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- UCP1 (uncoupling protein 1 (mitochondrial, proton carrier))
Other Symbols:
SLC25A7, UCP
Disease relevance:
UCP1 -3826G allele has been found to be associated with obesity with a gender-related effect (Ramis et al., 2004).
References:
Ramis JM, González-Sánchez JL, Proenza AM, Martínez-Larrad MT, Fernández-Pérez C, Palou A, Serrano-Ríos M. The Arg64 allele of the beta 3-adrenoceptor gene but not the -3826G allele of the uncoupling protein 1 gene is associated with increased leptin levels in the Spanish population. Metabolism. 2004 Nov;53(11):1411-6. PMID: 15536594
- UCP2 (uncoupling protein 2 (mitochondrial, proton carrier))
Other Symbols:
BMIQ4, SLC25A8, UCPH
Disease relevance:
UCP2 polymorphisms may be related to fat metabolism, obesity and diabetes (Jia et al., 2009). People with functional promoter variants in UCP2 and UCP3 may have higher risk of type 2 diabetes, and the risk is increased by obesity (Gable et al., 2006). Genetic variations in the UCP2-UCP3 gene cluster are suggested to be involved in elevating serum lipid levels and indices of abdominal obesity (Salopuro et al., 2009).
For example, non-synonymous rs660339 in the human UCP2 gene in men, and the haplotype (UCP3 rs2075577-UCP2 rs660339) in women are considered good obesity markers (Kosuge et al., 2008). Those with a 45bp insertion allele of UCP2+3474 ins/del have been found to have a higher risk of developing obesity (Lee et al., 2008).
In Taiwanese, UCP2 A55V variant is linked to obesity, and Val55 allele is related to population-attributable risk for 9.5% of obesity (Wang et al., 2007). The V-A-T haplotype within UCP2-UCP3 gene cluster is linked to obesity. In Tonga, a uncoupling protein 2 insertion/deletion polymorphism may be may be associated with obesity and type 2 diabetes (Duarte et al., 2003). In obese middle-aged humans, a polymorphism G allele in the promoter may increase the obesity risk but decrease the risk of type 2 diabetes (Krempler et al., 2002).
References:
Duarte NL, Colagiuri S, Palu T, Wang XL, Wilcken DE. A 45-bp insertion/deletion polymorphism of uncoupling protein 2 in relation to obesity in Tongans. Obes Res. 2003 Apr;11(4):512-7. PMID: 12690079
Gable DR, Stephens JW, Cooper JA, Miller GJ, Humphries SE. Variation in the UCP2-UCP3 gene cluster predicts the development of type 2 diabetes in healthy middle-aged men. Diabetes. 2006 May;55(5):1504-11. PMID: 16644712
Jia JJ, Zhang X, Ge CR, Jois M. The polymorphisms of UCP2 and UCP3 genes associated with fat metabolism, obesity and diabetes. Obes Rev. 2009 Sep;10(5):519-26. Epub 2009 Apr 21. PMID: 19413708
Kosuge K, Soma M, Nakayama T, Aoi N, Sato M, Haketa A, Uwabo J, Izumi Y, Matsumoto K. Human uncoupling protein 2 and 3 genes are associated with obesity in Japanese. Endocrine. 2008 Aug-Dec;34(1-3):87-95. PMID: 18956255
Krempler F, Esterbauer H, Weitgasser R, Ebenbichler C, Patsch JR, Miller K, Xie M, Linnemayr V, Oberkofler H, Patsch W. A functional polymorphism in the promoter of UCP2 enhances obesity risk but reduces type 2 diabetes risk in obese middle-aged humans. Diabetes. 2002 Nov;51(11):3331-5. PMID: 12401727
Lee YH, Kim W, Yu BC, Park BL, Kim LH, Shin HD. Association of the ins/del polymorphisms of uncoupling protein 2 (UCP2) with BMI in a Korean population. Biochem Biophys Res Commun. 2008 Jul 11;371(4):767-71. PMID: 18460338
Salopuro T, Pulkkinen L, Lindström J, Kolehmainen M, Tolppanen AM, Eriksson JG, Valle TT, Aunola S, Ilanne-Parikka P, Keinänen-Kiukaanniemi S, Tuomilehto J, Laakso M, Uusitupa M. Variation in the UCP2 and UCP3 genes associates with abdominal obesity and serum lipids: the Finnish Diabetes Prevention Study. BMC Med Genet. 2009 Sep 21;10:94. PMID: 19769793
Wang TN, Huang MC, Lin HL, Hsiang CH, Ko AM, Chang WT, Ko YC. UCP2 A55V variant is associated with obesity and related phenotypes in an aboriginal community in Taiwan. Int J Obes (Lond). 2007 Nov;31(11):1746-52. PMID: 17502873
- UCP3 (uncoupling protein 3 (mitochondrial, proton carrier))
Other Symbols:
SLC25A9
Disease relevance:
Those with functional promoter variants in UCP2 and UCP3 may have higher risk of type 2 diabetes, which may be increased by obesity (Gable et al., 2006). Overproduction of UCP3 in glycolytic muscles in mice may cause mitochondrial uncoupling and resistance to high-fat diet-induced obesity (Tiraby et al., 2007).
References:
Gable DR, Stephens JW, Cooper JA, Miller GJ, Humphries SE. Variation in the UCP2-UCP3 gene cluster predicts the development of type 2 diabetes in healthy middle-aged men. Diabetes. 2006 May;55(5):1504-11. PMID: 16644712
Tiraby C, Tavernier G, Capel F, Mairal A, Crampes F, Rami J, Pujol C, Boutin JA, Langin D. Resistance to high-fat-diet-induced obesity and sexual dimorphism in the metabolic responses of transgenic mice with moderate uncoupling protein 3 overexpression in glycolytic skeletal muscles. Diabetologia. 2007 Oct;50(10):2190-9. PMID: 17676309
- CETP (cholesteryl ester transfer protein, plasma)
[HDLCQ10]
In diabetic obesity, CETP may have an antiatherogenic effect (MacLean et al., 2003).
References:
MacLean PS, Bower JF, Vadlamudi S, Osborne JN, Bradfield JF, Burden HW, Bensch WH, Kauffman RF, Barakat HA. Cholesteryl ester transfer protein expression prevents diet-induced atherosclerotic lesions in male db/db mice. Arterioscler Thromb Vasc Biol. 2003 Aug 1;23(8):1412-5. PMID: 12791674
- SLC15A1 (solute carrier family 15 (oligopeptide transporter), member 1)
[RP11-130L10.1, HPECT1, HPEPT1, PEPT1]
In diet-induced obesity, a hypercaloric diet has been found to lead to a 46% decrease in PepT1-specific transport, with a 30% reduction in PepT1 protein, and a 50% reduction in PepT1 mRNA levels (Hindlet et al., 2009).
References:
Hindlet P, Bado A, Kamenicky P, Deloménie C, Bourasset F, Nazaret C, Farinotti R, Buyse M. Reduced intestinal absorption of dipeptides via PepT1 in mice with diet-induced obesity is associated with leptin receptor down-regulation. J Biol Chem. 2009 Mar 13;284(11):6801-8. PMID: 19144638
- SLC16A1 (solute carrier family 16, member 1 (monocarboxylic acid transporter 1))
[FLJ36745, HHF7, MCT, MCT1, MGC44475]
In obesity, MCT1 expression is associated with changes in oxidative parameters visceral adipose tissue content (Metz et al. 2008).
References:
Metz L, Mercier J, Tremblay A, Alméras N, Joanisse DR. Effect of weight loss on lactate transporter expression in skeletal muscle of obese subjects. J Appl Physiol. 2008 Mar;104(3):633-8. PMID: 18079261
- SLC16A4 (solute carrier family 16, member 4 (monocarboxylic acid transporter 5))
[MCT4, MCT5]
In obesity, muscle MCT4 is increased, showing the need to release more muscle lactate, while weight loss has caused reduced MCT4 (Metz et al., 2008).
References:
Metz L, Mercier J, Tremblay A, Alméras N, Joanisse DR. Effect of weight loss on lactate transporter expression in skeletal muscle of obese subjects. J Appl Physiol. 2008 Mar;104(3):633-8. PMID: 18079261
- SLC2A1 (solute carrier family 2 (facilitated glucose transporter), member 1)
[DYT17, DYT18, GLUT, GLUT1, MGC141895, MGC141896, PED]
Single nucleotide polymorphisms (SNPs) may be related to higher susceptibility to spina bifida (Davidson et al., 2008).
References:
Davidson CM, Northrup H, King TM, Fletcher JM, Townsend I, Tyerman GH, Au KS. Genes in glucose metabolism and association with spina bifida. Reprod Sci. 2008 Jan;15(1):51-8. PMID: 18212354
- SLC2A4 (solute carrier family 2 (facilitated glucose transporter), member 4)
[GLUT4]
The level of GLUT4 protein was higher in omental than in subcutaneous adipose tissue (Veilleux et al., 2009). In visceral obesity, GLUT4 levels in omental and subcutaneous were decreased.
References:
Veilleux A, Blouin K, Rhéaume C, Daris M, Marette A, Tchernof A. Glucose transporter 4 and insulin receptor substrate-1 messenger RNA expression in omental and subcutaneous adipose tissue in women. Metabolism. 2009 May;58(5):624-31. PMID: 19375584
- SLC6A14 (solute carrier family 6 (amino acid transporter), member 14)
[RP3-452H17.1, ATB(0+), BMIQ11]
The SLC6A14 gene locus has been associated with obesity (Durand et al., 2005). SLC6A14 gene has been found to be a novel candidate for treatment of obesity since it encodes an amino acid transporter (Suviolahti et al., 2003). It regulates tryptophan availability for serotonin synthesis may be involved in appetite control.
References:
Durand E, Boutin P, Meyre D, Charles MA, Clement K, Dina C, Froguel P. Polymorphisms in the amino acid transporter solute carrier family 6 (neurotransmitter transporter) member 14 gene contribute to polygenic obesity in French Caucasians. Diabetes. 2004 Sep;53(9):2483-6. Erratum in: Diabetes. 2005 Feb;54(2):587. PMID: 15331564
Suviolahti E, Oksanen LJ, Ohman M, Cantor RM, Ridderstrale M, Tuomi T, Kaprio J, Rissanen A, Mustajoki P, Jousilahti P, Vartiainen E, Silander K, Kilpikari R, Salomaa V, Groop L, Kontula K, Peltonen L, Pajukanta P. The SLC6A14 gene shows evidence of association with obesity. J Clin Invest. 2003 Dec;112(11):1762-72. PMID: 14660752
- SLC6A3 (solute carrier family 6 (neurotransmitter transporter, dopamine), member 3)
[DAT, DAT1]
Genetic variants of the dopamine transporter gene has been associated with obesity in African-American smokers (Epstein et al., 2002).
References:
Epstein LH, Jaroni JL, Paluch RA, Leddy JJ, Vahue HE, Hawk L, Wileyto EP, Shields PG, Lerman C. Dopamine transporter genotype as a risk factor for obesity in African-American smokers. Obes Res. 2002 Dec;10(12):1232-40. PMID: 12490667
- SLC6A4 (solute carrier family 6 (neurotransmitter transporter, serotonin), member 4)
[5-HTT, 5-HTTLPR, 5HTT, HTT, OCD1, SERT, hSERT]
The S allele of the SLC6A4 promoter variant is related to overweight as a genetic risk factor for obesity (Sookoian et al., 2007). The SS genotype of 5-HTTLPR has been found to be a factor of higher BMI level and obesity in non-elderly stroke patients, but not in elderly patients (Lan et al., 2009). There may be an age-dependent regulation for the function of the 5-HTTLPR on development of obesity. In adult male population, 5-HTTLPR polymorphism is associated with BMI, overweight, and obesity (Sookoian et al., 2008). It is considered a risk factor for the obesity phenotype.
References:
Lan MY, Chang YY, Chen WH, Kao YF, Lin HS, Liu JS. Serotonin transporter gene promoter polymorphism is associated with body mass index and obesity in non-elderly stroke patients. J Endocrinol Invest. 2009 Feb;32(2):119-22. PMID: 19411808
Sookoian S, Gemma C, García SI, Gianotti TF, Dieuzeide G, Roussos A, Tonietti M, Trifone L, Kanevsky D, González CD, Pirola CJ. Short allele of serotonin transporter gene promoter is a risk factor for obesity in adolescents. Obesity (Silver Spring). 2007 Feb;15(2):271-6. PMID: 17299098
Sookoian S, Gianotti TF, Gemma C, Burgueño A, Pirola CJ. Contribution of the functional 5-HTTLPR variant of the SLC6A4 gene to obesity risk in male adults. Obesity (Silver Spring). 2008 Feb;16(2):488-91.PMID: 18239665
AQP9 (aquaporin 9)
[HsT17287, SSC1]
Glycerol production and its efflux from adipocytes to the liver are crucial to modulate lipid and glucose homeostasis. Aquaporin 7 (AQP7) is an aquaglyceroporin functioning as the adipose glycerol channel. Aquaporin 9 (AQP9) is the specific channel operating in the liver. AQP7 and AQP9 mediate the trafficking of glycerol from adipose and hepatic tissue. Both aquaporins have been found to act in a coordinated manner (Miranda et al., 2009). Visceral adipose tissue AQP7 expression levels were found to be higher than subcutaneous (SAT) AQP7. Subcutaneous adipose tissue AQP7 were associated with both visceral (VAT) AQP7 and hepatic AQP9 messenger RNA expression. The correlation between SAT AQP7 and liver AQP9 was observed stronger in intolerant and type 2 diabetes mellitus patients.
Increased mRNA expression of VAT AQP7 in obesity and reduced hepatic AQP9 expression have been observed in obese type 2 diabetes mellitus (T2DM) patients (Catalán et al., 2008). Such effects facilitate glycerol release from adipose tissue and decrease glycerol entry into hepatocytes in obesity and T2DM.
References:
Catalán V, Gómez-Ambrosi J, Pastor C, Rotellar F, Silva C, Rodríguez A, Gil MJ, Cienfuegos JA, Salvador J, Vendrell J, Frühbeck G. Influence of morbid obesity and insulin resistance on gene expression levels of AQP7 in visceral adipose tissue and AQP9 in liver. Obes Surg. 2008 Jun;18(6):695-701. PMID: 18401671
Miranda M, Ceperuelo-Mallafré V, Lecube A, Hernandez C, Chacon MR, Fort JM, Gallart L, Baena-Fustegueras JA, Simó R, Vendrell J. Gene expression of paired abdominal adipose AQP7 and liver AQP9 in patients with morbid obesity: relationship with glucose abnormalities. Metabolism. 2009 Dec;58(12):1762-8. PMID: 19615702
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