New gene influences apple or pear shape, risk of future disease

IMAGE:Yellow coloring highlights the location of fat cells in this pair of zebrafish. In the adult fish at the top, which is about 10 mm, fat is deposited throughout the... view more

Credit: James E. Minchin

DURHAM, N.C. - Scientists have known for some time that people who carry a lot of weight around their bellies are more likely to develop diabetes and heart disease than those who have bigger hips and thighs. But what hasn't been clear is why fat accumulates in different places to produce these classic "apple" and "pear" shapes.

Now, researchers have discovered that a gene called Plexin D1 appears to control both where fat is stored and how fat cells are shaped, known factors in health and the risk of future disease.

Acting on a pattern that emerged in an earlier study of waist-to-hip ratios in 224,000 people, the study, which appears March 23 in the Proceedings of the National Academy of Sciences, found that zebrafish that were missing the Plexin D1 gene had less abdominal or visceral fat, the kind that lends some humans a characteristic apple shape. The researchers also showed that these mutant zebrafish were protected from insulin resistance, a precursor of diabetes, even after eating 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," said John F. Rawls, Ph.D., senior author of the study and associate professor of molecular genetics and microbiology at Duke University School of Medicine. "Moving forward, the components of that pathway can become potential targets to address the dangers associated with visceral fat accumulation."

Unlike the subcutaneous fat that sits beneath the skin of the hips, thighs, and rear of pear-shaped individuals, visceral fat lies deep within the midsection, wedged between vital organs like the heart, liver, intestine, and lungs. From there, the tissue emits hormones and other chemicals that cause inflammation, triggering metabolic diseases like high blood pressure, heart attack, stroke, and diabetes.

Despite the clear health implications of body fat distribution, relatively little is known about the genetic basis of body shape. A large international study that appeared in Nature in February began to fill in this gap by looking for regions of the human genome associated with a common metric known as the waist-to-hip ratio, which uses waist measurements as a proxy for visceral fat and hip measurements as a proxy for subcutaneous fat. The researchers analyzed samples from 224,000 people and found dozens of hot spots linked to their waist-hip ratio, including a few near a gene called Plexin D1 which is known to be involved in building blood vessels.

Rawls and his postdoctoral fellow James E. Minchin, Ph.D., were curious about how a gene for growing blood vessels might control the storage and shape of fat cells. When they knocked out the Plexin D1 gene in mice, all of the mutant animals died at birth. So they turned to another model organism, the zebrafish, to conduct the rest of their experiments. Because these small aquarium fish are transparent for much of their lives, the researchers could directly visualize how fat was distributed differently between animals that had been genetically engineered to lack Plexin D1 and those with the gene still intact.

By using a chemical dye that fluorescently stained all fat cells, the researchers could see that the mutant zebrafish had less visceral fat than their normal counterparts. They also noticed that the shape or morphology of the fat cells themselves was different. The zebrafish without the Plexin D1 gene had visceral fat tissue that was composed of smaller, but more numerous cells, a characteristic known to decrease the risk of insulin resistance and metabolic disease in humans. In contrast, their normal siblings had visceral fat tissue containing larger, but fewer fat cells of the kind known to be more likely to leak inflammatory substances that contribute to illness.

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New gene influences apple or pear shape, risk of future disease