Everyone struggling against obesity wishes for a safe, effective treatment to keep them from putting on the pounds. But, as this ScienCentral News video reports, a natural hormone thought to do just that is turning out to be tougher to test than was hoped for.
A Weighty Problem
In 2002, researchers from Imperial College in London discovered that a natural hormone made in the gut called PYY3-36 appears to signal to the brain that the stomach is full. They reported it reduced food intake and body weight in rodents, and in a small study in humans.
"By giving this hormone we naturally cause the brain to feel less like eating, and this is an important breakthrough in the possibilities for treating obesity," Steve Bloom, a researcher at Hammersmith Hospital and professor at Imperial College, told ScienCentral last year. "This is a very interesting discovery because for once, the scientist has found something that means an active treatment quite quickly. And what we are hoping is that we will be able to go to a direct demonstration of real weight loss and no side effects."
But for those or any scientific results to be accepted by other scientists, they need to be confirmed in similar experiments. Obesity researcher Matthias Tschoep was one of 42 scientists from 12 different labs around the world that independently tested PYY3-36 in rodents. His lab at the University of Cincinnati Medical Center's Genome Research Institute repeatedly failed to see the same results, finding no significant effect on food intake or body weight.
"All my colleagues and I have been very excited when we saw the very elegant studies of Dr. Bloom and his colleagues two years ago and we thought well, maybe, for a moment there, maybe there is a magic bullet," says Tschoep. "But it turned out not to be a magic bullet, at least in our hands. And the more groups we talked to, the more negative findings turned up. Therefore we started to put the data together, trying to define the exact conditions where it actually might work."
Tschoep and the 41 other authors reported their negative findings in the journal Nature. The journal also published Bloom and his colleagues' reply questioning the negative results. Bloom says the failed experiments could be due to stress, pointing out that rodents' eating behaviors are very sensitive to even subtle stresses. If animals are already eating less than normal due to stress, that would confound any measurement of their food intake or PYY's effects.
|image: NBC News|
"We have reproducible results in animals because we take enormous care not to stress them," he says. "Rodents are very nervous creatures and if you frighten them they definitely eat less."
Bloom also points out that stress does not have such profound effects on humans' eating behaviors, and that "the human experiments are highly reproducible and no one has shown a failure to get an effect."
Tschoep says he and his co-authors did control for stress. He agrees there may be something he and others are overlooking but adds that obesity may be a lot more complex than they had hoped. "There must be some specific condition that some of us are overlooking or where the experimental design is not exactly the same," says Tschoep. "This only exemplifies how difficult that all is, how complex the system is, and that there will be no magic bullet to decrease body weight, to decrease fat mass, so that we have to understand all the little details to be able to develop a good anti-obesity drug. What we're hoping now by sharing these data and by starting this discussion [is] that around the world we can hopefully find a solution and define the specific conditions where PYY3-36 might work, and all of us might learn something about the regulation of body weight."
Rudy Leibel, director of the Naomi Berry Diabetes Center at Columbia University, has discovered other weight-regulating molecules, and says discrepancies like this one aren't that unusual in science. But he adds they need to be resolved so studies can move forward.
"The so-called gold standard in science is that any experiment which is important will be repeated and it should be reproducible among different labs and different investigators in order to confirm its importance and relevance to the science at hand," says Leibel. "Right now we've sort of got a standoff; one group can't detect the effects using their techniques, another group keeps seeing the effects so we need to settle this before we take the next steps, if we're going to take them." Leibel also points out that some drugs do turn out to work much better in people than in animals, and that it may be too soon to rule out PYY3-36 as an important player. "This is a very, very interesting molecule and I'm quite certain you're going to hear more about it."
Meanwhile, human clinical trials are moving forward. A company called Nastech recently announced positive results in a small human clinical trial of a nasal spray it has developed containing PYY. Those results have not been published in a peer-reviewed journal.
Bloom's research was published in the Sept 4, 2003 issue of The New England Journal of Medicine and the August 8, 2002 issue of Nature, and was funded by Hammersmith Hospital, Imperial College, London. Tschoep and his colleagues' research was published online in the July 8 2004 issue of Nature and was funded by the University of Cincinnati Genome Research Institute; German Institute of Human Nutrition; Charité University Hospital, Berlin, Germany; Institute for Zoo and Wildlife Research, Berlin, Germany; University of Alabama at Birmingham; Johns Hopkins University School of Medicine; University of Leipzig, Germany; University of Leeds, UK; Novo Nordisk A/S; Boehringer-Ingelheim Pharma GmbH and Co.; University of Pittsburgh; Biomeasure Incorporated/Ipsen Group; Eli Lilly & Co. Research Laboratories; Imperial College, Hammersmith Hospital, UK.