Many people who have already tried to lose weight by reducing calories know this frustrating reality: at some point, the body stops losing pounds. It senses the reduced calorie intake and reacts by slowing down the metabolism, burning fewer calories than before the diet. This happens because the body senses potential starvation and adapts by conserving energy while continuing to perform essential functions. It may seem incredibly unfair that the body doesn’t recognize the goal of weight loss and instead works against it by conserving calories. Now a new study from the University of Southern Denmark has found a possible way to maintain calorie burning even when calorie consumption is lower. This discovery could be particularly important for patients taking weight loss or diabetes medications such as Wegovy and Ozempic.
Weight Loss Through Metabolic Control
Many people taking these medications find that their weight loss stagnates after losing about 20-25% of their body weight. According to Kim Ravnskjaer, study leader and associate professor at the Department of Biochemistry and Molecular Biology at the University of Southern Denmark, this stalling is probably due to the body’s natural response: “Initially, things usually go well, but when people lose some of the weight they want to lose, their progress comes to a halt because the body’s metabolism adjusts,” he said. If it were possible to control this metabolic adjustment, it could be a game changer for anyone trying to lose weight.
A drug that could counteract this effect could prolong the benefits of treatments such as Wegovy, which often stop working after a certain point. This is where the new study by Kim Ravnskjaer and colleagues, published in the journal Cell Metabolism, comes in. “If we could develop a drug that keeps fat or sugar burning at its original high level, people could continue to lose weight beyond the usual plateau,” he explains. However, he emphasizes that the team’s findings are currently based on mouse models, which means that human trials are still a long way off and potential treatments are even further in the future. The researchers’ discovery came unexpectedly when they were studying the function of a gene called Plvap in certain mouse liver cells.
Understanding Plvap Could Help Diabetics Better Regulate their Blood Sugar Levels in the Future and Pave New Ways to Treat Diseases
The team knew from previous studies that people born without this gene have problems with their lipid metabolism, a link the research team wanted to investigate. It turned out that the Plvap gene enables the body’s metabolism to switch from burning sugar to burning fat during fasting. And when Plvap is switched off – as the researchers did in their lab mice – the liver does not recognize that the body is fasting and continues to burn sugar. In other words, the research team has found a completely new way of regulating the liver’s metabolism, which could potentially have medical applications. According to the researchers, if the liver’s sugar and fat burning could be controlled, the effectiveness of drugs for weight loss and diabetes treatment could also be increased.
In addition to the fascinating ability of the Plvap knockout to “trick” the liver into thinking it is not fasting, the researchers made several other important observations in their study:
- The signal that triggers metabolic changes during fasting comes from the liver’s stellate cells and not from hepatocytes, the most abundant cells in the liver that are 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 type of cell-to-cell communication.
- Although fat was redirected to the muscles instead of the liver, the mice showed no negative effects. In fact, they showed improved insulin sensitivity and lower blood glucose levels.
It is known that elevated blood glucose levels can lead to chronic complications in people with type 2 diabetes. Understanding Plvap could help diabetics to better regulate their blood sugar levels in the future. This discovery could have far-reaching implications – not only for the treatment of obesity, but also for a better understanding of how fat and sugar are processed in metabolic diseases. In the long term, it could open up new avenues for the treatment of diseases such as type 2 diabetes and steatotic liver disease.
The Liver Continues to Burn Sugar
The research team discovered that the Plvap gene, which plays a role in fat metabolism in mammals, is expressed in stellate cells in the liver of mice. This was surprising as stellate cells were not previously associated with fat metabolism. To investigate this further, the researchers switched off the Plvap gene in the stellate cells and observed the mice. At first they were disappointed – the mice appeared to be completely normal. But when they allowed the mice to fast, everything changed. The mice’s livers were unable to burn fat and produce ketones, which is the case in all healthy mammals during fasting. The metabolic programs responsible for this process were simply not activated. Although fat was released from adipose tissue into the bloodstream, the liver did not absorb it as expected. Instead, the fatty acids were diverted to the skeletal muscles. Interestingly, a liver without the Plvap gene does not “recognize” that the body is fasting. Therefore, it continues to burn sugar in a process that appears to be beneficial for overall metabolism.