How we evolved to be obese: ‘RAGE protein’ our ancient ancestors developed to survive starvation is now confusing our bodies – driving our bodies to stop burning fat as we overeat

• Over 70% of Americans are overweight or obese 
• But beating obesity is not as simple as going on a diet and exercising – and the metabolic processes that underlie it are poorly understood 
• Since 1992, New York University scientists have been studying a protein called RAGE that lives on the surface of fat cells
• Stress, including that caused to the body by overeating and inflammation turns on the RAGE protein which evolved to help us conserve fat to burn for energy 
• The lab is now developing a drug to block the effects of RAGE to aid weight loss 

Humans are getting fatter but, ironically, our obesity epidemic may be driven by a biological trick we evolved to keep us from starving to death, a new study suggests. 

The trouble is that overeating puts a similar kind of stress on the body that starvation does, triggering a famine survival mode that makes us store fat more securely. 

Scientists at New York University discovered a fat cell protein that keeps them from being broken down when our bodies are stressed. 

The researchers are now trying to design a way to disrupt that protein and keep the body’s anti-starvation mechanisms from overriding weight loss regimens and surgery.    

A protein on the surface of fat cells gets turned on in stressful situations to put the ‘brakes’ on fat-burning so we have enough energy stored in case of starvation or a sudden need to flee. But over-eating and obesity itself may turn on the fat-saving protein, too, a new study found 

Over 70 percent of Americans are overweight or obese, putting them at risk for chronic disease like diabetes, heart disease and early death, to name a few dangers.

A predisposition to obesity is partially genetic, but many lifestyle factors explain the condition as well. 

The Western Diet is certainly a significant contributor to the obesity epidemic, as highly processed foods have been proven to encourage over-eating. 

Plus, Americans as well as residents of at least 45 other countries have sedentary lifestyles and, without sufficient physical activity, we don’t stand much of a chance to shed extra pounds. 

But metabolism and weight-gain are far more complicated than simply eating less and moving more. 

This was clear in a 2016 study of contestants from ‘The Biggest Loser.’ 

Just six years after being placed on intensive diet and exercise routines for the six-week competition, most of the 14 contestants studied had re-gained the weight, and their metabolisms were slower and they had hormonal changes that made them more hungry than ever. 

It was a disheartening, but illuminating finding. 

Now, a follow-up study has shed some light on why biology might betray even the best efforts to fight obesity. 

The scientists examined a protein called RAGE. 

RAGE lives on the surface of fat cells in mammals. 

Its job is to preserve our fat stores so there is a plentiful supply when we really need it, like when adrenaline signals that we need extra energy to burn when we need to run from a threat, when we’re freezing, starving or panicking.  

THE WESTERN DIET EXPLAINED 

The Western diet is loosely defined as one full of fatty and sugary foods, such as burgers, fries and soda.  

People often eat foods that are high in

• Saturated fats
• Red meats
• ‘Empty’ carbohydrates
• Junk Food

And low in

• Fresh fruits and vegetables
• Whole Grains
• Seafood 
• Poultry 

Health effects have been linked to things such as hypertension, heart disease, diabetes, obesity, colorectal cancer and dementia. 

But in obese, aging or diabetic people, advanced glycation endproducts (AGEs) tend to form in the bloodstream. 

In younger people, these accumulate when you eat certain kinds of foods and those cooked at high temperatures. 

For people with obesity, the problem is likely two-fold: their diets are often high in these kinds of foods, plus obesity itself leads to oxidative stress and inflammation, through mimicking the natural process of aging or the disease state of diabetes. 

‘Normally our bodies clear these [AGEs] really well, but there are facets to obesity that are not yet understood, but they turn those protective mechanisms down,’ lead study author and NYU endocrinology professor Anne Marie Schmidt told DailyMail.com.

The NYU researchers found that these AGEs activate RAGE on the surface of fat cells, putting the protein into protective mode, locking in the excess fat cells.     

RAGE then acts as a ‘metabolic brake’ on our ability to burn off that fat for energy. 

It’s evolution turning against itself. 

‘Food and nutrients were not so predictable, so having the ability to store energy would be a benefit,’ Dr Schmidt said. 

‘However, when nutrition is in such high excess but that receptor is still present and active, it inhibits the otherwise natural energy expenditure.’ 

So her lab’s goal is to run interference on RAGE and stop it from stopping natural energy expenditure. 

In fact, Dr Schmidt and a multidisciplinary team have been following the RAGE pathway in their research, hopefully toward a drug, since 1992. 

‘We’ve been working very hard on that and have been working on this molecule for many, many years now, and we see potential based on experiments with animals,’ she said. 

‘Of course with experiments on animals, we don’t always see the same results on humans. 

‘But there’s a chance there’s hope, and obesity is a tantalizing endpoint.’

In fact, Dr Schmidt is hopeful that they might have an obesity drug ready for phase I clinical trials, in a small sample of patients, within five years. 

‘It’s really progressing beautifully, we just need to get the perfect molecule, that all the boxes are checked,’ she said. 

‘We’re totally committed to seeing this through.’   

Source: Read Full Article