review article obesogens as an environmental risk factor for obesity

Malaysian Journal of Public Health Medicine 2014, Vol. 14 (3): 63-70

REVIEW ARTICLE OBESOGENS AS AN ENVIRONMENTAL RISK FACTOR FOR OBESITY Radi F and Hasni M.J Department of Community Health, UKM Medical Centre, Kuala Lumpur, Malaysia

ABSTRACT Obesity is a main public health problem predisposes many to the obesity-related health problems worldwide. Malaysia was ranked as sixth in Asia with high prevalence of obesity by the World Health Organisation in 2010. It is multifactorial origin and depends on many internal and external interactions; between human beings and the environment. In this review article, the focus will be on the example of chemical obesogens that present silently in the daily diet, pharmaceutical or industrial compounds that predispose people to obesity through altering and disrupting normal bodily metabolic processes.

INTRODUCTION Obesity is one of the main public health problems affecting millions of people worldwide and predisposes many to the obesity-related health problems. This ‘disease’ is about the multifactorial origin and depends on many internal and external interactions; between human beings and the environment. In this review, the focus will be on the role of chemical obesogens and their relation to the obesity epidemic. The World Health Organisation (WHO) survey in 2010 ranked Malaysia as sixth in Asia for obesity problems. Overweight and obesity are known risk factors for a number of chronic diseases, including diabetes, cardiovascular disease and cancer. It occurs in the low, middle and high income countries, particularly in urban settings1. It’s a worldwide disease with ever-increasing prevalence all over regardless of wealth status, crossing continents in either developed or developing countries and unlimited to religion or culture. The environment runs a substantial part in predisposing humans to develop obesity through many pathways and one of them is through ingestion of chemicals called obesogens2. Some of these chemicals either from dietary, pharmaceutical or industrial compounds may predispose people to obesity through altering and disrupting normal bodily metabolic processes3. The study on obesogens is rather a new field in the study of obesity and was first proposed in the year 2002, when Paula Baillie Hamilton wrote an article that was published in the Journal of Alternative and Complementary Medicine back then. She came up with the estimate that certain chemicals in the environment could be leading to the obesity epidemic4.

A noble pathway of research ensued and began attracting scientists worldwide to investigate the theory and hypotheses behind these so-called obesogens. In her article, she presented evidence from earlier scientific toxicology researches, dating even from the 1970s, on chemicals that predisposed weight gain in experimental animals. Obesity According to the World Health Organization (WHO) in 1998, obesity is defined as a disease in which excess body fat has accumulated to an extent that health may be adversely affected5. The underlying disease is the process of undesirable positive energy balance and weight gain. It is related with multiple chronic diseases, and obesity related lifethreatening chronic health problems that can be grouped into four main areas: (a) cardiovascular problems, including hypertension, stroke and coronary heart diseases; (b) conditions associated with insulin resistance, namely type 2 diabetes mellitus; (c) certain types of cancers, mainly hormone related and large bowel cancers; and (d) gallbladder disease. Obesity has been generally acknowledged and accepted as a factor for a multitude of health problems, mainly cardiovascular diseases and metabolic syndrome6. The foundation of obesity classification was presented by WHO in 1997 and the next year, the National Heart, Lung, Blood Institute (NHLBI) outlined a guide to selecting treatment for overweight and obesity7. Body mass index (BMI) is universally accepted as a measure of overweight and obesity and will be used for the purpose of this study even though it underestimates the prevalence of both conditions, defined as an excess of body fat8. Obesity is formally recognised as a disease by the American Medical Association (AMA) in June, 20139. Relative to normal weight, obesity has been found to be associated with higher all-cause


mortality in a systematic review from electronic databases in Pub Med and EMBASE of 97 studies, with a combined sample size of more than 2.88 million individuals and more than 270,000 deaths10. It is a global epidemic involving lists of countries and in this problem, Malaysia is not spared 11. More than 35.0% of adults aged 20 and older amounting approximately 1.4 billion of the world population were overweight and of these over 200 million men and nearly 300 million women were obese in 2008. In Malaysia, the 4th National Health and Morbidity Survey (NHMS) 2011, the national prevalence of obesity in the population group aged 18 years old and above is 15.1% while 29.4% of the people of the same age group were overweight12. Obesity is a product of excess energy balance that leads to deposition of fat in the human body that can adversely affect health (WHO 1998)13. There are many environmental factors that are associated with the obesity epidemic, but the main ones are called the ‘Big Two’, which is a low physical activity and unhealthy dietary intake especially increased food portion. Many studies have found the significant influence of these two environmental factors towards the development of obesity and its related phenotypes14.

Human beings are now living in an environment where foods are readily available compared to our ancestors who either had to cultivate or hunt for them. The recent epidemic of obesity is caused largely by an environment that promotes excessive food intake and discourages physical activity15. Obesogens Chemicals are abundant and can be found in the diet, cigarette smoke, pharmaceutical products, chemicals and in the environment (Table 1). They take many forms like pesticides, dyes, pigments, medicine, food flavouring and colouring, solvents, plastics, perfumes, resins and pigments. These chemicals had been shown to induce weight loss at high concentrations but at lower concentrations, might contribute to weight gain16. The term obesogens was first used by Felix Grun and Bruce Blumberg of University of Carolina, Irvine in 2005 and described these environmental xenobiotic compounds that can disrupt the normal developmental and homeostatic controls over adipogenesis and energy balance17. Obesogens can be functionally defined as chemicals that inappropriately alter lipid homeostasis and fat storage, metabolic set points, energy balance, or the regulation of appetite and satiety to promote fat accumulation and obesity18.

Table 1: The main obesogens according to its sources and major effects Source Diet Smoking

Pharmaceuticals

Industrial Chemicals

Organophosphate pesticides Other environmental pollutants

Obesogens Fructose Genistein Monosodium glutamate Nicotine

Diethylstilbestrol (DES) Thiazolidinediones (TZD) Estradiol Atypical antipsychotics (olanzapine) Bisphenol A (BPA) Organotins Perfluorooctanoic acid (PFOA) Diethylhexyl phthalates (DEHP) Polybrominated diphenyl ethers (PBDE) Parathion Diazinon Chlorpyrifos Benzopyrene Fine particulate matter (PM 2.5) Lead

Sources: Extracted and modified from Holtcamp (2012)3.

Major effects Disruption of sex steroid regulation and metabolic set points. Prenatal exposure leads to disruption of the cholinergic system and results in postnatal weight gain. Disrupt metabolic sensors, sex hormone regulation and neuroendocrine effects. Disruption of metabolic sensors, causing sex steroid dysregulation and metabolic set points abnormality. Disruption of metabolic sensors and central integration of energy balance. Metabolic sensors, sex steroid regulation and energy balance disruption.


Obesogens work through different mechanisms of action depending on the chemical characteristics. According to Grun and Blumberg17, their mechanism can be simplified into four different pathways: i) Obesogens action on metabolic sensors. ii) Obesogenic effect mediated by sex steroid dysregulation. iii) Obesogens and central integration of energy balance. iv) Obesogens and programming of metabolic set points. Obesogen action on metabolic sensors The body metabolic sensors serve for the control of lipid synthesis and adipose tissue generation (Figure 1). For someone to progress to obesity there should be an increase of adipocyte number and lipid content. These two conditions are regulated by metabolic sensors and regulators, which determine the number of lipid influx following metabolism and the proliferation and accumulation of adipocyte. Peroxisome proliferator activated receptors alpha and gamma (PPARα and PPARγ) are nuclear hormone receptors that act as a regulator by functioning as obligate heterodimers with the 9-cis retinoic acid receptor (RXR). RXR act as a metabolic ligand receptor for multiple fat-loving hormones, dietary fatty acids and their metabolites. RXR-PPARα combination results in peroxisome activation and β-oxidation of fat and thus results in metabolic burning of fat. Contrary to that, the RXR-PPARγ combination leads to lipid biosynthesis and storage as well as accumulation of adipocytes in adipose tissues. PPAR is a candidate gene, which its chromosome is located at 3p25 and is highly related to obesity. One of its variants is PPARγ (Pro12Ala) which is associated with lower BMI, better insulin sensitivity and lipid profiles among diabetics. However, another variant which is the PPARγ (Pro115Gln), it is found to be associated with lipid storage and reduced insulin sensitivity and results in obesity. Some chemicals act as agonists to PPARγ and lead to changes in lipid metabolism programs such as thiazolidinediones (TZD), rosiglitazones and pioglitazones. These pharmaceutical agents were used earlier as oral hypoglycemic agents but were later taken off of the market due to its side effects. One of the most common side effects includes the peripheral edema and persistent weight gain with prolonged use. TZD and others from its family act as PPARγ agonists that resulted in an overabundance of adipose tissue. Therefore, TZD is pharmaceutical obesogens. PPARα

antagonists on the other hand, have been used successfully to promote weight loss and reduce adiposity in experimental animals18. There are other worth-mentioning chemicals that act through this same pathway. One of them is a member of organotins persistent organic pollutants (POPs) such as tributyltin and triphenyltin. These chemicals are usually found in marine anti-fouling paints, wood catalysts, slimicides on industrial water systems and fungicides on foods. They act on the same RXR- PPARγ pathway leading to precocious lipid accumulation and adipocyte formation in animals19. Organotins are also found in contaminated seafood, agricultural products, drinking water and also leaching from plastics. Several studies have been conducted in the US and European countries to detect the levels of these chemicals in humans albeit the technical difficulties. The conclusions derived are that certain parts of our population are vulnerable to high organotin exposure levels, especially those working in the plastics industry and agriculture that may lead to increased adiposity and obesity in the long run. Another group of chemicals acting through this pathway includes bisphenol A (BPA) from polycarbonate plastics, phthalate plasticizers used to soften polyvinyl chloride (PVC) plastics and other perfluoroalkyl compounds (PFC) which are used mainly as surfactants and surface repellants on plastics and other consumer products. Toxicogenomic analysis has confirmed the action of these phthalates and surfactants on the RXRPPARα pathway which in the initial stages would lead to weight loss as mentioned earlier. Other groups include Diethylhexyl phthalate (DEHP) and perfluorooctanoic acid (PFOA) also exert their effect on PPARα and will cause weight loss initially. However the metabolites produced from this interaction are the one seen to be responsible in predisposing towards obesity in the long run and these types of xenobiotics compound are classified as obesogens. Obesogenic effect mediated by sex steroid dysregulation Sex steroid hormones have been demonstrated to play a role in the development of obesity through adipose tissue formation, mobilization of fat to target areas as well as regulating adipocytes hypertrophy and hyperplasia. There are several notable nuclear receptors for sex steroid hormones that have been studied on knockout models of sex steroid dysregulation and they include FSH receptor (FORKO), aromatase (ArKO), oestrogen receptor (αERKO) and androgen receptor (ARKO). Sex steroids also noted, in conjunction with growth


hormones (GH), function in lipid mobilization and counteracts with the insulin and cortisol effects on lipid accumulation. Imbalances of these regulatory sex hormones can lead to several disorders like

Cushing’s syndrome, polycystic ovarian syndrome, GH-deficiency, aging and menopause.

RXR-PPARγ combination leads to lipid biosynthesis and ↑ adipose tissue formation

RXR-PPARα combination leads to fat metabolization and weight loss

Metabolic Sensors: Nuclear Hormone Receptors through peroxisome proliferator activated receptor alpha and gamma Figure 1. Obesogens action on metabolic sensors. (PPARα and PPARγ) and 9-cis retinoic acid receptor (RXR) Obesogenic effect mediated by sex steroid dysregulation combination. Sex steroid hormones have been demonstrated to play a role in the development of obesity

Thiazolidinediones (TZD), rosiglitazones and pioglitazones. → leads to peripheral edema and persistent weight gain with prolonged use.

Organotins class of persistent organic pollutants (POPs) such as tributyltin (TBT) and triphenyltin (TPT). → leads to lipid accumulation and adipocyte formation.

Bisphenol A (BPA) from polycarbonate plastics; Diethylhexyl phthalate (DEHP) and perfluorooctanoic acid (PFOA) → metabolites lead to obesity in the long run.

Figure 1: Obesogens action on metabolic sensors. One of the similar physical attributes of the syndromes mentioned above is weight gain and obesity where most of the sufferers develop increased adiposity and obesity in general. The hormonal effects can be seen in altered androgen/oestrogen levels, lowered growth hormone secretion and hypercortisolemia and reduced insulin sensitivity. One example of chemical agents that causes hormonal imbalance would be the anti-androgenic medications used in prostate cancer and PCOS. The suppression of

androgen relates to increased adiposity and weight gain among patients16. Another famous agent that acts on this pathway is diethylstilbestrol (DES) which was widely used until 1971, in the primary management of miscarriages. DES exposed mothers developed an increase possibility of developing breast cancer while their daughters had higher reproductive and urinary tract abnormalities. An experiment on female mice noted that in the long run, obesity


was one of the effects upon exposure to DES. This later brought to the discontinuation of this agent. Retha Newbold, a retired developmental biologist claimed that DES would cause larger adipocytes rather than increasing its number. Oestrogens, on the other hand, were noted to have anti-obesogenic effects for menopausal adults with the main action on adipose tissue remodeling. This has become handy for post-menopausal women to help in controlling their body weight in the long run. However, fetal or neonatal exposure of estrogens was noted to be associated with increased risk of obesity later in life. Another estrogenic compound that was associated with its obesogenic effect is Bisphenol A (BPA). It was noted that prolonged exposure to this estrogenic obesogen were seen as a result of leaching from polycarbonate plastics and later contributed towards increased body weight and hyperlipidaemia in rodents16. A study demonstrated a positive correlation between BPA levels in obese and PCOS females. BPA was abundant in the past in canned foods, medical devices and cash register receipts. An expert who studied the effects of BPA for 15 years, professor Frederick vom Saal of University of Missouri, BPA exposure in humans lead to increased abdominal fat and glucose intolerance. He claims that the level needed for BPA to exert its effect through either sex hormone dysregulation or affect on metabolic sensors are far lower than those permitted by the food regulatory agency and this is a worrying issue. This pathway is an important area that needs further study since many of the hormonal therapy used today are virtually sex steroid hormones that may alter the physiological balance of human and will lead to the development of obesity. Obesogen and central integration of energy balance The mechanism of appetite control and regulation is maintained through the hypothalamic-pituitaryadrenal (H-P-A) axis, which serves a critical role in the prevention of hyperphagia and control of energy homeostasis (Figure 2). Some of the signals from the digestive tract, adipose tissue and brain are targeted for environmental obesogens and this association has been seen in several neurological disorders and drugs used in treating them. The pathways in which the energy balance is disrupted are through neuroendocrine effects, peptidergic hormones and endocannabinoid signalling.

a) Neuroendocrine effects Certain psychological conditions like schizophrenia, bipolar disorders and depressive disorders have been treated with pharmaceutical agents, especially selective serotonin reuptake inhibitors (SSRI), atypical antipsychotics or mood stabilizers and tricyclic antidepressants (TCA). Prolonged uses have been associated with weight gain. One notable example of atypical antipsychotic is olanzapine20. This drug caused elevation of serum glucose, reduced insulin sensitivity and predisposes patients to obesity and diabetes mellitus compared to typical antipsychotics. b) Peptidergic hormones Peptidergic hormones are essential to the integrity of hypothalamic regulation of appetite and satiety and when unbalanced, can lead to obesity. Examples of these hormones include brain-derived neuropeptide Y (NPY), agouti related peptides (AgRP), orexins, melanin concentrating hormones and peripheral hormones like ghrelin are major appetite stimulators21. In contrast, neuroendocrine, pancreatic and gastrointestinal hormones or metabolites like insulin, peptide YY, glucagon-like peptide 1 and cholecystokinin are effective satiety signals that can lead to obesity when absent. Some environmental obesogens like organotins for example, mainly TBT can disrupt the balance of peptidergic H-P-A responses through disrupting oestrogen receptor signalling thus leading to the obesity. Other obesogens like BPA and Diethylhexyl phthalate (DEHP) can disrupt NPY in midbrain and resulted in shifting of normal appetite. c) Endocannabinoid signalling (ECS) This is the final pathway involved in the integration of energy balance. The main receptor involved in this pathway is the cannabinoid receptor type 1 (CB1) where most agonists, either endogenous or dietary will act on and exert its orexigenic effect on hypothalamus and impact metabolic functions in adipose tissues. One easy way to observe this effect is by the effect of tetrahydrocannabis (THC)


from smoking marijuana leads to behavioural changes and lead to modest weight gain even in a short term.

put it is that CB1 function and effect on ECS is dependent on the mediation of 5’-AMP-activated protein kinase (AMPK) which serves as the regulator for cellular and bodily energy levels. So, different agonists or environmental obesogens that mimics the effect on ECS and directly target AMPK will result in positive obesogenic responses.

Elevated levels of endocannabinoid are seen in obese patients and this demonstrates that hyperactive cannabinoid activity leads to obesogenic effects. A simple way to

Neuroendocrine effects

Peptidergic hormones

Atypical antipsychotics (olanzapine), SSRI and TCA

Brain-derived neuropeptide Y (NPY), agouti related peptide (AgRP) and orexins are major appetite stimulators

→ ↑ serum glucose, ↓ insulin sensitivity and lead to → obesogens disrupt balance Figure 2.obesity Obesogen and central integration of energy balance between stimulator and suppressants.

Endocannabinoid signaling

Central integration of energy balance through hypothalamicpiruitaryadrenal/thyroid (HPA/HPT) axis.

(ECS) Cannabinoid receptor type 1 (CB1) interaction with obesogens → orexigenic effects and weight gain.

Figure 2: Obesogen and central integration of energy balance Obesogens and programming of metabolic set points The hypothalamus functions in the regulation of metabolism by altering the metabolic efficiency and establishing metabolic set points. The delicate balance between basal metabolic rate, diet induced thermogenesis and metabolic cycles are essential in controlling the internal environment of energy balance in our body. One important axis that regulates the weight equilibrium in our body is the hypothalamicpituitary-thyroid (HPT) axis. This axis regulates

systemic thyroid hormone release that is essential in lipid, carbohydrate and protein metabolism. Type 2 deiodinase (DIO2) is the responsible hormone in locally converting thyroxine (T 4) to triiodothyronine (T3), a thyroid hormone receptor (TR) agonist22. TR signalling which combines with sympathetic activity leads to expression of respiratory components like Uncoupling Protein 1 (UCP1) which increases energy expenditure and reduces metabolic efficiency. UCP1 is one of the candidate genes that their variations can lead to specific obesity phenotypes.


Polybrominated diphenyl ethers (PBDE) exposure is a likely agent that can trigger this pathway. PBDEs are used extensively in human populations and function as flame retardants for manufactured goods. It had been demonstrated in animal studies that prolonged exposure, from 2-4 weeks to PBDEs resulted in lower circulating T4 levels and lower lipolysis activity23. The hypothalamic-pituitary-adrenal (HPA) axis is also important in determining metabolic set points through the regulation of glucocorticoid hormones. Glucocorticoid hormones function in adipocytes differentiation and regulating metabolism in peripheral tissues and the stress response. Overstimulation of glucocorticoid production along with reduced metabolism of cortisol through modulating the hormone 11β-steroid dehydrogenase type 1 (11β-HSD1) related to its metabolism as well as glucocorticoid receptor (GR) signalling leads to the development of obesity. A commonly used sweetening agent, known as glycyrrhetinic acid, acts by inhibiting the 11ß-HSD function and later associated with obesity. This is one example of obesogens that can disrupt this pathway and chronic exposures will lead to weight gain and increased adiposity.

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The study of obesogens is still in its maiden phase with too many loopholes and questions that needs answering to. So far, we have been served by convincing studies, albeit animal experiments in some cases, which points and emphasizes the impact of these chemical compounds. These chemicals are everywhere around us and the understanding on how it reacts with our body, especially in mechanisms leading towards obesity can help us in controlling the obesity prevalence in our future generations.

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