Fat chance: the biology of obesity
Better understanding of fat-cell hormones will
help us attack the twin epidemics of obesity and diabetes
Imagine this public-health drama as a film with two
parallel plot lines.
Here’s the first plot line: The U.S. has a problem,
a big problem. We’re increasingly becoming
a nation of overweight—and often downright obese—people.
Just look at the numbers. Statistics from 1985 show
that less than 10% of the populations of New York and
California qualified as being obese. Fast forward to
2001, and that number jumps all the way to 24%.
While obesity plays a big role in other diseases
ranging from cardiovascular disease to cancer,
it tracks particularly well with the epidemic
of diabetes. |
The second plot line unravels another drama: The onslaught
of type 2 diabetes. This disease, afflicting nearly
10% of adults and a rapidly increasing number of children,
is the leading cause of blindness and kidney failure,
and ranks sixth on the list of killers. And the number
of cases is soaring.
You’ve probably guessed the first plot twist:
Both stories star the same villain.
While obesity plays a big role in other diseases ranging
from cardiovascular disease to cancer, it tracks particularly
well with the epidemic of diabetes. The state of Mississippi
offers one telling example. While the rates of obesity
there climbed from ten percent to over 25% during the
1990s, rates of type 2 diabetes climbed from 6% to over
10%.
In a Supersized nation where Burger King’s latest
breakfast sandwich weighs in at 730 calories and 47
grams of fat, more and more people have trouble squeezing
their stomachs behind the steering wheel as they head
over to the drive-through.
But the plot thickens yet again: Advances in medical
understanding of the biology of obesity offer hope for
a happy ending.
As these twin epidemics explode, so has our knowledge
of the key molecules and mechanisms responsible for
giving fat a bad name—findings that many pharma
companies are now trying to exploit with anti-obesity
therapies.
Harvey Lodish,
a Founding Whitehead Member and professor of biology
at MIT, has pioneered this field. Lodish opened up the
field of glucose transport regulation by cloning the
first protein that transports this sugar across cell
membranes. He also has been a leader in studying the
hormones that fat cells secrete, comments diabetes researcher
Jeffrey Flier of Harvard University.
The Lodish lab has helped to reveal why obesity is
not only so toxic to an organism but also why it is
so correlated with type 2 diabetes.
Shuttling sugar
Not all diabetes is related to obesity. Type 1 diabetes,
often referred to as juvenile diabetes, has nothing
to do with body weight. Rather, it’s a condition
in which the immune system attacks the insulin-producing
cells in the pancreas, causing blood sugar levels to
skyrocket. In type 2 diabetes, often called adult-onset
diabetes, the cells in muscle and fat tissue start becoming
resistant over time to the signals that insulin sends.
Once again, blood sugar levels skyrocket.
It’s been known for about 80 years that insulin
is the hormone chiefly responsible for regulating glucose,
the sugar in your blood that gives you energy. In fact,
insulin is the first biotechnology product ever, manufactured
in the 1920s to treat type 1 diabetes.
“Basically, insulin is part of a regulatory circuit,”
says Lodish, much of whose work has focused on the exact
signaling process by which insulin communicates with
cells.
Here’s how it works:
Whenever you eat or drink, your digestive system releases
glucose into your bloodstream. But the glucose can’t
make it into your cells without help from insulin.
As the glucose level in your blood mounts, certain
cells in your pancreas start producing insulin and releasing
it into your bloodstream. The insulin molecules make
their way to muscle cells, where they bind to receptor
proteins on the surface and send signals to proteins
deep in the cytoplasm called glucose transporters—a
class of proteins that was first identified in Lodish’s
lab in 1985.
Insulin lets these proteins know that there is a crowd
of glucose molecules outside the cell eager to get in.
The glucose transporters wake up from their cytoplasmic
slumber and travel to the cell surface. Here, they merge
into the cell surface membrane and morph into a kind
of trap door, allowing individual glucose molecules
to pass through one at a time into the cell.
But in obese people, this entire process begins to
break down. “The insulin signal is sent, but the
transporters respond sluggishly,” says Lodish.
“Eventually, they barely respond at all.”
If glucose stays at high levels in the blood, diabetes
sets in, with all its nasty complications. As Lodish
describes it, though, type 2 diabetes is not so much
a disease like lung cancer or Parkinson’s. Rather,
it’s a cluster of symptoms that in many cases
can be eliminated through diet and exercise. When the
symptoms vanish, the person is technically no longer
a diabetic.
So the key to understanding this condition is located
squarely in the plump center of the fat cell.
Size matters
For many years, fat cells were seen simply as cells
that were. . .well. . . fat. That is, nothing
more than passive repositories of triglycerides, the
chief component of fats and oils. But that assumption
took a hit in 1994 when Rockefeller University researcher
Jeffrey Friedman discovered a hormone called leptin.
Studying mice that were genetically modified to be
obese, Friedman found that leptin acts as a sort of
thermostat for fat. When the mice ate too much, fat
cells released leptin into the brain, where it would
release a series of signals dictating that enough’s
enough.
Further studies showed that mice who were deficient
in leptin couldn’t stop eating and would thus
become grossly obese. Once they were administered the
hormone intravenously, their appetites returned to normal.
As it turns out, a small percentage of people are leptin-deficient
and can be treated the same way. Undoubtedly, leptin
is a “good” hormone.
But here’s the real kicker: Friedman had found
that leptin was produced by fat cells. So fat
cells were no longer seen as inert units for triglyceride
storage. They were active players secreting important
metabolic hormones.
The following year, the Lodish lab made an equally
startling discovering when it found another fat-cell-secreted
hormone called adiponectin, which acts in concert with
insulin in helping the cells to absorb glucose from
the blood. Adiponectin also helps the body to burn off
fat and sugar by stimulating the same chemical pathway
that is activated when we exercise.
“Clearly,” says Lodish, “adiponectin
is a good thing to have.”
The real power of adiponectin became clear in a paper
that Lodish and co-workers published in the journal
<i>Proceedings from the National Academy of Sciences</i>
in 2001. Here, the researchers studied a group of mice
that had been made obese through what Lodish refers
to as a “cafeteria diet.”
A cafeteria diet is exactly what it sounds like. These
mice were fed all the butter and sugar they wanted—and
their desire knew no limit.
Once the mice were suitably obese, Lodish and his team
injected them with adiponectin. The mice in turn increased
their “burning” of the stored fat and lost
weight—results that appeared to be almost miraculous.
“We tried to publish this in one of the major
journals but couldn’t because the reviewers simply
didn’t believe it,” Lodish recalls. “The
fact that injecting adiponectin caused these mice to
increase the burning of fatty acids was just too startling.
Once we got it published I had to keep reminding the
media over and over again how mice aren’t people.
Many scientists didn’t believe our work until
it was confirmed by two other labs the following fall.”
Adiponectin is a great hormone to have in abundance,
and it’s a terrible hormone to lack. Rare genetic
conditions that cause adiponectin deficiency may cause
diabetes and heart trouble.
But here’s where things get counterintuitive.
If leptin and adiponectin are manufactured by fat cells,
and if having them in abundance is beneficial, then
doesn’t it stand to reason that the bigger you
are, the more of these hormones you produce, and thus
the healthier you should be? Isn’t there some
kind of bigness benefit?
Before you reach for those Super-sized fries, the answer
is no.
As it turns out, obese people become resistant to leptin.
What’s more, fat cells in obese tissue start to
underproduce adiponectin, so obese people become deficient
in this crucial hormone.
Inflammatory news
Now things get worse. Recent studies comparing fat
tissue from normal-weight people and from obese people
have provided further evidence that not all fat cells
are created equal.
In people with normal weight, fat tissue contains precisely
what you’d expect to find: lots of fat cells (known
as “adipocytes” in the scientific parlance).
But in obese people, fat tissue is loaded with cells
called macrophages, cells that normally ingest pathogens
and other foreign materials. When they ingest these
foreign objects, they release inflammatory hormones
that alert the immune system, hormones such as macrophage-produced
tumor necrosis factor alpha (TNFa), a hormone that is
elevated in arthritis and is also related to cancer
and other conditions.
This makes perfect sense, because obesity is essentially
an inflammatory disease, comments Gökhan Hotamisligil,
professor of genetics and metabolism at the Harvard
School of Public Health. “Excess calories affect
the fat cells in such a way that they mount an immune
response,” he says. “You’re activating
the immune system without a legitimate pathogen,”
Hotamisligil continues. “You’re constantly
activating your immune system at a low level in such
a way that it releases chemicals that start contributing
to inflammation.”
Obesity, then, causes stress, which alerts the immune
system, which leads to the production of inflammatory
mediators that interfere with the function of other
metabolic pathways, which in turn causes stress.
“It soon turns into a vicious cycle,” says
Hotamisligil.
Lodish points out that the inflammatory hormone TNFa,
which is found abundantly in fat tissue from obese people,
blocks the expression of many fat cell genes that are
vital for insulin action, including adiponectin (this
is why obese people have less adiponectin in their blood).
Hong Ruan, a postdoctoral researcher in Lodish’s
lab, found that high levels of TNFa alter gene expression
in such a way that fewer fatty acids are stored in the
fat cells. Instead they are released into the blood,
creating insulin resistance in the muscle.
“This process goes on for many years, so eventually
you wind up with low levels of adiponectin, high levels
of fatty acids in the blood, and high levels of glucose
in the blood,” says Lodish.
But how might all these new insights into the biology
of obesity lead toward therapies?
Of mice and medicine
Hanging on the wall of Lodish’s office, near
copies of the bestselling molecular biology textbook
he co-authored, is Whitehead’s patent on the hormone
adiponectin, the molecule responsible for making those
obese cafeteria-diet mice lean and mean.
While Lodish may be a hero to the world’s millions
of rodents, the hormone has yet to work the same kind
of magic in people. Serono, the world’s largest
biotech, ended up acquiring rights to the molecule.
And it’s apparently hard at work trying to develop
an adiponectin product that can be injected into people—perhaps
the closest we could ever come to realizing every couch
potato’s fantasy of losing weight simply by taking
your medicine.
We’ve recently discovered seven other molecules
in the genome that work the same way as adiponectin,”
adds Lodish. He just signed a licensing agreement with
Wyeth Pharmaceuticals to work on these hormones.
The research joins hundreds of other projects shooting
for weight-reduction drugs. And even though adiponectin
activates the very same metabolic pathways stimulated
by exercise, it probably won’t be a chocoholic’s
dream come true. The molecular complexities of fat tissue
and the difficulties of production and delivery still
pose serious obstacles.
And despite all the research advances, obesity is still
in many respects uncharted terrain.
“We don’t even know yet the location of
the genes that very likely make people susceptible to
obesity,” says Harvard’s Flier. “These
genes could be active in the brain, or in the fat cells,
or in the muscle cells, or really everywhere.”
Flier believes that the answer most likely will come
from large-scale population studies.
Will there ever be a “cure” for obesity?
“It’s really too early to say,” says
Lodish. “I doubt a single molecule will ever do
the trick. But one might help reduce the problem, especially
in the early stages.”
In the meantime, here’s his prescription: “Diet
and exercise.”
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