When you've spent the weekend splurging on greasy fast foods, your bathroom scale isn't alone in reeling from the impact. Your brain does, too. New research shows just how saturated fat tricks us into eating more and elucidates the evolutionary basis for the propensity for poundage in developed nations. Our brain physiology, it seems, is glaringly out-of-date in the modern world.

Researchers have long known that the hormones leptin and insulin play key roles in appetite and food intake. In healthy people leptin, which is secreted by fat tissue, acts as a molecular measuring tape for our waistlines, quashing feelings of hunger. Insulin spikes when the pancreas gets a whiff of the blood sugar increase after a meal; once the brain detects the spike, it knows to tamp down the desire for food.

Certain foods and metabolic disorders, however, can disrupt our ability to respond appropriately to these hormonal signals. In a study published in the September issue of The Journal of Clinical Investigation, scientists report unraveling a central biochemical mechanism behind fat's effect on the mammalian brain . They found that after only three days on a diet high in saturated fat—a common ingredient in beef and cheese—the brains of rats and mice became resistant to leptin and insulin. In contrast, unsaturated fats, such as those found in olive oil, did not trigger resistance.

As a result of the hormone resistance, a meal high in saturated fat can crank up our appetite well after dessert. "Taking time off from a healthy diet to eat most fast foods may have consequences that last for some days, even after one resumes the healthy diet," says University of Cincinnati behavioral neuroscientist Stephen Benoit, who led the study. He believes the findings are likely to apply to humans, too.

Sensing leptin and insulin is like keeping an eye on the body's nutrient status, says Gary Schwartz, a neuroscientist at the Albert Einstein College of Medicine in New York City, who was not involved in the research. "If that eye starts to go blind because you keep giving it too much nutrient, then it can't respond. It can't tell you, 'look, don't eat.'" The result can spark a vicious cycle of metabolic problems and weight gain, he remarks.

But if the hormones are supposed to keep our metabolism from spinning out of control, why would saturated fat—the very thing that obese people have too much of—make us insensitive to them?

"There is a basic mystery here," says William Banks of the Saint Louis Veterans Affairs Medical Center. A leptin expert, he has shown that high levels of saturated fat in the bloodstream block the hormone's passage into the brain, further blinding it to those extra pounds below the neck.

One hint at an explanation for these counterintuitive effects comes from the physiology of starvation. When we starve, our body begins to break down its blubber for energy. As a result, the blood gets flooded with fat, just as it does in obesity and overeating. Apparently erring on the side of caution, our brain interprets free fat (no matter its source) as a starvation alert—had it done otherwise in our evolutionary history, we probably wouldn't be around to worry about it. Says Banks: "In the history of evolution, we've been faced with caloric shortages and starvation much more than we've ever been faced with a wealth of calories."

But as Benoit notes, a neurological response "that was useful at some point in history is no longer useful when there is a McDonald's and a Taco Bell on your way home." So in our battle against the empty calories, sticking to a Mediterranean diet—rich in olive oil and vegetables—might help us outsmart our obsolete brain physiology.