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FTO genotype and aging: pleiotropic longitudinal effects on adiposity, brain function, impulsivity and diet

Abstract

Although overweight and obesity are associated with poor health outcomes in the elderly, the biological bases of obesity-related behaviors during aging are poorly understood. Common variants in the FTO gene are associated with adiposity in children and younger adults as well as with adverse mental health in older individuals. However, it is unclear whether FTO influences longitudinal trajectories of adiposity and other intermediate phenotypes relevant to mental health during aging. We examined whether a commonly carried obesity-risk variant in the FTO gene (rs1421085 single-nucleotide polymorphism) influences adiposity and is associated with changes in brain function in participants within the Baltimore Longitudinal Study of Aging, one of the longest-running longitudinal aging studies in the United States. Our results show that obesity-related risk allele carriers of FTO gene show dose-dependent increments in body mass index during aging. Moreover, the obesity-related risk allele is associated with reduced medial prefrontal cortical function during aging. Consistent with reduced brain function in regions intrinsic to impulse control and taste responsiveness, risk allele carriers of FTO exhibit dose-dependent increments in both impulsivity and intake of fatty foods. We propose that a common neural mechanism may underlie obesity-associated impulsivity and increased consumption of high-calorie foods during aging.

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References

  1. Puhl RM, Peterson JL, DePierre JA, Luedicke J . Headless, hungry, and unhealthy: a video content analysis of obese persons portrayed in online news. J Health Commun 2013; 18: 686–702.

    Article  Google Scholar 

  2. Decaria JE, Sharp C, Petrella RJ . Scoping review report: obesity in older adults. Int J Obesity 2012; 36: 1141–1150.

    Article  CAS  Google Scholar 

  3. Hassing LB, Dahl AK, Pedersen NL, Johansson B . Overweight in midlife is related to lower cognitive function 30 years later: a prospective study with longitudinal assessments. Dement Geriatr Cogn Disord 2010; 29: 543–552.

    Article  Google Scholar 

  4. Whitmer RA, Gunderson EP, Quesenberry CP Jr, Zhou J, Yaffe K . Body mass index in midlife and risk of Alzheimer disease and vascular dementia. Curr Alzheimer Res 2007; 4: 103–109.

    Article  CAS  Google Scholar 

  5. Shock NW Gruelich R Andres R Arenberg D Costa PT Lakatta E et al. Normal Human Aging: The Baltimore Longitudinal Study of Aging. US Government Printing Office: Washington, DC, USA, 1984.

    Google Scholar 

  6. Jueptner M, Weiller C . Review: does measurement of regional cerebral blood flow reflect synaptic activity? Implications for PET and fMRI. Neuroimage 1995; 2: 148–156.

    Article  CAS  Google Scholar 

  7. Ferrucci L . The Baltimore Longitudinal Study of Aging (BLSA): a 50-year-long journey and plans for the future. J Gerontol A Biol Sci Med Sci 2008; 63: 1416–1419.

    Article  Google Scholar 

  8. Kawas C, Gray S, Brookmeyer R, Fozard J, Zonderman A . Age-specific incidence rates of Alzheimer's disease: the Baltimore Longitudinal Study of Aging. Neurology 2000; 54: 2072–2077.

    Article  CAS  Google Scholar 

  9. APA. Diagnostic and Statistical Manual of Mental Disorders: DSM-III-R. American Psychiatric Association: Washington, DC, 1987.

  10. McKhann G, Drachman D, Folstein M, Katzman R, Price D, Stadlan EM . Clinical diagnosis of Alzheimer's disease: report of the NINCDS-ADRDA Work Group under the auspices of Department of Health and Human Services Task Force on Alzheimer's Disease. Neurology 1984; 34: 939–944.

    Article  CAS  Google Scholar 

  11. Resnick SM, Goldszal AF, Davatzikos C, Golski S, Kraut MA, Metter EJ et al. One-year age changes in MRI brain volumes in older adults. Cereb Cortex 2000; 10: 464–472.

    Article  CAS  Google Scholar 

  12. Dina C, Meyre D, Gallina S, Durand E, Korner A, Jacobson P et al. Variation in FTO contributes to childhood obesity and severe adult obesity. Nat Genet 2007; 39: 724–726.

    Article  CAS  Google Scholar 

  13. 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; 316: 889–894.

    Article  CAS  Google Scholar 

  14. 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; 3: e115.

    Article  Google Scholar 

  15. Ho AJ, Stein JL, Hua X, Lee S, Hibar DP, Leow AD et al. A commonly carried allele of the obesity-related FTO gene is associated with reduced brain volume in the healthy elderly. Proc Natl Acad Sci USA 2010; 107: 8404–8409.

    Article  CAS  Google Scholar 

  16. Kivimaki M, Jokela M, Hamer M, Geddes J, Ebmeier K, Kumari M et al. Examining overweight and obesity as risk factors for common mental disorders using fat mass and obesity-associated (FTO) genotype-instrumented analysis: The Whitehall II Study, 1985-2004. Am J Epidemiol 2011; 173: 421–429.

    Article  Google Scholar 

  17. Terracciano A, Balaci L, Thayer J, Scally M, Kokinos S, Ferrucci L et al. Variants of the serotonin transporter gene and NEO-PI-R neuroticism: no association in the BLSA and SardiNIA samples. Am J Med Genet B Neuropsychiatr Genet 2009; 150B: 1070–1077.

    Article  CAS  Google Scholar 

  18. Melzer D, Perry JR, Hernandez D, Corsi AM, Stevens K, Rafferty I et al. A genome-wide association study identifies protein quantitative trait loci (pQTLs). PLoS Genet 2008; 4: e1000072.

    Article  Google Scholar 

  19. McGandy RB, Barrows CH Jr., Spanias A, Meredith A, Stone JL, Norris AH . Nutrient intakes and energy expenditure in men of different ages. J Gerontol 1966; 21: 581–587.

    Article  CAS  Google Scholar 

  20. Costa PT McCrae RR . Revised NEO Personality Inventory (NEO PI-R) and NEO Five-Factor Inventory (NEO FFI): Professional Manual. Psychological Assessment Resources: Odessa, FL, USA, 1992.

    Google Scholar 

  21. Hallfrisch J, Muller D, Drinkwater D, Tobin J, Andres R . Continuing diet trends in men: the Baltimore Longitudinal Study of Aging (1961-1987). J Gerontol 1990; 45: M186–M191.

    Article  CAS  Google Scholar 

  22. Tucker KL, Hallfrisch J, Qiao N, Muller D, Andres R, Fleg JL et al. The combination of high fruit and vegetable and low saturated fat intakes is more protective against mortality in aging men than is either alone: the Baltimore Longitudinal Study of Aging. J Nutr 2005; 135: 556–561.

    Article  CAS  Google Scholar 

  23. Pinheiro J Bates D DebRoy S Sarkar D, The R Development Core Team. nlme: Linear and Nonlinear Mixed Effects Models. R package version 31-108, 2013.

    Google Scholar 

  24. Sutin AR, Costa PT Jr, Chan W, Milaneschi Y, Eaton WW, Zonderman AB et al. I know not to, but i can't help it: weight gain and changes in impulsivity- related personality traits. Psychol Sci 2013; 24: 1323–1328.

    Article  Google Scholar 

  25. Rolls ET . Functions of the orbitofrontal and pregenual cingulate cortex in taste, olfaction, appetite and emotion. Acta Physiol Hung 2008; 95: 131–164.

    Article  CAS  Google Scholar 

  26. Rolls ET, Yaxley S, Sienkiewicz ZJ . Gustatory responses of single neurons in the caudolateral orbitofrontal cortex of the macaque monkey. J Neurophysiol 1990; 64: 1055–1066.

    Article  CAS  Google Scholar 

  27. Albuquerque D, Nobrega C, Manco L . Association of FTO polymorphisms with obesity and obesity-related outcomes in Portuguese children. PloS One 2013; 8: e54370.

    Article  CAS  Google Scholar 

  28. Hunt SC, Stone S, Xin Y, Scherer CA, Magness CL, Iadonato SP et al. Association of the FTO gene with BMI. Obesity (Silver Spring) 2008; 16: 902–904.

    Article  CAS  Google Scholar 

  29. Ntalla I, Panoutsopoulou K, Vlachou P, Southam L, William Rayner N, Zeggini E et al. Replication of established common genetic variants for adult BMI and childhood obesity in Greek adolescents: the TEENAGE study. Ann Hum Genet 2013; 77: 268–274.

    Article  Google Scholar 

  30. Silventoinen K, Kaprio J . Genetics of tracking of body mass index from birth to late middle age: evidence from twin and family studies. Obes Facts 2009; 2: 196–202.

    Article  Google Scholar 

  31. Fakhouri TH, Ogden CL, Carroll MD, Kit BK, Flegal KM . Prevalence of obesity among older adults in the United States, 2007-2010. NCHS Data Brief 2012; 106: 1–8.

    Google Scholar 

  32. American Federation for Aging R. Boom, Boom, Boom : obesity among baby boomers and older adults : issues and options. American Federation for Aging Research: New York, NY, USA, 2005.

  33. Li S, Loos RJ . Progress in the genetics of common obesity: size matters. Curr Opin Lipidol 2008; 19: 113–121.

    Article  CAS  Google Scholar 

  34. 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; 359: 2558–2566.

    Article  CAS  Google Scholar 

  35. Glass TA, Rasmussen MD, Schwartz BS . Neighborhoods and obesity in older adults: the Baltimore Memory Study. Am J Prev Med 2006; 31: 455–463.

    Article  Google Scholar 

  36. Rampersaud E, Mitchell BD, Pollin TI, Fu M, Shen H, O'Connell JR et al. Physical activity and the association of common FTO gene variants with body mass index and obesity. Arch Intern Med 2008; 168: 1791–1797.

    Article  Google Scholar 

  37. Tabara Y, Osawa H, Guo H, Kawamoto R, Onuma H, Shimizu I et al. Prognostic significance of FTO genotype in the development of obesity in Japanese: the J- SHIPP study. Int J Obes 2009; 33: 1243–1248.

    Article  CAS  Google Scholar 

  38. Reynolds B, Ortengren A, Richards JB, de Wit H . Dimensions of impulsive behavior: Personality and behavioral measures. Pers Individ Dif 2006; 40: 305–315.

    Article  Google Scholar 

  39. Swann AC, Bjork JM, Moeller FG, Dougherty DM . Two models of impulsivity: relationship to personality traits and psychopathology. Biol Psychiatry 2002; 51: 988–994.

    Article  Google Scholar 

  40. Keller L, Xu W, Wang HX, Winblad B, Fratiglioni L, Graff C . The obesity related gene, FTO, interacts with APOE, and is associated with Alzheimer's disease risk: a prospective cohort study. J Alzheimers Dis 2011; 23: 461–469.

    Article  CAS  Google Scholar 

  41. Hess ME, Hess S, Meyer KD, Verhagen LA, Koch L, Bronneke HS et al. The fat mass and obesity associated gene (Fto) regulates activity of the dopaminergic midbrain circuitry. Nat Neurosci 2013; 16: 1042–1048.

    Article  CAS  Google Scholar 

  42. Jo YS, Lee J, Mizumori SJ . Effects of prefrontal cortical inactivation on neural activity in the ventral tegmental area. J Neurosci 2013; 33: 8159–8171.

    Article  CAS  Google Scholar 

  43. Steketee JD . Neurotransmitter systems of the medial prefrontal cortex: potential role in sensitization to psychostimulants. Brain Res Brain Res Rev 2003; 41: 203–228.

    Article  CAS  Google Scholar 

Download references

Acknowledgements

We are grateful to the Baltimore Longitudinal Study of Aging participants and neuroimaging staff for their dedication to these studies and the staff of the Johns Hopkins University PET facility for their assistance. This work was supported in part by research and development contract N01-AG-3-2124 from the Intramural Research Program, National Institute on Aging, National Institutes of Health.

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Correspondence to M Thambisetty.

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Chuang, YF., Tanaka, T., Beason-Held, L. et al. FTO genotype and aging: pleiotropic longitudinal effects on adiposity, brain function, impulsivity and diet. Mol Psychiatry 20, 133–139 (2015). https://doi.org/10.1038/mp.2014.49

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