Gene may influence body shape, metabolic disease risk, study finds

Researchers at Duke University have identified a protein that may help determine whether a person will develop an apple- or pear-shaped body, which could point to his or her risk of diabetes or heart disease.

In the study, published Monday in the journal Proceedings of the National Academy of Sciences, scientists analyzed zebrafish with and without the Plexin D1 gene, and found that those missing the gene had less visceral fat and were less likely to develop insulin resistance, a precursor of diabetes, even after eating a high-fat diet, according to a news release. A study published in February in the journal Nature also linked Plexin D1, among dozens of other genomic hotspots, to waist-to-hip regulation.

Heart disease is tied to greater visceral  fat accumulation in the belly, or an apple-shaped body, compared to subcutaneous fat accumulation in the hips and thighs, which are characteristics of pear-shaped bodies. Fat concentration in the midsection is thought to induce inflammation and trigger metabolic diseases including high blood pressure, stroke and diabetes.

"This work identifies a new molecular pathway that determines how fat is stored in the body, and as a result, affects overall metabolic health," senior study author John F. Rawls, associate professor of molecular genetics and microbiology at Duke University School of Medicine, said in the news release. "Moving forward, the components of that pathway can become potential targets to address the dangers associated with visceral fat accumulation."

Rawls and postdoctoral fellow James E. Minchin studied the zebrafish because they found that mice died when they knocked out the Plexin D1 gene. According to the news release, the zebrafish were easy to study because they are transparent for most of their lives, so researchers could visualize fat distribution differences between those that contained the gene and those that were genetically engineered to lack it.

Scientists used a chemical dye that fluorescently stained the animals’ fat cells, which indicated that the mutant zebrafish had less visceral fat than those that still contained the Plexin D1 gene. Researchers also observed that those without the gene had visceral fat tissue composed of smaller but more numerous cells— a factor known to reduce the risk of metabolic disease in humans— compared to the fish that still had the gene.

After study authors fed the fish a high-fat diet for a few weeks, they saw even stronger differences of fat distribution between the groups of fish. When they gave the fish glucose, the genetically modified fish also cleared sugar from their bloodstream more efficiently, which in humans points to a reduced risk of diabetes and heart disease. Researchers at the Karolina Institute in Sweden analyzed human patient samples and similarly discovered a link between elevated Plexin D1 levels and a greater risk of type 2 diabetes.

"We think that Plexin D1 is functioning within blood vessels to pattern the environment in visceral fat tissue," Minchin, who was lead author of the study, said in the news release. “That is, the genes that build blood vessels are also setting up structures to house fat cells. And this role skews the distribution and shape of fat in one direction or another. It is probably just one of many of different genes that each contribute to overall body shape and metabolic health."