Duke: 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.
To
determine how these findings related to metabolic disease, Minchin put
the zebrafish on a high-fat diet. After a few weeks of adding egg yolks
to their typical chow, Minchin found that the differences in fat
distribution between the mutant and the normal zebrafish became even
more pronounced. He then gave the fish a glucose tolerance test to see
how their bodies responded to sugar. The mutants did a better job of
clearing sugar out of their bloodstream and seemed to be protected from
developing insulin resistance, a risk factor for diabetes and heart
disease.
Bolstering the zebrafish findings, collaborators at the
Karolinska Institute in Sweden analyzed human patient samples and showed
that levels of Plexin D1 were higher in individuals with type 2
diabetes, suggesting it may play a similar role in humans.
“We
think that Plexin D1 is functioning within blood vessels to pattern the
environment in visceral fat tissue," said Minchin, who was lead author
of the study. 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,” he said.
“It is probably just one of many of different genes that each contribute
to overall body shape and metabolic health.”
The researchers
are actively searching for other genes as well as environmental factors
that are involved in the biology of body fat, again using zebrafish
models.
“Our results indicate that the genetic architecture of
body fat distribution is shared between fish and humans, which
represents about 450 million years of evolutionary divergence," Rawls
said. "For these pathways to have been conserved for so long suggests
that they are serving an important role.”
The research was
supported in part by grants from the National Institutes of Health
(DK081426, DK091356, DK093399, HL092263, R01HL118768), UNC UCRF Pilot
Research Project Award, a Pew Scholars in Biomedical Sciences Award, and
American Heart Association Postdoctoral Fellowships (11POST7360004,
13POST1690097).
CITATION: "Plexin D1 determines body fat
distribution by regulating the type V collagen microenvironment in
visceral adipose tissue," James E.N. Minchin, Ingrid Dahlman,
Christopher J. Harvey, Niklas Mejhert, Manvendra K. Singh, Jonathan A.
Epstein, Jesús Torres-Vázquez, and John F. Rawls. Proceedings of the
National Academy of Sciences, March 23, 2015. DOI:
10.1073/pnas.1416412112