A New Shot at Fighting Obesity

In another sign that people in the United States are losing the battle of the bulging waistlines, the New York Times recently ran a front-page story on the legion of people resorting to drastic obesity-fighting operations such as gastric bypass surgery. “Doctors and hospitals across the country are scrambling to satisfy the booming demand for surgery that shrinks the stomachs of severely obese people,” the paper noted.

These are people unable to control their weight through diet and exercise. And current appetite suppressants aren’t effective enough for them or pose a health risk when taken for long periods.

Researchers who recognize the need for new obesity-fighting drugs are searching for such medicines among the complex web of biochemical signals that controls appetite. Two recent reports suggest that investigators are making progress in their quest but that its end is far from near.

Both studies come from a London-based group led by Stephen R. Bloom of Hammersmith Hospital. Among obesity researchers, Bloom has been one of the most outspoken and optimistic about the potential for finding natural ways to trick a body into wanting less food. His group recently identified a hormone, made by the intestine, that appears to shut off hunger after a meal. Dubbed PYY, short for peptide YY3–36, it appears to be a natural counterpart to the hunger-inducing hormone ghrelin, (SN: 2/16/02, p. 107: The Hunger Hormone?). Whereas ghrelin concentrations in the blood rise before a meal and plummet after, PYY does the opposite. The stomach secretes ghrelin, the small intestine secretes PYY, and both signals appear to act on regions in the brain that control appetite.

Last year, Bloom and his colleagues showed that people of normal weight injected with PYY ate about one-third less at a buffet than did untreated individuals (SN: 8/10/02, p. 83: Available to subscribers at Fullness Factor: Gut hormone tells brain the stomach is well fed). Now, in the Sept. 4 New England Journal of Medicine (NEJM), they report that PYY similarly suppresses appetite in lean and overweight human volunteers. That’s a potentially critical finding, given the roller-coaster history of leptin, another hormone that stirred dreams of a miracle weight-loss drug. While leptin can also stifle the drive to eat, most obese people don’t lack the hormone. Instead, they seem to be resistant to its effects, so leptin injections haven’t produced much weight loss in many of the obese people tested so far.

In contrast to leptin, obese people have less PYY in their blood than lean people do, Bloom and his colleagues report in their NEJM paper. Furthermore, the obese individuals released less PYY into their bloodstreams after a meal. These findings suggest that PYY could be at the heart of at least some cases of human obesity, the researchers contend.

Highlighting the complexity of appetite regulation, however, PYY has a hormone relative called pancreatic polypeptide (PP). Its blood concentration also rises after a meal. Furthermore, studies of obese people and people with the undereating syndrome called anorexia nervosa–groups that have low and high blood concentrations of PP, respectively–have hinted that the hormone influences food intake. Bloom and his colleagues have now proven that.

In the August Journal of Clinical Endocrinology and Metabolism, they report that people of normal weight injected with PP before a buffet lunch ate about 21 percent less than if they received a premeal injection of an inert saline solution. People getting the PP also reported feeling less hungry.

Whereas PYY appears to suppress appetite by lowering ghrelin concentrations in the blood, PP doesn’t seem to alter ghrelin, leptin, or any other hormone linked to eating. Bloom says that PYY is a more promising drug lead since it suppresses appetite at lower doses than PP does. Given obesity researchers’ disappointment with leptin, however, he’s wary of expressing too much confidence in PYY’s chances.

“Leptin failed because the overweight turned out to have very high levels and were resistant–not the case for PYY. Since PYY is responsible for loss of appetite after every meal . . . I am hopeful,” Bloom told Science News.

In a commentary accompanying the NEJM report on PYY, Judith Korner and Rudolph Leibel, both of Columbia University, also express cautious optimism that scientists’ growing insight into the control of appetite regulation will pay off. “It is unlikely that any one molecule or derivative will provide a magic bullet to induce and maintain weight loss. Successful pharmacological treatment for obesity may be possible only by simultaneously targeting the interlocking, redundant systems that drive food intake and act to resist the loss of body fat,” they conclude.

From the Nature Index

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