Obesogen
Encyclopedia
Obesogens are foreign chemical compound
s that disrupt normal development
and balance of lipid
metabolism
, which in some cases, can lead to obesity
. Obesogens may be functionally defined as chemicals that inappropriately alter lipid homeostasis
and fat storage, change metabolic setpoints, disrupt energy balance or modify the regulation of appetite and satiety to promote fat accumulation and obesity
.
There are many different proposed mechanisms through which obesogens can interfere with the body's adipose tissue
biology. These mechanisms include alterations in the action of metabolic sensors; dysregulation of sex steroid
synthesis, action or breakdown; changes in the central integration of energy balance including the regulation of appetite and satiety; and reprogramming of metabolic setpoints. Some of these proposed pathways include inappropriate modulation of nuclear receptor
function which therefore allows the compounds to be classified as endocrine disrupting chemicals
that act to mimic hormones in the body, altering the normal homeostasis maintained by the endocrine system .
Obesogens have been detected in the body both as a result of intentional administration of obesogenic chemicals in the form of pharmaceutical drugs such as diethylstilbestrol
, selective serotonin reuptake inhibitor
, and thiazolidinedione
and as a result of unintentional exposure to environmental obesogens such as tributyltin
, bisphenol A
, diethylhexylphthalate
, and perfluorooctanoate
. Emerging evidence from laboratories around the world suggests that other chemicals will be confirmed as falling under this proposed classification in the near future, and that there may be some serious biological effects due to exposure to these chemicals that still remain undiscovered.
The term obesogen was coined by Bruce Blumberg of the University of California, Irvine
. The topic of this proposed class of chemical compounds and how to counteract their effects is explored at length in the book The New American Diet
.
lipid homeostasis and proliferation and differentiation on adipocytes. The major group of regulators that is targeted is a group of nuclear hormone receptors known as peroxisome proliferator activated receptors (PPARα, δ, and γ). These hormone receptors sense a variety of metabolic ligands including lipophilic hormones, dietary fatty acids, and their metabolites, and, depending on the varying levels of these ligands, control transcription of genes involved in balancing the changes in lipid balance in the body. In order to become active and properly function as both metabolic sensors and transcription regulators, the PPAR receptors must heterodimerize with another receptor known as the 9-cis retinoic acid receptor
(RXR). The RXR receptor, itself, is the second major target of obesogens next to the PPAR receptors.
The PPARα receptor, when complexed with RXR and activated by the binding of a lipid, promotes peroxisome
proliferation leading to increased fatty acid β-oxidation. Substances, such a xenobiotics that target and act as agonists of PPARα typically act to reduce overall serum concentrations of lipids. In contrast, the PPARγ receptor, when complexed with RXR and activated by the binding of fatty acids or their derivatives promotes lipid biosynthesis and storage of lipids is favored over fatty acid oxidation. In addition, activation promotes differentiation of preadipocytes and the conversion of mesenchymal progenitor cells to preadipocytes in adipose tissues. Substances that target and act as agonists of PPARγ/RXR complex typically act to increase overall serum concentrations of lipids.
Obesogens that target the PPARγ/RXR complex mimic the metabolic ligands and activate the receptor leading to upregulation of lipid accumulation which explains their obesogenic effects. However, in the case of obesogens that target the PPARα/RXR complex, which when stimulated reduces adipose mass and body weight, there are a few different explanations as to how they promote obesity.
The ligand binding pockets of PPARs are very large and unspecified, allowing for different isoforms of the receptor(PPARα, δ, and γ)to be activated by the same agonist ligands or their metabolites. In addition, fatty acid oxidation stimulated by PPARα requires continuous stimulation while only a single activation event of PPARγ is required to permanently increase adipocyte differentiation and number. Therefore it may be the case that metabolites of PPARα targeting obesogens are also activating PPARγ, providing the single activation event needed to potentially lead to a pro-adipogenic response.
A second explanation points to specific PPARα targeters that have been shown to additionally cause abnormal transcriptional regulation of testicular steroidogenesis when introduced during fetal development. This abnormal regulation leads to a decreased level of androgen
in the body which, itself is obesogenic.
Finally, if PPARα activation occurs during critical periods of development, the resulting decrease in lipid concentration in the developing fetus is recognized by the fetal brain as undernourishment. In this case, the developing brain makes what will become permanent changes to the bodies metabolic control, leading to long term upregulation of lipid storage and maintenance.
This alteration in sex steroid levels due to obesogens can vary enormously according to both the sex of the exposed individual as well as the timing of the exposure. If the chemicals are introduced at critical windows of development, the vulnerability of an individual to their effects is much higher than if exposure occurs later in adulthood. It has been shown that obesogenic effects are apparent in female mice exposed to both phytoestrogens and DES during their neonatal periods of development,as they, though born with a lower birth weight, almost always developed obesity, high leptin levels, and altered glucose response pathways. Both phytoestrogen and DES exposed male mice did not develop obesity and rather, showed decreased body weights with increased exposure confirming the role of gender differences in exposure response. Further studies have shown positive correlations for serum BPA levels with obese females in the human population, along with other xenoestrogen compounds suggesting the parallel roles that these effects may be having on humans.
Neurological disorders may enhance the susceptibility to develop the metabolic syndrome
that includes obesity. Many neuropharmacueticals used to alter behavioral pathways in patients with neurological disorders have shown to have metabolic altering side-affects leading to obesogenic phenotypes as well. These findings give evidence to conclude that an increase in lipid accumulation can result from the targetting of neurotransmitter receptors by foreign chemicals.
Several peptidergic hormone pathways controlling appetite and energy balance, such as those involving ghrelin
, neuropeptide Y
, and agouti-related peptide
, are really sensitive to changes in nuclear receptor signaling pathways and can therefore be easily altered by the introduction of endocrine disruptor
s. Such an alteration can lead to induced feelings of hunger and decreased feelings of fullness causing an increase in food intake and inability to feel satisfied, both characteristic of obesity.
Some xenoestrogens such as BPA
, nonylphenol
, and DEHP have all shown to act is this way, altering NPY expression and significantly shifting the feeding behaviors of exposed mice. In addition, organotin
s such as TBT
, TMT
, and TET
can exert there effects through similar pathways. TBT can locally disrupt aromatase
regulation in the hypothalamus
causing the responses of the HPA axis to hormones to become abnormal. TMT works in a similar but unique way, inducing NPY and NPY2 receptor expression initially which later is counteracted by neuronal degeneration in lesions causing decrease in signaling ability.
While an increase in food intake is often the case after exposure, weight gain involves the body's maintenance of its metabolic setpoint as well. Given this information, it is particularly important to note that exposure during development and initial programming of these setpoints can be extremely significant throughout the remainder of life.
A wide range of environmental organotins that mimic petidergic hormones in the HPA axis as mentioned before, additionally mimic lipid activators of the cannabinoid system and inhibit AMPK activity. Endocannaboid levels are high in those suffering from obesity due to hyperactivity of cannaboid signalling pathways. It is these high levels that have been found to be closely associated with increased fat stores linking the lipid activator mimics to the actual disease.
Regions in the hypothalmus control the responses that establish an individuals metabolic setpoint and metabolic efficiency. These responses are adaptive in that they vary according the the individual's needs, always working to restore the metabolic setpoint through the increase or decrease of metabolic functions depending on varying energy needs. Since it is adapted, it is expected that it would be able to achieve equilibrium if the lipid balance was altered by hormones via the mechanisms mentioned above. However since obesogenic phenotypes persist, it can be concluded that adaptive response components of the hypothalmus may be a target of obesogens as well.
A person's body composition is very much predetermined before birth and changes rarely occur in adulthood. Adipocyte numbers increase during development and come to a plateau over time. After the plateau adipocytes become restricted to mostly hypertrophic growth and don't seem to change much in terms of cell number. This is demonstrated by the difficulty in altering somatotypes or more simply by the difficulty that goes along with trying to lose weight past a certain point.
A particular study on PBDEs, a commonly used chemical in flame retardants, made its role in altering the functions of the thyroid
hormone axis apparent. This finding leads to increased concern as neonatal thyroid status plays a large role in the integration of maternal environmental signals during development in the womb that is used for long-term body weight programming.
, and pioglitazone
are all used to treat diabetes. These drugs act as agonists of the PPAR-γ receptor leading to insulin
sensitizing effects that can improve glycemic control and serum triglyceride
levels. Despite the positive effects these chemicals can have in treating diabetes patients, administration also lead to unwanted PPAR-γ mediated side effects such as peripheral edema
which can be followed by persistent weight gain if the drug is used over a long period of time. These side effects are particularly prominent in diabetes 2 patients, a disease that tends to result from an overabundance of adipose tissue.
is a synthetic estrogen that was once prescribed to women to decrease the risk of miscarraige until it was found to be causing abnormalities in exposed offspring. This same chemical has been shown to cause weight gain in female mice when exposed during neonatal development. While exposure didn't lead to an abnormal brith weight, significant weight gain occurred much later in adulthood.
Although studies that have directly measured organotin levels in human tissue and blood are limited, it has been determined that vulnerability of a portion of the general population to organotin exposure at levels high enough to activate RXRs and PPARγ receptors is very probable. The high usage of organotins in both plastics and agricultural maintenance as well as the high affinity of the chemicals further confirms this conclusion.
Liver samples from the late 1990s in Europe and Asia contained on average 6 and 84 ng/g wet wt respectively for total organotin levels, while later studies foung levels of total organotins in US blood samples averaged around 21 ng/mL with TBT comprising around 8 ng/mL (~ 27 nM) Even more recent analyses of European blood samples found the predominant species to be TPT rather than TBT at 0.09 and 0.67 ng/mL (~0.5-2 nM). Only occasional trace amounts of TBT were found. These results indicate that organtin exposure to humans, while found to be present among many different populations, can vary in terms of type of organatin and level of exposure from region to region.
(TBT) and triphenyltin (TPT) are highly selective and act as very potent agonists of both the retinoid X receptors (RXR α,β, and γ) and PPARγ. This ability to target both receptors at the same time, is more effective than single receptor activation, as adopogenic signaling can be mediated through both components of the heterodimer complex. This highly effective activation mechanism can pose detrimental, long-term adipogenic effects especially if exposure occurs during development and early life.
from polycarbonate
plastics, phthalate plasticizers used to soften PVC plastics, and various perfluoroalkyll compounds (PFCs)that are widely used surfactants and surface repellents in consumer products are all potentially obesogenic when introduced in the body. Phthalates and PFCs in particular have been found to function as agonists for one or more of the PPARs Additionally, metabolites of DHEP such as MEHP also activate PPARγ leading to a proadipogenic response.
Because the mechanisms behind the different effects of obesogens are so complex and not well understood, the extent to which they play in the current obesity epidemic may be greater than once thought. Epigenetic changes due to obesogen exposure must also be considered as a possibility, as they open up the potential for misregulated metabolic functions to be passed on from generation to generation. Epigenetic processes via hypermethylation of regulatory regions could lead to overexpression of different proteins, and therefore, amplification of acquired environmental effects. research will be required in order to gain a better understanding of the mechanism of action these chemicals are involved in before the extent of the risk of exposure can be determined and methods of prevention and removal from the environment can be established.
Chemical compound
A chemical compound is a pure chemical substance consisting of two or more different chemical elements that can be separated into simpler substances by chemical reactions. Chemical compounds have a unique and defined chemical structure; they consist of a fixed ratio of atoms that are held together...
s that disrupt normal development
Human development (biology)
Human development is the process of growing to maturity. In biological terms, this entails growth from a one-celled zygote to an adult human being.- Biological development:...
and balance of lipid
Lipid
Lipids constitute a broad group of naturally occurring molecules that include fats, waxes, sterols, fat-soluble vitamins , monoglycerides, diglycerides, triglycerides, phospholipids, and others...
metabolism
Metabolism
Metabolism is the set of chemical reactions that happen in the cells of living organisms to sustain life. These processes allow organisms to grow and reproduce, maintain their structures, and respond to their environments. Metabolism is usually divided into two categories...
, which in some cases, can lead to obesity
Obesity
Obesity is a medical condition in which excess body fat has accumulated to the extent that it may have an adverse effect on health, leading to reduced life expectancy and/or increased health problems...
. Obesogens may be functionally defined as chemicals that inappropriately alter lipid homeostasis
Homeostasis
Homeostasis is the property of a system that regulates its internal environment and tends to maintain a stable, constant condition of properties like temperature or pH...
and fat storage, change metabolic setpoints, disrupt energy balance or modify the regulation of appetite and satiety to promote fat accumulation and obesity
Obesity
Obesity is a medical condition in which excess body fat has accumulated to the extent that it may have an adverse effect on health, leading to reduced life expectancy and/or increased health problems...
.
There are many different proposed mechanisms through which obesogens can interfere with the body's adipose tissue
Adipose tissue
In histology, adipose tissue or body fat or fat depot or just fat is loose connective tissue composed of adipocytes. It is technically composed of roughly only 80% fat; fat in its solitary state exists in the liver and muscles. Adipose tissue is derived from lipoblasts...
biology. These mechanisms include alterations in the action of metabolic sensors; dysregulation of sex steroid
Sex steroid
Sex steroids, also known as gonadal steroids, are steroid hormones that interact with vertebrate androgen or estrogen receptors. Their effects are mediated by slow genomic mechanisms through nuclear receptors as well as by fast nongenomic mechanisms through membrane-associated receptors and...
synthesis, action or breakdown; changes in the central integration of energy balance including the regulation of appetite and satiety; and reprogramming of metabolic setpoints. Some of these proposed pathways include inappropriate modulation of nuclear receptor
Nuclear receptor
In the field of molecular biology, nuclear receptors are a class of proteins found within cells that are responsible for sensing steroid and thyroid hormones and certain other molecules...
function which therefore allows the compounds to be classified as endocrine disrupting chemicals
Endocrine disruptor
Endocrine disruptors are chemicals that interfere with endocrine in animals, including humans. These disruptions can cause cancerous tumors, birth defects, and other developmental disorders...
that act to mimic hormones in the body, altering the normal homeostasis maintained by the endocrine system .
Obesogens have been detected in the body both as a result of intentional administration of obesogenic chemicals in the form of pharmaceutical drugs such as diethylstilbestrol
Diethylstilbestrol
Diethylstilbestrol is a synthetic nonsteroidal estrogen that was first synthesized in 1938. Human exposure to DES occurred through diverse sources, such as dietary ingestion from supplemented cattle feed and medical treatment for certain conditions, including breast and prostate cancers...
, selective serotonin reuptake inhibitor
Selective serotonin reuptake inhibitor
Selective serotonin re-uptake inhibitors or serotonin-specific reuptake inhibitor are a class of compounds typically used as antidepressants in the treatment of depression, anxiety disorders, and some personality disorders. The efficacy of SSRIs is disputed...
, and thiazolidinedione
Thiazolidinedione
The thiazolidinediones , also known as glitazones, are a class of medications used in the treatment of diabetes mellitus type 2. They were introduced in the late 1990s.- Mechanism of action :...
and as a result of unintentional exposure to environmental obesogens such as tributyltin
Tributyltin
Tributyltin compounds are a group of compounds containing the 3Sn moiety, such as tributyltin hydride or tributyltin oxide. They are the main active ingredients in certain biocides used to control a broad spectrum of organisms...
, bisphenol A
Bisphenol A
Bisphenol A is an organic compound with two phenol functional groups. It is used to make polycarbonate plastic and epoxy resins, along with other applications....
, diethylhexylphthalate
Bis(2-ethylhexyl) phthalate
Bisphthalate, commonly abbreviated DEHP, is an organic compound with the formula C6H42. It is sometimes called dioctyl phthalate and abbreviated DOP. It is the most important "phthalate," being the diester of phthalic acid and the branched-chain 2-ethylhexanol. This colourless viscous liquid is...
, and perfluorooctanoate
Perfluorooctanoic acid
Perfluorooctanoic acid , also known as C8 and perfluorooctanoate, is a synthetic, stable perfluorinated carboxylic acid and fluorosurfactant. One industrial application is as a surfactant in the emulsion polymerization of fluoropolymers. It has been used in the manufacture of such prominent...
. Emerging evidence from laboratories around the world suggests that other chemicals will be confirmed as falling under this proposed classification in the near future, and that there may be some serious biological effects due to exposure to these chemicals that still remain undiscovered.
The term obesogen was coined by Bruce Blumberg of the University of California, Irvine
University of California, Irvine
The University of California, Irvine , founded in 1965, is one of the ten campuses of the University of California, located in Irvine, California, USA...
. The topic of this proposed class of chemical compounds and how to counteract their effects is explored at length in the book The New American Diet
The New American Diet
The New American Diet is the first diet book to investigate the effects of "obesogens" on our bodies, and to propose a prescriptive diet plan to reverse what they call "The Obesogen Effect." Author Stephen Perrine and co-author Heather Hurlock The New American Diet (Rodale, 2009) is the first...
.
Metabolic sensors
Both obesogenic drugs and chemicals have been shown to target transcription regulators found in gene networks that function to control intracellularIntracellular
Not to be confused with intercellular, meaning "between cells".In cell biology, molecular biology and related fields, the word intracellular means "inside the cell".It is used in contrast to extracellular...
lipid homeostasis and proliferation and differentiation on adipocytes. The major group of regulators that is targeted is a group of nuclear hormone receptors known as peroxisome proliferator activated receptors (PPARα, δ, and γ). These hormone receptors sense a variety of metabolic ligands including lipophilic hormones, dietary fatty acids, and their metabolites, and, depending on the varying levels of these ligands, control transcription of genes involved in balancing the changes in lipid balance in the body. In order to become active and properly function as both metabolic sensors and transcription regulators, the PPAR receptors must heterodimerize with another receptor known as the 9-cis retinoic acid receptor
Retinoic acid receptor
The retinoic acid receptor is a type of nuclear receptor that is activated by both all-trans retinoic acid and 9-cis retinoic acid. There are three retinoic acid receptors , RAR-alpha, RAR-beta, and RAR-gamma, encoded by the , , genes, respectively...
(RXR). The RXR receptor, itself, is the second major target of obesogens next to the PPAR receptors.
The PPARα receptor, when complexed with RXR and activated by the binding of a lipid, promotes peroxisome
Peroxisome
Peroxisomes are organelles found in virtually all eukaryotic cells. They are involved in the catabolism of very long chain fatty acids, branched chain fatty acids, D-amino acids, polyamines, and biosynthesis of plasmalogens, etherphospholipids critical for the normal function of mammalian brains...
proliferation leading to increased fatty acid β-oxidation. Substances, such a xenobiotics that target and act as agonists of PPARα typically act to reduce overall serum concentrations of lipids. In contrast, the PPARγ receptor, when complexed with RXR and activated by the binding of fatty acids or their derivatives promotes lipid biosynthesis and storage of lipids is favored over fatty acid oxidation. In addition, activation promotes differentiation of preadipocytes and the conversion of mesenchymal progenitor cells to preadipocytes in adipose tissues. Substances that target and act as agonists of PPARγ/RXR complex typically act to increase overall serum concentrations of lipids.
Obesogens that target the PPARγ/RXR complex mimic the metabolic ligands and activate the receptor leading to upregulation of lipid accumulation which explains their obesogenic effects. However, in the case of obesogens that target the PPARα/RXR complex, which when stimulated reduces adipose mass and body weight, there are a few different explanations as to how they promote obesity.
The ligand binding pockets of PPARs are very large and unspecified, allowing for different isoforms of the receptor(PPARα, δ, and γ)to be activated by the same agonist ligands or their metabolites. In addition, fatty acid oxidation stimulated by PPARα requires continuous stimulation while only a single activation event of PPARγ is required to permanently increase adipocyte differentiation and number. Therefore it may be the case that metabolites of PPARα targeting obesogens are also activating PPARγ, providing the single activation event needed to potentially lead to a pro-adipogenic response.
A second explanation points to specific PPARα targeters that have been shown to additionally cause abnormal transcriptional regulation of testicular steroidogenesis when introduced during fetal development. This abnormal regulation leads to a decreased level of androgen
Androgen
Androgen, also called androgenic hormone or testoid, is the generic term for any natural or synthetic compound, usually a steroid hormone, that stimulates or controls the development and maintenance of male characteristics in vertebrates by binding to androgen receptors...
in the body which, itself is obesogenic.
Finally, if PPARα activation occurs during critical periods of development, the resulting decrease in lipid concentration in the developing fetus is recognized by the fetal brain as undernourishment. In this case, the developing brain makes what will become permanent changes to the bodies metabolic control, leading to long term upregulation of lipid storage and maintenance.
Sex steroid dysregulation
Sex steroids normally play a significant role in lipid balance in the body. Aided by other peptide hormones such as growth hormone, they act against the lipid accumulation mediated by insulin and cortisol by mobilizing lipid stores that are already present. Exposure to obesogens often leads to a deficiency or change in the ratio between androgen and estrogen sex steroid levels, which modifies this method of lipid balance resulting in lowered growth hormone secretion, hypocortisolemia (low levels of circulating cortisol), and increased resistance to insulin effects.This alteration in sex steroid levels due to obesogens can vary enormously according to both the sex of the exposed individual as well as the timing of the exposure. If the chemicals are introduced at critical windows of development, the vulnerability of an individual to their effects is much higher than if exposure occurs later in adulthood. It has been shown that obesogenic effects are apparent in female mice exposed to both phytoestrogens and DES during their neonatal periods of development,as they, though born with a lower birth weight, almost always developed obesity, high leptin levels, and altered glucose response pathways. Both phytoestrogen and DES exposed male mice did not develop obesity and rather, showed decreased body weights with increased exposure confirming the role of gender differences in exposure response. Further studies have shown positive correlations for serum BPA levels with obese females in the human population, along with other xenoestrogen compounds suggesting the parallel roles that these effects may be having on humans.
Central Balance of Energy
While hormone receptors tend to be the most obvious candidates for targets of obesogens, central mechanisms that balance and regulate the bodies nutritional changes on a day to day basis as a whole cannot be overlooked. The HPA axis (hypothalmic-pituitary-adrenal) is involved in controlling appetite and energy homeostasis circuits which are mediated by a large number of monoaminoergic, peptidergic (use of hormones as neurotransmitters), and endocannabinoid signals that come from the digestive tract, adipose tissues, and from within the brain. It is these types of signals that provide a likely target for obesogens that have shown to have weight altering effects:Neuroendocrine effects
Neurological disorders may enhance the susceptibility to develop the metabolic syndrome
Metabolic syndrome
Metabolic syndrome is a combination of medical disorders that, when occurring together, increase the risk of developing cardiovascular disease and diabetes. It affects one in five people in the United States and prevalence increases with age...
that includes obesity. Many neuropharmacueticals used to alter behavioral pathways in patients with neurological disorders have shown to have metabolic altering side-affects leading to obesogenic phenotypes as well. These findings give evidence to conclude that an increase in lipid accumulation can result from the targetting of neurotransmitter receptors by foreign chemicals.
Peptidergic hormones
Several peptidergic hormone pathways controlling appetite and energy balance, such as those involving ghrelin
Ghrelin
Ghrelin is a 28 amino acid peptide and hormone that is produced mainly by P/D1 cells lining the fundus of the human stomach and epsilon cells of the pancreas that stimulates hunger. Ghrelin levels increase before meals and decrease after meals. It is considered the counterpart of the hormone...
, neuropeptide Y
Neuropeptide Y
Neuropeptide Y is a 36-amino acid peptide neurotransmitter found in the brain and autonomic nervous system."NPY has been associated with a number of physiologic processes in the brain, including the regulation of energy balance, memory and learning, and epilepsy." The main effect is increased food...
, and agouti-related peptide
Agouti-related peptide
Agouti-related protein also called Agouti-related peptide is a neuropeptide produced in the brain by the AgRP/NPY neuron. It is only synthesised in NPY containing cell bodies located in the ventromedial part of the arcuate nucleus in the hypothalamus...
, are really sensitive to changes in nuclear receptor signaling pathways and can therefore be easily altered by the introduction of endocrine disruptor
Endocrine disruptor
Endocrine disruptors are chemicals that interfere with endocrine in animals, including humans. These disruptions can cause cancerous tumors, birth defects, and other developmental disorders...
s. Such an alteration can lead to induced feelings of hunger and decreased feelings of fullness causing an increase in food intake and inability to feel satisfied, both characteristic of obesity.
Some xenoestrogens such as BPA
Bisphenol A
Bisphenol A is an organic compound with two phenol functional groups. It is used to make polycarbonate plastic and epoxy resins, along with other applications....
, nonylphenol
Nonylphenol
Nonylphenol is a family of closely related organic compounds, a subset of the alkylphenols. This collection of compounds is a precursor to commercially important detergents...
, and DEHP have all shown to act is this way, altering NPY expression and significantly shifting the feeding behaviors of exposed mice. In addition, organotin
Organotin
Organotin compounds or stannanes are chemical compounds based on tin with hydrocarbon substituents. Organotin chemistry is part of the wider field of organometallic chemistry. The first organotin compound was diethyltin diiodide, discovered by Edward Frankland in 1849...
s such as TBT
Tributyltin
Tributyltin compounds are a group of compounds containing the 3Sn moiety, such as tributyltin hydride or tributyltin oxide. They are the main active ingredients in certain biocides used to control a broad spectrum of organisms...
, TMT
TMT
TMT may refer to:* Tandem mass tag, a label used for quantitative mass spectrometry–based proteomics* Tarsometatarsal articulations* Technology, Media, Telecommunications – an investment sector, e.g., late-1990s TMT bubble...
, and TET
TET
TET/PRAO is a part of the Finnish and Swedish primary schooling system where students experience working at a real workplace....
can exert there effects through similar pathways. TBT can locally disrupt aromatase
Aromatase
Aromatase is an enzyme responsible for a key step in the biosynthesis of estrogens. It is a member of the cytochrome P450 superfamily , which are monooxygenases that catalyze many reactions involved in steroidogenesis. In particular, aromatase is responsible for the aromatization of androgens into...
regulation in the hypothalamus
Hypothalamus
The Hypothalamus is a portion of the brain that contains a number of small nuclei with a variety of functions...
causing the responses of the HPA axis to hormones to become abnormal. TMT works in a similar but unique way, inducing NPY and NPY2 receptor expression initially which later is counteracted by neuronal degeneration in lesions causing decrease in signaling ability.
While an increase in food intake is often the case after exposure, weight gain involves the body's maintenance of its metabolic setpoint as well. Given this information, it is particularly important to note that exposure during development and initial programming of these setpoints can be extremely significant throughout the remainder of life.
Endocannabinoid signaling
A wide range of environmental organotins that mimic petidergic hormones in the HPA axis as mentioned before, additionally mimic lipid activators of the cannabinoid system and inhibit AMPK activity. Endocannaboid levels are high in those suffering from obesity due to hyperactivity of cannaboid signalling pathways. It is these high levels that have been found to be closely associated with increased fat stores linking the lipid activator mimics to the actual disease.
Programming of metabolic set points
Regions in the hypothalmus control the responses that establish an individuals metabolic setpoint and metabolic efficiency. These responses are adaptive in that they vary according the the individual's needs, always working to restore the metabolic setpoint through the increase or decrease of metabolic functions depending on varying energy needs. Since it is adapted, it is expected that it would be able to achieve equilibrium if the lipid balance was altered by hormones via the mechanisms mentioned above. However since obesogenic phenotypes persist, it can be concluded that adaptive response components of the hypothalmus may be a target of obesogens as well.
A person's body composition is very much predetermined before birth and changes rarely occur in adulthood. Adipocyte numbers increase during development and come to a plateau over time. After the plateau adipocytes become restricted to mostly hypertrophic growth and don't seem to change much in terms of cell number. This is demonstrated by the difficulty in altering somatotypes or more simply by the difficulty that goes along with trying to lose weight past a certain point.
A particular study on PBDEs, a commonly used chemical in flame retardants, made its role in altering the functions of the thyroid
Thyroid
The thyroid gland or simply, the thyroid , in vertebrate anatomy, is one of the largest endocrine glands. The thyroid gland is found in the neck, below the thyroid cartilage...
hormone axis apparent. This finding leads to increased concern as neonatal thyroid status plays a large role in the integration of maternal environmental signals during development in the womb that is used for long-term body weight programming.
Pharmaceutical obesogens
Obesogens detection in the body and resulting obesogenic effects can result as side effects from intentional administration of obesogenic chemicals in the form of pharmaceutical drugs. These pharmaceutical obesogens can show their effects through a variety of targets.Metabolic sensors
Thiazolidinediones (TZD), rosiglitazoneRosiglitazone
Rosiglitazone is an antidiabetic drug in the thiazolidinedione class of drugs. It works as an insulin sensitizer, by binding to the PPAR receptors in fat cells and making the cells more responsive to insulin...
, and pioglitazone
Pioglitazone
Pioglitazone is a prescription drug of the class thiazolidinedione with hypoglycemic action.Pioglitazone is marketed as trademarks Actos in the USA, Canada, the UK and Germany, Glustin in Europe,"Glizone" and "Pioz" in India by Zydus CND and USV respectively and Zactos in Mexico by Takeda...
are all used to treat diabetes. These drugs act as agonists of the PPAR-γ receptor leading to insulin
Insulin
Insulin is a hormone central to regulating carbohydrate and fat metabolism in the body. Insulin causes cells in the liver, muscle, and fat tissue to take up glucose from the blood, storing it as glycogen in the liver and muscle....
sensitizing effects that can improve glycemic control and serum triglyceride
Triglyceride
A triglyceride is an ester derived from glycerol and three fatty acids. There are many triglycerides, depending on the oil source, some are highly unsaturated, some less so....
levels. Despite the positive effects these chemicals can have in treating diabetes patients, administration also lead to unwanted PPAR-γ mediated side effects such as peripheral edema
Edema
Edema or oedema ; both words from the Greek , oídēma "swelling"), formerly known as dropsy or hydropsy, is an abnormal accumulation of fluid beneath the skin or in one or more cavities of the body that produces swelling...
which can be followed by persistent weight gain if the drug is used over a long period of time. These side effects are particularly prominent in diabetes 2 patients, a disease that tends to result from an overabundance of adipose tissue.
Sex steroid dysregulation
DESDiethylstilbestrol
Diethylstilbestrol is a synthetic nonsteroidal estrogen that was first synthesized in 1938. Human exposure to DES occurred through diverse sources, such as dietary ingestion from supplemented cattle feed and medical treatment for certain conditions, including breast and prostate cancers...
is a synthetic estrogen that was once prescribed to women to decrease the risk of miscarraige until it was found to be causing abnormalities in exposed offspring. This same chemical has been shown to cause weight gain in female mice when exposed during neonatal development. While exposure didn't lead to an abnormal brith weight, significant weight gain occurred much later in adulthood.
Central integration of energy balance
SSRI, tricyclic antidepressants, and antypical antipsychotics are all neuropharmaceuticals that target neurotransmitter receptors that are involved with brain circuits that regulate behavior. Often the function of these receptors overlaps with metabolism regulation, such as that of the H1 receptor which when activated decreases AMPK activity. As a result, the administration of these drugs can have side effects including increased lipid accumulation that can result in obesity.Metabolic setpoints
The mechanisms behind SSRI, tricyclic antidepressants, and atypical antipsychotics function allow them all to have potential roles in the alteration of metabolic setpoints. TZD, in particular has been linked to regulatory function in the HPT Axis, however, no conclusive evidence has been determined thus far and further research is required to confirm these hypotheses.Environmental obesogens
While obesogens can be introduced to the body intentionally via administration of obesogenic pharmaceuticals, exposure can also occur through chemical exposure to obesogens found in the environment such as organotins and xenobioticsOrganotins and Human Exposure
Organotins (tin-based chemicals), used in marine anti-fouling paints, wood catalysts, plasticizers, slimicides, in industrial water systems, and fungicides on food have recently been linked to obesogenic properties when introduced in the body. Human exposure to these major environmental sources most commonly occurs through ingestion of contaminated seafood, agricultural products, and drinking water as well as from exposure to leaching from plastics.Although studies that have directly measured organotin levels in human tissue and blood are limited, it has been determined that vulnerability of a portion of the general population to organotin exposure at levels high enough to activate RXRs and PPARγ receptors is very probable. The high usage of organotins in both plastics and agricultural maintenance as well as the high affinity of the chemicals further confirms this conclusion.
Liver samples from the late 1990s in Europe and Asia contained on average 6 and 84 ng/g wet wt respectively for total organotin levels, while later studies foung levels of total organotins in US blood samples averaged around 21 ng/mL with TBT comprising around 8 ng/mL (~ 27 nM) Even more recent analyses of European blood samples found the predominant species to be TPT rather than TBT at 0.09 and 0.67 ng/mL (~0.5-2 nM). Only occasional trace amounts of TBT were found. These results indicate that organtin exposure to humans, while found to be present among many different populations, can vary in terms of type of organatin and level of exposure from region to region.
Obesogenic organotins
Particular members of the organotin class of persistent organic pollutants (POPs), namely tributyltinTributyltin
Tributyltin compounds are a group of compounds containing the 3Sn moiety, such as tributyltin hydride or tributyltin oxide. They are the main active ingredients in certain biocides used to control a broad spectrum of organisms...
(TBT) and triphenyltin (TPT) are highly selective and act as very potent agonists of both the retinoid X receptors (RXR α,β, and γ) and PPARγ. This ability to target both receptors at the same time, is more effective than single receptor activation, as adopogenic signaling can be mediated through both components of the heterodimer complex. This highly effective activation mechanism can pose detrimental, long-term adipogenic effects especially if exposure occurs during development and early life.
Obesogenic xenobiotics
Other common xenobiotics found in the environment have been shown to have PPAR activity, posing even further threats to dysregulated metabolic balance. BPABisphenol A
Bisphenol A is an organic compound with two phenol functional groups. It is used to make polycarbonate plastic and epoxy resins, along with other applications....
from polycarbonate
Polycarbonate
PolycarbonatePhysical PropertiesDensity 1.20–1.22 g/cm3Abbe number 34.0Refractive index 1.584–1.586FlammabilityV0-V2Limiting oxygen index25–27%Water absorption – Equilibrium0.16–0.35%Water absorption – over 24 hours0.1%...
plastics, phthalate plasticizers used to soften PVC plastics, and various perfluoroalkyll compounds (PFCs)that are widely used surfactants and surface repellents in consumer products are all potentially obesogenic when introduced in the body. Phthalates and PFCs in particular have been found to function as agonists for one or more of the PPARs Additionally, metabolites of DHEP such as MEHP also activate PPARγ leading to a proadipogenic response.
Future Research
Most of the environmental obesogens currently identified are either classified into the category of chemical mimics of lipophilic hormones or hormone metabolism inhibitors. Because they fall into these two categories, extensive opportunities for complex interactions and varied sites of action as well as multiple molecular targets are open for consideration. Changing dose ranges tend to result in varying phenotypes and timing of exposure, gender, and gender predisposition introduce even more levels of complexity in how these substances effect the human body.Because the mechanisms behind the different effects of obesogens are so complex and not well understood, the extent to which they play in the current obesity epidemic may be greater than once thought. Epigenetic changes due to obesogen exposure must also be considered as a possibility, as they open up the potential for misregulated metabolic functions to be passed on from generation to generation. Epigenetic processes via hypermethylation of regulatory regions could lead to overexpression of different proteins, and therefore, amplification of acquired environmental effects. research will be required in order to gain a better understanding of the mechanism of action these chemicals are involved in before the extent of the risk of exposure can be determined and methods of prevention and removal from the environment can be established.