International Journal of Obesity (2004) 28, S29–S36. doi:10.1038/sj.ijo.0802808

Genes, lifestyles and obesity

A Marti1, M J Moreno-Aliaga1, J Hebebrand2 and J A Martínez1

  1. 1Department of Physiology and Nutrition, University of Navarra, Pamplona, Spain
  2. 2Child and Adolescent Psychiatry, University of Marburg, Marburg, Germany

Correspondence: Prof. JA Martínez, Department of Physiology and Nutrition, University of Navarra, C/Irunlarrea, Pamplona, Spain. E-mail:



OBJECTIVE: To review the role of genes and lifestyle factors, particularly dietary habits and physical activity patterns, in obesity risk as well as their potential interactions.

DESIGN AND MEASUREMENTS: A descriptive report of a number of genes definitely ascribed or potentially implicated in excessive fat accumulation leading to obesity as assessed by different research approaches (Mendelian transmission, genetic animal models, epidemiological association/linkage studies and genome-wide scans). Also, the involvement of macronutrient intake and composition (fat/carbohydrate) as well as the role of activity-linked energy expenditure in obesity onset is reviewed.

RESULTS: Examples of the role of the genotype as well as of the dietary macronutrient composition/intake and sedentary/low energy cost of physical activities in obesity prevalence are reported.

CONCLUSIONS: Both genes and everyday life environmental factors such as cultural and social mediated food intake and reduced domestic and living work activities are involved in the obesity pandemia. The occurrence of gene times gene and gene times environmental factors interactions makes it more difficult to interpret the specific roles of genetics and lifestyle in obesity risk.


genetics, lifestyle factors, nutritional habits, physical activity



Body weight stability and the associated regulatory processes depend upon nutrient intake, but are also influenced by compensatory genetic-dependent metabolic and neuroendocrine mechanisms.1, 2 Indeed, despite the daily fluctuations in both components of the energy balance equation (energy intake vs energy expenditure), body weight and adiposity remain in a dynamic steady state for long periods of time (often within plusminus1% variation over many years), which has been attributed to the participation of a powerful control system to fine–tune the dietary macronutrient supply to body fuel demands.3 The control of the maintenance of body composition has been the subject of a number of theories or pathways (Figure 1) such as the occurrence of a physiological set point for body weight, glucostatic or glycogen drives for feeding, metabolic/nutrient partitioning approaches, the participation of the nervous system, an adipostat mediated by signals from the adipose tissue, all of which might be under genetic control and explain individual variability.4 In this context, it has been hypothesised that the stability of body weight and composition depends upon an axis with three inter-related and self-controlled components: (1) food intake; (2) nutrient turnover and thermogenesis, and (3) body fat stores.5 All three elements underlie complex inter-related feedback mechanisms, which are affected by the individual's genetic background.3, 4

It should be emphasised that body weight is ultimately determined by the interaction of genetic, environmental, physiological and psychosocial factors6, 7, 8 Furthermore, the specific distribution of energy expenditure requirements and individual substrate partitioning3, 7 are known to influence the energy balance equation depending on the genetic make-up.

A positive energy balance between the amount of energy consumed over the energy spent in everyday life underlies weight gain.8, 9 Indeed, the excessive fat accumulation in adipose tissue leading to obesity is the result of a chronic overconsumption of foods and drinks over the energy expenditure requirements, in which dietary and lifestyle habits, sociological factors, metabolic and neuroendocrine alterations as well as hereditary components are involved.10 Obesity similar to other chronic diseases with a recognised monogenic or polygenic origin is associated with a number of pathological dysfunctions and disturbances with important implications for the individual's and community health (hyperinsulinaemia, diabetes, hypertension, immunological alterations, certain cancer types, etc), which is worsened by the growing rates of obesity prevalence (20 and 40% of the EU population are overweight or obese).11

The rapid increase in obesity incidence over recent years suggests that environmental and lifestyle influences in addition to other physiopathological or genetic determinants are independently affecting the energy balance equation adjustment.12, 13 Thus, it is estimated that 40–70% of the variation in BMI is heritable, while cultural and societal factors may explain at least 30% of the variation.14, 15

The rise in obesity rates in populations whose gene pool has been relatively constant confirms that environmental factors are assuming a rising role.16 Indeed, the processes of modernisation and economic restructuration in both low- and high-income countries have influenced nutritional and physical activity patterns that contribute to the increasing rates of obesity.17, 18, 19 Actually, the growing prevalence of obesity around the world is mainly attributed to changes in lifestyle (increase of the consumption of high-energy-yielding foods enriched with carbohydrates and fats, reduction of the physical activity, etc) that specifically may impact genetic susceptibility.20 Also, from an evolutionary point of view, the individuals with thrifty or 'saver' genes are more resistant to malnutrition, explaining why large proportions of diverse populations are susceptible to become obese.16 The mutual interactions between the genetic make-up and the environment undoubtedly complicate the understanding of the specific roles of genes and external influences in obesity.21


Genetics of obesity

Physiological functions and differentiation traits among living organisms are based on the genetic information contained in the deoxyribonucleic acid (DNA), which acts as a code.22 The chromosomes are comprised of proteins and DNA molecules, anchoring the functional units of genes (about 30 000 in humans). In February 2001, the first complete version of the human genome was released.23, 24 The DNA carries out a triple biological function, being the basis of inheritance, individualisation and change; that is, this nucleic acid transmits the specific characters of the species, allowing differentiation among individuals. These properties constitute the molecular framework for evolution through stable and transferable changes in DNA, which have allowed the human being to adapt through genetic selection to changing situations.25

The individual's genetic information (genotype) has the capacity to codify both cell development and functions throughout life. Intrinsic and extrinsic noticeable characters and features in each person (phenotype) are the result of the interaction of the genotype with environmental influences.26 Any inheritable change in the sequence of DNA constitutes a mutation that can occur in a single nucleotide (SNPs) through inversion, deletion, repetition, insertion or translocation within chromosomal segments.25 The term polymorphism refers to differences in a specific sequence of DNA among individuals occurring in more than 1% of the population. The process of inter-relating a gene with a phenotype is rendered difficult not only by the low density of functionally coded DNA (<5%) and the magnitude of the genetic material of the human genome, but also by multiple interactions among genes and lifestyle factors.27

The commonly observed coexistence of several obese members within a family suggests the involvement of genetic factors in obesity.26 The risk of excessive weight gain in children of some families with obese parents is increased two- to three-fold for moderate obesity and up to eight times for severe obesity.28 Moreover, twin and adoption studies substantiate a role for genetics in obesity. The discovery of populations such as Pima Indians with shared alterations in basal metabolism rates or in fat oxidation after food intake corroborates such hypothesis,29 as well as the fact that genetic factors can modulate the effects of physical activity and diet on weight and body composition.30, 31

Furthermore, several studies carried out in large numbers of families encompassing members of different degrees of relatedness have allowed to quantify the statistical association regarding objective indicators of obesity (BMI or %fat) depending on the degree of the relationship32, 33 The correlation coefficient (r2) for BMI is lower between husband and wife (0.10–0.19) and uncle and nephews (0.08–0.14), and increases between parents and children (0.15–0.23) and among siblings (0.24–0.34). The correlation for BMI is higher in monozygotic (0.70–0.88) and dizygotic twins (0.15–0.42). Also, studies of dietary intervention, based on positive and negative energy balances in identical twins, convincingly pointed out that the differences in the susceptibility to overfeeding or periods of semistarvation seem to be partially explained by genetic factors.26 Family studies have largely revealed that the heritability of the Quetelet index is about 25–50%, while twin studies have mostly estimated the contribution of genetic factors at 70–80%.34 However, this information is not enough to prove unequivocally the genetic origin of obesity, since the families share besides the genes, other factors implied in obesity such as lifestyle, dietary habits and environment.26

In this context, genetic association studies search for statistical relationships among a gene polymorphism with a given phenotype, generally among nonrelated individuals.35 This research strategy can consider the comparison between cases and controls, analysis of the variability for specific loci or the discrimination between mutation carriers and noncarriers regarding a given character. On the other hand, genetic linkage studies imply the persistence or cosegregation of a genetic marker or locus and a phenotypical character within a family.36 Furthermore, quantitative genetics allow to assess the influence of environmental factors on the hereditary variability,37 which can be based on diverse genes (polygenic interaction). The studies of gene expression constitute another approach to relate the specific participation, both quantitative and qualitative, of different genes in energy homeostasis processes.38

Obesity as a complex syndrome with a multifactorial origin may be explained in some circumstances by monogenic mutations, but in most cases appears as a polygenic condition, which may be additionally affected by a myriad of environmental influences.26, 39 A widely accepted hypothesis assumes that complex diseases such as obesity are likely to be based on a limited number of predisposing alleles, each conferring a small increase in the risk to the individual. Heterogeneity in complex phenotypes implies that the genetic predisposition may also result from any one of several rare variants in a number of genes.40 The role of a genetic predisposition in obesity has long been assumed to affect both sides (intake/expenditure) of the energy equation.41 In this context, evidence from human single-gene mutations (leptin: LEP; leptin receptor: LEPR; pro-opiomelanocortin: POMC; melanocortin 4 receptor: MCR4; protein convertase 1: PC1; etc) has solely implicated energy intake; however, Mendelian syndromes with obesity as a clinical feature (eg Prader–Willi syndrome) have also revealed reductions in energy expenditure as contributing to obesity. Relevant genes are currently being detected via animal models (transgenic animals, genetically obese rodents, classical breeding studies in connection with quantitative trait loci mapping), and association and linkage studies in humans (nuclear families, twins and adoption studies) including genome-wide scans.42

Genes may determine afferent and efferent signals as well as central mechanisms involved in body weight regulation.41 Thus, the transferable genetic information involved in short- and long-term stable body weight regulation and diet composition maintenance43, 44 is acting via (1) different peptides and monoamines involved in the regulation of the appetite, (2) variations in energy and nutrient utilisation resting metabolic rate or response to physical activity, and (3) individual differences in adipocyte metabolism. The possible mechanisms through which the genetic susceptibility (Figure 2) could be acting include reduced rates of basal metabolism and macronutrients oxidation, alterations of adipogenesis and quantitative and qualitative deviations of food intake.41, 45 Also, other factors such as the hormonal profile, energy exercise efficiency and thermogenesis could be specifically involved in the genetic processes affecting the energy balance equation.7, 32

Figure 2.
Figure 2 - Unfortunately we are unable to provide accessible alternative text for this. If you require assistance to access this image, please contact or the author

Some genes involved in body weight homeostasis categorised by processes.

Full figure and legend (18K)

The 2003 update of the human obesity gene map revealed that the numbers of genes or markers that have been directly and indirectly linked with human obesity are increasing rapidly and now are higher than 425.42 Some of these genes or chromosomal regions, such as the uncoupling proteins (UCPs), leptin (LEP), leptin receptor (LEPR), adrenergic receptors (ADRbeta2, ADRbeta3), peroxisome proliferator activated receptors (PPARs), fatty acid binding protein (FABP), etc, have been related to energy metabolism control37 and may be specifically affected by dietary intake and composition, and also by physical activity.30, 31 Other genes are specifically involved in control of food intake (NPY, POMC, CCK, MCH, etc), while some others influence different metabolic and signalling pathways, adipogenesis, etc (PPAR, FABP, PKA, c/EBP, etc), affecting the energy equation and consequently body weights of those individuals who are carriers of specific defective gene mutations/polymorphisms with an influence on fat deposition.26 Variations in ADRbeta2 and LEPR have been specifically shown to contribute to weight gain.46

Association studies have supplied important information for the characterisation of genes with a small contribution to the obesity phenotype; however, their interpretation requires caution, and values of at least P<0.01 are required to avoid noncausal relationships.26, 42 In that sense, diverse obesity phenotype indicators (subcutaneous skin folds, BMI, etc) have shown positive associations (P<0.01) with the variants of some genes such as apolipoprotein B (ApoB), apolipoprotein D (ApoD), adenosine deaminase (ADA), tumour necrosis factor alpha (TNF-alpha), dopamine D2 receptor (DRD2), low-density lipoprotein receptor (LDLR), melanocortin 4 receptor (MCR4), melanocortin 5 receptor (MCR5), pro-opiomelanocortin (POMC), leptin (LEP) and their receptor (LEPR), insulin (INS), glucocorticoid receptor (GLR), peroxisome proliferator activated receptors (PPAR), beta-adrenergic receptors 1, 2 and 3 (ADRA2B, ADRB2 and ADRB3), fatty acid binding protein (FABP2), angiotensinogen (AGT), among others.36, 37 For many of these genes, the findings are not unequivocal.

Currently, the best evidence for a causal role in the aetiology of obesity other than the rare autosomal recessive forms of obesity stems from findings pertaining to diverse mutations in the melanocortin 4 receptor gene, of which more than 40 have been detected so far. Family studies revealed that male and female mutation carriers are on average 5 and 10 kg/m2 heavier than their relatives with the wild-type genotype.47 The MC4R V103I polymorphism has recently been found to be negatively associated with obesity (odds ratio approx. 0.7); a meta-analysis encompassing over 7500 individuals revealed that among obese cases the carrier frequency is about 2%, whereas in nonobese controls the rate is 3.5%.48 These results indicate that large-scale association studies will most likely be required to pick up such small effects particularly if they are attributable to alleles with frequencies below 5%.

The strategy of genetic linkage can be applied to candidate genes or to polymorphisms segregating within a family. These linkage protocols can be used with panels of nuclear families or within larger pedigrees; detection of linkage in complex phenotypes requires the presence of a rather strong genetic effect (major gene effect) operative in a sizeable proportion of the families.26 An alternative to this procedure consists in the study of sibling pairs regarding a genetic marker and a certain phenotype. The existence of a genetic linkage between BMI and other phenotypic indices of obesity (subcutaneous skin fold, fat content, etc) has been demonstrated with high statistical evidence for some genes such as alkaline phosphatase 1 (ACP1), glucocorticoid receptor (GRL), tumour necrosis factor alpha (TNF-alpha), leptin (LEP), Kell blood group (KEL), melanocortin 4 and 5 receptor (MC4R and MC5R) and adenosine deaminase (ADA), although some discrepancies and contradictions exist for some of these.36, 37, 42

Genome-wide scans have been able to identify specific chromosomal regions such as those on chromosomes 2, 3, 5,6, 7, 10, 11, 17 and 20.49, 50 Monogenic forms of obesity are rare; from a public health viewpoint, only the functionally relevant MC4R mutations, which occur in 2–4% of extremely obese individuals, appear to be relevant.51 Furthermore, additive effects of mutations in the beta3-adrenergic receptor and uncoupling protein 1 (UCP1) genes on weight maintenance have been found,52 which reveal potential interactions between genes; such findings do however require confirmation. Also, gender and age have been reported as effect modifiers on obesity risk in subjects carrying beta2 and beta3 adrenoceptor polymorphisms, respectively.53, 54

The studies concerning interactions of the genotype with environmental factors constitute a new challenge to establish the role of diet and physical activity in the genetics of obesity as well as those investigations devoted to evaluate the impact of lifestyle on gene expression.55, 56 Indeed, genes predisposing to obesity potentially have an impact on the dietary intake as well as with physical activity performance.30, 31


Lifestyle factors affecting obesity

Environmental and lifestyle influences promoting excessive caloric intake and sedentary patterns are known to induce a positive energy balance leading to weight gain.19 Indeed, the current food industries have increased the availability of energy-dense meals, while sedentary patterns facilitated by motorised transport and other common physically inactive pursuits (TV viewing, computer work, etc) have markedly risen in the last decades.18, 20 On the other hand, cross-sectional data show a strong association between unhealthy dietary habits and physical inactivity, which have contributed to explain the observed obesity pandemia.10, 57 In this context, a high intake of nonstarch polysaccharides/fibre has been considered as a protective factor against obesity, while a high consumption of fast food and sweetened sugar drinks and fruit juices is viewed as a obesity risk factor.19 Furthermore, prospective studies provide additional evidence suggesting that an increase in physical activity and small changes in dietary behaviour may help to prevent a disproportionate weight gain.13

Dietary habits

The influence of dietary fat on obesity prevalence is controversial.58, 59, 60 Thus, arguments often presented against an important involvement of dietary fat in obesity onset are based on observational longitudinal and ecological studies, which suggest that shifts in fat/sugar consumption and the frequent use of low caloric food products in some countries have been associated with a paradoxical increase in the prevalence of obesity due to a reverse interaction.61 Furthermore, although low-fat diets may be helpful in decreasing body fatness or preventing weight gain, current scientific evidence seems to indicate that dietary fat reduction should be mainly seen as a means to reduce the dietary energy density.62 On the other hand, weight gainers have been found to consume relatively more savoury snacks.46, 63 Furthermore, populations consuming very low-fat diets usually do not show high rates of obesity prevalence, while a meta-analysis of intervention studies has revealed that in free-living subjects a plausible weight loss occurs in individuals with reduced fat consumption.59 Some investigations as to the role of complex carbohydrate/sugar ratio intake in the prevalence of obesity as assessed through epidemiological and laboratory studies revealed that groups consuming the highest proportion of energy as sugars were less likely to be obese than low sugar consumers, which has been explained by inversely reciprocal values for fat intake.64 However, two randomised trials inducing weight loss with low-carbohydrate diets (otherwise with a moderate to high fat content) as compared to low-fat diets revealed no major differences in the intermediate term weight reduction.65, 66 Interestingly, in these studies, a somewhat more beneficial lipid profile was found in those individuals who had consumed the high-fat diets. Furthermore, the role of simple and complex carbohydrates as well as the involvement of the glycaemic load in slimming dietary programmes is still unclear.67 Some of these contrasting results may be explained by confounding or modifying factors such as genetic predisposition, gender and physical activity differences.

Most individuals reach a state of body weight maintenance in which the average composition of the fuels they oxidise matches the energy nutrient distribution in their diets, which is genetically controlled.3 The view that burning as much fat as is consumed is an important factor in avoiding obesity is further supported by the fact that adjustment of fat oxidation to increased fat intake occurs more slowly in obese than in lean subjects.68 Therefore, the adjustment of the composition of the substrate mix oxidised to the macronutrient distribution in the diet may play a role in enabling short-term weight stability in susceptible individuals.

Other genetically mediated metabolic predictors of weight gain are low basal metabolic rate, low sympathetic nervous system activity, insulin sensitivity and low plasma leptin concentrations.69 The response to hypocaloric diets with different macronutrient composition also appears to depend on basal fat oxidation capacity (Black, personal communication).

Physical activity patterns

The energetic cost of physical activity has been identified as a major but variable component of energy expenditure that may influence body weight and composition.70 However, reliable information about trends in energy expenditure, which shows that the increased prevalence of obesity seems to parallel a reduction in physical activity patterns and a rise in sedentary behaviours in various populations, has only been available since the 1980s, with special impact on children and adolescents.20, 21, 71 Actually, studies and surveys using indirect indicators of physical activity such as TV viewing, number of cars by household or leisure-time physical activity are consistent with the view that a reduction in energy expenditure may be a major determinant of the current epidemic of obesity.57, 72 Furthermore, cross-sectional data have often found associations of leisure-time physical activity (inverse) and total amount of time spent sitting (direct) with BMI.18 Furthermore, a low participation in sport activities, a lack of interest in being involved in exercise (precontemplation) and increments in the time spent sitting down at work are statistically significant predictors of obesity.19, 57 In fact, participation in physical activity is among the best predictors for weight maintenance.70, 71

In this context, calculations concerning the introduction of labour-saving gadgets between the 1950s and the 1990s have meant that men and women participate in much less exercise today than they did a generation ago.4 An analysis of time-budget surveys revealed that the time required for earning a living and domestic work has declined appreciably over recent decades.17 In fact, fewer occupations would now be classified as physically active as compared to some decades ago. The previous data, however, do not allow the assessment of cause or effect relationships between the inverse association of BMI and physical activity, making it difficult to know whether obese individuals are less active because they are obese or whether a low level of activity caused their obesity (or both). In any case, it has been demonstrated that weight gainers are less active during leisure time as compared with nonweight gainers.46 Also, a survey involving 3549 men and 3184 women between 18 and 98 y has convincingly demonstrated that both inactivity and age affect body fat and fat-free mass.73 The magnitude of the energy impact of domestic mechanisation and labour-saving devices was estimated at 111 kcal/day.74

The prevention of excessive fat deposition and adiposity has been associated with regular physical activity and favourable rural vs urban environments and transport systems.19 Despite the fact that most available evidence suggests that a lower energy expenditure as a result of physical inactivity is an important contributor to the increasing prevalence of obesity, a genetically dependent blunted thermogenic response to exercise and a highly efficient resting energy expenditure may also have an impact on weight gain.75 However, some current evidence does not support a major role of defects in resting energy metabolism rate, energy-induced thermogenesis and the energy cost of physical activity as significant causes of obesity. The interactions between heredity and sedentarism have been assessed in twin pairs, and such studies concluded that the genetic predisposition may modify the effect of physical activity on weight change and a sedentary lifestyle may have an obesity-promoting effect depending on a genetic predisposition.15, 31


Interactions between genetics and lifestyle

The interactions between the genotype and the environment (G times E) are relevant when the phenotypic response (for example, excessive fat mass) to environmental changes depends on the individual's genotype.26 The classic pattern to evaluate genotype–environment (G times E) interactions implies the classification of individuals in groups by means of scanning molecular markers (genetic susceptibility) and the presence or absence of the risk factor by means of appropriate questionnaires (lifestyle).

Although it is well known that interindividual differences in the reaction to diverse dietary interventions or to physical exercise exist, relatively few attempts have been carried out to determine whether such differences are dependent on the genotype. Indeed, some polymorphisms and allele variants of diverse genes (PPAR, ADRbeta2, LEP, TNF-alpha, etc) are presumed to be involved in obesity via interactions with the dietary intake of fatty acids, carbohydrates, etc,76, 77, 78 as well as with the physical activity carried out.78, 79 Thus, an example of an interaction between genes and lifestyle can be seen in the observation that individuals carrying the Trp64Arg polymorphism in the beta3 adrenoceptor gene have a notably increased risk of becoming obese when they remain sedentary.80 Moreover, other interactions have also been described between genetics and nutrition with regard to prevalence of obesity, as is the case for the Pro12Ala mutation of the PPARitalic gamma gene, or the Glu27Glu polymorphism for the beta2 adrenoceptor gene, where a relatively high consumption of carbohydrates (more than 49% of the caloric value of the diet) increases BMI in individuals carrying such polymorphisms, respectively.81, 82



The involvement of genes and lifestyle on body weight maintenance is well established, but the relative participation of genetic and environmental factors to the growing obesity epidemic is a matter of debate (Figure 3).

Figure 3.
Figure 3 - Unfortunately we are unable to provide accessible alternative text for this. If you require assistance to access this image, please contact or the author

Gene–environment interaction on obesity risk.

Full figure and legend (45K)

Initial observations revealed that the risk of becoming obese is higher in some families than in others and that the survival of both animals and humans in times of food deprivation may in evolutionary terms underlie the widespread distribution of genotypes favouring weight gain. On the other hand, the most likely environmental factor contributing to the current obesity epidemic is a continuing decline in daily energy expenditure that is not matched by an equivalent reduction in energy intake, thus implying a risk factor for not only obesity but also different chronic diseases.

Actually, the impact of energy intake/nutrient composition and a sedentary lifestyle on the development of obesity is affected by the occurrence of mutations/polymorphisms, which make some individuals more prone to weight gain than others. Also, the ability to lose weight as induced by hypocaloric diets appears to be influenced by the genotype. Future studies should not only address research on new candidate genes and polymorphisms, but also attempt to quantify their expression in different circumstances as well as to analyse polygenic and gene times nutrient interactions.



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