Association of the FTO gene with obesity and cancer in dogs

Yıl 2023, , 118 - 131, 31.12.2023

Dina Bedik , Gizem Kırmızıoğlu , Iraz Akış

https://doi.org/10.30704/http-www-jivs-net.1349652

Öz

Nowadays, obesity is one of the most serious problems that significantly affect health in both human and animal populations. Fat mass and obesity-associated gene (FTO), increases the risk of obesity and other metabolic diseases such as cancer, with taking part in many complex molecular pathways. On the other hand, environmental and genetic factors cause changes in FTO gene variants and expression levels, which result in phenotypic differences. Advanced knowledge on the genetic basis of human FTO gene and its association with cancer and obesity, has paved the way for the investigation of FTO gene in animals as well. In this review, we summarized current state of knowledge about the FTO gene, which is considered as an important marker of obesity in humans, as well as obesity, cancer and the association of FTO polymorphisms with these diseases in dogs by considering humans with other animal species. Understanding the molecular background of the FTO gene in dogs will be leading to the development of individual treatment methods and prediction of possible phenotypic effects in other species.

Anahtar Kelimeler

cancer, dog, FTO, obesity, RNA demethylase

Kaynakça

• Adams V. J., Evans K. M., Sampson J., & Wood J. L. N. (2010). Methods and mortality results of a health survey of purebred dogs in the UK. Journal of Small Animal Practice, 51(10), 512-524.
• Akey, J. M., Ruhe, A. L., Akey, D. T., Wong, A.K., Connelly, C. F., Madeoy, J., Nicholas, T. J., & Neff, M. W. (2010). Tracking footprints of artificial selection in the dog genome. Proceedings of the National Academy of Sciences, 107(3), 1160-1165.
• Animal Cancer Foundation. Retrieved from: http://www.acfoundation.org Access: March, 2023.
• Bravard, A., Lefai, E., Meugnier, E., Pesenti, S., Disse, E., Vouillarmet, J., Peretti, N., Rabasa-Lhoret, R., Laville, M., Vidal, H., & Rieusset, J. (2011). FTO is increased in muscle during type 2 diabetes, and its overexpression in myotubes alters insulin signaling, enhances lipogenesis and ROS production, and induces mitochondrial dysfunction. Diabetes, 60(1), 258-268.
• Breen, M. (2008). Canine cytogenetics–from band to basepair. Cytogenetic and Genome Research, 120(1-2), 50-60.
• Brennan, P., McKay, J., Moore, L., Zaridze, D., Mukeria, A., Szeszenia-Dabrowska, N., Lissowska, J., Rudnai, P., Fabianova, E., Mates, D., Bencko, V., Foretova, L., Janout, V., Chow, W. H., Rothman, N., Chabrier, A., Goborieau, V., Timpson, N., Hung, R.J., & Smith, G. D. (2009). Obesity and cancer: Mendelian randomization approach utilizing the FTO genotype. International Journal of Epidemiology, 38(4), 971-975.
• Bronson, R. T. (1982). Variation in age at death of dogs of different sexes and breeds. American Journal of Veterinary Research, 43(11), 2057-2059.
• Calle E. E., & Kaaks R. (2004). Overweight, obesity and cancer: epidemiological evidence and proposed mechanisms. Nature Reviews Cancer, 4(8), 579-591.
• Calle E. E., Rodriguez, C., Walker-Thurmond, K. & Thun, M. J. (2003). Overweight, obesity, and mortality from cancer in a prospective studied cohort of U.S. adults. New England Journal of Medicine, 348(17), 1625-1638.
• Cecil, J. E., Tavendale, R., Watt, P., Hetherington, M. M., & Palmer, C. N. (2008) An obesity-associated FTO gene variant and increased energy intake in children. New England Journal of Medicine, 359(24), 2558-2566.
• Chen, X., Luo, Y., Jia, G., Liu, G., Zhao, H., & Huang, Z. (2017). FTO promotes adipogenesis through inhibition of the Wnt/β-catenin signaling pathway in porcine intramuscular preadipocytes. Animal Biotechnology, 2 (4), 268-274.
• Church, C., Lee, S., Bagg, E. A., McTaggart, J. S., Deacon, R., Gerken, T., Lee, A., Moir, L., Mecinović, J., Quwailid, M. M., Schofield, C. J., Ashcroft, F. M., & Cox, R. D. (2009). A mouse model for the metabolic effects of the human fat mass and obesity associated FTO gene. PLoS Genetics, 5(8), e1000599.
• Church, C., Moir, L., McMurray, F., Girard, C., Banks, G. T., Teboul, L., Wells, S., Brüning, J. C., Nolan, P.M., Ashcroft, F.M, & Cox, R. D. (2010). Overexpression of Fto leads to increased food intake and results in obesity. Nature Genetics, 42(12), 1086-1092.
• Clifton, I. J., McDonough, M. A., Ehrismann, D., Kershaw, N. J., Granatino, N., & Schofield, C. J. (2006). Structural studies on 2-oxoglutarate oxygenases and related double-stranded β-helix fold proteins. Journal of Inorganic biochemistry, 100(4), 644-669.
• Colliard, L., Ancel, J., Benet, J. J., Paragon, B. M., & Blanchard, G. (2006). Risk factors for obesity in dogs in France. Journal of Nutrition, 136(7), 1951S-1954S.
• Courcier, E. A., Thomson, R. M., Mellor, D. J., & Yam, P. S. (2010). An epidemiological study of environmental factors associated with canine obesity. Journal of Small Animal Practice, 51(7), 362-367.
• Cui, Q. I., Shi, H., Ye, P., Li, L., Qu, Q., Sun, G., Sun, G., Lu, Z., Huang, Y., Yang, C. G., Riggs, A. D., He, C. & Shi, Y. (2017). m6A RNA methylation regulates the self-renewal and tumorigenesis of glioblastoma stem cells. Cell Reports, 18(11), 2622-2634.
• Da Cunha, P. A., de Carlos Back, L. K., Sereia, A. F. R., Kubelka, C., Ribeiro, M.C. M., Fernandes, B. L., & de Souza, I. R. (2013). Interaction between obesity-related genes, FTO and MC4R, associated to an increase of breast cancer risk. Molecular Biology Reports, 40, 6657-6664.
• Davis, B. W., & Ostrander, E. A. (2014). Domestic dogs and cancer research: a breed-based genomics approach. ILAR Journal, 55(1), 59-68.
• Delahanty, R. J., Beeghly-Fadiel, A., Xiang, Y. B., Long, J., Cai, Q., Wen, W., Xu, W. H., Cai, H., He, J., Gao, Y. T., Zheng, W., & Shu, X. O. (2011). Association of obesity-related genetic variants with endometrial cancer risk: a report from the Shanghai Endometrial Cancer Genetics Study. American Journal of Epidemiology, 174(10), 1115-1126.
• Dina, C., Meyre, D., Gallina, S., Durand, E., Körner, A., Jacobson, P., Carlsson, L. M. S, Kiess, W., Vatin, V., Lecoeur, C., Delplanque, J., Vaillant, E., Pattou, F., Ruiz, J., Weill, J., Levy-Marchal, C., Horber, F., Potoczna, N., Hercberg, S., Le Stunff, C., Bougnères, P., Kovacs, P., Marre, M., Balkau, B., Cauchi, S., Chèvre, J. C., & Froguel, P. (2007). Variation in FTO contributes to childhood obesity and severe adult obesity. Nature Genetics, 39(6), 724-726.
• Dobson, J. M.(2013). Breed-predispositions to cancer in pedigree dogs. International Scholarly Research Notices, 1-23.
• Dobson, J. M., Samuel, S., Milstein, H., Rogers, K., & Wood, J. L. N. (2002). Canine neoplasia in the UK: estimates of incidence rates from a population of insured dogs. Journal of Small Animal Practice, 43(6), 240-246.
• Ensembl genome browser 109. Retrieved from: http://www.ensembl.org/ Access: March, 2023.
• Fan, B., Du, Z. Q., & Rothschild, M. F. (2009). The fat mass and obesity-associated (FTO) gene is associated with intramuscular fat content and growth rate in the pig. Animal biotechnology, 20(2), 58-70.
• Finucane, M. M., Stevens, G. A., Cowan, M. J., Danaei, G., Lin, J. K., Paciorek, C. J., Singh, G. M., Gutierrez, H. R., Lu, Y., Bahalim, A. N., Farzadfar, F., Riley, L. M. & Ezzati, M. (2011). National, regional, and global trends in body-mass index since 1980: systematic analysis of health examination surveys and epidemiological studies with 960 country-years and 9· 1 million participants. The Lancet, 377(9765), 557-567.
• Fischer, J., Emmerling, C., & Rüther, U. (2008). On the history of Fto. Obesity facts, 1(1), 43.
• Fischer, J., Koch, L., Emmerling, C., Vierkotten, J., Peters, T., Brüning, J. C., & Rüther, U. (2009). Inactivation of the Fto gene protects from obesity. Nature, 458(7240), 894-898.
• Fontanesi, L., Scotti, E., Buttazzoni, L., Davoli, R., & Russo, V., (2009). The porcine fat mass and obesity associated (FTO) gene is associated with fat deposition in Italian Duroc pigs. Animal genetics, 40(1), 90-93.
• Frayling, T. M., Timpson, N. J., Weedon, M. N., Zeggini, E., Freathy, R. M., Lindgren, C. M., Perry, J. R. B., Elliot, K. S, Lango, H., Rayner, N. W., Shields, B, Harries, L. W., Barret, J. C., Ellard, S., Groves, C. J., Knight, B., Patch, A. M., Ness, A. R., Ebrahim, S., Lawlor, D. A., Ring, S. M., Ben-Shlomo, Y., Jarvelin, M. R., Sovio, U., Bennet, A. J., Melzer, D., Ferrucci, L., Loos, R. J. F., Barroso, I., Wareham, N. J., Karpe, F., Owen, K. R., Cardon, L. R., Walker, M., Hitman, G. A., Palmer, C. N. A., Doney, A. S. F., Morris, A. D., Smith, G. D., Hattersley, A. T., & McCarthy, M. I. (2007). A common variant in the FTO gene is associated with body mass index and predisposes to childhood and adult obesity. Science, 316(5826), 889-894.
• Fredriksson, R., Hägglund, M., Olszewski, P. K., Stephansson, O., Jacobsson, J. A., Olszewska, A. M., Levine, A. S., Lindblom, J., & Schiöth, H. B. (2008). The obesity gene, FTO, is of ancient origin, up-regulated during food deprivation and expressed in neurons of feeding-related nuclei of the brain. Endocrinology, 149(5), 2062-2071.
• Gardner, H. L., Fenger, J. M., & London, C. A. (2016). Dogs as a model for cancer. Annual review of animal biosciences, 4, 199-222.
• Gene Ontology and GO Annotations. https://www.ebi.ac.uk/QuickGO/ Access: March, 2023.
• Gerken, T., Girard, C. A., Tung, Y. C. L., Webby, C. J., Saudek, V., Hewitson, K S., Yeo, G. S. H., McDonough, M. A., Cunliffe, S., McNeill, L. A., Galvanovskis, J., Rorsman, P., Robins, P., Prieur, X., Coll, A. P., Ma, M., Jovanovic, Z., Farooqi, I. S., Sedgwick, B., Barroso, I., Lindahl, T., Ponting, C. P., Ashcroft, F. M., O'Rahilly, S., & Schofield, C. J. (2007). The obesity-associated FTO gene encodes a 2-oxoglutarate-dependent nucleic acid demethylase. Science, 318(5855), 1469-1472.
• German, A. J. (2006). The growing problem of obesity in dogs and cats. The Journal of nutrition, 136(7), 1940S-1946S.
• Goodwin, P. J., & Stambolic, V. (2015). Impact of the obesity epidemic on cancer. Annual review of medicine, 66, 281-296.
• Grzemski, A., Stachowiak, M., Flisikowski, K., Mankowska, M., Krzeminska, P., Gogulski, M., Aleksiewicz, R., Szydlowski, M., Switonski, M., & Nowacka-Woszuk, J. (2019). FTO and IRX3 genes are not promising markers for obesity in Labrador retriever dogs. Annals of Animal Science, 19(2), 343-357.
• Grzes, M., Szczerbal, I., Fijak-Nowak, H., Szydlowski, M., & Switonski, M. (2011). Two candidate genes (FTO and INSIG2) for fat accumulation in four canids: chromosome mapping, gene polymorphisms and association studies of body and skin weight of red foxes. Cytogenetic and Genome Research, 135(1), 25-32.
• Haidar, Y. M., & Cosman, B. C. (2011). Obesity epidemiology. Clinics in colon and rectal surgery, 24(04), 205-210.
• Han, Z., Niu, T., Chang, J., Lei, X., Zhao, M., Wang, Q., Cheng, W., Wang, J., Feng, Y., & Chai, J. (2010). Crystal structure of the FTO protein reveals basis for its substrate specificity. Nature, 464(7292), 1205-1209.
• Hassanein, M. T., Lyon, H. N., Nguyen, T. T., Akylbekova, E. L., Waters, K., Lettre, G., Tayo, B., Forrester, T., Sarpong, D. F., Stram, D. O., Butler, J. L., Wilks, R., Liu, J., Le Marchand, L., Kolonel, L. N., Zhu, X., Henderson, B., Cooper, R., McKenzie, C., Taylor, H. A., Haiman, C. A., & Hirschhorn, J. N. (2010). Fine mapping of the association with obesity at the FTO locus in African-derived populations. Human molecular genetics, 19(14), 2907-2916.
• Haupt, A., Thamer, C., Staiger, H., Tschritter, O., Kirchhoff, K., Machicao, F., Häring, H. U., Stefan, N., & Fritsche, A. (2008). Variation in the FTO gene influences food intake but not energy expenditure. Experimental and Clinical Endocrinology & Diabetes, 194-197.
• Hernández-Caballero, M. E., & Sierra-Ramírez, J. A. (2015). Single nucleotide polymorphisms of the FTO gene and cancer risk: an overview. Molecular biology reports, 42, 699-704.
• Hess, M. E., & Brüning, J. C. (2014). The fat mass and obesity-associated (FTO) gene: Obesity and beyond?. Biochimica et Biophysica Acta (BBA)-Molecular Basis of Disease, 1842(10), 2039-2047.
• Hess, M. E., Hess, S., Meyer, K. D., Verhagen, L. A., Koch, L., Brönneke, H. S., Dietrich, M. O., Jordan, S. D., Saletore, Y., Elemento, O., Belgardt, B. F., Franz, T., Horvath, T. L., Rüther, U., Jaffrey, S. R., Kloppenburg, P., & Brüning, J. C. (2013). The fat mass and obesity associated gene (Fto) regulates activity of the dopaminergic midbrain circuitry. Nature neuroscience, 16(8), 1042-1048.
• Huđek, A., Škara, L., Smolkovič, B., Kazazić, S., Ravlić, S., Nanić, L., Osvatić, M. M., Jelčić, J., Rubelj, I., & Bačun-Družina, V. (2018). Higher prevalence of FTO gene risk genotypes AA rs9939609, CC rs1421085, and GG rs17817449 and saliva containing Staphylococcus aureus in obese women in Croatia. Nutrition research, 50, 94-103.
• Huvenne, H., Dubern, B., Clément, K., & Poitou, C. (2016). Rare genetic forms of obesity: clinical approach and current treatments in 2016. Obesity facts, 9(3), 158-173.
• Jeusette, I., Greco, D., Aquino, F., Detilleux, J., Peterson, M., Romano, V., & Torre, C. (2010). Effect of breed on body composition and comparison between various methods to estimate body composition in dogs. Research in veterinary science, 88 (2), 227-232.
• Jevsinek Skok, D., Kunej, T., Kovac, M., Malovrh, S., Potocnik, K., Petric, N., Zgur, S., Dovc, P., & Horvat, S. (2016). FTO gene variants are associated with growth and carcass traits in cattle. Animal Genetics, 47(2), 219-222.
• Jia, G., Yang, C.G., Yang, S., Jian, X., Yi, C., Zhou, Z., & He, C. (2008). Oxidative demethylation of 3-methylthymine and 3-methyluracil in single-stranded DNA and RNA by mouse and human FTO. FEBS letters, 582(23-24), 3313-3319.
• Jia, X., Nie, Q., Lamont, S. J., & Zhang, X. (2012). Variation in sequence and expression of the avian FTO, and association with glucose metabolism, body weight, fatness and body composition in chickens. International journal of obesity, 36(8), 1054-1061.
• Kaklamani, V., Yi, N., Sadim, M., Siziopikou, K., Zhang, K., Xu, Y., Tofilon, S., Agarwal, S., Pasche, B., & Mantzoros, C. (2011). The role of the fat mass and obesity associated gene (FTO) in breast cancer risk. BMC medical genetics, 12, 1-10.
• Köksal, M. (2019). Fazla kilolu ve obez çocuklarda fto gen polimorfizmlerinin insülin direnci ile ilişkisi. Master’s thesis, Ondokuz Mayıs University, Health Sciences Institute, Samsun, Turkey.
• Kronfeld, D. S., Donoghue, S., & Glickman, L. T. (1991). Body condition and energy intakes of dogs in a referral teaching hospital. The Journal of Nutrition, 121(suppl_11), S157-S158..
• Kucher, A. N. (2020). The FTO Gene and Diseases: The role of genetic polymorphism, epigenetic modifications, and environmental factors. Russian Journal of Genetics, 56, 1025-1043.
• Lan, N., Lu, Y., Zhang, Y., Pu, S., Xi, H., Nie, X., Liu, J., & Yuan, W. (2020). FTO–a common genetic basis for obesity and cancer. Frontiers in genetics, 11, 559138.
• Larder, R., Cheung, M. M., Tung, Y. L., Yeo, G. S., & Coll, A. P. (2011). Where to go with FTO?. Trends in Endocrinology & Metabolism, 22(2), 53-59.
• Lequarré, A. S., Andersson, L., André, C., Fredholm, M., Hitte, C., Leeb, T., Lohi, H., Lindblad-Toh, K., & Georges, M. (2011). LUPA: a European initiative taking advantage of the canine genome architecture for unravelling complex disorders in both human and dogs. The Veterinary Journal, 189(2), 155-159.
• Lewis, S. J., Murad, A., Chen, L., Davey Smith, G., Donovan, J., Palmer, T., Hamdy, F., Neal, D., Lane, J. A., Davis, M., Cox, A., & Martin, R. M. (2010). Associations between an obesity related genetic variant (FTO rs9939609) and prostate cancer risk. PLoS One, 5(10), e13485.
• Li, H., Wu, Y., Loos, R. J., Hu, F. B., Liu, Y., Wang, J., Yu, Z., & Lin, X. (2008). Variants in the fat mass–and obesity-associated (FTO) gene are not associated with obesity in a Chinese Han population. Diabetes, 57(1), 264-268.
• Li, T., Wu, K., You, L., Xing, X., Wang, P., Cui, L., Liu, H., Cui, Y., Bian, Y., Ning, Y., Zhao, H., Tang, R., & Chen, Z. J. (2013). Common variant rs9939609 in gene FTO confers risk to polycystic ovary syndrome. PloS one, 8(7), e66250.
• Lin, Y., Ueda, J., Yagyu, K., Ishii, H., Ueno, M., Egawa, N., Nakao, H., Mori, M., Matsuo, K., & Kikuchi, S. (2013). Association between variations in the fat mass and obesity-associated gene and pancreatic cancer risk: a case–control study in Japan. Bmc Cancer, 13, 1-6.
• Loos, R. J., & Yeo, G. S. (2014). The bigger picture of FTO—the first GWAS-identified obesity gene. Nature Reviews Endocrinology, 10(1), 51-61.
• Loos, R. J. F., & Bouchard, C. (2008). FTO: the first gene contributing to common forms of human obesity. Obesity reviews, 9(3), 246-250.
• Lund, E. M., Armstrong, P. J., Kirk, C. A., & Klausner, J. S. (2006). Prevalence and risk factors for obesity in adult dogs from private US veterinary practices. International Journal of Applied Research in Veterinary Medicine, 4(2), 177.
• Madsen, M. B., Birck, M. M., Fredholm, M., & Cirera, S. (2009). Expression studies of the obesity candidate gene FTO in pig. Animal Biotechnology, 21(1), 51-63.
• Mauer, J., Luo, X., Blanjoie, A., Jiao, X., Grozhik, A. V., Patil, D. P., Linder, B., Pickering, B. F., Vasseur, J. J., Chen, Q., Gross, S. S., Elemento, O., Debart, F., Kiledjian, M., & Jaffrey, S. R. (2017). Reversible methylation of m6Am in the 5′ cap controls mRNA stability. Nature, 541(7637), 371-375.
• McGreevy, P. D., Thomson, P. C., Pride, C., Fawcett, A., Grassi, T., & Jones, B. (2005). Prevalence of obesity in dogs examined by Australian veterinary practices and the risk factors involved. Veterinary Record, 156(22), 695-702.
• McMurray, F., Church, C. D., Larder, R., Nicholson, G., Wells, S., Teboul, L., Tung, Y. C. L., Rimmington, D., Bosch, F., Jimenez, V., Yeo, G. S. H., O'Rahilly, S., Ashcroft, F. M., Coll, A. P., & Cox, R. D. (2013). Adult onset global loss of the fto gene alters body composition and metabolism in the mouse. PLoS genetics, 9(1), e1003166.
• Merlo, D. F., Rossi, L., Pellegrino, C., Ceppi, M., Cardellino, U., Capurro, C., Ratto, A., Sambucco, P. L., Sestito, V., Tanara, G., & Bocchini, V. (2008). Cancer incidence in pet dogs: findings of the Animal Tumor Registry of Genoa, Italy. Journal of veterinary internal medicine, 22(4), 976-984.
• National Center for Biotechnology Information. http://www.ncbi.nlm.nih.gov/ Access: March, 2023.
• Ng, M., Fleming, T., Robinson, M., Thomson, B., Graetz, N., Margono, C., Mullany, E. C., Biryukov, S., Abbafati, C., Abera, S. F., Abraham, J.P., Abu-Rmeileh, N. M. E., Achoki, T., AlBuhairan, F.S., Alemu, Z. A., Alfonso, R., Ali, M. K., Ali, R., Guzman, N. A., Ammar, W., & Gakidou, E. (2014). Global, regional, and national prevalence of overweight and obesity in children and adults during 1980–2013: a systematic analysis for the Global Burden of Disease Study 2013. The Lancet, 384(9945), 766-781.
• Nijland, M. L., Stam, F., & Seidell, J. C. (2010). Overweight in dogs, but not in cats, is related to overweight in their owners. Public health nutrition, 13(1), 102-106.
• Ohashi, J., Naka, I., Kimura, R., Natsuhara, K., Yamauchi, T., Furusawa, T., Nakazawa, M., Ataka, Y., Patarapotikul, J., Nuchnoi, P., Tokunaga, K., Ishida, T., Inaoka, T., Matsumura, Y., & Ohtsuka, R. (2007). FTO polymorphisms in oceanic populations. Journal of human genetics, 52(12), 1031-1035.
• Ozer, A., & Bruick, R. K. (2007). Non-heme dioxygenases: cellular sensors and regulators jelly rolled into one?. Nature chemical biology, 3(3), 144-153.
• Peters, T., Ausmeier, K., & Rüther, U. (1999). Cloning of Fatso (Fto), a novel gene deleted by the Fused toes (Ft) mouse mutation. Mammalian genome, 10 (10), 983-986.
• Phillips, C. M. (2013). Nutrigenetics and metabolic disease: current status and implications for personalised nutrition. Nutrients, 5(1), 32-57.
• Pierce, B. L., Austin, M. A., & Ahsan, H. (2011). Association study of type 2 diabetes genetic susceptibility variants and risk of pancreatic cancer: an analysis of PanScan-I data. Cancer Causes & Control, 22, 877-883.
• Popović, A. M., Huđek Turković, A., Žuna, K., Bačun-Družina, V., Rubelj, I., & Matovinović, M. (2023). FTO Gene Polymorphisms at the Crossroads of Metabolic Pathways of Obesity and Epigenetic Influences. Food Technology and Biotechnology, 61(1), 14-26.
• Wu, Q., Saunders, R. A., Szkudlarek-Mikho, M., de la Serna, I., & Chin, K.V. (2010). The obesity-associated Fto gene is a transcriptional coactivator. Biochemical and biophysical research communications, 401(3), 390-395. Ricci, R., & Bevilacqua, F. (2012). The potential role of leptin and adiponectin in obesity: a comparative review. The Veterinary Journal, 191(3), 292-298.
• Robbens, S., Rouzé, P., Cock, J. M., Spring, J., Worden, A. Z., & Van de Peer, Y. (2008). The FTO gene, implicated in human obesity, is found only in vertebrates and marine algae. Journal of Molecular Evolution, 66, 80-84.
• Robertson, I. D. (2003). The association of exercise, diet and other factors with owner-perceived obesity in privately owned dogs from metropolitan Perth, WA. Preventive veterinary medicine, 58(1-2), 75-83.
• Ronkainen, J., Huusko, T. J., Soininen, R., Mondini, E., Cinti, F., Mäkelä, K. A., Kovalainen, M., Herzig, K. H., Järvelin, M. R., Sebert, S., Savolainen, M. J., & Salonurmi, T. (2015). Fat mass-and obesity-associated gene Fto affects the dietary response in mouse white adipose tissue. Scientific reports, 5(1), 9233.
• Russell, M. A., & Morgan, N. G. (2011). Conditional expression of the FTO gene product in rat INS-1 cells reveals its rapid turnover and a role in the profile of glucose-induced insulin secretion. Clinical Science, 120(9), 403-413.
• Sarfstein, R., Friedman, Y., Attias-Geva, Z., Fishman, A., Bruchim, I., & Werner, H. (2013). Metformin downregulates the insulin/IGF-I signaling pathway and inhibits different uterine serous carcinoma (USC) cells proliferation and migration in p53-dependent or-independent manners. PloS one, 8(4), e61537.
• Scuteri, A., Sanna, S., Chen, W. M., Uda, M., Albai, G., Strait, J., Najjar, S., Nagaraja, R., Orrú, M., Usala, G., Dei, M., Lai, S., Maschio, A., Busonero, F., Mulas, A., Cao, A., Lakatta, E., & Abecasis, G. R. (2007). Genome-wide association scan shows genetic variants in the FTO gene are associated with obesity-related traits. PLoS genetics, 3(7), e115.
• Sebert, S. P., Hyatt, M. A., Chan, L. L. Y., Yiallourides, M., Fainberg, H. P., Patel, N., Sharkey, D., Stephenson, T., Rhind, R. M., Bell, R. C., Budge, H., Gardner, D. S., & Symonds, M. E. (2010). Influence of prenatal nutrition and obesity on tissue specific fat mass and obesity-associated (FTO) gene expression. Reproduction, 139(1), 265-274.
• Song, R. B., Vite, C. H., Bradley, C. W., & Cross, J. R. (2013). Postmortem evaluation of 435 cases of intracranial neoplasia in dogs and relationship of neoplasm with breed, age, and body weight. Journal of veterinary internal medicine, 27(5), 1143-1152.
• Speakman, J. R., Rance, K. A., & Johnstone, A. M. (2008). Polymorphisms of the FTO gene are associated with variation in energy intake, but not energy expenditure. Obesity, 16(8), 1961-1965.
• Speakman, J. R., Van Acker, A., & Harper, E. J. (2003). Age‐related changes in the metabolism and body composition of three dog breeds and their relationship to life expectancy. Aging cell, 2(5), 265-275.
• Stratigopoulos, G., Padilla, S. L., LeDuc, C. A., Watson, E., Hattersley, A. T., McCarthy, M. I., Zeltser, L. M., Chung, W. K., & Leibel, R. L. (2008). Regulation of Fto/Ftm gene expression in mice and humans. American Journal of Physiology-Regulatory, Integrative and Comparative Physiology, 294(4), R1185-R1196.
• Switonski, M., & Mankowska, M. (2013). Dog obesity–the need for identifying predisposing genetic markers. Research in veterinary science, 95(3), 831-836.
• Tan, A., Dang, Y., Chen, G., & Mo, Z. (2015). Overexpression of the fat mass and obesity associated gene (FTO) in breast cancer and its clinical implications. International journal of clinical and experimental pathology, 8(10), 13405.
• Tang, H., Dong, X., Hassan, M., Abbruzzese, J. L., & Li, D. (2011). Body Mass Index and Obesity-and Diabetes-Associated Genotypes and Risk for Pancreatic CancerObesity-Related Genes Modify Pancreatic Cancer Risk. Cancer epidemiology, biomarkers & prevention, 20(5), 779-792.
• Tanofsky-Kraff, M., Han, J C., Anandalingam, K., Shomaker, L. B., Columbo, K. M., Wolkoff, L. E., Kozlosky, M., Elliott, C., Ranzenhofer, L. M., Roza, C. A., Yanovski, S. Z., & Yanovski, J. A. (2009). The FTO gene rs9939609 obesity-risk allele and loss of control over eating. The American journal of clinical nutrition, 90(6), 1483-1488.
• The GenoMEL Consortium. (2013). A variant in FTO shows association with melanoma risk not due to BMI. Nature Genetics, 45, 428–432.
• Timpson, N. J., Emmett, P. M., Frayling, T. M., Rogers, I., Hattersley, A. T., McCarthy, M. I., & Davey Smith, G. (2008). The fat mass–and obesity-associated locus and dietary intake in children. The American journal of clinical nutrition, 88 (4), 971-978.
• Tsai, K. L., Clark, L. A., & Murphy, K. E. (2007). Understanding hereditary diseases using the dog and human as companion model systems. Mammalian Genome, 18, 444-451.
• Tung, Y. C. L., Ayuso, E., Shan, X., Bosch, F., O'Rahilly, S., Coll, A. P., & Yeo, G. S. (2010). Hypothalamic-specific manipulation of Fto, the ortholog of the human obesity gene FTO, affects food intake in rats. PloS one, 5(1), e8771.
• Vail, D. M., & Macewen, E. G. (2000). Spontaneously occurring tumors of companion animals as models for human cancer. Cancer investigation, 18 (8), 781-792.
• Hoeven, F. V. D., Schimmang, T., Volkmann, A., Mattei, M. G., Kyewski, B., & Rüther, U. (1994). Programmed cell death is affected in the novel mouse mutant Fused toes (Ft). Development, 120(9), 2601-2607.
• Villalobos‐Comparán, M., Flores‐Dorantes, M. T., Villarreal‐Molina, M. T., Rodríguez‐Cruz, M., García‐Ulloa, A. C., Robles, L., Huertas-Vázquez, A., Saucedo-Villarreal, N., López-Alarcón, M., Sánchez-Muñoz, F., Domínguez-López., A., Gutiérrez-Aguilar, R., Menjivar, M., Coral-Vázquez, R., Hernández-Stengele, G., Vital-Reyes, V. S., Acuña-Alonzo, V., Romero-Hidalgo, S., Ruiz-Gómez, D. G., Riaño-Barros, D., Herrera, M. F., Gómez-Pérez, F. J., Froguel, P., García-García, E., Tusié-Luna, M. T., Aguilar-Salinas, C. A. & Canizales‐Quinteros, S. (2008). The FTO gene is associated with adulthood obesity in the Mexican population. Obesity, 16(10), 2296-2301.
• Wåhlén, K., Sjölin, E., & Hoffstedt, J. (2008). The common rs9939609 gene variant of the fat mass-and obesity-associated gene FTO is related to fat cell lipolysis. Journal of lipid research, 49(3), 607-611.
• Wang, S., Liu, S., Yuan, T., & Sun, X. (2021). Genetic effects of FTO gene insertion/deletion (InDel) on fat-tail measurements and growth traits in Tong sheep. Animal biotechnology, 32(2), 229-239.
• Wardle, J., Llewellyn, C., Sanderson, S., & Plomin, R. (2009). The FTO gene and measured food intake in children. International journal of obesity, 33(1), 42-45.
• Wei, J., Liu, F., Lu, Z., Fei, Q., Ai, Y., He, P. C., Shi, H., Cui, X., Su, R., Klungland, A., Jia, G., Chen, J., & He, C. (2018). Differential m6A, m6Am, and m1A demethylation mediated by FTO in the cell nucleus and cytoplasm. Molecular cell, 71(6), 973-985.
• World Health Organization (2021, June 9). Obesity and overweight. Retrieved from https://www.who.int/news-room/fact-sheets/detail/obesity-and-overweight. Access: March, 2023.
• Zhang, B., Li, Y., Li, L., Chen, M., Zhang, C., Zuo, X. B., Zhou, F. S., Liang, B., Zhu, J., Li, P., Huang, Z., Xuan, H., Li, W., & Chen, Z. D. (2014). Association study of susceptibility loci with specific breast cancer subtypes in Chinese women. Breast cancer research and treatment, 146, 503-514.
• Zhang, G. W., Gao, L., Chen, S. Y., Zhao, X. B., Tian, Y. F., Wang, X., Deng, X. S., & Lai, S. J. (2013). Single nucleotide polymorphisms in the FTO gene and their association with growth and meat quality traits in rabbits. Gene, 527(2), 553-557.
• Zielke, L. G., Bortfeldt, R. H., Reissmann, M., Tetens, J., Thaller, G., & Brockmann, G. A. (2013). Impact of variation at the FTO locus on milk fat yield in Holstein dairy cattle. PLoS One, 8(5), e63406.