December 2004 - Materials Science Institute - University of Oregon

news other genes involved in the breakdown of
SCAN
fat. He showed that activating PPAR-delta
raised metabolism and helped animals burn
more fat. For his latest study, Evans and his
colleagues from Seoul National University
wanted to know if PPAR-delta had measurable
effects in terms of weight change.
SKIP THE TREADMILL? Compared with the leg muscle tissue of normal mice (left), that of mice
genetically modifi ed to produce excess PPAR-delta (right) consists of more slow-twitch fi bers
(dark blue)—a change similar to that induced by sustained exercise.
LEANER BUT
SHORTER LIVES?
Boosting metabolism may
drive weight loss, but it may
also reduce life span, some
investigators fear. Indeed, a
calorie-restricted diet promotes
longevity because it slows
metabolism and thereby may
reduce the amount of oxidative
damage in the body. Whether the
genetically modifi ed “marathon
mice” will die sooner than their
normal brethren, however, is not
yet known. In fact, the transgenic
mice may actually live longer
because they are in better
physical shape and have lower
sugar, insulin and fat levels.
So they genetically engineered mice to
produce extra PPAR-delta in their muscle.
When put on a high-fat, high-calorie diet for
13 weeks, the transgenic mice gained only
a third of the weight that their unmodifi ed
brethren did. What is more, mice on this
diet remained resistant to obesity even when
they were kept inactive.
To accomplish its remarkable metabolic
and antiobesity tasks, PPAR-delta evidently
modifi es the composition of skeletal muscle
in the mice. Muscle consists of fast-twitch
fi bers, which rely on sugar for fuel and are
used primarily for rapid movements, and
slow-twitch fi bers, which convert fat into energy
and are responsible for sustained activity.
The transgenics had double the amount
of the fat-burning, slow-twitch muscle compared
with normal littermates.
The increase in slow-twitch fi bers, usually
associated with long-lasting, vigorous
exercise, also translated into greater endurance.
On the mouse treadmill, the transgenics
could run 1,800 meters, twice the
distance a mouse normally runs before exhaustion,
and for an hour longer than the
usual 90 minutes. “We nicknamed them
‘marathon mice’ because they behave like
conditioned athletes,” says Evans, whose
study appears in the October PLoS Biology.
He suspects that changes have also occurred
in the cardiovascular and nervous systems,
both of which are intimately linked to the
muscles. He has not yet seen any serious side
effects from the extra PPAR-delta.
Although Evans recognizes the potential
for abuse by athletes, he believes that
his work has more practical implications
in treating metabolic ailments, including
obesity and heart disease. Patients with
such conditions often cannot exercise because
of their weight or other complicating
problems. “This work could lead to an
exercise pill that gives many of the benefi ts
of training without the need to sweat,” Evans
predicts. Indeed, in a separate experiment
he gave normal mice a drug called
GW501516, which activates PPAR-delta
directly. The drug caused many of the same
changes in muscle and metabolism as those
in the transgenic mice, including protection
against weight gain.
Whether such a pill also works in humans
may be answered sooner than expected.
Pharmaceutical giant GlaxoSmithKline
is currently testing GW501516 in obese and
diabetic patients as a way of improving their
good cholesterol, or HDL, levels. The company
says that it has not looked to see how
the drug affects endurance or weight but
that it plans to do further tests.
Although the alteration of other genes
has produced animals with more slowtwitch
fi bers, none of the changes have infl
uenced metabolism like PPAR-delta. “This
is major step forward in understanding how
muscles and metabolism are linked,” says
Nadia Rosenthal, head of the Mouse Biology
Program at the European Molecular Biology
Laboratory in Rome. The creation of the
marathon mice is reminiscent of Rosenthal’s
earlier work that led to “Schwarzenegger
mice,” rodents that bulked up after receiving
gene therapy with the muscle-building gene
IGF-1. In that case, however, taking IGF-1 in
pill form did not produce the same effects.
It is too soon to label PPAR-delta as an
obesity cure, warns Paul Root Wolpe, a bioethicist
at the University of Pennsylvania. In
the early days of functional genomics, many
genes and proteins have been touted as panaceas.
“The desire to fi nd a drug, protein
or gene that will solve all ills is ancient,”
Wolpe notes. “That desire hasn’t changed
much over thousands of years, only the technology
has.”
Diane Martindale is based in Toronto.
24 SCIENTIFIC AMERICAN DECEMBER 2004
COPYRIGHT 2004 SCIENTIFIC AMERICAN, INC.
YONG-XU WANG ET AL. IN PLO S BIOLOGY, VOL. 2, NO. 10, E294; OCTOBER 2004