X-Message-Number: 30316
Date: Mon, 14 Jan 2008 12:28:23 -0700
From: hkhenson <>
Subject: The Skinny Fat

This is the kind of fundamental work that may 
bring us to much longer lives.  Keith

  Volume 22 | Issue 1 | Page 28

The Skinny Fat FRANKLYN RODGERS / SCIENCE PHOTO LIBRARY
All Fat Cell images courtesy of Patrick Seale What if you could make
fat cells burn energy rather than store it?
By Bruce Spiegelman

 From an outsider's perspective, obesity seems like a simple problem to
solve: Eat less, exercise more. But, the body regulates food intake and
feelings of satiety as part of a tightly regulated homeostatic process.
Once a person becomes obese, it's these same regulatory feedback loops
that also defend the obese state as the new "normal." Losing weight is
difficult, in part, because of the starvation signals that your body
sends in order to keep your weight constant.

Today a full third of all Americans are obese, more than 50% are
overweight, and 300,000 die annually from obesity-related metabolic
diseases such as diabetes, hypertension, cardiovascular disease and
cancer.

Most therapies are geared at blocking fat absorption or curbing
appetite, yet the precise contribution of overeating to obesity is
unclear. Studying diet in obese patients is confounded by the fact that
these patients tend to underreport their food intake by as much as 30%.
Overeating can be gauged only in relation to that individual's energy
expenditure.

We're missing a big opportunity by focusing so much on the molecular
control of food consumption. If obesity comes from an imbalance in the
"energy consumed-energy burned" equation, we should also be focusing on
the molecular basis of energy expenditure. That's exactly where I've
devoted much of the last 10 years of my research.

I haven't always been interested in issues of obesity and metabolic
disease. As a biochemist and cell biologist back in the early 1980s, I
was fascinated by the coordination of cellular systems in development.
We used adipocytes as a model to study developmental signaling. It was a
lucky choice, as the United States was beginning to notice the growing
numbers of obese people. That the study of fat cell differentiation and
the study of metabolic disease would converge was, with the benefit of
hindsight, inevitable. Tracing the connection between fat cell
development and the prevention of obesity has been a long and eventful
journey.

When I started my own lab at Dana Farber Cancer Institute and Harvard
Medical School in 1982, I was committed to researching fat-cell
regulation. More than a decade of study led me, in 1998, to the
metabolically hyperactive member of the fat-cell family that is abundant
in infants but almost absent in adults. Our search for a trigger that
could be important in obesity also revealed other mechanisms involved in
diseases unrelated to obesity.
If obesity comes from an imbalance in the "energy consumed-energy
burned" equation, we should also be focusing on the molecular basis of
dissipating energy.
The number of fat cells does not increase in adults with morbid obesity.
This suggests more fat cell differentiation in the development of morbid
obesity. My lab's major goal starting in 1982 was to identify the
molecular switch that triggered fat cell differentiation.

I was interested in the fat cell differentiation pathway as a model for
understanding a basic process that might be applicable in other
differentiation systems and to the loss of cell differentiation in
cancer. We first identified genes that were expressed specifically in
fat cells compared to preadipocytes, fat cell precursors. Then we looked
upstream for the enhancers and transcription factors that turned on the
genes.

We had a catalog of hundreds of genes that were turned on during fat
cell differentiation, but among them the aP2 gene stood out because it
was abundant and seemed an appropriate model system. So we set out to
find out what controlled expression of aP2, and that was how we first
came across the peroxisome proliferation-activated receptor gamma
(PPAR ) in 1994. Researchers now recognize it as the "master gene" of
fat cell development as well as the receptor for a few antidiabetic
drugs. Reed Graves and Peter Tontonoz spent years dissecting the aP2
enhancer and found that one DNA binding complex, which we called ARF6,
seemed to have all the properties suggesting that it could be the "key"
factor. Peter and Erding Hu cloned ARF 6, and showed it was PPAR  in
complex with RXR. PPAR  had been just described as a new member of
the nuclear receptor family, but nothing was known about its function.
When Peter transduced the gene for PPAR  into fibroblasts using viral
vectors and provided a ligand, they differentiated into fat cells.

We were ecstatic, because this suggested that we might have found the
switch for fat cell formation. I think that this was one of the most
important findings that's come out of my laboratory to date.
Brown fat is commonly found in infants, where the cell type helps
generate enough heat for the child's survival. Brown fat cells have no
reason for existing except to generate heat.
It took quite a few years of work and the combined effort of several
labs to work out the pathway by which PPAR  functioned. We now had a
good idea of how to turn on the production of new white fat cells. Other
labs had shown that PPAR  also played a key role in brown fat
differentiation, which was a little surprising, given how functionally
different the two cell types are.

Brown fat is commonly found in infants, where the cell type helps
generate enough heat for the child's survival. Brown fat cells have no
reason for existing except to generate heat. They do this by leaking
hydrogen ions across the inner membrane of the mitochondria, generating
heat, instead of converting it into ATP for other metabolic processes
(see Energy-burning baby fat
<http://www.the-scientist.com/2008/1/1/31/1> ).

While it's abundant in infants, brown fat is almost absent (or at least
difficult to find) in adults. Both cell types can originate from the
same precursor cells, so we thought (and still think) that if we could
find the specific trigger of brown fat, we might be able to increase the
number of brown fat cells in obese adults. If we could find the right
switch, we'd have a way for obese individuals to siphon excess energy
into heat via brown fat cells, rather than into the storage chambers of
white fat cells.

Pere Puigserver and I decided to try to find the fat cell-specific
triggers of PPAR . We screened brown fat gene libraries for molecules
that interacted with PPAR , and in 2004 we published our findings on
a molecule that bound to PPAR  and activated genes important to brown
fat-specific differentiation. With great originality, we called this
protein PGC-1, for PPAR  coactivator-1. When the gene for PGC-1 was
expressed in white fat cells, it increased mitochondrial respiration and
mitochondrial biogenesis and induced the expression of an uncoupling
protein (UCP) that makes mitochondria energetically leaky. Instead of
retaining the energy that mitochondria produces, the UPC causes its
release as heat. It's the reason why brown fat is so much more abundant
in hibernating animals and babies who cannot rely solely on shivering to
provide sufficient heat.
Although preadipocyte cells are not abundant in adults, a change of 1-2%
might be enough to create a significant change in obesity over time.
PGC-1 alpha has turned out to be a key regulator of those brown fat
genes linked to mitochondrial biogenesis and thermogenesis. It is also a
key regulator of mitochondrial gene expression and respiration in many
if not most tissues. In fact, PGC-1 alpha is turned on in many tissues
by external stimuli such as exercise (in muscle) or cold (in brown fat),
and it mediates the effects of those stimuli on mitochodrial number and
function. Moreover, PGC-1 alpha also causes muscles to switch their
fiber-type to more oxidative fibers - something that consistent exercise
is known to do.

Most recently we realized that although PGC-1 alpha controls the
mitochondrial biology and thermogenesis of brown fat, it does not
control all the genes characteristic of brown fat. Patrick Seale and I
reasoned that if PGC-1 turned on multiple, but not all, brown fat
functions, there had to be another regulator that was located upstream
genetically that was acting as the "master regulator" of brown fat
differentiation.

We assayed a published database of all the transcriptional components of
the mouse genome, around 2,000 of them, for components that were
specific to brown fat. We then screened the subset of the 20 that we
found and discovered that only three genes were selective for expression
in pure brown cells versus pure white cells. Of those three, PRDM16 was
the only one that fit the bill. It was almost nonexistent in white fat.
Moreover, PRDM16 not only activated the PGC-1 gene, but it also ramped
up expression of nine other brown fat-specific genes that we had
identified when we expressed it in fibroblasts, destined to otherwise
become white fat cells. When PRDM16 expression was knocked down with
interfering RNA, brown fat cells lost their characteristic phenotype and
looked more like white fat cells, from a genetic perspective. We
published our results in July 2007.

It wasn't too far-fetched to think that if we found a way to activate
PRDM16 in human white fat, we could tip the energetic balance in the
direction of passive energy expenditure. However, we could get the brown
fat phenotype only when we turned on PRDM16 in undifferentiated adipose
cells in culture, but not those that had already become white fat cells.
While this result may seem discouraging in terms of applying it to
humans, it's not as bad as it seems. Although preadipocyte cells are not
abundant in adults, a change of 1-2% might be enough to create a
significant change in obesity over time.

I'm betting that there will be an effect on obesity in humans. We've
recently started working with the Broad Institute in Boston to screen
every FDA approved drug for possible effects on PRDM16. Just because a
drug is being used for another purpose doesn't mean it won't have other
effects that we haven't yet discovered in the body. Also, we're looking
for a small change over time that might not be picked up by clinicians.
If we find an approved compound or combination of compounds that work,
they would already have safety and pharmacokinetic information
associated with them - immensely speeding the process of bringing the
drug to patients.

I had set out with the goal of understanding differentiation pathways.
It's fortunate that the model system I used happened to reveal pathways
that are so important in basic physiology.

While looking for the genetic switch for fat cell differentiation (brown
and white), we realized that these brown-fat molecules, PRDM16 and
PGC-1, were important in many other pathways. When we knocked out the
PGC-1 in mice, the first and most obvious effects we saw were the
changes in the brain. Although we didn't see changes in body weight in
this model, the mouse was very sensitive to cold, showing an inability
to generate heat through uncoupled mitochondrial respiration.

How can brain functions share the same pathways as fat cells? The whole
point of brown fat is expanded and accelerated mitochondrial biology.
Brown fat produces energy through a proton leak process that releases
heat instead of converting the energy into ATP. The brain, like the
heart, is extremely expensive energetically, and these are usually the
first organs to show the effects of malfunctioning mitochondria. Our
PGC-1 knockouts were much more sensitive to oxidative damage in the
brain from reactive oxygen species, which the mitochondria produce. In
2006 we published our findings showing that when the gene for PGC-1
alpha is expressed in cells, it increases mitochondrial respiration
while at the same time increasing the enzymes responsible for
detoxification of the reactive species.

We're very interested in the possible role these two molecules have in
the brain, and there are suggestions that PRDM16 may be important in
Huntington's disease. It may seem dangerous to try fiddling with genes
that are so important in regulating mitochondria - the cell's
powerhouse. But, to be useful in obesity we're looking for a drug that
might change the balance by 1-2%. Over time and with other management
methods, that could make an important difference for an obese
individual.

The more we learn about them, the more PRDM16 and PGC-1 alpha appear to
be crucial for many functions. Indeed, researchers studying different
tissues in other fields could have discovered them first. But because
brown fat so emphasizes these pathways, they've been the best tool for
finding the "master" mitochondrial regulators. If we ever had had a
really good idea, the study of this cell type was probably it.

Bruce Spiegelman is a professor of cell biology at Harvard Medical
School and the Dana-Farber Cancer Institute.

Source: TheScientist
http://www.the-scientist.com/article/display/54033/

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