A molecule that puts the brakes on appetite

That heaping pile of golden crisp French fries looks delectable, but polishing off the plate may be a tall order. New research from Yale scientists suggests that a family of phospholipids tells the brain when an animal has had its fill of fat—findings that help explain the physiologic mechanism that wards off a deep-fried feeding frenzy. And these phospholipids, called N-acylphosphatidylethanolamines, or NAPEs, may hold the key to new treatments for obesity.

The human body has several built-in systems that keep us from stuffing ourselves silly. Leptin, for example, tells the brain to put the brakes on eating when fat stores are abundant. Now a team led by Gerald I. Shulman, M.D., Ph.D., the George R. Cowgill Professor of Physiological Chemistry, professor of medicine and of cellular and molecular physiology and a Howard Hughes Medical Institute investigator, has identified a new class of appetite-suppressing molecules—the NAPEs—that become synthesized in rats after a high-fat meal, as reported in November in the journal Cell.

The researchers teased apart the function of NAPEs by synthesizing the most physiologically abundant NAPE and injecting it into rodents. They found that the higher the concentration of the phospholipid, the less the rodents ate. Furthermore, like someone sitting back after a feast, the NAPE-injected mice lounged about and groomed themselves even though they ate only a mini-meal.

Shulman’s group discovered that NAPEs, like certain other chemicals that help to control appetite, exert their effects via the central nervous system. They appear to be synthesized in the small intestine after a high-fat meal but they then get dumped into the blood and lymphatic system, putting them on a fast track to the brain. When Shulman’s team injected nanomolar amounts of NAPE directly into rodent brains, it slashed the animals’ appetites by more than 50 percent and shut down the activity of NPY neurons, which stimulate appetite.

On a roll, the researchers decided to treat the rats with NAPE for five straight days. They found that the rodents ate 30 percent less food and shed a significant amount of weight.

The race is now on to see whether these rodent findings translate to humans. Shulman’s team is investigating NAPE regulation in humans following feeding, and the researchers soon plan to treat monkeys with NAPEs to observe the effects on appetite. Provided those studies pan out, Shulman is eager to see whether NAPEs can reduce food intake in humans. If they do, NAPEs could serve as the basis of novel appetite-suppressant or obesity-fighting drugs. “Obesity is a major health problem, and we have very few treatments available,” Shulman said. “We are always looking to better understand appetite regulation, and NAPEs may be a new physiological regulator of appetite.”