New research on mice suggests that a mechanism that likely exists to prevent starvation could be contributing to obesity.

The mechanism involves the protein receptor for advanced glycation end products (RAGE). Researchers at NYU School of Medicine in New York City, together with colleagues from other research centers across the United States, fed two groups of mice a high-fat diet. Before the experiment began, the scientists removed RAGE from the fat cells of one group of mice while leaving the other group unchanged.

After 3 months on the high-fat diet, the mice that did not have RAGE in their fat cells gained 75% less weight than the unmodified mice. Both groups of mice consumed the same amount of food and performed the same level of physical activity.

In another experiment, the researchers transplanted RAGE-free fat tissue from the modified mice into normal mice and placed them on a high-fat diet for 3 months. These mice also gained less weight than the unmodified mice.

The researchers note that it makes sense that the body has evolved a mechanism for storing energy when nutrients are scarce. However, the experiments suggest that an abundance of nutrients may activate the same mechanism.

“We have discovered,” says senior study author Ann Marie Schmidt, M.D., a professor of endocrinology at NYU School of Medicine, “an anti-starvation mechanism that has become a curse in times of plenty because it sees cellular stress created by overeating as similar to stress created by starvation—and puts the brakes on our ability to burn fat.”

RAGE blocks the burning of fat in order to conserve energy. This survival mechanism normally works during starvation, exposure to cold, or injury. However, the same mechanism also responds to overeating because it places stress on cells and triggers the same biological signals.

Findings from both the recent and previous studies show that advanced glycation end products (AGEs) trigger RAGE in human tissues. AGEs form when blood glucose combines with fats and proteins. People who are aging, have diabetes, or have obesity typically have higher levels of these compounds.

Other molecules can also trigger RAGE to block fat burning. These include substances that cells release when stress causes them to die and spill their contents.

In previous work, the research team experimented with compounds that could block RAGE activity and potentially remove the brake on fat burning.

The next step will be to refine these RAGE-blocking compounds and determine whether they could help prevent weight gain in people who have undergone treatments to lose weight, such as bariatric surgery.

Because RAGE has evolutionary roots in the immune system, the researchers believe that RAGE blockers may have additional applications. These could include reducing inflammation signals, such as those that promote insulin resistance, which is a precursor to diabetes.