New Discovery Could Help Break Weight Loss Plateaus
Many people who try to lose weight by cutting calories are familiar with the frustrating plateau where the body stops shedding pounds. When calorie intake decreases, the body responds by slowing down metabolism, causing it to burn fewer calories than before the diet.
This happens because the body sees reduced calories as a potential starvation threat and adapts by conserving energy, even as it carries out essential functions. It feels unfair that the body doesn’t recognize the goal of weight loss and instead works against it by holding on to calories.
A new study from the University of Southern Denmark has found a potential way to keep the body burning calories even with fewer consumed. This could be particularly significant for those using weight-loss or diabetes medications like Wegovy and Ozempic, where weight loss often plateaus after about 20-25% of body weight is lost.
According to Kim Ravnskjaer, a principal investigator and associate professor at the Department of Biochemistry and Molecular Biology at the University of Southern Denmark, the stall in weight loss is likely due to the body’s natural response: “It usually goes well at first, but as people lose weight, progress stalls because the body’s metabolism adapts,” he said.
If this metabolic adaptation could be controlled, it could be a game-changer for anyone trying to lose weight. A medication that counteracts this effect might help extend the benefits of treatments like Wegovy, which often stop working after a while.
This is where the new study, published in Cell Metabolism, comes in. Ravnskjaer explains, “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.”
However, Ravnskjaer emphasizes that the study’s findings are based on mouse models, and human trials are still far off. “It is a long way from insights in mouse experiments to bringing a drug to market—but this is obviously the potential in our research,” he says.
The discovery came when the researchers were investigating a gene called Plvap, which is active in certain liver cells in mice. They knew from previous studies that humans born without this gene struggle with lipid metabolism, so they set out to study its role.
They found that the Plvap gene helps the body switch from burning sugar to burning fat when fasting. When Plvap was turned off in the lab mice, their livers didn’t recognize the fasting state and kept burning sugar.
This discovery reveals a new way that the liver’s metabolism is regulated, with potential 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,” Ravnskjaer says.
The study also made other important observations:
- The signal that triggers metabolic changes during fasting comes from the liver’s stellate cells, not hepatocytes (the liver’s main cells). This suggests that stellate cells play a new role in controlling liver metabolism by directing other cell types.
- 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.
Ravnskjaer finds this especially exciting: “It’s well known that elevated blood sugar can 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 wide-reaching implications, not just for obesity treatments, but also for understanding how fat and sugar are processed in metabolic diseases. In the long term, it could lead to new treatments for conditions like type 2 diabetes and fatty liver disease.
How the Study Was Done
The research team discovered that the Plvap gene, involved in lipid metabolism, is expressed in stellate cells in the liver of mice—a surprising finding since stellate cells were not previously associated with lipid metabolism.
To explore this further, they turned off the Plvap gene in the stellate cells and observed the mice. Initially, they saw no changes, but when they fasted the mice, everything changed.
The mice’s livers were unable to burn fat and produce ketones, a process that usually occurs during fasting in healthy mammals. While fat was released from adipose tissue into the bloodstream, the liver failed to absorb it as expected. Instead, fatty acids were redirected to the skeletal muscles.
Interestingly, a liver without the Plvap gene “does not recognize” that the body is fasting and continues burning sugar, which appears beneficial for overall metabolism.
