Skip to main content
SpringerLink
Log in

Genetics of Energy and Macronutrient Intake in Humans

  • Genetics (GVZ Dedoussis, Section Editor)
  • Published:
Current Nutrition Reports Aims and scope Submit manuscript

Abstract

Food intake is an important determinant of health in humans. Family studies have shown that energy and macronutrient intake is a heritable trait. Several genome-wide scans and candidate gene association studies have been conducted to identify the important genes in human feeding behavior. Many studies focus on obesity genes that are involved in energy homeostasis and expressed in the arcuate nucleus of hypothalamus, such as fat mass and obesity-associated (FTO) and melanocortin-4 receptor (MC4R). Most recently, common variants near the fibroblast growth factor 21 (FGF21) gene were identified in genome-wide association studies of macronutrient intake. In this review, the results from genetic studies of energy and macronutrient intake will be discussed.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Similar content being viewed by others

References

Papers of particular interest, published recently, have been highlighted as: • Of importance •• Of major importance

  1. Cordain L, Eaton SB, Sebastian A, Mann N, Lindeberg S, Watkins BA, et al. Origins and evolution of the Western diet: health implications for the 21st century. Am J Clin Nutr. 2005;81(2):341–54.

    CAS  PubMed  Google Scholar 

  2. Nestle M, Wing R, Birch L, DiSogra L, Drewnowski A, Middleton S, et al. Behavioral and social influences on food choice. Nutr Rev. 1998;56(5 Pt 2):S50–64. discussion S-74.

    CAS  PubMed  Google Scholar 

  3. Rankinen T, Bouchard C. Genetics of food intake and eating behavior phenotypes in humans. Annu Rev Nutr. 2006;26:413–34.

    Article  CAS  PubMed  Google Scholar 

  4. Tucker KL. Assessment of usual dietary intake in population studies of gene-diet interaction. Nutr Metab Cardiovasc Dis: NMCD. 2007;17(2):74–81.

    Article  CAS  PubMed  Google Scholar 

  5. Cai G, Cole SA, Bastarrachea RA, Maccluer JW, Blangero J, Comuzzie AG. Quantitative trait locus determining dietary macronutrient intakes is located on human chromosome 2p22. Am J Clin Nutr. 2004;80(5):1410–4.

    CAS  PubMed  Google Scholar 

  6. Cai G, Cole SA, Butte N, Bacino C, Diego V, Tan K, et al. A quantitative trait locus on chromosome 18q for physical activity and dietary intake in Hispanic children. Obesity Silver Spring, Md. 2006;14(9):1596–604.

    Article  CAS  PubMed  Google Scholar 

  7. de Castro JM. Genetic influences on daily intake and meal patterns of humans. Physiol Behav. 1993;53(4):777–82.

    Article  PubMed  Google Scholar 

  8. de Castro JM. Independence of genetic influences on body size, daily intake, and meal patterns of humans. Physiol Behav. 1993;54(4):633–9.

    Article  PubMed  Google Scholar 

  9. Wade J, Milner J, Krondl M. Evidence for a physiological regulation of food selection and nutrient intake in twins. Am J Clin Nutr. 1981;34(2):143–7.

    CAS  PubMed  Google Scholar 

  10. Collaku A, Rankinen T, Rice T, Leon AS, Rao DC, Skinner JS, et al. A genome-wide linkage scan for dietary energy and nutrient intakes: the Health, Risk Factors, Exercise Training, and Genetics (HERITAGE) Family Study. Am J Clin Nutr. 2004;79(5):881–6.

    CAS  PubMed  Google Scholar 

  11. Choquette AC, Lemieux S, Tremblay A, Chagnon YC, Bouchard C, Vohl MC, et al. Evidence of a quantitative trait locus for energy and macronutrient intakes on chromosome 3q27.3: the Quebec Family Study. Am J Clin Nutr. 2008;88(4):1142–8.

    CAS  PubMed  Google Scholar 

  12. Klupa T, Malecki MT, Pezzolesi M, Ji L, Curtis S, Langefeld CD, et al. Further evidence for a susceptibility locus for type 2 diabetes on chromosome 20q13.1-q13.2. Diabetes. 2000;49(12):2212–6.

    Article  CAS  PubMed  Google Scholar 

  13. Lee JH, Reed DR, Li WD, Xu W, Joo EJ, Kilker RL, et al. Genome scan for human obesity and linkage to markers in 20q13. Am J Hum Genet. 1999;64(1):196–209.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  14. Tao YX. Molecular mechanisms of the neural melanocortin receptor dysfunction in severe early onset obesity. Mol Cell Endocrinol. 2005;239(1–2):1–14.

    Article  CAS  PubMed  Google Scholar 

  15. Farooqi IS, Keogh JM, Yeo GS, Lank EJ, Cheetham T, O'Rahilly S. Clinical spectrum of obesity and mutations in the melanocortin 4 receptor gene. N Engl J Med. 2003;348(12):1085–95.

    Article  CAS  PubMed  Google Scholar 

  16. Merali Z, McIntosh J, Anisman H. Role of bombesin-related peptides in the control of food intake. Neuropeptides. 1999;33(5):376–86.

    Article  CAS  PubMed  Google Scholar 

  17. Kubota N, Yano W, Kubota T, Yamauchi T, Itoh S, Kumagai H, et al. Adiponectin stimulates AMP-activated protein kinase in the hypothalamus and increases food intake. Cell Metab. 2007;6(1):55–68.

    Article  CAS  PubMed  Google Scholar 

  18. Dastani Z, Hivert MF, Timpson N, Perry JR, Yuan X, Scott RA, et al. Novel loci for adiponectin levels and their influence on type 2 diabetes and metabolic traits: a multi-ethnic meta-analysis of 45,891 individuals. PLoS Genet. 2012;8(3):e1002607.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  19. Drewnowski A. Taste preferences and food intake. Annu Rev Nutr. 1997;17:237–53.

    Article  CAS  PubMed  Google Scholar 

  20. Keskitalo K, Knaapila A, Kallela M, Palotie A, Wessman M, Sammalisto S, et al. Sweet taste preferences are partly genetically determined: identification of a trait locus on chromosome 16. Am J Clin Nutr. 2007;86(1):55–63.

    CAS  PubMed  Google Scholar 

  21. Chu AY, Workalemahu T, Paynter NP, Rose LM, Giulianini F, Tanaka T, et al. Novel locus including FGF21 is associated with dietary macronutrient intake. Hum Mol Genet. 2013;22(9):1895–902. One of the first genome-wide association studies of macronutrient intake.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  22. Tanaka T, Ngwa JS, van Rooij FJ, Zillikens MC, Wojczynski MK, Frazier-Wood AC, et al. Genome-wide meta-analysis of observational studies shows common genetic variants associated with macronutrient intake. Am J Clin Nutr. 2013;97(6):1395–402. One of the first genome-wide association study of macronutrient intake.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  23. Kliewer SA, Mangelsdorf DJ. Fibroblast growth factor 21: from pharmacology to physiology. Am J Clin Nutr. 2010;91(1):254S–7.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  24. Domouzoglou EM, Maratos-Flier E. Fibroblast growth factor 21 is a metabolic regulator that plays a role in the adaptation to ketosis. Am J Clin Nutr. 2011;93(4):901S–5.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  25. Badman MK, Pissios P, Kennedy AR, Koukos G, Flier JS, Maratos-Flier E. Hepatic fibroblast growth factor 21 is regulated by PPARalpha and is a key mediator of hepatic lipid metabolism in ketotic states. Cell Metab. 2007;5(6):426–37.

    Article  CAS  PubMed  Google Scholar 

  26. Inagaki T, Dutchak P, Zhao G, Ding X, Gautron L, Parameswara V, et al. Endocrine regulation of the fasting response by PPARalpha-mediated induction of fibroblast growth factor 21. Cell Metab. 2007;5(6):415–25.

    Article  CAS  PubMed  Google Scholar 

  27. Coskun T, Bina HA, Schneider MA, Dunbar JD, Hu CC, Chen Y, et al. Fibroblast growth factor 21 corrects obesity in mice. Endocrinology. 2008;149(12):6018–27.

    Article  CAS  PubMed  Google Scholar 

  28. Sarruf DA, Thaler JP, Morton GJ, German J, Fischer JD, Ogimoto K, et al. Fibroblast growth factor 21 action in the brain increases energy expenditure and insulin sensitivity in obese rats. Diabetes. 2010;59(7):1817–24.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  29. Zhang X, Yeung DC, Karpisek M, Stejskal D, Zhou ZG, Liu F, et al. Serum FGF21 levels are increased in obesity and are independently associated with the metabolic syndrome in humans. Diabetes. 2008;57(5):1246–53.

    Article  CAS  PubMed  Google Scholar 

  30. Galman C, Lundasen T, Kharitonenkov A, Bina HA, Eriksson M, Hafstrom I, et al. The circulating metabolic regulator FGF21 is induced by prolonged fasting and PPARalpha activation in man. Cell Metab. 2008;8(2):169–74.

    Article  PubMed  Google Scholar 

  31. Tan BK, Hallschmid M, Adya R, Kern W, Lehnert H, Randeva HS. Fibroblast growth factor 21 (FGF21) in human cerebrospinal fluid: relationship with plasma FGF21 and body adiposity. Diabetes. 2011;60(11):2758–62.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  32. 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(5826):889–94.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  33. 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(24):2558–66.

    Article  CAS  PubMed  Google Scholar 

  34. Bauer F, Elbers CC, Adan RA, Loos RJ, Onland-Moret NC, Grobbee DE, et al. Obesity genes identified in genome-wide association studies are associated with adiposity measures and potentially with nutrient-specific food preference. Am J Clin Nutr. 2009;90(4):951–9.

    Article  CAS  PubMed  Google Scholar 

  35. Hakanen M, Raitakari OT, Lehtimaki T, Peltonen N, Pahkala K, Sillanmaki L, et al. FTO genotype is associated with body mass index after the age of seven years but not with energy intake or leisure-time physical activity. J Clin Endocrinol Metab. 2009;94(4):1281–7.

    Article  CAS  PubMed  Google Scholar 

  36. Hasselbalch AL, Angquist L, Christiansen L, Heitmann BL, Kyvik KO, Sorensen TI. A variant in the fat mass and obesity-associated gene (FTO) and variants near the melanocortin-4 receptor gene (MC4R) do not influence dietary intake. J Nutr. 2010;140(4):831–4.

    Article  CAS  PubMed  Google Scholar 

  37. 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;117(4):194–7.

    Article  CAS  PubMed  Google Scholar 

  38. Lear SA, Deng WQ, Pare G, Sulistyoningrum DC, Loos RJ, Devlin A. Associations of the FTO rs9939609 variant with discrete body fat depots and dietary intake in a multi-ethnic cohort. Genet Res. 2011;93(6):419–26.

    Article  Google Scholar 

  39. Lee HJ, Kim IK, Kang JH, Ahn Y, Han BG, Lee JY, et al. Effects of common FTO gene variants associated with BMI on dietary intake and physical activity in Koreans. Clin Chim Acta. 2010;411(21–22):1716–22.

    Article  CAS  PubMed  Google Scholar 

  40. Liu G, Zhu H, Lagou V, Gutin B, Stallmann-Jorgensen IS, Treiber FA, et al. FTO variant rs9939609 is associated with body mass index and waist circumference, but not with energy intake or physical activity in European- and African-American youth. BMC Medl Genet. 2010;11:57.

    Article  Google Scholar 

  41. Speakman JR, Rance KA, Johnstone AM. Polymorphisms of the FTO gene are associated with variation in energy intake, but not energy expenditure. Obes Silver Spring, Md. 2008;16(8):1961–5.

    Article  CAS  Google Scholar 

  42. 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;90(6):1483–8.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  43. 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;88(4):971–8.

    CAS  PubMed  Google Scholar 

  44. Wardle J, Llewellyn C, Sanderson S, Plomin R. The FTO gene and measured food intake in children. Int J Obes (2005). 2009;33(1):42–5.

    Article  CAS  Google Scholar 

  45. Dougkas A, Yaqoob P, Givens DI, Reynolds CK, Minihane AM. The impact of obesity-related SNP on appetite and energy intake. Br J Nutr. 2013;110(6):1151–6.

    Article  CAS  PubMed  Google Scholar 

  46. Hubacek JA, Pikhart H, Peasey A, Kubinova R, Bobak M. FTO variant, energy intake, physical activity and basal metabolic rate in Caucasians. HAPIEE study Physiol Res. 2011;60(1):175–83.

    CAS  Google Scholar 

  47. Lappalainen T, Lindstrom J, Paananen J, Eriksson JG, Karhunen L, Tuomilehto J, et al. Association of the fat mass and obesity-associated (FTO) gene variant (rs9939609) with dietary intake in the Finnish Diabetes Prevention Study. Br J Nutr. 2012;108(10):1859–65.

    Article  CAS  PubMed  Google Scholar 

  48. McCaffery JM, Papandonatos GD, Peter I, Huggins GS, Raynor HA, Delahanty LM, et al. Obesity susceptibility loci and dietary intake in the Look AHEAD Trial. Am J Clin Nutr. 2012;95(6):1477–86. Candidate gene association study of obesity genes and dietary intake in multiethnic population.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  49. Park SL, Cheng I, Pendergrass SA, Kucharska-Newton AM, Lim U, Ambite JL, et al. Association of the FTO obesity risk variant rs8050136 with percentage of energy intake from fat in multiple racial/ethnic populations: the PAGE study. Am J Epidemiol. 2013;178(5):780–90. The largest candidate gene association study investigating obesity genes (including FTO) with dietary intake.

    Article  PubMed  Google Scholar 

  50. Steemburgo T, Azevedo MJ, Gross JL, Milagro FI, Campion J, Martinez JA. The rs9939609 polymorphism in the FTO gene is associated with fat and fiber intakes in patients with type 2 diabetes. J Nutrigenetics Nutrigenomics. 2013;6(2):97–106.

    Article  CAS  Google Scholar 

  51. 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(6):724–6.

    Article  CAS  PubMed  Google Scholar 

  52. 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(7):e115.

    Article  PubMed Central  PubMed  Google Scholar 

  53. Gong J, Schumacher F, Lim U, Hindorff LA, Haessler J, Buyske S, et al. Fine Mapping and Identification of BMI Loci in African Americans. Am J Hum Genet. 2013;93(4):661–71.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  54. Xi B, Cheng H, Shen Y, Chandak GR, Zhao X, Hou D, et al. Study of 11 BMI-associated loci identified in GWAS for associations with central obesity in the Chinese children. PLoS One. 2013;8(2):e56472.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  55. 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;318(5855):1469–72.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  56. Fischer J, Koch L, Emmerling C, Vierkotten J, Peters T, Bruning JC, et al. Inactivation of the Fto gene protects from obesity. Nature. 2009;458(7240):894–8.

    Article  CAS  PubMed  Google Scholar 

  57. den Hoed M, Westerterp-Plantenga MS, Bouwman FG, Mariman EC, Westerterp KR. Postprandial responses in hunger and satiety are associated with the rs9939609 single nucleotide polymorphism in FTO. Am J Clin Nutr. 2009;90(5):1426–32.

    Article  Google Scholar 

  58. Wardle J, Carnell S, Haworth CM, Farooqi IS, O'Rahilly S, Plomin R. Obesity associated genetic variation in FTO is associated with diminished satiety. J Clin Endocrinol Metab. 2008;93(9):3640–3.

    Article  CAS  PubMed  Google Scholar 

  59. Bell CG, Walley AJ, Froguel P. The genetics of human obesity. Nat Rev Genet. 2005;6(3):221–34.

    Article  CAS  PubMed  Google Scholar 

  60. Qi L, Kraft P, Hunter DJ, Hu FB. The common obesity variant near MC4R gene is associated with higher intakes of total energy and dietary fat, weight change and diabetes risk in women. Hum Mol Genet. 2008;17(22):3502–8.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  61. Loos RJ, Lindgren CM, Li S, Wheeler E, Zhao JH, Prokopenko I, et al. Common variants near MC4R are associated with fat mass, weight and risk of obesity. Nat Genet. 2008;40(6):768–75.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  62. Loos RJ, Rankinen T, Rice T, Rao DC, Leon AS, Skinner JS, et al. Two ethnic-specific polymorphisms in the human Agouti-related protein gene are associated with macronutrient intake. Am J Clin Nutr. 2005;82(5):1097–101.

    CAS  PubMed  Google Scholar 

  63. Argyropoulos G, Rankinen T, Bai F, Rice T, Province MA, Leon AS, et al. The agouti-related protein and body fatness in humans. Int J Obes Relat Metab Disord. 2003;27(2):276–80.

    Article  CAS  PubMed  Google Scholar 

  64. Mayfield DK, Brown AM, Page GP, Garvey WT, Shriver MD, Argyropoulos G. A role for the Agouti-Related Protein promoter in obesity and type 2 diabetes. Biochem Biophys Res Commun. 2001;287(2):568–73.

    Article  CAS  PubMed  Google Scholar 

  65. Argyropoulos G, Rankinen T, Neufeld DR, Rice T, Province MA, Leon AS, et al. A polymorphism in the human agouti-related protein is associated with late-onset obesity. J Clin Endocrinol Metab. 2002;87(9):4198–202.

    Article  CAS  PubMed  Google Scholar 

  66. Aubert R, Betoulle D, Herbeth B, Siest G, Fumeron F. 5-HT2A receptor gene polymorphism is associated with food and alcohol intake in obese people. Int J Obes Relat Metab Disord. 2000;24(7):920–4.

    Article  CAS  PubMed  Google Scholar 

  67. Herbeth B, Aubry E, Fumeron F, Aubert R, Cailotto F, Siest G, et al. Polymorphism of the 5-HT2A receptor gene and food intakes in children and adolescents: the Stanislas Family Study. Am J Clin Nutr. 2005;82(2):467–70.

    CAS  PubMed  Google Scholar 

  68. Fumeron F, Betoulle D, Aubert R, Herbeth B, Siest G, Rigaud D. Association of a functional 5-HT transporter gene polymorphism with anorexia nervosa and food intake. Mol Psychiatry. 2001;6(1):9–10.

    Article  CAS  PubMed  Google Scholar 

  69. Stice E, Spoor S, Ng J, Zald DH. Relation of obesity to consummatory and anticipatory food reward. Physiol Behav. 2009;97(5):551–60.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  70. Eny KM, Corey PN, El-Sohemy A. Dopamine D2 receptor genotype (C957T) and habitual consumption of sugars in a free-living population of men and women. J Nutrigenetics Nutrigenomics. 2009;2(4–5):235–42.

    Article  CAS  Google Scholar 

  71. Epstein LH, Wright SM, Paluch RA, Leddy JJ, Hawk Jr LW, Jaroni JL, et al. Relation between food reinforcement and dopamine genotypes and its effect on food intake in smokers. Am J Clin Nutr. 2004;80(1):82–8.

    CAS  PubMed  Google Scholar 

  72. Epstein MP, Duren WL, Boehnke M. Improved inference of relationship for pairs of individuals. Am J Hum Genet. 2000;67(5):1219–31.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

Download references

Compliance with Ethics Guidelines

Conflict of Interest

Toshiko Tanaka declares that he has no conflict of interest.

Human and Animal Rights and Informed Consent

This article does not contain any studies with human or animal subjects performed by any of the authors.

Author information

Authors and Affiliations

  1. Translational Gerontology Branch, NIA at Harbor Hospital, 3001 S. Hanover Street, Baltimore, MD, 21225, USA

    Toshiko Tanaka

Authors
  1. Toshiko Tanaka
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Toshiko Tanaka.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Tanaka, T. Genetics of Energy and Macronutrient Intake in Humans. Curr Nutr Rep 3, 170–177 (2014). https://doi.org/10.1007/s13668-014-0083-5

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s13668-014-0083-5

Keywords

Search

Navigation