James Ntambi scopes out developing fat cells.
©
1997,The Why Files, University of Wisconsin-Madison. Photo by Dave
Tenenbaum. |
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cake, quickly
bought rights to the Rockefeller University discovery
for a record $20 million.
And sure enough, researchers who gave leptin to the leptin-less obese mice
saw their weight drop by 30 percent -- a number that made the fen-phen
study look positively cheesy.
The leptin changes its spots
But just as leptin was starting to look like a magic bullet -- take the drug,
pig out, and still lose weight -- Friedman found that a different strain of
obese mouse did not respond to it. Apparently leptin was only one cause of
obesity in mice.
The story grew more complicated when scientists found that obese people,
unlike tubby mice, actually had a lot of leptin in their blood. Researchers
began shifting their attention from blood leptin levels to the network that
reads the leptin signal.
"We thought the same problem [low levels] would occur in humans, but it
didn't," says Ntambi. Ntambi suspects that the leptin signal is not getting
through because of a defect in the leptin receptor -- the molecule on the
surface of brain cells that normally "reads" the leptin signal. Or the
problem could be in the mechanism that carries that leptin signal to the
nucleus of the brain cell -- presumably telling the cell to make a protein to
regulate appetite.
There's also evidence that leptin does not just alert the brain when the
spare tire has ballooned sufficiently -- it also seems to slow metabolism
in
fat cells. "Leptin also appears to act via pathways that are independent
of the brain," says Purdue University biochemistry professor Ki-Han Kim.
"My thinking is that it works by inhibiting the synthesis of fat in fat cells
and increasing the burning of fat in muscle cells."
(That reminds us of CLA, which we covered already.)
Just in from the University of Georgia: Leptin seems to cause rat fat cells
to undergo programmed cell death, or apoptosis. Professor of nutrition
Clifton Baile and post-doctoral fellow Hao Qian have found that the fat
cells of the leptin-treated rats clearly showed apoptosis -- a process the
body uses to get rid of unwanted cells.
Leptin may also be a signal to start puberty -- which could explain the
delayed puberty in extremely thin girls, who lack the fat cells that make
leptin. (See "Chemical Tied to Fat..." in the bibliography)
Exciting. But does it affect human
obesity?
Curiously, it was not until June, 1997 that researchers found the first
obese humans who lacked the leptin gene. One of the two cousins was a
two-year-old who weighed 64 pounds (see "Genetic Cause Found for Some
Cases" in the bibliography).
Although scientists are still unsure how much human obesity is related to
leptin, Amgen's first trial showed that leptin caused a moderate weight
loss in people. Among all subjects who completed 28 days of the study, 19
percent of those who got the dummy drug and diet and weight counseling
lost at least two kilograms, compared to 30 to 45 percent of those who
took leptin (at the dose to be used in future trials). A similar weight loss
occurred among the 30 obese subjects who stayed on the study for 90
days.
The first study was intended mainly to check safety -- no small
consideration in the wake of the fen-phen
fiasco. No detrimental side effects were found, aside from a local
reaction near the injection site. The next study, now getting under way,
will look more closely at the actual effectiveness of the leptin injections.
Injections? Did somebody say "shots"? Yes, and that's a big drawback --
the stuff must be injected every day, since, like insulin, it would
decompose in the stomach.
And while leptin retains promise, it's probably not the kind of magic bullet
that can shave 30 percent of body weight from people as it did in mice. Bad
genes were the culprit in those genetically obese mice, but in people,
social and psychological factors can be the criminals in the complex
calculus of chubbiness.
Want to meet a compound that prevents the body from
making fat cells in the first place?
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