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
of HHMI at Rockefeller University. The name leptin is derived
from the Greek root
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
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
This latest research stems from the earlier cloning of
which was reported by Friedman's group in the journal
last year. Data in the
that the instructions to make leptin are coded by a gene that is defective
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
gene result in massive obesity in mice as part
of a syndrome that resembles obesity in humans. "The new findings indicate
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
gene are overweight and also have a form of
paper, Friedman and colleagues measured the amounts
of leptin in the blood of mice and found that those mice with a defective
gene did not make the hormone. Another kind of overweight mouse
that was also studied has a mutation in a gene called
-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
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,
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
mice had 9.1 grams
of fat while untreated
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
failure of leptin to reduce body weight or food intake in
is consistent with earlier suggestions that these mutant mice are missing
the leptin receptor and are thus resistant to the effects of the hormone,"
Leptin treatment not only reduced food consumption in the
but also increased their energy expenditure. Four days after starting leptin
mice consumed about 60 percent less food than untreated
mice. When untreated
mice were placed on a low calorie
diet in which they were fed only as much food as eaten by the treated
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
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.