Researchers at the Max Delbrueck Center (MDC) for Molecular Medicine have identified a protein that appears to be involved in controlling the cellular uptake of fatty acids by fat cells, and which may play a role in obesity. Studies in obese mice and overweight humans found decreased expression levels of the protein, EHD2, in fat tissue. “We have discovered that overweight people produce less EHD2 than people with normal weight,” said Claudia Matthaeus, PhD, who first observed the phenomenon in the brown adipose tissue of mice during her work at the MDC and who is now a postdoc at the NIH. The researchers reported on their findings in the Proceedings of the National Academy of Sciences (PNAS), in a paper titled, “EHD2-mediated restriction of caveolar dynamics regulates cellular fatty acid uptake.”

Live imaging of mouse cells: The spots moving in and beneath the cell membrane are mostly caveolae. [Claudia Matthaeus, MDC]

Many foods contain lots of fat, and while fatty acids are among the essential nutrients that people need to survive, if we eat more than we can immediately convert into energy, the extra is stored in tissues, to serve as a reserve supply. The quantity of fatty acids that are transported by blood and deposited in tissues is determined by a wide range of factors.

The protein EHD2 has been studied extensively by co-author Oliver Daumke, PhD, professor and group leader at the MDC. The structural biologist has been working to characterize the protein for more than ten years. As a membrane protein, EHD2 resides inside muscle and fat cells. During the inward folding of the cell envelope, small flask-shaped membrane structures called caveolae are formed. These invaginations are particularly abundant in adipocytes, the authors commented. They can either remain on the surface of the cell membrane or they can be pinched off to carry foreign material—potentially including fatty acids—into the cell. It’s a process known as endocytosis. Prior studies have indicated that caveolae may be involved in lipid uptake. The authors wrote, “These results suggest that caveolae are involved in lipid accumulation in adipocytes and may promote FA uptake. However, the molecular mechanisms of caveolae-dependent fat uptake have remained obscure.”

Daumke believes that the EHD2 protein assembles into ring-like structures around the neck of the membrane vessel, which then stymies the pinch-off process. He reasons that if EHD2 is not present as a stabilizer, caveolae can pinch off more frequently and the cell takes up more fat. This is what Matthaeus and her colleagues examined.

The researchers worked with mice in which the EHD2 gene had been switched off. Using an electron microscope, Matthaeus observed that compared with normal mice, in the tissues of the EHD2-knockout mice there were many more caveolae that had become detached from the plasma membrane.

Matthaeus was also able to determine that fatty acid uptake was greater in cells lacking EHD2 and that the lipid droplets, which are intracellular accumulations of fat, were larger in these cells. “We established a link between higher caveolar mobility induced by EHD2 loss and increased cellular fatty acid uptake,” the authors stated. “Concurrently, lipid droplets were enlarged in various tissues of EHD2-lacking mice … The loss of EHD2 on the cellular level led to increased fat deposits on the organismic level, which was particularly evident in older animals.”

The study also indicated a role for EHD2 in human fat metabolism in humans. Matthaeus and a colleague from Leipzig University studied tissue samples from men and women with different body weights. The results showed the fat cells of overweight individuals who had a body mass index of 25 or higher produced less EHD2 than those of people with normal weight. EHD2 expression levels were also lower in two mouse models of obesity than in control mice. “Remarkably, the expression levels of EHD2 were strongly reduced in WAT from obese patients, as well as in WAT of two obese mouse models,” the team stated. It is not clear yet why this is the case. Matthaeus presumes that there is a correlation between frequent membrane pinch-off and the formation of fat depots. “During obesity, we observed that the number of caveolae and their detachment from the membrane get out of sync,” Matthaeus said.

“Our data suggest that EHD2 controls a cell-autonomous, caveolae-dependent fatty acid uptake pathway,” the authors concluded. Notably, obese patients express only low levels of EHD2, implicating a role of EHD2-controlled caveolar dynamics in obesity … We speculate that an imbalance in number, lifetime, and mobility of caveolae may accompany the development and progression of obesity.”

Lipid droplets (colored) in a fat cell that lacks EHD2.[Claudia Matthaeus, MDC]
Based on their new insights, Matthaeus and her colleagues, including researchers from the MDC research group led by Daumke, reason that EHD2 controls a metabolic pathway that regulates fatty acid uptake in fat cells. Matthaeus now has a position at the National Institutes of Health, where she plans to continue her research into caveolae and fat metabolism, and is now particularly interested in investigating the transport of fatty acids within the cell and the formation of lipid droplets. “There are still many unanswered questions,” she commented.

 

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