Obesogens, Stem Cells, and the Maternal Programming of Obesity
Bruce Blumberg, PhD, Department of Developmental and Cell Biology and
Pharmaceutical Sciences, University of California, Irvine, CA
(Presented at the 2011 BCERP National Meeting. Summary by Lora Arduser.)
Obesity and metabolic syndrome disease have exploded into epidemic proportions.
In fact, 34 percent of Americans are obese and 68 percent are overweight. Obesity is
also linked to a variety of cancers, including breast cancer.
The prevailing wisdom on how people become overweight is that they eat too much
and exercise too little. Therefore, when we talk about obesity we talk about genetics
and behavior. In this presentation, however, Blumberg argued that it may not that
simple and he offered an alternative model that examines the role that chemicals
called obesogens play in obesity.
In the research presented in this forum, Blumberg specifically discussed whether
disturbances in endocrine signaling pathways, the pathways the endocrine system
uses to release hormones to act on distant target cells in the body, caused by
endocrine disruptors are involved in the development of fat cells and obesity.
Research shows that chemicals in the environment, obesogens, affect the
development of fat in the body. Because these chemicals affect the endocrine system
and hormones, they also can encourage fat development by increasing our appetite
or inhibiting the response to stop eating when we feel full. They can also make more
undifferentiated cells (stem cells) develop into fat cells (instead of bone) or by
telling existing fat cells to store more fat.
Research
The researchers hypothesized that one of the reasons more people are obese today
than in the past is because obesogens are affecting the way stem cells differentiate.
To examine this question and study the role of obesogens, the research team set up
an experiment in mice. They introduced a control substance, rosiglitazone (Avandia,
used for type 2 diabetes treatment), or the chemical compound tributltin (TBT), a
well-known endocrine disruptor, into pregnant mice.
They gave one dose of the substances at day 16 of gestation. To control for the
possibility of the effect of TBT lingering through nursing, they left some pups with
the mother and gave others to an unexposed surrogate mouse. When the pups
reached eight weeks of age, the stem cells were harvested to determine how many
of the cells could become fat cells, bone cells or cartilage. The findings revealed that
while there was no difference between the pups left with their mothers or those left
with the surrogates and that TBT had no effect on the development of cartilage cells,
it did affect the stem cells that became fat cells or bone cells. If the pregnant mice
were given rosiglitazone or TBT prenatally, almost twice as many stem cells could
become fat cells. At the same time, fewer cells became bone cells. In other words, the
stem cells that might have become bone or fat cells become predisposed to become
fat cells.
TBT did this by activating Peroxisome Prolifertor Activated Receptor gamma
(PPARγ) and retinoid X receptor (RXR) at very low levels (parts per billion).
PPARγ and RXR are hormone receptors, proteins that bind to specific hormones or
hormone-like chemicals and turn genes on or off directly. The development of fat
cells is under control of a variety of hormones but PPARγ is the master regulator of
fat cell development. If PPARγ is expressed in an undifferentiated cell, the cell can
become a pre-fat cell. If it is activated in a pre-fat cell, that cell becomes a fat cell. If
PPARγ is activated in an existing fat cell, that cells stores more fat.
Conclusion
Blumberg concluded his presentation with a summary of what we know and what
we don’t know at this point about the relationship between obesity, TBT, and fat cell
development.
We know that obesogens inappropriately stimulate fat cells and the storage of fat
into those cells. We know that there are environmental contaminants that cause
increased numbers of fat cells and obesity in animal studies. We also know that
certain drugs, like many used for treatment for diabetes and depression alter fat cell
development and physiology to promote obesity; therefore, it is logical that
chemicals in the environment that work through the same pathways could have the
same effect. We know that prenatal exposures to obesogens re-programs an animal
to be fat despite normal diet and exercise. These effects appear to be associated with
epigenetic modifications that change the expression of important genes in stem
cells, and these effects can be transgenerational, that is, passed from parents to
offspring .
We also know that TBT causes stem cells to become fat cells by activating RXR and
PPARγ during development in mice, rats, frogs, and fish. It affects fat cell size and
gene expression in animals despite the fact that the animals ate normal diets.
What we don’t know for certain yet is whether or not adults exposed to TBT and
other environmental chemicals are becoming obese in part because of that
exposure. The research presented here, however, suggests that diet and exercise
are an insufficient explanation for why we have an obesity epidemic. Therefore, we
need to shift the paradigm from treating obese people to preventing children from
being obese in the first place. To do this we need to decrease exposure during
critical windows of development and promote optimal nutrition.