Solving the mystery of the weight-loss plateau

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Scientists are slowly chipping away at one of the most mysterious aspects of weight loss: why does the lost weight often seem to come back?

It's now clear that it's not simply a matter of willpower. 

"We know people are good at losing weight with diet and exercise," said Gregory Steinberg, Canada Research Chair in Metabolism and Obesity at McMaster University. "It's not that people just give up."

The problem is rooted in the body's physiology. After people lose weight, their bodies' energy use also changes by burning fewer calories.

"Quickly you hit a plateau at five to 10 per cent weight loss and you can't lose more weight than that because your metabolism slows down too much," said Steinberg. "This explains why relapse weight gain is so high."

But why the body's calorie-burning capacity drops has so far not been explained.

"No one knows why," said Steinberg.

There are theories that something is putting the brakes on the body's ability to turn up its fat-burning machinery. And last week, a new paper published in Cell Reports, describes one possible system.

At NYU School of Medicine, Ann Marie Schmidt is studying a receptor on fat cells that appears to interfere with weight loss. When she created a mouse model without any of those receptors the mice didn't get fat even though they ate more food.

"When you delete [the receptor] it completely resets their metabolic program so that they are resistant to the diet-induced obesity," said Schmidt. "It's totally unexpected and it has so many implications for human health."

Although scientists have identified the receptor — called RAGE — in humans, so far most of the research has been done in mice.

"I've been in the business long enough to know that a lot of things have been discovered in mice have never translated into humans very well," said professor David Hart, a researcher at the University of Calgary.

Hart said the RAGE receptor is found in a variety of human cell types, making the situation more complex.

Will it be possible to use drugs to target the receptor so it releases the brakes on fat burning without interfering with its other functions? That's one of the big questions Schmidt's team is trying to answer.

"The puzzle has a lot more pieces to be worked out, for sure," said Schmidt.

"Clearly whether or not turning on energy expenditure or manipulating this pathway can be achieved without altering its many other functions in the body will be an important question. But certainly it's really intriguing," said Steinberg, who is chasing a similar target in his own research.

A few years ago Steinberg and his colleagues at McMaster discovered another system that also seems to keep the brakes on the body's natural fat burning system using a mechanism involving serotonin. It appears to prevent the body's brown fat from burning more energy.

Search for 'the quick fix'

The search for a calorie-burning trigger is based on a serendipitous discovery when scientists first realized that adults had a type of fat known as "brown" fat. They knew it existed in mice and also in human infants. But no one realized it was also present in adults.

"We always thought babies lost it," said Steinberg.

Brown fat was discovered when researchers noticed metabolically active areas on adults who were undergoing PET scans for cancer. 

"They didn't know what it was," said Steinberg. Then they did biopsies and proved it was the exact same protein found in mice or rats that allowed them to survive in the winter and maintain their body temperature."

"The discovery 10 years ago that adult humans had this tissue is really the key discovery which has opened up this whole field in trying to figure out how we can burn more calories," said Steinberg.

Both Steinberg and Schmidt are trying to develop drugs to release the body's fat-burning brakes and help people push past the weight loss plateau to maintain a lower weight.

Right now the only available drugs to treat obesity either suppress appetite or prevent the body from absorbing fat from food. At this point there are no drugs that target the slowing down of the body's fat burning metabolism.

"I think it's another interesting direction," said Hart, who is also scientific director of Alberta's Bone & Joint Health Strategic Clinical Network. "I guess as a society we're always looking for the quick fix, the pill that's going to fix it for me."

"People are discovering more and more molecules and whether any one is going to come through as the magic target, I'm not convinced at this point."

"Obesity is complex so the solutions are likely not going to be simple."

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