Health & Wellbeing

Ancient anti-starvation mechanism may be driving modern obesity epidemic

Ancient anti-starvation mechan...
What kept out ancient ancestors from starvation may be exactly the same evolutionary mechanism that makes it so hard to lose weight and keep it off
What kept out ancient ancestors from starvation may be exactly the same evolutionary mechanism that makes it so hard to lose weight and keep it off
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What kept out ancient ancestors from starvation may be exactly the same evolutionary mechanism that makes it so hard to lose weight and keep it off
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What kept out ancient ancestors from starvation may be exactly the same evolutionary mechanism that makes it so hard to lose weight and keep it off

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

10 comments
SimonClarke
I was born in the mid 60s, all of the way through the 70s and into the 80s I was always told, 'eat everything that is on your plate.' this stems from people not having enough food to eat so everyone was given their share. Continue this ingrained policy on into later life and everything on the plate still gets eaten except now there is more on offer.
dfmd
Tiny bits of knowledge strewn across a vast metabolic field. May I also strew? Xenobiotics with quantum signatures that confuse our metabolic minds. Obesity is a form of metabolic autism. My hypothesis is just as good as the RAGE one. Obesity research is scarce even as most humans slide down toward a lumbering existence and their tired faces send an unreadable message. The baboons circle the Medical Obelisk.
bwana4swahili
Hunter/gatherer societies don't have access to food on a daily basis and sometimes have to go for weeks with very little to eat. The body adapts. In our modern agricultural society food is more readily available and obesity can, and often does, result... We haven't quite evolved to handle the change.
McDesign
@SimonClarke - my wife and discuss this very thing, how our upbringing has made it very hard to leave anything on our plate.
Wolf0579
There was an obesity epidemic that coincided with the coming of the personal computer. That's your culprit, not the ancient genes.
amazed W1
I agree with Bwana4swahili, if your meals are few and far between then you need to store everything you can when there is a lot of food about and then to avoid using up the store unnecessarily in times of dearth. So the reduced RMR should be expected to have evolved to be reasonably the same in both situations, once it has been initiated.
Douglas Bennett Rogers
I also see a lot more ghastly thin people than I used to. All of the advertising seems to be aimed at weight reduction. I was skinny for a long time and these people are as desperate for change as the fat people. The ectomorph can still get fat but will still look sort of thin. People will say "You can carry the weight." but you really can't. Feet and knees break down and you can't do body weight exercises.
owlbeyou
All the posters have provided interesting perspectives. I too grew up with the eat-everything-on-your-plate culture. To discover that my metabolic rate ain't what it had been a bunch of years ago was an irritating wake up call - a cruel fate for food lovers. So now my plates are smaller and only eat one larger meal a day, but it's still not easy. It's a daily struggle. The more you eat the more you get hungry. Even if their pantry is full, hunter gatherers have a deep insecurity of not knowing where their next meal will come from so they chow down. Television and computers have been enormous players of this outcome not just because of the sedentary lifestyle they help to create, but the relentlessly tempting barrage of happy and slim people chomping down on all that tasty processed food in commercials. Eat less meat. There are many other delicious and healthy sources of proteins. Eat more veggies; much better for you. You can still be overweight but at least your health will be better. Take it easy on the carbs. You can eat out, but home cooking is still the best.
Nobody
Strange that the fact our meats are filled with anabolic steroids to grow bigger and fatter livestock was not mentioned. Nor was there any mention of the huge amount of sugar consumed by modern man. The reduced nutrition of processed foods also failed to get any consideration. All these factors are pretty obvious. Worse yet, as I get older, eating is the only thing I can still do three times a day.
Majki
Nobody is on the spot, at least for my wife and I. We also were raised with eat all on your plate mentality (she's from Ukraine, I am from Serbia) but we were never overweight, until we moved to North America. And you can see how most of Europeans look like, not many overweight people. We are trying to buy organic as much as we can but it's hard now to ger rid of what's been put on for past 20+ years of loving here...