User:Hortonsb/sandbox
Obesogens are
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
Obesogens have been detected in the body both as a result of intentional administration of obesogenic chemicals in the form of
The term obesogen was coined by Bruce Blumberg of the University of California, Irvine.[8] 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.
Mechanisms of action
Effects mediated by metabolic sensors
Both obesogenic drugs and chemicals have been shown to target transcription regulators found in gene networks that function to control intracellular lipid homeostasis and proliferation and differentiation on adipocytes. The major group of regulators that is targetted is a group of nuclear hormone receptors known as
The PPARα receptor, when complexed with RXR and activated by the binding of a lipid, promotes
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.[5][6]
The ligand binding pockets of PPARs are very large and unspecified, allowing for different
A second explanation points to specific PPARα targetters that have been shown to additionally cuases abnormal transcriptional regulation of testicular
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. [16]
Effects mediated by 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, and increased resistance to insulin effects.[17]
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.[5][6] 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.[18][19][20] 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.[21][19][20] Further studies have shown positive correlations for serum BPA levels with obese females in the human population, along with other xenoestrogen compounds suggesting the role the parallel roles that these effects may be having on humans.[22]
Effect on central integration of energy balance
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
Neuroendocrine effects
Neurological disorders often open up an enhanced possibility for a variety of metabolic syndromes including obesity.[23] 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.[5][6]
Peptidergic hormones
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 disruptors. 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. [5][6]
Some xenoestrogens such as
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.[5][6]
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. [5][6] 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. [28]
Effect on programming of metabolic set points
Regions in the
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
A particular study on
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 varity of targets.
Target: Metabolic Sensors
Target: Sex Steroid Dysregulation
As referenced above, DES, a synthetic estrogen that was once prescribed to women to decrease the risk of miscarraige until it was found to be causing cancers and abnormalities in exposed offspring, 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 occured much later in adulthood. [19][20]
Target: Central Integration of Energy Balance
Target: 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.[5][6]
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.
Organotins, 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. [36] 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.[37][38][39]
Although studies that have directly measures 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.[5][6]
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) [40] 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.[41][42] 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.
Particular members of the organotin class of
Other common
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. Becuase 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.[5][6]
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.
See also
- Endocrine disruptor
- Metabolic syndrome
- The New American Diet
- PPAR
- RXR
- Adipogenesis
- Organotin
References
- PMID 17657605.)
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: CS1 maint: date and year (link - PMID 16690801.)
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: CS1 maint: date and year (link - ^ Begley, Sharon (2009-09-21). "Why Chemicals Called Obesogens May Make You Fat". Newsweek. Retrieved 2010-04-29.
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(help) - PMID 20160124.)
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: CS1 maint: date and year (link) CS1 maint: multiple names: authors list (link - ^ PMID 19433244.)
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: CS1 maint: date and year (link - ^ PMID 19372238.)
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: CS1 maint: date and year (link - PMID 19502515.)
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: CS1 maint: date and year (link) CS1 maint: multiple names: authors list (link - ^ Daley B (2008-01-14). "Is plastic making us fat?". The Boston Globe. Retrieved 2010-08-05.
- doi:10.2337 (inactive 2023-08-02).)
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value (help)CS1 maint: DOI inactive as of August 2023 (link) CS1 maint: date and year (link - PMID 10549292.)
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: CS1 maint: date and year (link) CS1 maint: multiple names: authors list (link - ^ PMID 12805656.)
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: CS1 maint: date and year (link) CS1 maint: multiple names: authors list (link - PMID 11099646.)
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: CS1 maint: date and year (link) CS1 maint: multiple names: authors list (link - PMID 16815795.)
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- PMID 18335098.)
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: CS1 maint: date and year (link) CS1 maint: multiple names: authors list (link - ^ PMID 17604389.)
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: CS1 maint: date and year (link) CS1 maint: multiple names: authors list (link - ^ PMID 17321108.)
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: CS1 maint: date and year (link) CS1 maint: multiple names: authors list (link - PMID 15118266.)
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Further reading
- Grün, F.; Blumberg, B. (Aug 2009). "Minireview: the case for obesogens". Molecular Endocrinology (Baltimore, Md.). 23 (8): 1127–1134. PMID 19372238.
- Grün F, Blumberg B (June 2007). "Perturbed nuclear receptor signaling by environmental obesogens as emerging factors in the obesity crisis". Rev Endocr Metab Disord. 8 (2): 161–71. PMID 17657605.)
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: CS1 maint: date and year (link - Newbold, R.; Padilla-Banks, E.; Jefferson, W.; Heindel, J. (Apr 2008). "Effects of endocrine disruptors on obesity". International Journal of Andrology. 31 (2): 201–208. PMID 18315718.
- Newbold, R.; Padilla-Banks, E.; Jefferson, W. (Jun 2006). "Adverse effects of the model environmental estrogen diethylstilbestrol are transmitted to subsequent generations" (Free full text). Endocrinology. 147 (6 Suppl): S11–S17. PMID 16690809.
- Boberg, J.; Metzdorff, S.; Wortziger, R.; Axelstad, M.; Brokken, L.; Vinggaard, A.; Dalgaard, M.; Nellemann, C. (Sep 2008). "Impact of diisobutyl phthalate and other PPAR agonists on steroidogenesis and plasma insulin and leptin levels in fetal rats". Toxicology. 250 (2–3): 75–81. PMID 18602967.
- Hines, E.; White, S.; Stanko, J.; Gibbs-Flournoy, E.; Lau, C.; Fenton, S. (May 2009). "Phenotypic dichotomy following developmental exposure to perfluorooctanoic acid (PFOA) in female CD-1 mice: Low doses induce elevated serum leptin and insulin, and overweight in mid-life". Molecular and Cellular Endocrinology. 304 (1–2): 97–105. PMID 19433254.
- Chen, J.; Brown, T.; Russo, J. (Jul 2009). "Regulation of energy metabolism pathways by estrogens and estrogenic chemicals and potential implications in obesity associated with increased exposure to endocrine disruptors". Biochimica et Biophysica Acta (BBA) - Molecular Cell Research. 1793 (7): 1128–1143. PMID 19348861.
External links
Category:Obesity Category:Nutrition Category:Body shape Category:Receptors Category:Neologisms
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