Re: Decoding the Surprisingly Active Life Of Fat Cells

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Thank you Francesca. This offers a lot to ponder as well as for hope. - Ruth

From: Francesca Skelton <fskelton@...>

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Date: Mon, 12 Jul 2004 10:07:39 -0400

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Subject: [ ] Decoding the Surprisingly Active Life Of Fat Cells

By Rob Stein

For decades, scientists thought fat cells were passive blobs that did

nothing more than store energy, bloat flabby hips and bellies, and perhaps

wear down the body by forcing it to cart around a lot of extra weight.

But as the nation's obesity crisis has intensified scientific interest in

fat, researchers have fundamentally altered that view: Fat cells, they now

realize, are extraordinarily dynamic, complex and influential entities that

affect a staggering array of crucial bodily functions.

The new insights into fat's commanding, self-sustaining powers, scientists

say, have profound implications for understanding how flab forms, why it

hangs on so stubbornly, how it causes disease, and therefore possibly how to

help people shed pounds and avoid the devastating health problems wrought by

fat cells.

" They were always thought to be poor, dumb sacks of lard, " said

Unger, an obesity researcher at the University of Texas Southwestern Medical

Center. " It turns out that they end up being very talented, very versatile,

very important players. "

Instead of sitting idly by, waiting for a famine or a foot race, fat cells

continuously dispatch dozens of potent chemical signals to myriad tissues

throughout the body, including the brain, liver, muscles, reproductive

organs and immune system, orchestrating a host of activities.

" Knowing its whole communication network is going to help us answer many

important questions, and possibly lead us in a direction to cure obesity and

therefore the diseases caused by obesity, " said Barbara Corkey, a Boston

University scientist who serves as president of the North American

Association for the Study of Obesity.

Like guardians of the nation's strategic oil reserve, fat coordinates how,

when and where the body's energy supply is stored and how and when it is

mobilized. Fat also emits signals that can unleash, or damp down, the immune

system. Fat influences when blood clots and when blood vessels constrict.

Fat even tells the body when it can reproduce, and when it must await more

favorable conditions. And perhaps most insidiously, fat cells most likely

beget new fat cells, perpetuating their existence and magnifying their

effects.

" In the old days, people used to think fat tissue was a passive organ, "

said Rexford S. Ahima, an endocrinologist at the University of Pennsylvania.

" Now it's obvious that it makes and secretes more hormones and proteins than

probably any other. It's at the center of a very complex system. It

coordinates how much we eat, how much energy we burn, how the immune system

works, how we reproduce. The list goes on. "

And scientists suspect they have just begun to unravel the intricate web

of fat's reach, with perhaps dozens of other functions and signals awaiting

discovery, including some that probably affect mood and behavior beyond just

hunger and eating.

" Many people think your brain controls your fat, " said Gokhan S.

Hotamisligil, a professor of genetics and metabolism at the Harvard School

of Public Health. " We promote the idea that your fat controls your brain. "

The new understanding has led to the discovery of new chemical messengers

that fat cells deploy, and drug companies are scrambling to find ways to

manipulate those hormones to help people lose weight and avoid the health

problems associated with obesity.

" Once you know the players you can try to cage them in, " said Xavier

Pi-Sunyer, chief of endocrinology at St. Luke's-Roosevelt Hospital in New

York.

The new insights also may help alter societal views of obesity, further

undermining the notion that obesity is a sign of moral defect and bolstering

the case that it is a discreet and stubbornly self-perpetuating biological

state.

" The rules of the game have changed. The way you look at an individual who

is obese has to be radically changed as a result of this, " said Rudolph L.

Leibel, a molecular geneticist at Columbia University. " Before the naysayers

could say this is all free will and has nothing to do with biology. I don't

think anything could be farther from the truth. "

The pivotal discovery came in 1994, when scientists identified a hormone

produced by fat cells that they dubbed leptin. Among other things, leptin

tells the brain how much fat is in the body. That raised the hope that it

could be used as an anti-obesity drug, but that has yet to pan out. Still,

the discovery revealed for the first time a direct communication link

between the brain and fat cells.

That insight spawned a new wave of research that led to the identification

of other fat signals and the new paradigm for the role of fat in the body.

Scientists now call fat an " endocrine organ, " akin to the thyroid and

adrenal glands that orchestrate many body functions.

" But it's probably the biggest endocrine organ in the body, " said

M. Friedman of the Rockefeller University in New York, who led the team that

discovered leptin. " Fat tissue plays such a vital role for the survival of

any species that it should really come as no surprise that it would be

involved in such dynamic regulation. "

Scientists have long known, for example, that fat cells play a role in

synthesizing sex hormones such as estrogen, which enables the cells to

regulate the reproductive process. That explains, for example, why

ballerinas, female professional athletes and other women who are very thin

often stop menstruating.

" If a female doesn't have enough energy stored, the pregnancy can be in

jeopardy and so reproduction is shut down. The body is waiting for more

favorable conditions, " Friedman said.

But far beyond simply monitoring energy reserves, fat cells are the hub of

a complex communication system that regulates many metabolic functions,

continuously telling the brain how much energy the body has left, signaling

muscles when they can burn fat, instructing the liver and other organs when

to replenish fat stores, and controlling the flow of energy in and out of

cells.

One of the most important newly recognized players in that finely tuned

system is a protein called adiponectin, which affects the liver and muscles.

" This hormone lowers blood glucose by blocking its production in the liver

and by increasing the burning by muscle to make energy, " said Harvey Lodish,

a professor of biology at the Massachusetts Institute of Technology. " It

activates part of the same signaling pathway in muscles [that is] activated

by exercise. "

Adiponectin levels fall as fat levels rise. Because the hormone affects how

sensitive cells are to insulin, scientists believe it helps explain how

obesity increases the risk for diabetes.

" It's been pretty well established now that levels of this protein are a

good measurement of insulin sensitivity, " said Philipp Scherer, a cell

biologist at the Albert Einstein College of Medicine in New York who

identified the substance.

Drugs that affect adiponectin, therefore, may help prevent or treat

diabetes. The drugmaker Serono Inc., has started studying adiponectin, both

as a possible preventative for diabetes and as a weight-loss drug.

Soon after adiponectin's importance was recognized, scientists discovered

another fat cell hormone called resistin, which also appears to play a

crucial role in insulin sensitivity and energy storage.

" It's clearly important, but its exact mechanisms are still something

we're trying to understand, " said A. Lazar, an endocrinologist at

the University of Pennsylvania School of Medicine who discovered the

hormone. " So far we haven't found net changes in energy storage -- weight is

not affected in a significant way by either too much or too little

resistin. "

At the same time, scientists have come to the surprising conclusion that

fat has the power to mimic the effects of the body's immune system, in

particular by provoking an inflammatory response.

" There's a growing realization about the convergence of the medical

problems associated with obesity and chronic inflammation, which wasn't

appreciated for a long time but is coming to the fore scientifically, " Lazar

said. " Where does the inflammation come from? Surprise: It's the fat cells

themselves. "

But not from the fat cells alone. Scientists recently discovered that fat

tissue is comprised of far more than just fat cells -- it is a complex

amalgamation that includes key immune system cells called macrophages.

Macrophages and fat cells produce powerful substances called tumor necrosis

factor-alpha and interleukin-6, which help regulate the immune system.

Fat probably evolved a close connection to immune function because the body

needs energy when it is fending off threats, scientists say.

" It's like if you are sending troops into battle, " Hotamisligil said. " You

have to send not just rifles but bullets. "

But a surplus of fat cells and macrophages probably triggers unnecessary

inflammation, which most likely explains at least part of why obesity

increases the risk for so many diseases, including cancer, heart disease and

diabetes.

" As fat mass increases, this is associated with a systematic stress

response and inflammatory response, and that exhibits itself in a variety of

diseases, " Hotamisligil said.

Fat cells also send out signals that cause blood vessels to constrict,

raising blood pressure, and make blood clots form, which may explain how

obesity increases the risk for heart attack and stroke. At the same time,

fat cells emit signals that promote blood vessel and cell growth, which

could help explain why obesity increases the risk of cancer.

The more scientists learn about fat, the more intimidating it becomes.

Because fat is so vital to survival, nature has created a complex system of

overlapping feedback loops that make it very difficult to override the

body's imperative to store energy.

" What we're trying to do is do like the physicists do: Build a theory of

everything about fat tissue, " Leibel said. " We'd really like to understand

not only what the signals are but how they are integrated. There's so much

that we simply do not yet understand about this. "

© 2004 The Washington Post Company