Anti-Starvation Mechanism May Underlie Obesity Epidemic

RAGE is a protein found on the surface of fat cells that stops the breakdown of stored fat when we starve, freeze, get injured, panic, or ironically, overeat.

RAGE is short for Receptor for Advanced Glycation End products. It recognises sugar-modified proteins and lipids, called advanced glycation end products (AGEs), which are prevalent in people who are ageing, diabetic, and obese due to elevated blood sugar levels and oxidative stress.

This study found that mice engineered with fat cell specific deletion of Ager (the gene coding for RAGE) gained 75% less weight during a 3-month high-fat diet, compared to mice with activated RAGE that received the same amount of food and physical activity. Normal mice receiving transplants of adipose tissue lacking RAGE also gained less weight while on a high-fat diet, and were better able to thermoregulate during a cold challenge.

These findings suggest that RAGE normally acts as a ‘braking’ mechanism that restrains the burning of stored energy during metabolic stress. This would have been useful to help early humans defend against starvation or changes in temperatures. However, as the lead author of this study, Dr. Ann Marie Schmidt, pointed out, "[this] 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.”

There are efforts under way to therapeutically inhibit RAGE and/or its ligands in order to mimic the deletion effects seen in high-fat-diet mice. Schmidt’s group identified 13 small molecules that block the interaction between RAGE and its intracellular effector DIAPH1, which has been shown to be important in transducing the effects of RAGE. They aim to test how treatment with DIAPH1 competitive inhibitors may help bariatric surgery patients and other people undergoing weight loss regimes from regaining lost weight.

We must bear in mind that the research so far has been in mice, and findings from animal studies don’t always translate to humans. Obesity is a very complicated problem, and whilst RAGE may play a role in excess weight, there are other contributing factors to take into consideration, so we are still a long way from a one-and-done anti-obesity drug.