Scooping Barbara ( Studies on a Mouse Hormone Bear on Fatness in Humans)

Studies on a Mouse Hormone Bear on Fatness in Humans

By GINA KOLATA

N.Y. Times

Published: April 2, 2004


New studies in mice suggest that the hormone leptin can fundamentally
change the brain's circuitry in areas that control appetite. Leptin
acts during a critical period early in life, possibly influencing how
much animals eat as adults. And later in life, responding to how much
fat is on an animal's body, it can again alter brain circuitry that
controls how much is eaten.

Researchers say the findings, published today in the journal Science,
are a surprise and add new clues to why weight control is so difficult
in some humans.

Scientists knew that leptin is released by fat cells and tells the
brain how much fat is on the body. They knew that animals lacking
leptin become incredibly obese, as do a few humans who because of
genetic mutations did not make the hormone. Leptin injections
immediately made animals, and the patients with leptin deficiencies,
lose their appetites. Their weight returned to normal.

But it was thought that leptin acted like most other hormones,
attaching itself to brain cells and directly altering their activities.

Investigators did not anticipate that leptin could actually change
connections in the brain, strengthening circuits that inhibit eating
and weakening ones that spur appetite. And few considered the
possibility that there might be a critical period early in life when
the hormone shaped the brain's circuitry, possibly affecting appetite
and obesity in adulthood.

"It's fascinating," said Dr. Rudolph Leibel of Columbia University.
"Obviously, we don't know what this looks like in humans, but it is
possible that some of the differences in regulation of body weight that
have been attributed to psychological processes or fat cell effects may
be reflecting these central nervous system processes."

Dr. Jeffrey Flier of Beth Israel-Deaconess Hospital in Boston said the
effects of leptin reminded him of brain changes when memories are
stored. It is almost as if the brain is developing a memory for the
weight it wants the animals to be, Dr. Flier said, raising intriguing
possibilities about weight regulation in people.

"It all comes back to the same issues ‹ the whole issue of appetite and
weight regulation in humans," Dr. Flier said. "It is at the interface
of free will and determinism. There is certainly a strong biological
underpinning to our drive to eat and maintain certain weights. We knew
that before and we still know it.

"But now there is another layer of mechanisms by which things like
hormones not only can affect the neurochemistry that affects how hungry
you are but also can affect the wiring of your brain."

In the first of two papers in Science, Dr. Richard B. Simerly and Dr.
Sebastian G. Bouret at the Oregon Primate Research Center in Beaverton
examined leptin's effects on the brain early in life. Until now, they
had studied how sex hormones, like estrogen and testosterone, affected
brain development.

But they noticed an earlier paper by Dr. Flier showing that there is a
surge of leptin in the brains of newborn mice, looking a lot like the
surges of sex hormones that reshape the brain during critical periods
early in development. Could leptin, they asked, be doing something
similar?

"Bingo," Dr. Simerly said. "The lights went on."

As adults, mice with a genetic mutation preventing them from making
leptin had weaker nerve connections in the arcuate nucleus of the
hypothalamus, which controls eating behavior and develops soon after
birth. Perhaps, Dr. Simerly said, if he gave the leptin-deficient mice
a surge of leptin early in life, mimicking what normal mice experience,
he could reshape their brains, making them look like those of mice
without the genetic defect.

It worked, Dr. Simerly and Dr. Bouret reported, raising questions about
what happens normally during development in mice, and people, that
might determine whether they were destined to be fat or thin.

"Leptin acts on the brain to regulate food intake," Dr. Simerly said.
"If the brain pathway isn't there or is greatly reduced, you would
expect that process to be deficient. Your brain is perhaps not sensing
how fat you are."

In the second paper, by Dr. Jeffrey M. Friedman, a Howard Hughes
medical investigator at Rockefeller University, he and his colleagues
examined two brain pathways in adult mice, one that increases appetite
and another that decreases it. By examining the actual nerves in slices
of brain, they said, they saw that mice that make no leptin have strong
brain circuits that signal them to eat. They have correspondingly weak
circuits that signal them to stop eating.

Then they gave the animals leptin. Within six hours, their brain
circuits were like those in normal animals, the researchers said. Two
days after being treated with leptin, the mice lost their huge
appetites.

The researchers also tested another hormone, ghrelin, whose effects are
the opposite of leptin's, giving it to normal mice. Four days later,
the animals were eating more and their brains were rewired in the
opposite direction, the researchers said. Dr. Friedman said he was
taken aback.

"I'd always imagined this system had a fixed architecture, like a
plumbing system," he said. "A certain number of pipes were laid out or
fixed." He said he had thought the flow of signals in the hypothalamus
was regulated by the equivalent of opening or closing valves. But that
was not what happened.

"In this case, the brain is adding and subtracting pieces of pipe," Dr.
Friedman said. "Nerves are not appearing or disappearing, but the way
they are connected to each other is.

"Right now there is an assumption on the part of the public that
differences in weight are accounted for by discipline."

It is thought, he said, that with will power, anyone can lose weight
and keep it off.

"That assumes that the drive to eat is the same in all people," Dr.
Friedman said, "but this says there is not only a dynamic system that
controls weight but that the wiring diagram is different in the obese.
It at least raises the question, To what extent is the wiring diagram
different in obese humans?"

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