In a frustrating quirk of evolution, our bodies are wired to conserve energy when food intake drops. While this adaptation might have kept our ancestors alive during times of scarcity, it also means that shedding those last few pounds before a summer holiday can feel like an uphill battle.
Now, scientists may have uncovered a way to prevent the body from slowing its metabolism during dieting—offering potential new strategies to enhance weight-loss treatments such as Ozempic and Wegovy.
In a recent study published in Cell Metabolism, researchers found that PLVAP, a protein found in liver stellate cells, plays a significant role in controlling how the liver shifts between burning fat and sugar in mice. The authors suggest that similar effects could be observed in humans as well.
“Here we have uncovered a new way in which fats and glucose are regulated at the cellular level in the liver,” Prof. Kim Ravnskjær, co-author of the new study, told BBC Science Focus. “This is a novel mechanism that has not been identified before.”
Many people who attempt to lose weight—whether through diet, exercise or weight-loss medications—experience an initial drop in pounds, only to hit a frustrating plateau. This occurs because the body, sensing reduced calorie intake, adapts by slowing metabolism to conserve energy.
Ravnskjær and his team found that PLVAP is crucial in this metabolic adaptation. In their experiments, mice that had PLVAP switched off in their liver cells did not shift to fat-burning mode when fasting. Instead, their livers continued burning sugar.
This meant that, even when food intake was reduced, their metabolism did not slow down as it normally would.
“If we can identify and study this mechanism, this may allow us to develop small-molecule drugs that could regulate metabolism,” Ravnskjær said. “This could allow us to circumvent this mechanism where, if we stop eating as much, our metabolism goes down.”
Beyond simply affecting metabolic rate, the study found that PLVAP suppression improves insulin sensitivity and lowers blood sugar levels in mice — other key levers for maintaining a healthy weight.
“It seems here at least that reducing PLVAP in the liver is a good thing,” Ravnskjær explained.
However, while these findings are exciting, Ravnskjær stressed that human applications are still a long way off. Further research is needed to understand how PLVAP functions in human liver cells and whether drugs could be developed to safely modulate its activity outside of mice.
“We’ve played with the switch and found out what it does, but now we really need to zoom in to the individual liver cells and see how it works properly,” Ravnskjær said.
About our expert
Kim Ravnskjaer is an associate professor in the Department of Biochemistry and Molecular Biology at the University of Southern Denmark. With a focus on the liver, his research group studies tissue fibrogenesis in the context of obesity and type-2 diabetes. Ravnskjaer is also the co-founder of the Research Unit for Functional Genomics and Metabolism and has had research published in journals such as Nature and Cell.
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