In effect, the body responds to
dieting or weight loss by pressuring
the brain to put pounds back on.
Early work on the hormone was promising.
Researchers pointed to an unusual genetic mutation
as a sort of extreme example of leptin’s role. People
born without the ability to produce leptin (a very rare
condition called congenital leptin de;ciency that affects
a few dozen people in the world) are constantly hungry
and quickly become obese, apparently proving the
hormone’s effect. When people with the condition were
given leptin injections, they lost weight.
Yet when researchers tried giving leptin to
ordinary overweight or obese people as a weight-loss treatment, the experiments were a bust.
“When this hormone was originally discovered,
there were some who thought this would be the
answer to human obesity,” Leibel says. “It turned
out it didn’t have that effect in obese or nonobese
individuals.” That’s a strong clue that leptin is just
one piece in a much larger puzzle that includes
genetics, environment, and lifestyle.
In the two decades since the discovery, our
understanding of leptin’s likely role has changed.
Instead of a “hunger hormone” that suppresses
appetite, it has a role in defending body weight. “The
reason people who lack it gain weight is [that] the brain
is lacking the signal that there is enough body fat, so
they keep eating,” Leibel says.
In fact, it’s a lot like the hormone insulin: Just as
LOST IN TRANSMISSION
some people are resistant to insulin’s signals, forcing
Yet even this ;nely calibrated
system is failing to keep up with
modern-world challenges, where calories
are easy to come by and moving about—
thanks to sedentary jobs—is not.
The deeply entrenched leptin response also
helps explain why dieting is so hard. When you
drop pounds, your body has fewer fat cells, and
therefore less leptin. That makes for a weaker
“radio signal” to the brain. “If you reduce a
200-pound person to 150 pounds, the [leptin]
signal isn’t strong enough for the [brain’s]
receiver,” says Columbia University Medical
Center geneticist Rudolph Leibel, MD, a pivotal ;gure in
the initial discovery of leptin more than 20 years ago.
“What the receiver perceives is that there’s not enough
LEPTIN IN ACTION
fat in my body to generate a suf;cient signal.”
Until weight goes back up to the levels the brain is
used to, the lower leptin levels produce a sort of panic
in regions of the brain responsible for hunger and
satiety. “It’s a very critical system in evolution,” Leibel
says, “designed to preserve body fat disturbed when we
reduce body weight to treat [type; 2] diabetes.” The brain
is interested in making sure there’s enough energy on
board in the form of stored fat, so people who have lost
weight get signals saying they don’t have enough body
weight. In effect, the body responds to dieting or weight
loss by pressuring the brain to put pounds back on.
When it was identi;ed in 1994, researchers thought that
leptin would act as a simple switch that would let doctors
turn off hunger pangs, solving the problem of obesity—
and potentially preventing millions of people from
developing type 2 diabetes, or putting it in remission.
When the gene responsible for producing leptin was
identi;ed, it was hailed as a blockbuster discovery that
the prestigious science journal Nature publicized on
its cover. Amgen, a California-based pharmaceutical
company, bought the patent for $20 million up front and
paid tens of millions more as research on the gene and
the hormone progressed.