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Bašić M, et al.

OBESITY: GENOME AND ENVIRONMENT INTERACTIONS
Arh Hig Rada Toksikol 2012;63:395-405 395

DOI:10.2478/10004-1254-63-2012-2244
Review

OBESITY: GENOME AND ENVIRONMENT
INTERACTIONS

Martina BAŠIĆ, Ana BUTORAC, Irena LANDEKA JURČEVIĆ, and Višnja BAČUN-DRUŽINA

Faculty of Food Technology and Biotechnology, University of Zagreb, Zagreb, Croatia

Received in March 2012
CrossChecked in July 2012
Accepted in July 2012

Obesity has become one of the major threats for public health in industrialised world among adults, but
also among adolescents and children. It is influenced by the interaction of genes, nutrition, environment,
and lifestyle. Environmental and lifestyle risk factors include foetal and lifelong environment, nutrient
quality, chemical and microbial exposure, and psychical stress, all of which are important contributing
influences. Removing or limiting chemical and pharmaceutical obesogens from human environment could
make a difference in the growing epidemic of obesity.
Additionally, nutrigenomics describes how modifications in individual diets can improve health and
prevent chronic diseases, as well as obesity, by understanding the effects of a genetic profile in the interaction
between food and increase in body weight. Furthermore, individual genetic variations in genome represent
an individual′s predisposition for obesity. Therefore, the use of individual genetic information, avoiding
obesogens, and a healthy lifestyle could help to improve the management of obesity and maintain a healthy
weight.

KEY WORDS: genes, nutrigenomics, nutrition, obesogens

The growing prevalence of obesity and the fact predisposition, metabolic, hormonal, environmental,
that its management is mostly ineffective are opening behavioural, social, and cultural aspects (12). This is
novel fields of research - investigation of genes, why it is important to better understand obesity and
environment, and their interactions with the intention its aetiology and find more effective prevention and
to create a concept of personalised medicine and treatment tools.
nutrition (1).
Obesity and its implications for human health Genetic aspect of obesity
decrease the quality of life and life expectancy Individual human differences and genetic variations
considerably, as they increase the risk of a great influence the risk of becoming obese (11). At present,
number of chronic diseases (2-10; table 1). Excess over 100 genes are under discussion for their effect
weight and obesity are the consequences of a higher on obese phenotypes. The latest update of the Human
energy intake and lower energy expenditure, which Obesity Gene Map, which was created in 2005,
results in a positive energy balance (11). Several focuses on 253 groups of genes related to obesity (13).
biological changes in our body are related with the This catalogue of obesity genes shows that putative
state of overweight and obesity (Figure 1). loci affecting obesity-related phenotypes are situated
Obesity is a disease which affects not only the on all chromosomes except Y. Table 2 displays five
individual, but also the public health. It is influenced categories of the most investigated obesity-related
by many factors such as genetic and epigenetic genes in recent years (13-16, Figure 1).

Besides the changes in the loss of body weight. complex set of histone modifications.396 Bašić M. melanocortin receptor 3 (MC3R). epigenetic status (33). fat mass. and interleukin 6 adrenergic receptors. 36). dietary intakes. (28) showed that Ala12 . leptin (LEP). and gut microbiome in certain investigated the effect of a polymorphism in the organisms (38-41). leptin appear to disrupt pathways involved in the regulation receptor (LEPR). and a set In studies involving adult monozygotic twins (19. (2001) reported that a G>A reviews see 30-32). Figure 1). Obviously. lifestyle. it was shown that the character involves complex gene-gene and gene- predisposition to increase or decrease body fat was environment interactions and their mutual interactions genetically based (1). and and a decrease in body mass index (BMI). Some of these genes have already been (29). mentioned: β-adrenergic receptor (ADBR). Also. inflammatory carriers of the Asn656 allele (27). and that body defence had. obesity polygenic exercise were restricted (21-23). carriers of a variant C and/or epigenetic changes in the genome. Heritable allele in the LEPR gene [Ser (T) 343Ser (C)] have lost changes in gene expression exclude any modification more weight in response to a low calorie intake than of the primary DNA sequence. lower levels of fasting against losing fat/weight is greater than that against plasma insulin. and the influence homozygotes for the Lys656 allele had a considerable of non-coding RNAs. in the same period of time. the weight loss response weight. and adipogenesis have been reported to but unlike Pro12 homozygotes. a In a study of the Lys656Asn variant within LEPR. 25). (IL-6) (18. The gene. POMC. compared to the factors (34). transition at position -2549 in the promoter region of the LEP gene is associated with obesity and that Environmental obesogens carriers of the -2549A allele have higher leptin levels Human diseases are entirely or partially caused by and lower weight loss as a response to low calorie environmental chemicals. Some studies have mechanisms (37). Many genes involved hypocaloric diet lost almost the same body weight as in the regulation of energy balance. Pro12Ala. uncoupling proteins. However. they gained more affect the risk of dietary intervention failure in some weight after the hypocaloric treatment was completed individuals. that result in multi-factorial obese phenotypes (for Mammes et al. Ala12 carriers on a to (dietary) interventions varies. waist circumference. lipid Pro12 homozygotes during a period of six months. In another study.OBESITY: GENOME AND ENVIRONMENT INTERACTIONS Arh Hig Rada Toksikol 2012. appetite. which introduce genetic intake (24. chromatin remodelling through DNA methylation. metabolism. all of which are contributing peroxisome proliferator-activated receptor γ (PPARγ) factors for obesity epidemic (42-44. systolic environmental chemicals affect cell transcriptional blood pressure. et al. of energy intake and expenditure and include pro-opiomelanocortin (POMC). regardless of the increased body gaining fat/weight (17). Table 2). melanocortin receptor 4 (MC4R). Furthermore. Ala12Ala homozygotes to weight gain or weight loss. PPARγ. However. of single nucleotide polymorphisms in the fat mass 20) who were overfed and whose energy intake or and obesity (FTO) locus. hormones (35.63:395-405 Figure 1 The physiological changes associated with obesity The studies on both humans and animals showed carriers increased body weight considerably in a that different genes play roles in different responses period of 10 years. Candidate gene variants for polygenic obesity uncoupling proteins (UCPs). Lindi et al. and leptin levels. they lead to the noncarriers (26).

sex and pioglitazone (45. adipogenesis. fat storage. 2011 (9) 12 % to 20 % of prostate cancer deaths connected with obesity Chronic musculoskeletal problems. Furthermore. 2007 (3) Hypertension visceral fat Elevated plasma insulin tissue concentrations Insulin resistance Hyperglycaemia Hyperlipidaemia Gout. and mortality through low physical activities. 45-48). obstructive 2011 (10) sleep apnoea . stress response. disrupting chemicals (EDCs) that inappropriately alter It has been proposed that dangerous environmental normal development and/or homeostasis of lipid obesogens can be categorised into the following metabolism. Decreased physical activity.63:395-405 397 most important molecular and/or cellular changes that foetal development.OBESITY: GENOME AND ENVIRONMENT INTERACTIONS Arh Hig Rada Toksikol 2012. kidney disease. obesity. 2008 (2) 85 % of children with type II diabetes are obese Term “diabesity” underscores the strong connection Cardiovascular diseases Correlation with obesity in 70 % of cases Lau.Bašić M. slimicides in Table 1 Obesity related diseases or disorders Disease / disorder Relation with obesity Source/publication Type II diabetes 80 % correlation of type II diabetes and obesity Lau. 2008 (2) Breast cancer Obesity associated with breast cancer recurrence Chlebowski. signalling systems that determine every aspect of antifungal agents in wood treatments. 2008 (6). calorie and fat intake.. EDCs can disrupt the gene-controlled. 2008 (2) Metabolic syndrome Higher risk associated with intraabdominal Kopelman.. Organotins are widespread persistent environmental production and utilisation of insulin. 47. diisobutyl phthalate. lumbago. et al. and groups of compounds: endocrine disrupting chemicals type 2 diabetes (4. and pharmaceutical the balanced system of hormones that regulate vital obesogens such as thiazolidinediones: rosiglitazone body functions such as growth. and changes in hormones Rose and Vona-Davis. 48). ability to reproduce. liver disease. 2010 (4) pulmonary problems. osteoarthritis Cancer Connection with colon and breast cancer 42 % Lau. 2005 (5). asthma and Strong connection with obesity and excess weight Newbold. perfluorooctanoic normal functions of the endocrine system by disrupting acid.2005 (8). EDCs can interfere with organotins and bisphenol A (BPA). normal They are used as fungicides and pesticides in crops. and metabolic organic pollutants with potent endocrine-disrupting rate. gall bladder Chlebowski. behaviour. BMI >30 Kanasaki and Koya. 2005 (5) disease. epidemiology are reflected on obesity phenotypes appearance are studies indicate that exposure to EDCs during the further described. development of a foetus is associated with excess Obesogens (Figure 1) are foreign endocrine weight and obesity later in life (49). skin problems. development. prostate cancer or biochemical recurrence) Cao and Ma. (high oestrogen production in adipose tissue) 2010 (7) Prostate cancer More aggressive forms are diagnosed in men with higher BMI (by 15 % to 21 % higher risk of fatal Strom et al. Recent experiments on animals confirmed that properties in both vertebrates and invertebrates. high Sauter et al.

63:395-405 Obesity phenotypes BMI ≥ 30 kg m-2 Figure 2 Possible targets of obesogens.body mass index). cells to differentiate into adipocytes (49). an agonist of both which improve serum triglycerides and glycaemic retinoid X receptor and peroxisome proliferator. when research studies will have clarified exposure to low doses of BPA (55). and -γ) and peroxisome surfactants. These classes of chemicals include various Organotins such as tributyltin (TBT) and triphenyltin perfluoroalkyl compounds and phthalate plasticisers are potent activators of nuclear hormone receptors that are widely used as surface repellents and retinoid X receptor (RXRα. regulations resulting in hypothalamic dysregulations EDCs can probably affect multiple target (54). in mammary gland tissues were found after perinatal the future. agricultural Perfluorooctanoic acid and phthalates can products. In addition to acting as an enzymatic activity or the activation of expression of androgen receptor antagonist. affected both mice and rats insomuch as their body in polyvinylchloride plastics. marine antifouling agents. alters the fate of stem cell mediated by PPARγ include weight gain in diabetics compartment by sensitising multipotent stromal stem when such agonists are used for a prolonged time (61. More 62). an increased risk of acute myocardial tetrabromobisphenol A modify hypothalamic gene infarction. . for recently. RXRs. PPARs . dental composites. BPA has a potential to bind to the nuclear as antagonists. BMI . thyroid hormone receptors (55). an increase in cardiovascular risks and. most frequent sources of organotins (50-52). control for type 2 diabetes. Exposure to low the network of reactions in the cell. mammalian cells through a variety of mechanisms. -β. beverage containers. PH – peptidergic hormones. Bisphenol A as a component of polycarbonate The most likely mechanism involves direct binding plastics is widely used in numerous products such as to nuclear receptors such as oestrogen receptor α polycarbonate baby bottles. seafood. and heart failure (63).peroxisome proliferator-activated receptors. rosiglitazone and adipocyte number. Contaminated drinking water. A variety of All proposed mechanisms may also interact with abnormalities in the female and male reproductive and each other creating a complex network. the organotin compound tributyltin.398 Bašić M. ER . 47. et al.Cytochrome aromatase p450. size. the and/or PPARγ acting as agonists.retinoid X receptors. (45. and leaching from plastics are the negatively affect the adipose homeostasis and lipids.OBESITY: GENOME AND ENVIRONMENT INTERACTIONS Arh Hig Rada Toksikol 2012. studies have confirmed that TBT and rosiglitazone. However. industrial water systems. Moreover. Another possibility linings of food cans.microRNA. stroke. and sealants would be their binding to nuclear receptors and acting (4). However. pioglitazone (thiazolidinediones) are PPARγ agonists.oestrogen receptor. a complete picture doses of BPA during prenatal and neonatal periods of interactions will be available. The indirect EDCs′ effect involves oestrogen receptor and interact with a variety of other disrupting hormone levels through the inhibition of targets in mammalian cells. proliferator-activated receptor γ which regulate Pharmaceutical obesogens. and function (53). and in the textile industry weight increased (57-60). CYP19 . 48). Environmental obesogens influence a variety of molecular and/or cellular targets that may act either alone or with each other creating a complex network that affects gene expression and results in obesity phenotypes (abbreviations: miRNA . side effects activated receptor γ. BPA interacts with P450 enzymes (4).

5-hydroxytryptamine (serotonin) receptor 2C Hyperphagia (abnormal regulation (HTR2C). group C.Bašić M. and gluconeogenesis were upregulated. The individual advice regarding nutrition and and the environment alternate the development of a lifestyle changes should be based on an analysis of disease. and food on on individual genetic variants (73) through the different/unique responses to food among individuals research of the influence of such variants on the and consequently. low density lipoprotein receptor (LDLR)] peroxisome proliferator-activated receptor γ (PPARγ). adiponectin (ADIPOQ). UCP3) dopamine receptor D2 (DRD2). β -3 subunit (GNB3). leptin receptor (LEPR). genetic predisposition for obesity will easily gain Evolution has brought about minor changes of weight and will have a different response to weight human genome but these are able to influence an treatment compared to those with low genetic individual′s metabolism and response to food (66). the relationship of that response connections between food and aetiology of obesity with the aetiology of common chronic diseases (64. resistin (RETN). Results from studies show that Nutrigenomics is related to the human genome high-fat diets may lead to obesity. much fat they ate and showed that the number of obese cancer) through the interactions between genes and individuals was higher among those on a high-fat diet the environment (food. tumour necrosis factor α (TNF)] Low physical activity dopamine receptor D2 (DRD2). For differences in food intake. and pharmaceuticals) compared with those on a low-fat diet. In the Framingham Heart Study. One study compared and. high levels of treatments and that genetic differences among which protect from cardiovascular diseases. These changes in adiponectin synthesis. It is known that interactions between genes. 69). et al. It also attempts to create a personalised nutrition weight changed differently in response to the for every individual. 2. melanocortin receptor 4 (MC4R) . PPARγ) are more sensitive variables in the Mediterranean population with to nutrition treatment/interventions than others. individuals could influence the occurrence of obesity In another study. insulin signalling. Sotos-Prieto et al. as already mentioned. β-2-adrenergic receptor and β-3 (ADRB2. nutrigenomics aims to develop a diet based in single-nucleotide polymorphisms). It has been shown that individuals with high 65). melanocortin receptor 4 of hunger and satiety) (MC4R). UCP2. genes (individual genetic variations Hence. interleukin-6 (IL6). according to a unique genetic restriction of calories from fat (1. vitamin D receptor Adipogenesis (fat storage) (VDR). profile (68. predisposition (11). (72) selected 31 genes in the liver Interactions between genes and the environment of obese C57BL/6J mice and showed that genes have also been associated with a decrease in the levels involved in fatty acid beta-oxidation. and oxidative stress defence system were Nutrigenomics investigates the effect of interactions downregulated with a high-fat diet. (77) showed and its health implications (71). their body (67). gender. and dietary poly-unsaturated fatty obesity). but Table 2 The list of obesity genes Genotype in obesity Genes Thriftiness (low metabolic rate. uncoupling protein 1. nuclear receptor subfamily 3. Kim et al. it tries to describe the cause the body mass indexes of individuals according to how of some chronic diseases (obesity. ADRB3).63:395-405 399 Nutrigenomics: nutrient and gene interaction genes involved in sterol biosynthesis. gender. example. interactions genes. (74). in order to achieve a better health status (70). that the rs1466113 polymorphism in the somatostatin It is important to emphasize that some nuclear receptor 2 gene was associated with anthropometric transcription factors (e.g. leptin (LEP). between a promoter polymorphism at the apolipoprotein When managing multifactorial diseases (including A1 gene. Also. inadequate thermogenesis) and 3 (UCP1. between lifestyle. hormone sensitive lipase (LIPE). member 1 (NR3C1) angiotensin-converting enzyme (ACE). diabetes mellitus. guanine Low rate of lipid oxidation nucleotide binding protein. fatty acid of hormone adiponectin.OBESITY: GENOME AND ENVIRONMENT INTERACTIONS Arh Hig Rada Toksikol 2012. it is crucial to point out that some genotypes acid intake modulated plasma concentrations of high- (haplotype combinations) are susceptible to nutrition density lipoprotein cholesterol (76). 75). pesticides.

OBESITY: GENOME AND ENVIRONMENT INTERACTIONS Arh Hig Rada Toksikol 2012. A between genetic and environmental factors (98). reactive protein (87. or fat cells. identification of markers that can predict the results In line with this. As the prevalence of obesity (RIPK3 and RNF216) in obese subjects receiving LCD continues to increase. Most genes of the metabolic pathways of reduction of body weight. Goyenechea et al. α-tocopherol. Ntalla et al. Steward-Knox different appearance of such disease among individuals. to create individual dietary treatments for maintaining and multiple types of cancer. Individuals who were Inflammation plays an important role in the willing to undertake a genetic test for creating development of health implications of obesity (80) personalised dietary interventions in most cases had and fat tissue is essential. loci for obesity and many for type 2 diabetes mellitus. for many current health problems in the population of (95) analysed the expression of two interacting genes western countries. 88) concentrations are associated To summarise. et al. liver subjects receiving a low-calorie diet (LCD) during a disease. Negative public opinion on genetic testing in order It is significant to underline that metabolic pathway to create a unique personalised diet. and/or inflammation (81): adipocytes. six-month weight maintenance period. central obesity. individually tailored nutrition. and showed that these compounds influenced inflammatory processes. may influence the genes have a role in the development of a disease and success of nutrigenomic intervention. (97) conducted a study in order to determine the which results in different risks for a specific disease opinion of people in Europe on genetic testing and (79). oxidative stress. However. green tea extract. (93) demonstrated the role metabolic diseases (hypertension. development of methods for intervention with antioxidative substances such as identifying biomarkers. showed Personalised nutrition that a single nucleotide polymorphism rs1501299 and Nutrigenetics and personalised nutrition can give fibre interaction was significantly associated with every individual an advice on a diet that is in line with adiponectin levels. Some food has environment information in the management and anti-inflammatory effects (89) and has been associated prevention of excess weight. and responsible use of C. omega-3 polyunsaturated fatty acids. et al. not obese were not willing to have a nutrigenomic Reduced adiponectin (85. it is important to better and the authors concluded that the expression of these understand the genetic aspect of obesity and the . intervention. (70) Consumption of refined carbohydrates contributes showed that nutrigenetically (gene-nutrition) tailored to the development of obesity and type 2 diabetes diets result in better compliance of patients.and anti-inflammatory adipokines (82-84). It to investigate the response to nutrition interventions represents a risk factor for cardiovascular and (94). The results of the study. gout. CONCLUSION How to maintain a healthy weight after low calorie/ low energy treatment is the issue of many studies (93). gall bladder disease). Overall. and Goyenechea et al. as obesity is associated with high blood cholesterol levels. vitamin measurement of markers. and lifestyle factors. 86) and increased C. Obesity is caused by the combined impact of Peripheral blood mononuclear cells (PBMCs) can help genetic. and improvement in glucose carbohydrates are associated with quantitative trait blood levels. Bakker et al. This decrease in inflammation can prevent health is the reason why it is important to include gene– complications associated with obesity. (78) investigated two genes in PBMCs could identify those obese whether variants of adiponectin gene interacted with subjects who will regain more weight after a successful food/specific components of food and influenced the initial weight loss. conducted on healthy school-aged children. it is the culprit healthy weight. Arkadianos et al. osteoarthritis. and tomato individual genetic information. personal genetic profile (96). levels of adiponectin. secrete high levels of stress. simple and available resveratrol. In another study. (92) conducted a dietary of dietary interventions. environmental. longer mellitus.63:395-405 level can cause obesity. of pro-inflammatory status in weight changes in obese insulin resistance. sleep apnoea. 91). kidney disease. This could help reproductive problems. hyper-insulinaemia. obesity involves an interaction with cardiovascular disease and type 2 diabetes.400 Bašić M. some issues with the decrease in the prevalence of some chronic of weight management are still crucial (15): diseases related to dietary and lifestyle habits (90. extract. and metabolism in individuals. type 2 diabetes. whereas individuals who were pro.

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hr . a pritom je potrebno poznavati utjecaj genskog profila na međudjelovanje hrane i porasta tjelesne mase.Bašić M. izloženost kemikalijama. tvari koje uzrokuju pretilost CORRESPONDING AUTHOR: Višnja Bačun-Družina Faculty of Food Technology and Biotechnology University of Zagreb P. Njezina je pojavnost pod utjecajem međudjelovanja gena. et al. genske varijacije u genomu pojedinih osoba stvaraju i njihovu predispoziciju za razvoj pretilosti. HR-10001 Zagreb. Croatia E-mail: visnjabd@pbf. uključujući čimbenike prisutne već u okruženju fetusa te one prisutne tijekom cijeloga života kao što su kvaliteta prehrane. Nadalje.63:395-405 405 Sažetak PRETILOST – MEĐUDJELOVANJE GENOMA I OKOLINE U industrijaliziranom svijetu među odraslim osobama. uključujući i pretilost. Uklanjanje ili ograničavanje kemijskih tvari i lijekova koji uzrokuju pretilost iz ljudske okoline moglo bi utjecati na opadanje epidemije pretilosti.O. nutrigenomika. Važni čimbenici rizika vezani su uz okolinu i način života. Dodatno. adolescentima i djecom pretilost je postala jedna od glavnih prijetnja za javno zdravlje ljudi. Box 625. nutrigenomika opisuje kako se promjenama u prehrani pojedinca može poboljšati zdravstveno stanje i spriječiti razvoj kroničnih bolesti. prehrana. mikroorganizmima i psihičkom stresu. izbjegavanjem tvari koje uzrokuju pretilost i zdravim načinom života može poboljšati kontrola pretilosti i održavati optimalna tjelesna masa.OBESITY: GENOME AND ENVIRONMENT INTERACTIONS Arh Hig Rada Toksikol 2012. prehrane. Stoga se zahvaljujući informacijama o genskom profilu pojedinca. KLJUČNE RIJEČI: geni. okoliša i načina života.