BioWorld International Correspondent

LONDON - An effective drug with minimal side effects could be available to treat obesity within five years. The drug, a natural peptide called PYY, may be able to drastically reduce the amount of food eaten by obese people.

The peptide would have to be injected, like insulin, but the team of researchers at Imperial College in London who have been studying it predict that within 10 years it could be available in a form that could either pass through the skin or be inhaled.

Stephen Bloom, professor of medicine and head of the Division of Investigative Science at Imperial College, who led the team, told BioWorld International: "We have shown that obese people lack the normal satiety hormone that switches off appetite after a meal. This offers us the possibility of giving them back this satiety factor by injection, so that they regain their ability to control their appetite."

Bloom described his team's discovery as "potentially very significant." No other means of controlling appetite are available, he said, nor are there any other good leads on how this might be possible.

Such strategies are urgently required, he said. "Obesity causes the premature death of 1,000 people a week in the UK alone. If we could get rid of it, we could halve the incidence of cancer - as well as cutting the incidence of diabetes, stroke, heart disease and arthritis, and reducing the numbers of suicides and failed marriages."

A report of the study appears in the Sept. 2, 2003, New England Journal of Medicine in a paper titled "Inhibition of Food Intake in Obese Subjects by Peptide YY3-36."

Bloom has been studying obesity, appetite control and natural hormones that influence appetite, such as PYY, since 1984. Like leptin, PYY interacts with two types of neurons - one that stimulates appetite and one that inhibits appetite - in a part of the brain called the arcuate nucleus.

Those that increase appetite normally release a neurotransmitter called NPY, which interacts with the post-synaptic receptor called Y1, which stimulates food intake. Those that reduce appetite release a neurotransmitter called alpha-MSH, which interacts with the post-synaptic receptor called MC4, which inhibits food intake.

PYY switches off the release of NPY, which normally stimulates appetite. It also, through interneuron connections, stimulates the release of the inhibitory alpha-MSH.

Obese people have high levels of leptin, but are resistant to its effects. Levels of PYY are low, however, in obese people, and they remain sensitive to it.

To test the effects of PYY on appetite, the researchers recruited six people in each of the following categories: healthy obese men, healthy obese women, healthy lean men and healthy lean women. Each person consumed similar food for 48 hours before each study day, and ate an identical meal between 7 p.m. and 8 p.m. on the evening before the study day. After 8 p.m. they could consume only water.

Each person attended twice, receiving a 90-minute intravenous infusion of either PYY or saline. Two hours after the end of each infusion, the study subjects were offered an unlimited buffet lunch. They also completed food diaries until 1 p.m. the following day. Neither the subjects nor the dietitians who assessed their calorie intakes knew who had received PYY and who had received saline.

Analysis of the results showed a dramatic decrease in the amount of food eaten by the subjects when they received PYY, whether they were lean or obese. Both groups showed about a 30 percent decrease in calorie intake, a drop that was highly statistically significant. Similarly, both lean and obese subjects ate significantly less in the 24 hours following the infusion of PYY than when they were given saline.

Blood samples taken throughout the study period showed that obese people had significantly lower levels of PYY in their blood when fasting and after meals. The lower an obese person's blood level of PYY, the greater their body-mass index tended to be. No one reported any side effects.

Bloom and his colleagues wrote in the New England Journal of Medicine: "Our findings are consistent with the hypothesis that a deficiency in circulating PYY may be involved in the pathogenesis of obesity. It is unclear whether low PYY levels initiate the development of obesity or whether PYY levels are reduced as a result of obesity."

The proof of the pudding will be in the eating, however. Bloom admits that an important study yet to be done will involve giving PYY to obese subjects every day and then finding out whether they lose weight. That item tops his research agenda.

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