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scientificamerican.com

Scientists Zero In on a New Target for

Obesity
Dina Fine Maron
5-6 minutos

A compound that helps rodents and monkeys slim down could offer
a promising approach for human therapies

For the 35 million American adults who are battling obesity, the
age-old advice to improve diet and exercise often falls short. And
surgical interventions that reduce stomach sizealthough
effectivecan prove risky.

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But there may be another alternative: flooding the body with a

protein that makes an individual prefer low-fat food and feel full
longer, and that activates neurons responsible for regulating the
bodys energy intake. Such a simple fix may sound too good to be
true, but the approach has shown promise in experiments with
mice, rats and monkeys. If the therapy can be improved and shown
to work well in humans, it could be an entirely new way to help
battle obesity, diabetes and related conditions. Currently there are a
few federally approved weight loss and insulin control agents on the
market, but they appear to work along different pathways than the
new therapy does. They can also cause serious side effects, and
are still not as effective as surgical weight-loss interventions.

In new work spearheaded by pharmaceutical company Amgen,

researchers took advantage of a protein linked with multiple
metabolic disorders to try to make thinner, healthier animals. In
multiple species, lean creatures appear to have naturally higher
concentrations of the protein GDF15 than their stouter
counterparts, the Amgen team noted. So they tried to boost levels
of the compound in obese animals via gene therapygiving
rodents injections of a form of the gene that would cause their
bodies to produce more of the protein than they would have
otherwise. In the short-term that seemed to help make the animals
healthier, but their bodies cleared the substance too quickly for it to
produce a lasting effect. So the researchers decided to bypass the
gene therapy approach and engineer two stable, longer-lasting
forms of GDF15 that they injected directly into the animals.

Weekly injections of either of these engineered molecules slimmed

down rodents and monkeys without causing any apparent serious
side effects, the scientists report Wednesday in Science

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Translational Medicine. After about a month of weekly treatments

with one of the two engineered forms of GDF15, treated rodents
sometimes lost as much as 17 or 24 percent of their body weight,
depending on what molecule they received, says senior author
Murielle Vniant, who studies metabolic disorders as a lead
researcher at Amgen. The treatment also helped monkeys shave
pounds. In the most extreme cases, the treated monkeys lost 5 or
10 percent of their body weight during that same time period, she
says. Meanwhile, untreated animals continued to gain weight. We
were very surprised to see improvements in body weight, glucose
and insulin levels as well as triglycerides, she adds.

Exactly how these weekly GDF15 treatments work remains murky.

As a whole, the findings suggest the proteins act on the gutbrain
axisthe collection of two-way nerve and chemical pathways that
communicate between the digestive tract and the brainand that
GDF15 might be a clinical target for metabolic disorders. The
specifics have yet to be ironed out, but the Amgen team has
uncovered a few clues in their rodent studies: They found treated
animals had increased activation of certain neurons in the brain that
detect blood sugar, and this may have helped them sense when it
was time to stop eating. The treated rodents stomachs also took
longer to empty outsuggesting they may have felt full longer and
that GDF15 may block the transmission of signals from the vagus
nerve, which connects the brain and digestive tract. Finally they
found animals receiving the therapy seemed to prefer a lower-fat
diet than those that did notalthough the researchers cannot yet
explain why taste preferences changed.

Some experts were cautiously optimistic about the findings. This

group really seemed to go a long way toward identifying what may

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be an interesting new approach to treatment, and thats fantastic,

says Paul Kenny, chair of the Department of Neuroscience at
Mount Sinai Health System, who was not involved with the Amgen
work. This is exciting, he adds, but the key will be [determining] if
its safe in humans. If this work makes it into human trials, he
notes, two areas to watch will be whether there is any significant
muscle mass loss with treatmentbecause treated animals lost
some lean mass alongside their fatand if the therapy causes any
serious side effects such as depression or mood changes, which
have been concerns with some other proposed weight-loss
products. Vniant declined to comment on Amgens next steps or
potential timeline for clinical trials in humans but says the company
plans to continue its work in this area. Clearly, she says, GDF15 is
a very interesting protein.

Dina Fine Maron

Dina Fine Maron is an award-winning journalist and an editor at

Scientific American covering medicine and health. She is based in
Washington, D.C.

Credit: Nick Higgins

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