Obesity, FTO, and Type 2

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The first report linking the FTO (fat mass and obesity-associated) gene (synonyms KIAA1752, MGC5149, ALKBH9) and obesity came from a genomewide association study linking FTO variants with type 2 diabetes in a European population. [1] The connection between FTO and was lost after correcting for body-mass index, suggesting that FTO -mediated susceptibility to type 2 diabetes was driven through a relationship between FTO and obesity.

Numerous studies have since confirmed the association of FTO with obesity in European populations. [2, 3, 4, 5] Although the strength of this association in other ethnic populations is not as striking, ample evidence suggests that FTO variants are related to obesity in nonwhite populations as well. [6, 7, 8, 9, 10]

In white populations, people who are homozygous for the at-risk allele of rs9939609 have an approximately 1.7-fold increased risk of obesity and are about 3kg heavier than average. Although the average weight difference attributable to common FTO variants is relatively modest, FTO is among the strongest known common genetic risk factors for obesity.

When FTO was first associated with obesity, its function was unknown; its mechanistic relationship with obesity still remains to be discovered. Bioinformatic analysis indicates that FTO is part of a family of enzymes involved in deoxyribonucleic acid (DNA) repair, fatty acid metabolism, and posttranslational modifications, and functional studies suggest that FTO is involved in nucleic acid demethylation. [11] However, it is unclear if and how nucleic acid demethylation is related to obesity.

Animal studies have demonstrated strong FTO expression in the hypothalamus, especially in the arcuate, paraventricular, dorsomedial, and ventromedial nuclei, all of which are key brain regions for the control of appetite. [11, 12] FTO -deficient mice display postnatal growth retardation, significant reduction in adipose tissue, and increased energy expenditure. [13] Conversely, mice who over-express FTO display increased adiposity and increased food intake, with no change in energy expenditure. [14]

In several human studies, individuals with at least 1 of the FTO obesity risk alleles reported increased food intake, especially of high-energy foods, as well as impaired satiety, [15, 16, 17, 18, 19, 20, 21] but changes in energy expenditure appear to be driven by changes in body mass. [22] Thus, while the exact biologic process linking FTO and obesity is unknown, it is clear that FTO variants mediate obesity by increasing energy input.

Before any clinical applications for genetic testing for FTO variants can be considered, the mechanistic link between FTO and obesity needs to be further clarified. One study showed that a loss-of-function FTO mutation in humans led to postnatal growth retardation, microcephaly, severe psychomotor delay, functional brain deficits, facial dysmorphism, and early lethality, [23] indicating that pharmacologic inhibition of FTO in an attempt to combat a predisposition to obesity could yield multiple adverse reactions.

Moreover, a clear link between FTO demethylase activity and obesity has yet to be made. It is possible that FTO plays a specialized role in the hypothalamus, perhaps as a transcriptional regulator, and mediates obesity in a manner independent of its catalytic activity, in which case pharmacologic inhibition would not be useful. On the other hand, it is also possible that the true in vivo effect of FTO has yet to be described.

The association of FTO variants with obesity certainly hints at a novel pathway to obesity and suggests ways in which genetic testing for FTO variants might play a role in potential clinical interventions down the road.

In the meantime, since diet and lifestyle changes seem to blunt the effects of a genetic predisposition toward obesity due to the presence of an FTO risk allele, [24] there may be a more immediate role for genetic testing in the clinic; such testing may provide a means of encouraging allele carriers to implement diet and lifestyle changes that discourage obesity and improve their overall health.

Frayling TM, Timpson NJ, Weedon MN, Zeggini E, Freathy RM, Lindgren CM, et al. A common variant in the FTO gene is associated with body mass index and predisposes to childhood and adult obesity. Science. 2007 May 11. 316(5826):889-94. [Medline]. [Full Text].

Dina C, Meyre D, Gallina S, Durand E, Körner A, Jacobson P, et al. Variation in FTO contributes to childhood obesity and severe adult obesity. Nat Genet. 2007 Jun. 39(6):724-6. [Medline].

Scuteri A, Sanna S, Chen WM, Uda M, Albai G, Strait J, et al. Genome-wide association scan shows genetic variants in the FTO gene are associated with obesity-related traits. PLoS Genet. 2007 Jul. 3(7):e115. [Medline]. [Full Text].

Hinney A, Nguyen TT, Scherag A, Friedel S, Brönner G, Müller TD, et al. Genome wide association (GWA) study for early onset extreme obesity supports the role of fat mass and obesity associated gene (FTO) variants. PLoS One. 2007 Dec 26. 2(12):e1361. [Medline]. [Full Text].

Hertel JK, Johansson S, Sonestedt E, Jonsson A, Lie RT, Platou CG, et al. FTO, type 2 diabetes, and weight gain throughout adult life: a meta-analysis of 41,504 subjects from the Scandinavian HUNT, MDC, and MPP studies. Diabetes. 2011 May. 60 (5):1637-44. [Medline].

Hassanein MT, Lyon HN, Nguyen TT, Akylbekova EL, Waters K, Lettre G, et al. Fine mapping of the association with obesity at the FTO locus in African-derived populations. Hum Mol Genet. 2010 Jul 15. 19(14):2907-16. [Medline]. [Full Text].

Villalobos-Comparán M, Teresa Flores-Dorantes M, Teresa Villarreal-Molina M, Rodríguez-Cruz M, García-Ulloa AC, Robles L, et al. The FTO gene is associated with adulthood obesity in the Mexican population. Obesity (Silver Spring). 2008 Oct. 16(10):2296-301. [Medline].

Liu Y, Liu Z, Song Y, Zhou D, Zhang D, Zhao T, et al. Meta-analysis added power to identify variants in FTO associated with type 2 diabetes and obesity in the Asian population. Obesity (Silver Spring). 2010 Aug. 18(8):1619-24. [Medline].

Vasan SK, Karpe F, Gu HF, Brismar K, Fall CH, Ingelsson E, et al. FTO genetic variants and risk of obesity and type 2 diabetes: a meta-analysis of 28,394 Indians. Obesity (Silver Spring). 2014 Mar. 22 (3):964-70. [Medline].

Fawwad A, Siddiqui IA, Basit A, Zeeshan NF, Shahid SM, Nawab SN, et al. Common variant within the FTO gene, rs9939609, obesity and type 2 diabetes in population of Karachi, Pakistan. Diabetes Metab Syndr. 2015 Feb 24. [Medline].

Gerken T, Girard CA, Tung YC, Webby CJ, Saudek V, Hewitson KS, et al. The obesity-associated FTO gene encodes a 2-oxoglutarate-dependent nucleic acid demethylase. Science. 2007 Nov 30. 318(5855):1469-72. [Medline]. [Full Text].

Stratigopoulos G, Padilla SL, LeDuc CA, Watson E, Hattersley AT, McCarthy MI, et al. Regulation of Fto/Ftm gene expression in mice and humans. Am J Physiol Regul Integr Comp Physiol. 2008 Apr. 294(4):R1185-96. [Medline]. [Full Text].

Fischer J, Koch L, Emmerling C, Vierkotten J, Peters T, Brüning JC, et al. Inactivation of the Fto gene protects from obesity. Nature. 2009 Apr 16. 458(7240):894-8. [Medline].

Church C, Moir L, McMurray F, Girard C, Banks GT, Teboul L, et al. Overexpression of Fto leads to increased food intake and results in obesity. Nat Genet. 2010 Dec. 42(12):1086-92. [Medline]. [Full Text].

Haupt A, Thamer C, Staiger H, Tschritter O, Kirchhoff K, Machicao F, et al. Variation in the FTO gene influences food intake but not energy expenditure. Exp Clin Endocrinol Diabetes. 2009 Apr. 117(4):194-7. [Medline].

Tanofsky-Kraff M, Han JC, Anandalingam K, Shomaker LB, Columbo KM, Wolkoff LE, et al. The FTO gene rs9939609 obesity-risk allele and loss of control over eating. Am J Clin Nutr. 2009 Dec. 90(6):1483-8. [Medline]. [Full Text].

Speakman JR, Rance KA, Johnstone AM. Polymorphisms of the FTO gene are associated with variation in energy intake, but not energy expenditure. Obesity (Silver Spring). 2008 Aug. 16(8):1961-5. [Medline].

Wardle J, Llewellyn C, Sanderson S, Plomin R. The FTO gene and measured food intake in children. Int J Obes (Lond). 2009 Jan. 33(1):42-5. [Medline].

Cecil JE, Tavendale R, Watt P, Hetherington MM, Palmer CN. An obesity-associated FTO gene variant and increased energy intake in children. N Engl J Med. 2008 Dec 11. 359(24):2558-66. [Medline].

Timpson NJ, Emmett PM, Frayling TM, Rogers I, Hattersley AT, McCarthy MI, et al. The fat mass- and obesity-associated locus and dietary intake in children. Am J Clin Nutr. 2008 Oct. 88(4):971-8. [Medline].

Luczyński W, Fendler W, Ramatowska A, Szypowska A, Szadkowska A, Młynarski W, et al. Polymorphism of the FTO Gene Influences Body Weight in Children with Type 1 Diabetes without Severe Obesity. Int J Endocrinol. 2014. 2014:630712. [Medline].

Do R, Bailey SD, Desbiens K, Belisle A, Montpetit A, Bouchard C, et al. Genetic variants of FTO influence adiposity, insulin sensitivity, leptin levels, and resting metabolic rate in the Quebec Family Study. Diabetes. 2008 Apr. 57(4):1147-50. [Medline].

Boissel S, Reish O, Proulx K, Kawagoe-Takaki H, Sedgwick B, Yeo GS, et al. Loss-of-function mutation in the dioxygenase-encoding FTO gene causes severe growth retardation and multiple malformations. Am J Hum Genet. 2009 Jul. 85(1):106-11. [Medline]. [Full Text].

Ahmad T, Lee IM, Paré G, Chasman DI, Rose L, Ridker PM, et al. Lifestyle Interaction With Fat Mass and Obesity-Associated (FTO) Genotype and Risk of Obesity in Apparently Healthy U.S. Women. Diabetes Care. 2011 Mar. 34(3):675-80. [Medline]. [Full Text].

Ali Torkamani, PhD Director of Genome Informatics and Drug Discovery, The Scripps Translational Science Institute; Assistant Professor of Integrative Structural and Computational Biology, The Scripps Research Institute

Disclosure: Nothing to disclose.

Keith K Vaux, MD Professor of , Clinical Chief and Division Director, Division of Medical , Department of , University of California, San Diego, School of Medicine; Director, Rare Disease Program, Rady Children’s Hospital San Diego and UC San Diego

Keith K Vaux, MD is a member of the following medical societies: American Academy of Pediatrics, Western Society for Pediatric Research

Disclosure: Nothing to disclose.

Mary L Windle, PharmD Adjunct Associate Professor, University of Nebraska Medical Center College of Pharmacy; Editor-in-Chief, Medscape Drug Reference

Disclosure: Nothing to disclose.

Obesity, FTO, and Type 2 Diabetes

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