Biochemistry

Edited by: Steve Bunk Richard D. Palmiter Jay C. Erickson, Kathy E. Clegg, Richard D. Palmiter, "Sensitivity to leptin and susceptibility to seizures of mice lacking neuropeptide Y," Nature, 381:415-8, 1996. (Cited in more than 205 papers since publication) Comments by Richard D. Palmiter , Howard Hughes Medical Institute investigator and University of Washington biochemistry professor Ah, for an ideal scientific world. In it, researchers demonstrate that injection of a specific neuropeptide into the brain stimulates feeding. So they develop a drug that blocks this peptide's activity. People take the drug, eat less, obesity is swept off its substantial feet, and the marketplace comes running. But in the real world, that particular transmitter, called neuropeptide Y (NPY), is not so cooperative. Yes, it does stimulate feeding when injected into the brain, but what happens if NPY is deleted from mice? They'll stop feeding without the need of a blocking drug, right? Wrong, as was demonstrated in this paper by a team under the leadership of Richard D. Palmiter. His NPY knockout mice exhibited normal food intake and body weight, became gluttonous after being deprived of food, and when treated with recombinant leptin, decreased their food intake and lost weight. In other words, they did not differ substantially from wild-type controls. Given the pharmaceutical industry's investment in developing ways to use NPY for obesity treatment, Palmiter isn't surprised by a common explanation offered by pharmacologists and others for the paper's findings. The brain is plastic, they point out; the mice somehow must have compensated for the NPY deletion. "We have spent a lot of time trying to find out what this compensatory mechanism is all about," he says. Although it's still possible that the answer will be found, he's losing hope. "We're beginning to think that maybe the pharmacology is giving the wrong answer." He notes that many substances injected in relatively high amounts into a test animal could produce results that are not normal. Perhaps NPY injected to stimulate feeding is a physiologically irrelevant result. Yet pharmaceutical companies continue to pursue the development of NPY antagonists to prevent overfeeding. And Palmiter does know of unpublished data that shows rats fattened on a Western or cafeteria diet will stop overfeeding when injected with a trial NPY antagonist, although he adds that more work needs to be done in those studies. A difficulty in working with NPY is that it is distributed throughout the nervous system and has been implicated in many functions, including mood modulation, cerebrocortical excitability, hypothalamic-pituitary signaling, and cardiovascular physiology. One way to approach such complexity is to locate and block specific NPY receptors thought to be important in the feeding response. Based on pharmacological data that identified the Y5 receptor as the key transducer, Palmiter's group inactivated it, only to find it, too, is not necessary for feeding.1 Nor have knockout studies by other teams produced positive results regarding other NPY receptors and feeding. Another approach is to find a molecule that compensates for the absence of NPY, a chemical redundancy that is common in biology. Palmiter's team is focusing on another neuropeptide produced by the same cells that make NPY, that might substitute when NPY is missing. In the meantime, they made the remarkable discovery that mice lacking NPY are alcoholics.2 Perhaps the most surprising of their findings was that NPY-deficient mice experienced occasional, mild seizures that remitted as they grew older. But this finding that the peptide is an important modulator of central nervous system excitability was not why the paper became significant to the scientific community, he thinks. "With regard to feeding, I guess the significance is, we've raised a flag. Without this paper, the NPY-and-feeding crowd would go merrily on their way. What we've said is, 'Hey, don't forget that mice without NPY eat normally.'" D.J. Marsh et al., "Role of the Y5 neuropeptide Y receptor in feeding and obesity," Nature Medicine, 4:718-21, June 1998. T.E. Thiele et al., "Ethanol consumption and resistance are inversely related to neuropeptide Y levels," Nature, 396:366-9, Nov. 26, 1998.

Biochemistry

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