Lipids to treat obesity?

The infamous “Freshman 15” could be on its way to becoming part of the past, thanks to a recent discovery by Yale researchers. Staff Reporter Jessica Letchford reports.

A research team, led by Gerald Shulman, professor of Medicine and Cellular & Molecular Physiology at the Yale School of Medicine, has found a group of lipids that could be used to fight obesity. The lipids, known as N-acylphosphatidylethanolamines, or NAPEs, are secreted by the small intestine into the bloodstream. When injected with additional NAPEs, rats ate less and lost weight. Shulman said these findings will help develop a drug to treat obesity — a growing health care problem that currently affects one in three American adults, according to the National Institutes of Health.

“There are not really many adequate or effective treatments for obese patients,” Shulman said in an interview with the News last week. “We are excited about these results because they may potentially set up a new pathway to treat obesity.”

But even if a NAPE-based drug is developed, it will not be able to single-handedly solve obesity. For one, the drug would cause weight loss only by suppressing appetite. Since a dose of NAPEs only lasts 12 hours, it would most likely be a daily drug, said Matt Gillum GRD ‘11, the head graduate student on the research team. The drug would not lead to sustained weight loss without accompanying behavioral changes, he said.

“Everybody wants a miracle solution to obesity that I don’t think is out there pharmacologically,” Gillum said. “This could be an adjunct drug for therapy but it certainly isn’t going to be a miracle drug.”

In an attempt to better understand how the brain recognizes and regulates fat intake, the researchers looked at different chemical components in rat blood, trying to identify molecules that increased when rats were fed a steady diet of fat. Using techniques drawn from Shulman’s previous experiments on type 2 diabetes and the mechanisms of insulin resistance, the team discovered that NAPE levels increased after rats ate fatty meals.

After injecting the rats with NAPE doses similar to naturally-occurring levels, the researchers found that food intake decreased proportionally to the dose size. Further studies revealed that NAPEs, when injected directly into the ventricles of the brain, shut down neurons responsible for stimulating feeding behavior and activated other appetite-reducing neurons.

After five days of consistently injecting the rats with NAPEs, the researchers observed a 25 percent reduction in body weight. Gillum said it is unclear how long the weight change lasts because they did not conduct specific experiments to monitor weight re-gain after drug abstinence.

The research began more than three years ago, but it is far from finished.

For instance, researchers think that NAPEs may be involved in the reward systems associated with eating high-fat food, but do not yet have sufficient data to verify the hypothesis.

“We want to look into how NAPEs are telling the brain that what you’ve eaten has a high nutrient value,” Gillum said. “It’s very likely that these may be involved in the physiologic high associated with eating fatty foods.”

Experiments are currently underway to study whether NAPE injections pose any negative side effects. The team is also conducting experiments to measure fluctuations in natural NAPE levels in humans after subjects drink a milkshake. If the experiments are successful, the next step will be to test NAPE injections in humans, but Shulman said there is a ways to go before this happens.

Still, a NAPE-based pill will certainly not be a cure-all “miracle drug.” Experts agree that obesity is a complicated issue that requires a multi-faceted solution.

Marlene Schwartz GRD ’94 ’96, deputy director of the Yale Rudd Center for Food Policy and Obesity, said while studies such as Shulman’s are valuable, obesity is a two-part problem involving both treatment and prevention.

“People who are already obese deserve treatment like this,” she said. “But we want a public model for preventing obesity in the first place. Where we’re really going to see the biggest impact is when people’s eating habits become better.”

The research, which was published in Cell in late November, is being funded by the Howard Hughes Medical Institute, the National Institutes of Health and The Endocrine Society.

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