Hitting a plateau after a steady run of weight loss has derailed many health and fitness plans. But what if you could flick a biological switch that would eradicate the plateau and speed up metabolism? Scientists may have just found the key to this – and it was by complete accident.
While studying the liver's role in metabolism, researchers from the University of Southern Denmark (USD) made a surprise genetic discovery, identifying how one known abundantly expressed gene – plasmalemma vesicle-associated protein, or Plvap – had a huge impact on how the body sources energy when fasting. And knocking out this gene blocked any metabolic changes, essentially "tricking" the body into thinking there's no fast and there's an abundance of energy.
"If we can control the liver's burning of sugar and fat, we might also increase the effectiveness of weight-loss and diabetes medications," said Kim Ravnskjaer, associate professor at the Department of Biochemistry and Molecular Biology at USD. "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."
In normal conditions, fasting will cause the liver to switch over to oxidizing fatty acids rather than burning carbohydrates (sugars, fat). But when Plvap was knocked out, this switchover stalled and the liver carried on without change, using up carbs. Essentially, this means that metabolism remains high and the liver uses up the fuel essential for weight loss.
Plvap has previously been solely linked to endothelial cell function. But the new study has identified its crucial role in burning fatty acids to keep the body going in times of "starvation" or much fewer consumed calories. Mice that were engineered without the Plvap gene maintained a high utilization of carbohydrates, and fat was redirected into the muscles rather than the liver. They also showed no ill effects from this altered function, suggesting that any fuel will do – and, for us, it's much better if we trick the liver into believing it's "business as usual" – this is the optimal weight loss mode.
The scientists think some sort of knockout therapy could make plateaus a thing of the past and be a complementary medicine alongside the likes of Wegovy. While these are absolutely game-changing weight-loss drugs, there's nonetheless a point at which things slow down – even if someone has much further to go.
"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," said Ravnskjaer.
Interestingly, Plvap exists in hepatic stellate cells (HSC), and has, until this study, been looking at the role it plays in liver fibrosis. And it's never been linked to lipid (fat) metabolism. News that the gene also regulates metabolism presents huge opportunities for research – into both obesity and metabolic diseases, but also type 2 diabetes.
"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," Ravnskjaer said.
"This is the first functional study of Plvap in non-endothelial cells and the first study to show liver sinusoidal pericyte involvement in metabolic regulation," the researchers wrote in the paper. "Loss of HSC Plvap increases hepatic insulin signaling and shifts liver fasting metabolism from preferential utilization of fatty acids to carbohydrates.
'"HSC-specific ablation of PLVAP in mice elevated hepatic insulin signaling and improved glucose tolerance," they added.
The study was published in the journal Cell Metabolism.
Source: University of Southern Denmark
