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Diet and lifestyle

Researchers seek to understand the biology of weight gain

Everyone who has tried to lose weight knows how difficult it is. Danish researchers have set out to investigate out how nature has shaped us to put weight on more easily than shedding the kilos again.

“Why can’t I get below 86 kilograms no matter what I do?”

This was the first question I asked Christoffer Clemmensen, Group Leader at the Novo Nordisk Foundation Center for Basic Metabolic Research of the University of Copenhagen.

His reply was not very encouraging, however. Christoffer Clemmensen, who is researching why losing weight is so unbelievably difficult, had to confess that sustaining weight loss is actually almost impossible.

Our body, our genes, the environment, our eating habits and hormones in the body prevent most people from achieving this.

However, this may become easier in the future if researchers like Christoffer Clemmensen can determine which hormones and signalling pathways cause the body to cling so tightly to its fat stores.

Nature predisposes us to gaining weight more easily than losing it. Researchers have a good understanding of the processes that regulate hunger and make us want to eat very delicious food, but they do not understand the mechanisms that limit weight gain. The fundamental pieces are missing from this physiological puzzle, and these pieces may well be the ones that are impaired when people’s weight keeps climbing upwards.

“There is a reason why your weight does not increase to 100 or 110 kilos. This is because you have several satiety signals that ultimately help control your weight. We all have biological boundaries that balance the calories expended and consumed by the body, and we assume that some key hormones are involved. We are trying to identify them, and if we can understand this system, it will open up a whole new way of treating people with obesity,” explains Christoffer Clemmensen.

Christoffer Clemmensen and colleagues recently published a review article in PLoS Biology on the poor understanding of these mechanisms that keep journalists and everyone else at a relatively fixed weight.

Easier to gain weight than lose it

In general, complex interaction between random genetic and epigenetic factors and social and environmental factors determines our weight.

This also means that even people who are adopted and thereby have their genes moved from environment A to environment B will continue to fulfil some predisposed and relatively fixed weight target.

However, research has repeatedly shown that this weight target can change and that it unfortunately usually moves in one direction – upwards. For some individuals, a stressful period combined with free access to highly rewarding food is sufficient for 86 kilos to become 92 kilos.

The problem arises when the period with the new weight becomes so long that the body begins to adjust to 92 kilos as the ideal weight instead of the previous 86 kilos. The brain then starts to ensure that calorie intake maintains the 92 kilos. A new set point has been created.

Here is the problem: if the person then goes on a diet and reaches 80 kilos, you might think that the body then sets its weight target to 80 kilos and adjusts the calorie intake based on that, but this simply does not happen.

“Apparently, the mechanisms that regulate weight gain do not apply to weight loss, which is why sustaining weight loss is so difficult or even nearly impossible. The body works towards a different weight than the one achieved because retaining fat has probably been more important evolutionarily than keeping weight down. Nevertheless, evolution has ensured that our ancestors did not become easy prey by gaining too much weight,” says Christoffer Clemmensen.

Our ancestors could not tolerate excess weight

Understanding the background to how our weight is regulated requires going back to the ancient savannah, where life for our species was very different from today.

In the distant past, before we humans reached the absolute top of the food chain, overeating was a serious hindrance because this meant carrying an extra 10 or 20 kilos around. This was especially true when running to escape hungry lions and hyenas.

Having a mechanism in the body that ensures somewhat low body weight therefore also became an advantage for us.

“When we overfeed people with more energy than they expend in our experiments, they quickly gain weight. But they also rapidly return to their normal body weight once they eat based on their appetite. This is a remnant of the past and emphasizes that some biological mechanisms prevent us from accumulating too much fat,” explains Christoffer Clemmensen.

The way people live has changed drastically over the past millennia, however, and the evolutionary mechanism that kept many of us from being killed by a sabretooth tiger has not been very strong in the modern era, because people are no longer endangered as prey.

Random mutations have therefore partly eroded our defence mechanism and made many modern people more or less susceptible to a society that promotes obesity.

A new target in combatting obesity?

Christoffer Clemmensen focuses the article in PLoS Biology on the poor understanding of some of the very basic mechanisms behind the current obesity epidemic.

His group at the University of Copenhagen wants to identify the signalling pathways and hormones that prevent us from continuing to eat after we become satiated.

If the researchers can identify these mechanisms and understand why they do not work equally well for all people, they will obtain new and unique knowledge that can be used to combat obesity.

Christoffer Clemmensen explains that, in the long term, this will hopefully also lead to better treatments than both the current ones and those that might be developed over the coming years.

For example, one of the most promising drugs for treating obesity is Novo Nordisk’s semaglutide. This has shown good results in a Phase 3 trial in which the participants lost about 16–20% of their body weight over about 1.5 years of treatment.

Christoffer Clemmensen emphasizes that no one knows the long-term effects of these drugs.

“It is like hitting the accelerator and the brake at the same time. If you stop taking the medicine, the body will again accelerate rapidly because the brain remembers how much you weighed before the treatment and the kilos will accumulate. The question is whether the body will get better and better at counteracting the weight loss achieved with drugs over 5–10 years. We think that better biological understanding of the mechanisms that regulate body weight is needed to develop drugs that are effective enough to curb the global obesity epidemic,” he adds.

Discovering the hormone and mechanism that prevent overeating

The researchers from the University of Copenhagen are conducting several experiments in which they will try to identify the molecules and mechanisms that cause dieting to fail.

One experiment involves overfeeding both mice and people, inducing them to eat more than they would naturally.

Then the researchers take blood samples and examine them for thousands of molecules to determine whether some are consistently very active when calorie intake is unusually high.

These may be the keys to understanding the mechanisms that prevent body weight from increasing.

“We have wanted to do this for many years, but the technology is now in place to identify potential candidates with adequate measurement sensitivity. We are therefore now ready to determine which molecules are active, where they come from and how they communicate their information between the body’s organs. Leptin is one substance that regulates appetite, and it comes from the adipose tissue. We believe that another signalling substance is similarly responsible for not overeating. We want to identify this substance and find out which organs and tissues communicate with each other through this molecule,” says Christoffer Clemmensen.

The unidentified hormonal defense against weight gain” has been published in PLoS Biology. The authors are employed at the Novo Nordisk Foundation Center for Basic Metabolic Research, University of Copenhagen.

Christoffer Clemmensen
Associate Professor
The Clemmensen Group studies the biological regulation of body weight and aims at transforming molecular and physiological insights into innovative therapeutic strategies that can correct obesity and its metabolic comorbidities.