October 01, 1995
Hormone Reduces Weight, Curbs Appetite and Accelerates Metabolism
In research that has captured the attention of the world and focused
the media spotlight on the scientists involved, three independent
laboratories have independently verified that a newfound hormone
reduces body weight and speeds up metabolism.
The findings may have important implications for understanding the
causes of obesity, but the authors note that new therapies for weight
control will require many more years of studies and testing. "The
current results suggest that the protein, leptin, is a novel hormone
that regulates body weight by signaling the amount of fat stored," said
senior author Jeffrey M.
Friedman of HHMI at Rockefeller University. The name leptin is
derived from the Greek root leptós, meaning "thin."
Friedman, with collaborator Stephen K. Burley, also of HHMI at
Rockefeller University, and several coinvestigators found that leptin
circulates in the blood of mice and humans. When administered to
overweight mice during two weeks of treatment, recombinant leptin
caused the mice to decrease food intake and increase energy
expenditure. The mice lost about 30 percent of their body weight and
almost all of their fat. Reports from two other research teams, one
from the Amgen Corporation that has licensed the ob gene from
Rockefeller University, and a second from Hoffmann-La Roche,
corroborated the work of Friedman's group.
The three teams published their work simultaneously in the July 28
issue of Science. This latest research stems from the earlier
cloning of the gene ob, which was reported by Friedman's group
in the journal Nature last year. Data in the Nature
article demonstrated that the instructions to make leptin are coded by
a gene that is defective in the obese (ob) mouse. The ob
mouse, long a staple of geneticists searching for molecular clues to
obesity, was identified by scientists at the Jackson Laboratory in Bar
Harbor, Me., in 1950.
Defects in the ob gene result in massive obesity in mice as
part of a syndrome that resembles obesity in humans. "The new findings
indicate that when ob is defective, leptin is not made and does
not transmit its signal to tell the brain to stop eating," says lead
author Jeffrey L. Halaas, a member of Friedman's team and a biomedical
fellow at Rockefeller. Consequently, mice with a faulty ob gene
are overweight and also have a form of diabetes.
In the Science paper, Friedman and colleagues measured the
amounts of leptin in the blood of mice and found that those mice with a
defective ob gene did not make the hormone. Another kind of
overweight mouse that was also studied has a mutation in a gene called
diabetes (db). The db-defective mice had leptin levels 10
times higher than normal, bolstering the theory that these mice have an
improperly functioning leptin receptor. The researchers also showed
that leptin circulates in the blood of six lean humans who were
studied.
In a four-week study, the scientists injected mouse leptin daily
into sets of 10 ob, db and normal mice. The leptin was
made in the laboratory by inserting the ob gene into bacteria. Each of
the mice in the study received 5 milligrams of leptin per kilogram of
body weight. For comparison, control mice received either injections of
a salt solution or no treatment.
"The effect of laboratory derived leptin on food intake and body
weight is dramatic," Burley said. After two weeks of treatment with
leptin, the ob mice lost 30 percent of their body weight without
any observable side effects. The reduced weight in these mice also came
exclusively from fat loss. At the end of the study, treated ob
mice had 9.1 grams of fat while untreated ob mice had 38.30
grams of fat. A normal, healthy adult mouse has between two and five
grams of fat.
In contrast, leptin treatment had no effect on the db mice.
"The failure of leptin to reduce body weight or food intake in
db mice is consistent with earlier suggestions that these mutant
mice are missing the leptin receptor and are thus resistant to the
effects of the hormone," Friedman said.
Leptin treatment not only reduced food consumption in the ob
mice, but also increased their energy expenditure. Four days after
starting leptin treatment, the ob mice consumed about 60 percent
less food than untreated ob mice. When untreated ob mice
were placed on a low calorie diet in which they were fed only as much
food as eaten by the treated ob mice, the food-restricted mice
lost less weight — an 11 gram loss in dieting mice versus a 16 gram
loss in mice receiving leptin. This result suggests that the protein
also increases energy expenditure, Friedman said.
Both mouse and human leptin reduced body weight in the ob
mice, raising questions of whether leptin might form the basis for a
weight-reducing drug of the future. Friedman answers cautiously: "The
fact that human leptin reduces weight in the mice raises the
possibility that giving leptin to people might have similar effects.
However, we must proceed cautiously to prove that the protein treatment
is safe in animals. Studies in humans cannot begin until the protein
has been confirmed to be without side effects."
Friedman, Halaas and Burley's coauthors include: Ketan S. Gajiwala;
Margherita Maffei; Steven L. Cohen, a graduate fellow; and Brian D.
Chait, all of Rockefeller; Daniel Rabinowitz, of Columbia University;
and Roger Lallone of Brookwood Biomedical in Birmingham, Ala. Gajiwala
also has an appointment with HHMI.
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