Harvard University. US: There are many reasons why people gain different amounts of weight
and why fat becomes stored in different parts of the body. Researchers
have now conducted the largest study of genetic variation to date to
home in on genetic reasons. Their findings were published Feb. 12, 2015,
in companion papers genome-wide association studies in the journal Nature.
By analyzing genetic samples from more than 300,000 individuals to
study obesity and body fat distribution, researchers in the
international Genetic Investigation of ANthropometric Traits (GIANT) Consortium
completed the largest study of genetic variation to date and found over
140 locations across the genome that play roles in various obesity
traits.
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By applying novel computational methods to the genetic results, they
discovered new biological pathways that are important in controlling
body weight and fat distribution.
This work is the first step toward finding individual genes that play
key roles in body shape and size. The proteins these genes help produce
could become targets for future drug development. Currently, there are
no safe long-term treatments to curb the global obesity epidemic.
Waist-to-hip ratios key for health risk
One paper focused on where fat is stored in the body, one determinant of health risk.
One of the observable traits linked to the genetic locations was
waist-to-hip circumference ratio. People with waistlines larger than hip
circumferences have more belly fat surrounding their abdominal organs.
This makes them more likely to have metabolic conditions, such as Type 2
diabetes, and cardiovascular problems than people with body fat
concentrated more in the hip area or distributed equally throughout the
body.
“We need to know these genetic locations because different fat depots pose different health risks,” said Karen Mohlke,
professor of genetics at the University of North Carolina School of
Medicine and a senior author of the paper that examined waist-to-hip
ratio of fat distribution.
“If we can figure out which genes influence where fat is deposited,
it could help us understand the biology that leads to various health
conditions, such as insulin resistance/diabetes, metabolic syndrome and
heart disease,” she said.
The genetic locations associated with fat depots are also associated
with genes previously identified as being important for the creation of
adipose tissue. Researchers also determined that 19 of the
fat-distribution genetic locations had a stronger effect in women; one
had a stronger effect in men.
“By finding genetic variants that play an important role in
influencing body fat distribution and the ways in which fat distribution
differs between men and women, we hope to zoom in on the crucial
underlying biological processes,” said senior author Cecilia Lindgren, scholar in residence at the Broad Institute of Harvard and MIT and an associate professor at the University of Oxford.
BMI linked to genetic factors and new biology
In the second Nature paper,
which focused on body mass index (BMI), researchers identified 97
genome-wide regions that influence obesity, a finding that tripled the
number of previously known regions.
“Our work clearly shows that predisposition to obesity and high BMI
is not due to a single gene or genetic change,” said senior author Elizabeth Speliotes, assistant professor of computational medicine and bioinformatics at the University of Michigan Health System.
“The large number of genes makes it less likely that one weight-loss
solution will work for everyone and opens the door to possible ways we
could use genetic clues to help defeat obesity,” she said.
Further, the researchers found that the genetic locations associated
with BMI are likely involved in neural processes, specifically brain
signaling, that control appetite and energy use.
“Using novel computational methods, we have pointed to new biological
pathways that act in the brain to regulate overall obesity and also to a
different set of pathways related to fat distribution that regulate key
metabolic processes,” said senior author Joel Hirschhorn,
HMS Concordia Professor of Pediatrics, HMS professor of genetics at
Boston Children’s Hospital and co-director of the Broad Institute
Metabolism Program.
Once better understood, these mechanisms may help explain why not all
of those who are obese develop related metabolic diseases, such as
diabetes and high cholesterol, and could lead to possible ways to treat
obesity or prevent metabolic diseases in those who are already obese.
The researchers noted that while some genes involved in obesity could
already have been implicated in other aspects of human health, others
could be part of novel pathways that are not yet understood. A better
understanding of their functions related to body fat and obesity could
provide a better picture of the roles these genes play in a variety of
diseases.
“Finding the genes that increase risk of obesity is only the end of the beginning,” said senior author Ruth Loos,
professor of preventive medicine at Mount Sinai Hospital and director
of the Genetics of Obesity and Related Metabolic Traits Program in the
Charles R. Bronfman Institute for Personalized Medicine.
“A major challenge now is learning about the function of these
genetic variations and how they indeed increase people’s susceptibility
to gain weight,” Loos said. “This will be the critical next step, which
will require input from scientists with a range of expertise, before our
new findings can be used towards targeted obesity prevention or
treatment strategies.”
Financial support for the international collaboration was provided in
part by the National Institutes of Health and Wellcome Trust.