NIH. US: Today, we hear a great deal about which foods to eat and which to
avoid to maintain a healthy body. Though we know that one of the
strongest contributors to body weight is heredity, there has been less
specific information available about the genetics underlying obesity.
But research in this area is progressing at a phenomenal pace, and new
genomic discoveries are helping to bring into better focus how our
bodies store fat and how the complex interplay of genetics, diet,
behavior, and other factors determine whether we can readily maintain a
healthy body weight, or whether it takes a lot of work to do so.
Two papers in Nature provide lots of fresh clues into the
genetic factors involved in predisposing to obesity. Researchers in the
international Genetic Investigation of ANthropometric Traits (GIANT)
Consortium, more than 500 strong and including some of the members of
my own NIH research lab (including me), examined the genomes of more
than half a million people to look for genes and regions of chromosomes
that play a role in body fat distribution and obesity. They turned up
over 140 genetic locations that, like low-intensity voices in a choir of
many, contribute to these traits. Further analyses of the specific
genes located in these regions suggest the possibility that the
programming behind how fat cells form may influence their distribution, a
discovery that could lead to exploitable findings down the road.
In the first study, the researchers
focused on genes that influence the waist-to-hip ratio, a standard
measure of fat distribution in the body [1]. People whose waistlines are
larger than their hip circumference have more belly fat around their
abdominal organs, placing them at more risk for cardiovascular disease
and diabetes than those whose extra pounds are deposited on their hips
and thighs. To identify genetic factors that play a role in this ratio,
GIANT researchers co-led by Karen Mohlke, a geneticist at the University
of North Carolina in Chapel Hill (whom, I am proud to say, trained with
me as a postdoctoral fellow at NIH 15 years ago), examined the genomes
of more than 224,000 individuals. The researchers discovered more than
49 locations throughout the genome that are linked to this trait. Of
these, 33 were previously undiscovered.
Genes in or near the 49 locations identified in this study were
linked to fat cell development, blood vessel formation, skeletal growth,
glucose control, and insulin resistance. Many of these associated sites
showed a larger effect in women than men, which suggests that fat
distribution differs by gender, perhaps helping to explain why men and
women gain weight in different ways.
The second paper focused on body mass index (BMI), a common
measurement derived from a formula that combines height and weight to
gauge overall body fat [2]. Previous studies suggest that about 50
percent of BMI is genetic. Elizabeth Speliotes, a geneticist-physician
at the University of Michigan in Ann Arbor, and her army of colleagues
examined the genomes of more than 339,000 individuals and discovered 97
sites in the genome that influence obesity, of which 56 were new
discoveries. The greater the number of these BMI-boosting sites a person
carries, the greater their BMI will tend to be—but this is not destiny.
Genetic risk factors are not predetermining, they are predisposing.
Some genes in or near the 97 locations play a role in appetite
regulation and feeding behavior. That’s to be expected. Others are
involved in processes we know less about, such as energy expenditure and
physical activity. But the big surprise is that most of the pathways
uncovered by this genetic approach to obesity seem to act in the brain
and peripheral nerves. They are linked to the development of neurons and
basic functions like signaling. How variations in such genes contribute
to obesity remains to be understood. We knew, of course, that the brain
is critical in determining appetite, but the prominence of the nervous
system genes in predisposing to obesity was unexpected.
Among the new discoveries are many that provide fresh targets for new
weight loss treatments, as well as insights into known ones. For
example, a glutamate receptor identified in this study may help identify
unknown glutamate pathways that affect body weight and reveal why an
anti-seizure drug (Topiramate), which affects glutamate levels, also
causes weight loss.
Some genetic changes that promote obesity also elevate risk of high
cholesterol, cardiovascular disease, and diabetes—but not equally so.
Two people with the same BMI may have different underlying causes of
obesity and in turn different risks of developing metabolic diseases. In
the future, our genetic information may be used to define obesity
subtypes, which could then be matched to a specific treatment.
We still have a long way to go to understand the genetics of obesity.
Despite this extensive list of genetic factors uncovered here, these
account for just an estimated 2.7 percent of the variation for BMI. What
we’re finding is that complex traits like obesity probably involve
hundreds of low-volume genetic risk factors, each with a small effect
that remains difficult to detect with our current techniques. What’s
more, just as musical notes can be combined in myriad ways, these
low-intensity genes will be expressed in different combinations in
different people. But we’re pushing the research needle in the right
direction. We know that a normal-sized person who has 104 BMI-increasing
genetic markers will on average be 20-plus pounds heavier than someone
of a similar build who has less than 78 BMI-increasing genetic markers.
These types of findings provide optimism that better times are ahead to
provide new approaches to prevent or control obesity.
References:
Genetic Studies of Body Mass Index Yield New Insights for Obesity Biology. Locke AE, Speliotes EK, et al. Nature 2015 Feb 12;518(7538):197-206.
New Genetic Loci Link Adipose and Insulin Biology to Body Fat Distribution. Shungin D, Mohlke KL, et al. Nature 2015 Feb 12;518(7538):187-196.