliorated the reduced levels of intracellular ATP in the LPS-challenged heart tissues and preserved mitochondrial membrane potential loss in primary adult mouse cardiomyocytes in LPS-challenged animals. Mechanistically, we confirmed that the inhibition of UCP2 promoted autophagy in response to LPS, as shown by an increase in LC3II and a decrease in p62. At last, the autophagy inhibitor 3-MA abolished UCP2 knockdown-afforded cardioprotective effects. Those results indicate that UCP2 drives septic cardiac dysfunction and that the targeted induction of UCP2-mediated autophagy may have important therapeutic potential.

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Mitochondrial uncoupling protein 2 (UCP2) gene polymorphisms are associated with childhood obesity and related metabolic disorders

Journal of Pediatric Endocrinology and Metabolism ◽

10.1515/jpem-2012-0267 ◽

2012 ◽

Vol 0 (0) ◽

pp. 1-7 ◽

Cited By ~ 1

Author(s):

Sibel Oguzkan-Balci ◽

Nilgun Col-Araz ◽

Muradiye Nacak ◽

Mustafa Araz ◽

Halime Sabanci ◽

...

Keyword(s):

Childhood Obesity ◽

Gene Polymorphisms ◽

Metabolic Disorders ◽

Uncoupling Protein ◽

Uncoupling Protein 2 ◽

Mitochondrial Uncoupling ◽

Mitochondrial Uncoupling Protein ◽

Ucp2 Gene

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Circulating levels of mitochondrial uncoupling protein 2, but not prohibitin, are lower in humans with type 2 diabetes and correlate with brachial artery flow-mediated dilation

Cardiovascular Diabetology ◽

10.1186/s12933-019-0956-4 ◽

2019 ◽

Vol 18 (1) ◽

Cited By ~ 1

Author(s):

Mamatha Kakarla ◽

Venkata K. Puppala ◽

Sudhi Tyagi ◽

Amberly Anger ◽

Kathryn Repp ◽

...

Keyword(s):

Mitochondrial Membrane ◽

Uncoupling Protein ◽

Uncoupling Protein 2 ◽

Flow Mediated Dilation ◽

Vascular Health ◽

Oxygen Species ◽

Inner Mitochondrial Membrane ◽

Artery Flow ◽

Circulating Levels

Abstract Background Excessive reactive oxygen species from endothelial mitochondria in type 2 diabetes individuals (T2DM) may occur through multiple related mechanisms, including production of mitochondrial reactive oxygen species (mtROS), inner mitochondrial membrane (Δψm) hyperpolarization, changes in mitochondrial mass and membrane composition, and fission of the mitochondrial networks. Inner mitochondrial membrane proteins uncoupling protein-2 (UCP2) and prohibitin (PHB) can favorably impact mtROS and mitochondrial membrane potential (Δψm). Circulating levels of UCP2 and PHB could potentially serve as biomarker surrogates for vascular health in patients with and without T2DM. Methods Plasma samples and data from a total of 107 individuals with (N = 52) and without T2DM (N = 55) were included in this study. Brachial artery flow mediated dilation (FMD) was measured by ultrasound. ELISA was performed to measure serum concentrations of PHB1 and UCP2. Mitochondrial membrane potential was measured from isolated leukocytes using JC-1 dye. Results Serum UCP2 levels were significantly lower in T2DM subjects compared to control subjects (3.01 ± 0.34 vs. 4.11 ± 0.41 ng/mL, P = 0.04). There were no significant differences in levels of serum PHB. UCP2 levels significantly and positively correlated with FMDmm (r = 0.30, P = 0.03) in T2DM subjects only and remained significant after multivariable adjustment. Within T2DM subjects, serum PHB levels were significantly and negatively correlated with UCP2 levels (ρ = − 0.35, P = 0.03). Conclusion Circulating UCP2 levels are lower in T2DM patients and correlate with endothelium-dependent vasodilation in conduit vessels. UCP2 could be biomarker surrogate for overall vascular health in patients with T2DM and merits additional investigation.

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215. Placental expression of uncoupling protein-2 is reduced by glucocorticoid treatment in late pregnancy: implications for placental oxidative stress

Reproduction Fertility and Development ◽

10.1071/srb08abs215 ◽

2008 ◽

Vol 20 (9) ◽

pp. 15

Author(s):

M. L. Jones ◽

P. J. Mark ◽

B. J. Waddell

Keyword(s):

Oxidative Stress ◽

Gestational Age ◽

Uncoupling Protein ◽

Late Pregnancy ◽

Uncoupling Protein 2 ◽

Dexamethasone Treatment ◽

Glucocorticoid Treatment ◽

Ucp2 Expression ◽

Endogenous Protection ◽

Placental Oxidative Stress

Placental oxidative stress plays a key role in the pathophysiology of placenta-related disorders in humans, most notably in preeclampsia (PE) and intrauterine growth restriction (IUGR). Protection from oxidative stress is provided by antioxidant enzymes including superoxide dismutase-1 and 2 (SOD-1 and –2) and catalase (CAT), which convert reactive oxygen species (ROS) to inert products. It has also been proposed that uncoupling protein-2 (UCP2) may limit oxidative stress by reducing ROS production, but little is known of UCP2 expression in placenta. Here we measured placental UCP2, SOD-1, SOD-2 and CAT mRNA expression (by qRT–PCR) in normal gestation and after glucocorticoid-induced IUGR. The latter was included because glucocorticoids can increase oxidative stress in other tissues, and placental glucocorticoid exposure is elevated in both PE and IUGR. Placentas were collected on days 16 and 22 of normal pregnancy (term = day 23) and on day 22 after dexamethasone treatment (0.75 mg/mL in drinking water from day 13). The two morphologically-distinct regions of the placenta, the junctional (JZ) and labyrinth (LZ) zones, were analysed separately because effectively all growth occurs in the LZ over this period. Expression of UCP2 in LZ exceeded that in JZ (P < 0.001) and increased in both zones between days 16 and 22 (LZ: 2.0-fold; JZ: 3.2-fold). Dexamethasone treatment reduced UCP2 in LZ (44%; P < 0.05) but not in JZ. SOD1 and SOD2 increased with gestational age in LZ (P < 0.01) and JZ (P < 0.05), but neither were affected by dexamethasone. CAT expression was higher (2.4-fold, P < 0.001) in LZ compared with JZ but did not change with gestational age or dexamethasone. In summary, these data suggest that endogenous protection against oxidative stress increases in the rat placenta during late pregnancy. Moreover, this protection may be compromised by reduced placental UCP2 expression in a model of glucocorticoid-induced IUGR.

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Abstract P160: Role of Uncoupling Protein 2 in Stroke Susceptibility of Stroke-prone Spontaneously Hypertensive Rat

Hypertension ◽

10.1161/hyp.66.suppl_1.p160 ◽

2015 ◽

Vol 66 (suppl_1) ◽

Author(s):

Speranza Rubattu ◽

Maria Cotugno ◽

Franca Bianchi ◽

Sara Di Castro ◽

Rosita Stanzione ◽

...

Keyword(s):

Oxidative Stress ◽

Protein Expression ◽

Mitochondrial Dysfunction ◽

Spontaneously Hypertensive Rat ◽

Uncoupling Protein ◽

Uncoupling Protein 2 ◽

Spontaneously Hypertensive ◽

Hypertensive Rat ◽

Ucp2 Expression

Mitochondrial dysfunction causes severe cellular derangements potentially underlying tissue injury and consequent diseases. Evidence of a direct involvement of mitochondrial dysfunction in hypertensive target organ damage is still poor. The gene encoding Uncoupling Protein 2 (UCP2), a inner mitochondrial membrane protein, maps inside stroke QTL/STR1 in stroke prone spontaneously hypertensive rat (SHRSP). We explored the role of UCP2 in stroke pathogenesis of SHRSP. Male SHRSP, stroke resistant SHR (SHRSR) and reciprocal STR1/congenic rats were fed with stroke permissive Japanese style diet (JD). A group of SHRSP received JD plus fenofibrate (150 mg/kg/die). Rats were sacrificed at stroke occurrence. Additional SHRSR and SHRSP rats were sacrificed at 1, 3, 6, 12 months of age upon regular diet. SBP, BW, proteinuria, stroke signs were monitored. Brains were used for molecular analysis (UCP2 gene and protein expression, Nf-kB protein expression, oxidative stress quantification) and for histological analyses. As a result, brain UCP2 expression was reduced to 20% by JD only in SHRSP (showing 100% stroke occurrence by 7 weeks of JD). Fenofibrate protected SHRSP from stroke and upregulated brain UCP2 (+ 100%). Congenic rats carrying STR1/QTL showed increased (+100%) brain UCP2 expression, as compared to SHRSP, when resistant to stroke, and, viceversa, decreased (-50%) brain UCP2 levels, as compared to SHRSR, when susceptible to stroke. Brain UCP2 expression progressively decreased with aging only in SHRSP, down to 15% level at one year of age (when SHRSP showed spontaneous stroke). Both brain Nf-kB expression and oxidative stress levels increased when UCP2 expression was downregulated, and viceversa. Histological analysis showed both ischemic and haemorrhagic lesions at stroke occurrence. Our results highlight a role of UCP2 in stroke predisposition associated to hypertension in an animal model of complex human disease.

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Uncoupling Protein 2 and Peroxisome Proliferator-Activated Receptor γ Gene Polymorphisms in Association with Diabetes Susceptibility in Chinese Han Population with Variant Glucose Tolerance

International Journal of Endocrinology ◽

10.1155/2018/4636783 ◽

2018 ◽

Vol 2018 ◽

pp. 1-16 ◽

Cited By ~ 1

Author(s):

Meicen Zhou ◽

Shuli He ◽

Fan Ping ◽

Wei Li ◽

Lixin Zhu ◽

...

Keyword(s):

Insulin Secretion ◽

Glucose Tolerance ◽

Impaired Glucose Tolerance ◽

Uncoupling Protein ◽

Uncoupling Protein 2 ◽

Peroxisome Proliferator ◽

Chinese Han ◽

Peroxisome Proliferator Activated Receptor ◽

Han Population ◽

Increased Risk

Objective. To investigate the association of polymorphisms in uncoupling protein 2 (UCP2) and peroxisome proliferator-activated receptor (PPARγ) with glucolipid metabolism in Chinese Han population. Methods. Five hundred eighty-nine subjects were divided into normal glucose tolerance (NGT) group (n=198) and abnormal glucose tolerance group (n=358). HbA1c, blood lipid profile, plasma glucose, and insulin were determined. Insulin sensitivity (HOMA-IR and Matsuda index (ISIM)) and insulin secretion indexes (HOMA-β, early and total phase disposition index) were evaluated. Eight potential functional SNPs in UCP2 and 7 in PPARγ were selected. SNPs were genotyped on Sequenom MassARRAY platform. Results. The GG genotype of rs2920502 in PPARγ was associated with decreased risk of impaired glucose tolerance (G allele: OR: 0.818, 95%CI: 0.526–0.969, P=0.042; GG: OR: 0.715, 95%CI: 0.527–0.97, P=0.031). The TT genotype of rs3856806 in PPARγ was associated with increased risk of impaired glucose tolerance (T allele: OR: 1.46, 95%CI: 1.055–2.017, P=0.022; TT: OR: 1.58, 95%CI: 1.104–2.761, P=0.032). The GG genotype of rs2920502 in PPARγ had better blood glucose and increased insulin secretion and had lower HOMA-IR than GC/CC genotypes. Conclusion. It probably could prevent insulin resistance in early stage by classifying the genotype of rs649446 and rs7109266 in UCP2. The GG genotype of rs2920502 in PPARγ had a decreased risk for diabetes. The TT genotype of rs3856806 in PPARγ had an increased risk for diabetes.

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