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Tipping the scales.
Researchers have shown why a high-protein diet may curb hunger.

Rachel Batterham/UCL

Hello Protein, Goodbye Fat

A high protein diet can prevent weight gain by curbing short-term appetite. But just how this diet works on a physiological level has remained a mystery. Now, a new study suggests that the key is a tiny protein fragment called peptide YY3-36 (PYY3-36), which dampens hunger in response to high levels of dietary protein.

In August 2002, endocrinologist Stephen Bloom and colleagues at Imperial College London showed that when they injected PYY3-36 into rodents and humans, it decreased hunger for 12 hours or more. Rodents on the peptide also curbed their weight gain, leading some to herald PYY3-36 as a potential new anti-obesity drug. However, not all groups have been able to replicate these results, leaving the peptide's promise in the lurch.

A former member of Bloom's team, endocrinologist Rachel Batterham of the University College London and colleagues, took another stab, this time from a different angle. They first fed a group of normal-weight and obese men a diet high in either protein, carbohydrate, or fat. As expected, volunteers on the high-protein diet felt significantly less hungry than those on the other diets for up to 3 hours after the meal. The high-protein dieters also had the highest levels of PYY3-36 in their blood than the other dieters. Mice showed similar effects, and high blood levels of PYY3-36 in the rodents corresponded to a reduction in the mRNA levels of certain fatness-inducing messenger proteins in the brain.

To seal the deal, the team created a knockout mouse that lacked the PYY gene. The knockouts were obese and loved to eat: by 10 weeks of age, PYY knockout mice weighed about 37.5% more than normal mice and had about 12% more body fat. A high-protein diet did not curb their hunger. Giving PYY3-36 to the knockout mice led to a drastic reduction in their eating habits and consequently their body fat and body weight. The wild-type mice showed little or no change with the same treatment, the researchers report in this month's issue of Cell Metabolism.

The new study hasn't entirely settled things. "There are still elements of controversy," says endocrinologist Jeffrey Flier at the Beth Israel Deaconess Medical Center in Boston, Massachusetts. The relationship between PYY levels and dietary protein is "extremely well supported by the data," he says, but in the light of previous work by two other groups who failed to get an obese phenotype with slightly different PYY knockout mice, future work is needed to reconcile this discrepancy.

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