Phoebeliza Jane Broola

MS Chemistry
University of the Philippines-Diliman
Outline
I. Overview of Obesity Epidemic
II. Obesogen Theory
III. Mechanism of Action
IV. Potential Obesogenic Compounds
V. Future
Obesity Global Statistics
Worldwide obesity has nearly doubled since 1980.

In 2008, 35% of adults (>20yrs old) were overweight and 11% were
obese.

65% of the world's population live in countries where overweight and
obesity kills more people than underweight.
Source: World Health Organization. Fact sheet N311. http://www.who.int/mediacentre/factsheets/fs311/en/. Last update: March
2013.
Figure 1. Obesity report of developed countries based on OECD
data.
[2]

Figure 2. Overweight prevalence (%) in Southeast Asia for adults
of both sexes
due to prolonged positive energy balance
Due to a prolonged disturbance in the homeostatic
regulation of energy metabolism that favors triglyceride
storage and adipocyte hypertrophy
Characterized by increased adipocyte number and lipid
content

Source: Grun, F., Blumberg B., Mol Endocrinol. 23 (8), 1127-1134.
Obesogens are compounds that disrupt the function and
development of adipose tissue or the normal metabolism of
lipids, leading to an increased risk of obesity and associated
diseases.
[1]

Obesogens are defined functionally as chemicals that
inappropriately alter lipid homeostasis to promote
adipogenesis and lipid accumulation.
[2]


Obesogen Mode of Action
Adipocytes act as:
1)storage of fat and
2)endocrine gland

Conditions for Obesogen Interaction
Molecular targets should be found in adipose tissues
Alters biology of adipose tissue (i.e. inc fat content,
inc. # of fat cells)
Latent effect


Pathways Susceptible to Obesogen Action

1. Metabolic sensors
Control of adipocyte function and differentiation
Nuclear hormone receptors, NRs, for lipophilic hormones, dietary fatty
acids, and their metabolites

PPAR-
peroxisome proliferator-activated receptors
master fat-cell-differentiation regulator
When activated, genes are turned on and
generate proteins that turn a cell into a fat cell
Inc. cell #
Inc. cell size
Increase amount of fat stored


Figure 3. Ligand-PPAR interaction.
[12]

2. Sex steroid dysregulation
sex steroids controls white adipose tissue metabolism
Estrogens (modulate lipogene, lipolysis, and adipogenesis)

3. Central integration of energy balance
Mechanisms that coordinate whole body response to daily fluctuations
Signals for satiety and appetite are potential obesogen targets

4. Programming of metabolic setpoints

Figure 4. List of a few known and suspected obesogens.
[11]

Obesogens
Diethylstilbestrol (DES)
[6]

Synthetic estrogen used in 1940s-70s to treat threatened
miscarriage
Also used as growth hormone for beef & poultry industry
Carcinogen
Molecular target: estrogen receptors

Figure 6. Representative photograph of Control and
DES-treated mice.
[7]




Genistein
[6
]


Phytoestrogen (Grp: isoflavones) used for its antioxidant and
anthelmintic properties
Soya, legumes, and some herbs
Similar chemical structure to estradiol (main natural
estrogen for humans)
At low doses, it was reported to induce adipose tissue
deposition esp. in males.


Fructose
Affects lifelong neuroendocrine function, appetite control, feeding
behaviour, adipogenesis, fat distribution and metabolic systems in
early stages of development (fetal, neonatal, etc.)






**Bisphenol A (BPA)
[8]


Synthetic compound widely used in plastic production, food
packaging, water pipes, electronic equipments, paper, toys,
etc.
higher BPA concentrations were noted in ground waters
situated near waste dumps that are deposits of plastic
materials
Largest source of exposure:
Food
Drinking H
2
O
Inhibit adiponectin production
[6]



**Pthalates
[6
]

Synthetic organic compounds
Components of plastics, cosmetic products, toys

**Organotin Compounds (TBT, MBT, TPT)
[6]

Organic agents constantly polluting the environment
Ship coating, preservative for wood
industry, H
2
O systems, fungicides in foods
Inhibits growth of fungi, barnacle, and is
reported to be toxic to other marine organisms



Source: http://www.ncbi.nlm.nih.gov/pubmed/21724975
References
[1] Philippine Association for the Study of Overweight
and Obesity. http://obesity.org.ph/v4/. Web. Date
accessed: March 7, 2014
[2] Downey Obesity Report.
http://www.downeyobesityreport.com/category/econo
mics/global-economic-perspective/. Last update: June 4,
2012. Date Accessed: March 9, 2013
[3] Bickerstaff, B. Obesity in Thailand: Behold the perfect
storm. http://www.burning-bison.com/obesity.htm. Last
update: July 14, 2013. Date accessed: March 9, 2013.
[4] Grn, F. and Blumberg, B. 2009. Endocrine disrupters
as obesogens. Molecular and Cellular Endocrinology. 304,
19-29.
[5] Blumberg, B. Lesson 7: Obesogens Module 1. [Online
lecture video] Retrieved from
http://igs.chem.cmu.edu/index.php?option=com_conten
t&view=article&id=248&Itemid=307.
[6] Garcia-Mayor, R. et.al. 2012. Endocrine disruptors and
obesity: Obesogens. Endocrinol. Nutr. 59(4), 261-267.
[7] Newbold, R.R., Padilla-Banks, E., Jefferson, W. 2009.
Environmental estrogens and obesity. Molecular and
Cellular Endocrinology. 304, 84-89.
[8] Michalowicz, J.,Bisphenol Andashsources, toxicity and
biotransformation, Environmental Toxicology and
Pharmacology (2014),
http://dx.doi.org/10.1016/j.etap.2014.02.003.
[9] Lustig, R. (editor) 2011. Obesity before Birth. Springer.
[Online]

[10] Janesick, A. and Blumberg, B. 2011. Minireview:
PPAR as the target of obesogens. Journal of Steroid
Biochemistry and Molecular Biology. 127, 4-8.
[11] Obesogens an environmental link to obesity. 2012.
Environmental Health Perspective. 120, 2.
[12] Retrieved from
http://www.thelancet.com/journals/lanonc/article/PIIS1
470204504015098/images?imageId=gr2&sectionType=gr
een&hasDownloadImagesLink=true. Date accessed:
March 10, 2013.
[13] Grun, F., Blumberg, B. 2009. Minireview: The
case for obesogens. Mol. Endocrinol. 23(8), 1127-
1134.
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC27187
50/#!po=5.95238
[14]