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Interaction between genes and lifestyle factors on obesity: Nutrition Society Silver Medal Lecture

  • Amelia Marti (a1), Miguel Angel Martinez-González (a1) and J. Alfredo Martinez (a1)
  • DOI:
  • Published online: 01 January 2008

Obesity originates from a failure of the body-weight control systems, which may be affected by changing environmental influences. Basically, the obesity risk depends on two important mutually-interacting factors: (1) genetic variants (single-nucleotide polymorphisms, haplotypes); (2) exposure to environmental risks (diet, physical activity etc.). Common single-nucleotide polymorphisms at candidate genes for obesity may act as effect modifiers for environmental factors. More than 127 candidate genes for obesity have been reported and there is evidence to support the role of twenty-two genes in at least five different populations. Gene–environment interactions imply that the synergy between genotype and environment deviates from either the additive or multiplicative effect (the underlying model needs to be specified to appraise the nature of the interaction). Unravelling the details of these interactions is a complex task. Emphasis should be placed on the accuracy of the assessment methods for both genotype and lifestyle factors. Appropriate study design (sample size) is crucial in avoiding false positives and ensuring that studies have enough power to detect significant interactions, the ideal design being a nested case–control study within a cohort. A growing number of studies are examining the influence of gene–environmental interactions on obesity in either epidemiological observational or intervention studies. Positive evidence has been obtained for genes involved in adiposity, lipid metabolism or energy regulation such as PPARγ2 (Pro12Ala), β-adrenoceptor 2 (Gln27Glu) or uncoupling proteins 1, 2 and 3. Variants on other genes relating to appetite regulation such as melanocortin and leptin receptors have also been investigated. Examples of some recently-identified interactions are discussed.

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*Corresponding author: Dr Amelia Marti, fax +34 948 425649, email
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12. AA Butler (2006) The melanocortin system and energy balance. Peptides 27, 281290.

13. A Marti , MC Corbalán , L Forga , JA Martínez , A Hinney & J Hebebrand (2003) A novel nonsense mutation in the the melanocortin-4 receptor associated with obesity in a Spanish population. Int J Obes Relat Metab Disord 27, 385388.

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19. MC Ochoa , A Marti & JA Martinez (2004) Obesity studies in candidate genes. Med Clin (Barc) 122, 542551.

20. T Macho-Azcárate , J Calabuig , A Marti & JA Martínez (2002) A maximal effort trial in Gln27Glu polymorphism genotyped obese women. J Physiol Biochem 58, 103108.

22. T Macho-Azcárate , A Marti , J Calabuig & JA Martínez (2003) Basal fat oxidation and after a peak oxygen consumption test in obese women with a beta 2-adrenoceptor gene polymorphism. J Nutr Biochem 14, 275279.

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24. MS Corbalán , A Marti , L Forga , MA Martínez-González & JA Martínez (2002) Beta2-adrenoceptor polymorphism and abdominal obesity risk: effect modification by gender and HDL-cholesterol levels. Eur J Nutr 41, 114118.

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26. MS Corbalán , A Marti , L Forga , MA Martínez-González & JA Martínez (2002) The obesity risk and the Trp64Arg polymorphism of the beta3-adrenoceptor gene: effect modification by age. Ann Nutr Metab 46, 152158.

27. MC Ochoa , A Marti , C Azcona , M Chueca , M Oyarzábal , R Pelach , A Patiño , MJ Moreno-Aliaga , MA Martínez-González & JA Martínez (2004) Gene-gene interaction between PPARgamma2 and ADRbeta3 increases obesity risk in children and adolescents. Int J Obes Relat Metab Disord 28, S37S41.

28. J Mozo , Y Emre , F Bouillaud , D Ricquier & F Criscuolo (2005) Thermoregulation: what role for UCPs in mammals and birds? Biosci Rep 25, 227249.

30. A Marti , E Larrarte , FJ Novo , M García , CH Warden & JA Martínez (2001) UCP2 muscle gene transfer modifies mitochondrial membrane potential. Int J Obes Relat Metab Disord 25, 6875.

31. E Larrarte , FJ Novo , A Marti & JA Martínez (2002) UCP1 Muscle gene transfer and mitochondrial proton leak mediated thermogenesis. Arch Biophys Biochem 404, 166171.

32. A Marti , J Vaquerizo , MA Zulet , MJ Moreno-Aliaga & JA Martínez (2002) Down-regulation of heart H-FABP and UCP2 gene expressions in diet-induced (cafeteria) obese rats. J Physiol Biochem 58, 6974.

33. A Marti , MS Corbalán , L Forga , MA Martínez-González & JA Martínez (2004) Higher obesity risk associated with the exon 8 insertion allele of the UCP2 gene in a Spanish case-control study. Nutrition 20, 498501.

34. LT Dalgaard & O Pedersen (2001) Uncoupling proteins: functional characteristics and role in the pathogenesis of obesity and Type II diabetes. Diabetologia 44, 946965.

35. MC Ochoa , JL Santos , C Azcona , MJ Moreno-Aliaga , MA Martínez-González , JA Martínez , A Marti & GENOI (2007) Association between obesity and insulin resistance with UCP2-UCP3 gene variants in Spanish children and adolescents. Mol Gen Metab 92, 351358.

36. A Alonso , A Martí , MS Corbalán , MA Martínez-González & JA Martínez (2005) Association of UCP3 gene –55C>T polymorphism and obesity in a Spanish population: a case-control study. Ann Nutr Metab 49, 183188.

37. J Margareto , A Marti & JA Martínez (2001) Changes in UCP mRNA expression levels in brown adipose tissue and skeletal muscle after feeding a high-energy diet and relationships with leptin, glucose and PPARG2. J Nutr Biochem 12, 130137.

38. I López , A Marti , F Milagro , MA Zulet , MJ Moreno-Aliaga & JA Martínez (2003) DNA microarray analysis of gene differentially expressed in diet-induced obese rats. Obes Res 11, 188194.

39. A Marti , MS Corbalán , MA Martínez-González , L Forga & JA Martínez (2002) CHO intake alters obesity risk associated with Pro12Ala polymorphism of PPARG gene. J Physiol Biochem 58, 219220.

40. M Stumvoll & H Häring (2002) The peroxisome proliferator-activated receptor-gamma2 Pro12Ala polymorphism. Diabetes 51, 23412347.

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42. MC Ochoa , MJ Moreno-Aliaga , MA Martinez-Gonzalez , Martinez & Marti A for GENOI (2007) Predictor factors for childhood obesity in a Spanish case-control study. Nutrition 23, 379384.

43. A Marti , MJ Moreno-Aliaga , J Hebebrand & JA Martínez (2004) Genes, lifestyles and obesity. Int J Obes Relat Metab Disord 28, S29S36.

46. A Memisoglu , FB Hu , SE Hankinson , JE Manson , I De Vivo , WC Willett & DJ Hunter (2003) Interaction between a peroxisome proliferator-activated receptor gamma gene polymorphism and dietary fat intake in relation to body mass. Hum Mol Genet 12, 29232929.

47. A Nieters , N Becker & J Linseisen (2002) Polymorphisms in candidate obesity genes and their interaction with dietary intake of n-6 polyunsaturated fatty acids affect obesity risk in a sub-sample of the EPIC-Heidelberg cohort. Eur J Nutr 41, 210221.

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49. A Marti , MC Corbalán , MA Martínez-González & JA Martínez (2002) Trp64Arg polymorphism of the beta3-adrenergic receptor gene and obesity risk: effect modification by a sedentary lifestyle. Diabetes Obes Metab 4, 428430.

51. MC Ochoa , MJ Moreno-Aliaga , MA Martínez-González , JA Martínez , GENOI & A Marti (2006) TV watching modifies obesity risk linked to the Gln27Glu polymorphism of ADRB2 gene in girls. Int J Ped Obes 1, 8388.

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