April 15, 2000
Chipping Away at Leptin's Effects
Using genechip technology—a powerful tool for analyzing the
expression patterns of thousands of genes at a time—researchers
have identified a number of genes that are specifically regulated by
the hormone leptin.
Leptin is produced by fat tissue and secreted into the bloodstream,
where it travels to the brain and other tissues, causing fat loss and
decreased appetite. Identifying genes regulated by leptin will improve
knowledge of how leptin causes its effects on weight and appetite, and
may also offer new targets for drugs designed to stimulate weight
loss.
“We were able to find at least half a dozen distinct clusters of genes that were specifically regulated by leptin and that were not regulated in the same way by food restriction.”
Jeffrey M. Friedman
Since the discovery of leptin in 1994, many have hoped that the
hormone would be a promising weight-loss treatment for humans. Studies
of the hormone's weight-reducing effects in humans are underway, but
researchers still have a way to go before they fully comprehend how the
hormone affects the brain and other tissues.
In experiments described in the April 15, 2000, issue of the journal
Genes & Development, Jeffrey
M. Friedman, an HHMI investigator at The Rockefeller University,
and Rockefeller colleagues Alexander Soukas, Paul Cohen and Nicholas D.
Socci report that they are beginning to probe the genetic program
orchestrated by leptin to induce weight loss.
"We knew that an animal given leptin eats less and loses fat," said
Friedman. "And while restricting food intake also causes weight loss,
we had reason to believe that the two weight-loss responses are very
different." For example, said Friedman, leptin triggers weight loss of
fat stores alone, while food-restriction robs the body of both fat and
muscle. Also, he said, a diet-restricted human or animal compensates
for decreased caloric intake by lowering energy expenditure, while
leptin treatment shows no such energy-robbing effect. Until now,
however, no one had explored the molecular basis of such differences in
detail, said Friedman.
Studying normal mice and a mutant strain that cannot produce leptin,
the researchers looked for differences in gene expression patterns
related to either leptin administration or caloric restriction.
After administering leptin to or restricting food intake in the two
groups of mice, the researchers analyzed gene expression in the mice by
extracting messenger RNA from their fat cells. Messenger RNA levels
reflect the expression levels of different genes. They applied these
collections of messenger RNA to a series of "oligonucleotide
microarrays," popularly known as genechips. Each kind of messenger RNA
"found" and adhered to its corresponding gene on the genechip.
Indicator molecules revealed the level of RNA present, showing the
expression levels of hundreds of fat-tissue-related genes.
Analyzing data from many such experiments with the mice, the
scientists were able to group the expressed genes into clusters that
appeared to behave similarly— increasing or decreasing in
expression in tandem— as the mice were subjected to different
regimes of leptin treatment or food restriction.
"We were able to find at least half a dozen distinct clusters of
genes that were specifically regulated by leptin and that were not
regulated in the same way by food restriction," said Friedman. "So,
leptin is doing a lot more than just leading to food intake
restriction."
The discovery of these leptin-regulated genes offers a glimpse of
the complex metabolic machinery controlled by leptin.
"We would infer that for each of the clusters of genes that behave
similarly in response to leptin and that there is some unifying
regulatory element," said Friedman.
In fact, he said, his group has uncovered evidence of just such a
regulatory element— finding that one cluster of genes is regulated
by a protein called SREBP-1, which regulates many of the genes that
control the synthesis of fatty acids.
"This finding tells us that we now need to explore how leptin alters
SREBP-1's effects," said Friedman. "It is also sort of a proof of
principle, suggesting that there are other important mechanisms
regulating the genes in the other leptin-regulated clusters."
"Now we can follow up to try to piece together the different
regulatory elements of these leptin-related responses," he said.
The new findings also open a promising pathway for understanding the
complexity of leptin's effects on different body tissues, said
Friedman. Although researchers know that leptin is produced by fat
cells and suppresses appetite by affecting the hypothalamus, the
hormone may also trigger metabolic changes in fat and other tissues.
Learning how changes in gene regulation lead to these effects is a goal
of future studies in Friedman's laboratory.
"We can begin to probe where these regulatory signals are coming
from by specifically knocking out leptin receptors in different
tissues— such as the brain or the liver or even in fat
itself— and studying the resulting effects on gene expression," he
said.
Overall, said Friedman, better understanding of the leptin-related
machinery is needed if the hormone is ever to become a basis for
clinical treatment of obesity in humans.
"These studies make it clear that leptin produces a very complicated
set of effects on the body, and we have much more to learn about them,"
he said.
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