Fat hormone faces problems

A paper published online with the July 8 issue of Nature delivers a heavy blow to the reputation of one of the prime candidates for a chemical treatment for obesity. Forty-two scientists, from 12 labs, report that they have failed to replicate the effects described in a 2002 study of the gut-derived hormone PYY3-36 on body mass and appetite in rodents.In 2002, Steve Bloom's lab at London's Imperial College reported that peripheral administration of PYY3-36 reduced appetite and body mass in rats. They followed this up with data showing that it also suppressed appetite in humans over a 24-hour period. The finding that endogenous PYY levels were lower in obese subjects suggested that the peptide plays a causal role in obesity. Furthermore, PYY levels dipped and peaked, respectively, before and after eating—evidence that it regulates appetite on a meal-to-meal basis. Matthias Tschöp's group at the University of Cincinnati's Obesity Research Center set about repeating the rodent work. Tschöp, first author of the 42-name paper, says he realized the significance of his own failure to find an effect of PYY when heard of similar experiences from other groups. "We decided to get together and share our data," he told The Scientist. "The credibility of our paper is largely derived from the fact that a large number of independent groups found these results.""We're cited as being the only other group to have supported [Bloom's work] and that's true to some extent," said Cambridge University geneticist Steve O'Rahilly, who is involved with neither Bloom's nor Tschöp's papers. "We show that if you give injections under certain circumstances to one strain of mice, we can get a persistent 24-hour suppression of food intake." But, O'Rahilly told The Scientist, "we don't see a persistent effect over 7 days."One potential reason PYY failed to work could be stress, according to an online response to Tschöp's paper. Bloom and his colleagues write that if appetite is already low, PYY will have less room for influence. As Jeffrey Flier of Beth Israel-Deaconess Medical Center explained, "more often than not, when you do something stressful to a laboratory mouse, it will eat less." Still, Bloom cited a new paper from Amylin Pharmaceuticals that supports the effect of PYY on food intake and body mass in a variety of rodent models.Recent work by Roger Cone of Oregon Health and Science University, who coauthored Bloom's response, supports PYY's role in appetite, but only under certain, low-stress experimental conditions. "Cone describes precisely what he does to create the non-stressed condition," said Flier, who is not connected to either study. "And when he does that, he sees an effect of PYY. When he doesn't do that, all the animals eat less." "We have reliable responses in nonstressed animals," said Bloom. "The fact that they [Tschöp et al.] are not getting responses makes me feel that their animals are stressed."But Tschöp said that strict acclimation protocols were applied. "We are not stressing our animals," he said. "They are eating normally, and we can show suppression of food intake with several other drugs."Meanwhile, Bloom's findings that PYY3-36 suppresses appetite in humans remain unchallenged, if unrepeated. Bloom said that longer-term human trials, which he had scheduled for this year, have been delayed by the implementation on May 1 of the European Union's clinical trials directive, which raises the requirements for animal toxicity testing before a molecule can be tried on humans.Bloom doesn't expect stress to be an obstacle to potential therapies in humans. "It's not going to be useful for a condemned man, or the night before you have a heart transplant, but I think as far as humans are concerned, it's going to be useful in any ordinary circumstance," he said.But few are so confident. "The bottom line is that PYY is less potent a factor than the earlier studies would have led you to believe," said Flier. "But I'm not prepared at this stage to say it's irrelevant." "It's not often in the pages of Nature that you see such an obvious face-off between one group and another," said O'Rahilly. "And the truth will be in its usual boring place, somewhere in the middle." "PYY is, at the very least, less robust as a factor than people had been thinking, hoping, or expecting," said Flier. "If this was a stock market for PYY, the price will have gone down substantially, but it may well be that this is a smart time for someone to buy!"

Fat hormone faces problems

, 12 labs fail to replicate effects of PYY3-36 on appetite and body mass

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