Ancient anti-starvation mechanism may be driving modern obesity epidemic

A few years ago scientists examined the metabolic activity of several contestants taking part in The Biggest Loser, a weight loss competition TV show. The research revealed a kind of metabolic adaptation occurred as the subjects rapidly lost weight. Measuring the resting metabolic rate (RMR) it was discovered that by the end of the competition the rapid weight loss has also slowed down each individual's metabolism.

A follow up study in 2016 looked at the same subjects six years later and discovered these metabolic changes had persisted. Despite the subjects regaining varying amounts of weight in the years that followed the competition, the slowing in RMR initially detected years ago had remained.

This was an unexpected result. It was hypothesized that RMR could more dynamically reflect weight fluctuations, so as individuals regained weight over the years their metabolism would reflect those changes. But this wasn't the case, and six years later those Biggest Loser contestants displayed the same average RMR as they did at the end of the competition, despite any weight regain.

The American Heart Association subsequently helped fund a new study to explore exactly what was going on to cause these metabolic changes in a human body following effective weight loss interventions. What was triggering this "metabolic brake", and why was it persisting so many years later?

The focus of this new study is a protein discovered several decades ago called RAGE, or the receptor for advanced glycation endproducts. RAGE sits on the surface of fat cells, and this new research suggests it activates in response to several stress triggers and blocks the body from converting those fat cells into energy.

Several mouse experiments revealed animals with normal RAGE activity gained 75 percent more weight than animals with their RAGE pathway blocked. This was despite the same levels of physical activity and caloric consumption. Removing RAGE from fatty tissue, and then transplanting that tissue into healthy mice resulted in similar positive effects, decreasing the animal's ability to gain weight even when being fed a high-fat diet.

All this suggests that RAGE is in some way responsible for modulating an animal's metabolic activity. But what activates RAGE in the first place?

Prior research has suggested that a number of different molecules activate RAGE, but most relevant is the work showing how this protein is more active when a body is metabolically stressed. What this means is that RAGE seems to have evolved as a protective mechanism to stall a body from burning fat in times of starvation, injury, or exposure to extreme environments. The researchers hypothesize RAGE is also activated in times of overeating, to signal to the body that these extra calories should be stored and not burned as energy.

"We discovered 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," explains lead author on the new research, Ann Marie Schmidt, who has been investigating RAGE for many years.

While this new study, revealing how weight gain is stifled by blocking RAGE, was only demonstrated in mouse models, prior work has effectively shown RAGE to be present and active in human tissue. How this translates to some kind of human obesity therapy is still unclear.

Interestingly, a number of RAGE inhibitors have been developed but only one so far has moved through any large scale human trial. Azeliragon, a RAGE inhibitor, was produced as a novel drug to treat Alzheimer's disease. Several types of brain cells are known to express RAGE, and research has found that RAGE is significantly upregulated in the brains of Alzheimer's patients, so the hypothesis was that blocking RAGE activity could slow down neurodegeneration associated with the disease. The drug unfortunately failed to meet efficacy endpoints in Phase 3 human trials and research was discontinued last year.

There is no implication that Azeliragon could be adapted for other uses, but instead, that prior research suggests at the very least that targeted RAGE inhibitors in human bodies can be deployed relatively safely. Schmidt suggests broader applications for RAGE inhibitors are plausible outcomes as the protein is found in a number of places across the human body and is activated in times of metabolic stress.

"Because RAGE evolved out of the immune system, blocking it may also reduce the inflammatory signals that contribute to insulin resistance driving diabetes," says Schmidt. "Further, such treatments may lessen the system-wide inflammation linked to risk for atherosclerosis, cancer, and Alzheimer's disease."

RAGE isn't the only evolutionary adaptation that may not be best suited to modern human lifestyles. A recent study uncovered a genetic variant that we evolved to help us clear glucose from our blood as farming spread around 10,000 years ago to offer us greater volumes of carbohydrates in our diet. Unfortunately, that particular variant is only found in about 50 percent of people, putting those with the older variant at higher risk of developing type 2 diabetes.

Over the last few generations humans have dramatically molded a society allowing for instant access to incredible volumes of food. And not only that, but we produce processed forms of food that amplify sugars, salts and fats. Evolution is a slow process and our bodies are still built to contend with challenging environments and inconsistent food supplies.

How quickly this new research can be translated into human obesity therapy is unknown but Schmidt's work offers incredibly fascinating insights into how the body evolved, and how our metabolism fundamentally struggles to deal with a modern world of always available unlimited calories.

The new research was published in the journal Cell Reports.

Source: NYU Langone Health