In 1994, when researchers discovered that a hormone called leptin causes satiety, they were convinced they had
found the weight-loss holy grail. Anyone who wanted to lose weight would pop a pill, feel full and push away from the table.

But over the last decade, scientists learned that it wasn’t so simple. Overweight people, they found, are not short
on leptin, they are overloaded with it—so much so that they’re now deaf to leptin’s message to stop eating. “Their brain shuts down the door to leptin,” says Umut Ozcan, MD, a Harvard Medical School endocrinologist.

That’s a shame, because leptin doesn’t just say you’ve had enough food, it also revs up the metabolism, making
you burn more calories.Now researchers are trying to figure out how to resensitize the brain to leptin. They believe the resistance may be caused by stress to cells in the brain’s hypothalamus. Ozcan has identified two medications that prompt the brain to “open its doors and hear the leptin,” as he puts it, and he is searching for even more effective compounds.

But people who want to increase their sensitivity to leptin can start closer to home—with changes in diet. New research suggests that even one high-fat binge can alter the brain’s responsiveness to leptin. So what you eat one
day has a direct effect on how much you’ll want to eat for days afterward.

To keep your brain open to leptin, it’s key to control your fat consumption. The best strategy is to target the
fats that are the most dangerous. For example, one new study suggests that palmitic acid, a saturated fat found
in cheese and beef, is the chief culprit in blunting leptin’s action. “These fats actually get into the brain and change the ability of hormones to regulate body weight,” says University of Texas Southwestern investigator Deborah Clegg, PhD. “So if you spend the weekend eating pizza, on Monday your brain is still desensitized with all that fat and is not paying attention to signals to slow down. As a result, you will feel hungry and will overeat in a self-perpetuating cycle.” In effect, she says, you’re being set up by your brain to gain weight.

Clegg suggests sticking to oleic acid, a heart-healthy fat found in olive oil that doesn’t have the same negative effect.