Researchers Find a Way To Trick the Body Into Changing How It Burns Fat

Scientists have identified the Plvap gene as a key regulator of metabolism during fasting. Disabling it in mice prevented the usual metabolic slowdown that leads to weight-loss plateaus, suggesting new treatment possibilities for obesity and diabetes.

Many people who have tried to lose weight by cutting calories are familiar with a common challenge: eventually, weight loss stalls. This occurs because the body detects the decrease in calorie intake and compensates by slowing metabolism, reducing the number of calories burned.

This response is a survival mechanism. When the body perceives a potential risk of starvation, it conserves energy while maintaining essential functions. Unfortunately, this adaptation works against weight loss efforts, making it harder to continue shedding pounds.

However, a new study from the University of Southern Denmark has identified a potential way to sustain calorie burning even when calorie intake is reduced.

This finding could be particularly significant for individuals using weight-loss or diabetes medications like Wegovy and Ozempic. Many people on these treatments experience a weight-loss plateau after losing approximately 20–25% of their body weight.

According to Kim Ravnskjaer, a Principal Investigator and associate professor at the Department of Biochemistry and Molecular Biology, University of Southern Denmark, this stall is likely due to the body’s natural response: “It usually goes well at first, but as people lose some of the weight they aim to shed, their progress stalls because the body’s metabolism adapts,” he said.

If it were possible to control this metabolic adaptation, it could be a game-changer for anyone trying to lose weight. A medication that could counteract this effect might extend the benefits of treatments like Wegovy, which often stop working after a certain point.

The Role of the Plvap Gene in Metabolism

This is where the new study by Kim Ravnskjaer and colleagues, published in the prestigious journal Cell Metabolism, comes into play.

“If we could develop a medication that helps maintain fat or sugar burning at its original high level alongside weight-loss treatments, people could continue losing weight beyond the usual plateau,” he explains.

However, he stresses that the team’s findings are currently based on mouse models, meaning human trials are still a long way off, and potential treatments even further down the line.

“It is a long way from insights in mouse experiments to bringing a drug to the market – but this is obviously the potential in our research,” says Kim Ravnskjaer.

The researchers’ discovery was unexpected when they were investigating the function of a gene called Plvap in certain liver cells in mice.

The team knew from previous studies that humans born without this gene have problems with their lipid metabolism, a connection the research team set out to investigate.

How Plvap Affects Metabolism

It turned out that the Plvap gene enables the body’s metabolic shift from burning sugar to fat when fasting. And when Plvap is turned off – as the researchers did in their laboratory mice – the liver does not recognize that the body is fasting and continues burning sugar.

In other words, the research team has found an entirely new way in which the liver’s metabolism is regulated, which may have medical applications.

“If we can control the liver’s burning of sugar and fat, we might also increase the effectiveness of weight-loss and diabetes medications,” says Kim Ravnskjaer.

Beyond the intriguing ability of Plvap knockout to “trick” the liver into thinking it is not fasting, the researchers made several other important observations in their study:

1. The signal that triggers metabolic changes during fasting comes from the liver’s stellate cells rather than hepatocytes, the liver’s most abundant cells responsible for carrying out metabolic processes. This suggests that stellate cells play a previously unknown role in controlling liver metabolism by directing other cell types, introducing a new mode of cell-to-cell communication.
2. Although fat was redirected to the muscles instead of the liver, the mice showed no negative effects. In fact, they experienced improved insulin sensitivity and lower blood sugar levels.

Kim Ravnskjaer finds this particularly exciting: “It’s well known that elevated blood sugar may lead to chronic complications for people with type 2 diabetes. Understanding Plvap could help diabetics better regulate their blood sugar in the future.”

This discovery could have far-reaching implications—not just for obesity treatments, but also for improving our understanding of how fat and sugar are processed in metabolic diseases. In the long run, it may open new avenues for treating conditions like type 2 diabetes and steatotic liver disease.

How was the study done?

The research team discovered that the Plvap gene, which plays a role in lipid metabolism in mammals, is expressed in the stellate cells in the liver of mice. This was surprising because stellate cells have not previously been associated with lipid metabolism.

To investigate this further, the researchers turned off the Plvap gene in the stellate cells and observed the mice. At first, they were disappointed—the mice appeared completely normal. But when they fasted the mice, everything changed.

The mice’s livers were unable to burn fat and produce ketone, which typically happens in all healthy mammals during fasting.

The metabolic programs responsible for this process simply didn’t activate. Although fat was released from adipose tissue into the bloodstream, the liver did not absorb it as expected. Instead, the fatty acids were redirected to the skeletal muscles.

Interestingly, a liver without the Plvap gene “does not recognize” that the body is fasting. As a result, it continues to burn sugar in a process that appears beneficial for overall metabolism.

Reference: “Hepatic stellate cells regulate liver fatty acid utilization via plasmalemma vesicle-associated protein” by Daniel Hansen, Jasmin E.R. Jensen, Christian A.T. Andersen, Peter R. Jakobsgaard, Jesper Havelund, Line Lauritsen, Samuel Mandacaru, Majken Siersbaek, Oliver L. Shackleton, Hiroshi Inoue, Jonathan R. Brewer, Robert F. Schwabe, Blagoy Blagoev, Nils J. Færgeman, Marko Salmi and Kim Ravnskjaer, 3 March 2025, Cell Metabolism.
DOI: 10.1016/j.cmet.2025.01.022

Funding: Danmarks Grundforskningsfond, Danmarks Frie Forskningsfond, Danish Diabetes Academy, Novo Nordisk Fonden

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