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The Problem With Fat People Is That Their Bodies Think That They Are Skinny

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 the city of New York, together with colleagues from
other United States research centers, fed two groups of mice a high-fat diet. They had removed
RAGE from the fat cells of one group and left the other group intact beforehand.
After 3 months on the high-fat diet, the mice without RAGE in their fat cells had gained 75% less
weight than the unmodified mice.
Both sets of mice ate the same amount of food and did the same amount of physical activity.
In another experiment, the team transplanted RAGE free fat tissue from the modified mice into
normal mice and put them on a high-fat diet for 3 months. These mice also gained less weight
than unmodified mice.
The researchers observe that it makes sense that the body has evolved a mechanism for hoarding
stored energy for when nutrients are scarce. However, these experiments suggest that an
abundance of nutrients has a similar effect.
"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 to conserve energy. The survival mechanism works for
starvation, cold, and injury. However, the same mechanism responds to overeating because that
also puts stress on cells and triggers the same signals.
Findings from the recent and previous studies have revealed that advanced glycation endproducts
(AGEs) trigger RAGE in human tissues.
AGEs form when blood glucose combines with fats and proteins. People who are aging, have
diabetes, or who have obesity typically have raised levels of the compounds.
Other molecules that can trigger RAGE to block fat burning are those that cells release when
stress causes them to die and disgorge their contents.
In previous work, the team had experimented with compounds that could block RAGE activity
and potentially take the brake off fat burning.

The next step will be to fine-tune the RAGE blockers and find out whether they could help
prevent weight gain in people who have undergone treatments to lose weight, such as bariatric
surgery.
Because RAGE evolutionary roots are in the immune system, the researchers can foresee other
applications for RAGE blockers. These include reduction of inflammation signals, such as those
that promote insulin resistance, which is a precursor of diabetes.