Zebra fish

Health researchers are keen to understand why apple-shaped people, who carry a lot of weight around the stomach, are more susceptible to diabetes and heart disease than their pear-shaped counterparts with bigger hips and thighs.

An important clue has come from a study of zebrafish, reported in Proceedings of the National Academy of Sciences, which shows that a gene called Plexin-D1 plays a key role in controlling where fat is stored and how fat cells are shaped. Earlier human studies comparing the DNA of people with different body shapes had suggested that Plexin-D1 might be involved but had provided little information about the mechanism.

The study team at Duke University in North Carolina first knocked out Plexin-D1 in laboratory mice. But unfortunately all the mice died. So the researchers turned to the zebrafish, another favourite for genetic research. It is less closely related to humans but has the advantage of partial transparency. This allowed the team to see differences in fat distribution between fish genetically engineered to lack Plexin-D1 – which survived, unlike the mice – and those with the gene intact. The fish without Plexin-D1 had less of the abdominal or visceral fat that gives people an apple shape. They were also protected from insulin resistance, a precursor of diabetes, which affects normal zebrafish on a high-fat diet.

“This work identifies a new molecular pathway that determines how fat is stored in the body and as a result affects overall metabolic health,” says John Rawls, senior author. “Moving forward, the components of that pathway can become potential targets to address the dangers associated with visceral fat accumulation.”

By staining all fat cells with fluorescent dye, the Duke researchers could see that the mutant fish not only had less visceral fat but also had smaller individual fat cells.

They believe the role of Plexin-D1 is to build blood vessels and set up structures that house fat cells, though many other genes must also play a part in determining body shape and metabolic health.

Photograph: James E. Minchin

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