Many health issues and chronic illnesses, such as type 2 diabetes and cardiovascular disease, are exacerbated by obesity. However, certain individuals who are obese may be more vulnerable to complications than others.
Identifying genes that are linked to obesity and may predispose individuals to these conditions has been a challenge for scientists, who have had to sift through hundreds of potential leads in their search.
In a new paper just published in Nature Genetics, a team of experts from the University of Chicago examined the effect of a genetic variation linked to a larger waist-to-hip ratio, a measure of abdominal fat that is necessary for the production of fat cells in humans.
In women, this particular variant is linked to increased levels of cholesterol and triglycerides in the blood, as well as excess fat accumulation due to diet in female mice. However, no such associations have been observed in men. These findings suggest that there may be certain genes that result in distinct patterns of fat distribution and varying risks for obesity-related diseases in women.
“We think about obesity as a primary disease or the source of morbidity, but,” according to senior author Marcelo Nobrega, “what obesity actually does is that it favors the appearance of cardiovascular and metabolic diseases like diabetes, heart attacks, and hypertension.
“These are all related, but the baffling part is that not all obese people develop these kinds of complications.”
Why fat distribution is important
The distribution of fat throughout the body seems to be a key factor in the development of illness. Increased insulin resistance and inflammation have been related to more fat being stored in the belly and around important organs, which indicates a greater risk of cardiovascular disease, kidney failure, and stroke.
The waist-to-hip ratio, which divides a person’s waist size by their hip measurement, is a typical way to determine how much abdominal fat a person has. Ratios of.99 or less for men and.90 or less for women are considered healthy.
To find genes associated with obesity and a larger waist-to-hip ratio, Nobrega’s team used various transcriptome-wide association studies (TWAS) that examined the genomes of hundreds of people.
The ratio is a sexually dimorphic feature, which means that men and females experience it in different ways. The ratios between men and women are inherently different, and the typical man’s physique is shaped differently from a woman’s.
Researchers analyzed 91 genes thought to have a role in fat distribution, and discovered that most of their effects were shown in females. The vast majority of genetic variations linked with these genes do not affect the sequence of the genes that code for proteins; rather, they exist in noncoding areas that are thought to regulate where and how much a gene is expressed.
It’s interesting to note that the majority of these variations belong to a group of DNA components known as Alu repeats or retrotransposons. These DNA elements are the byproducts of ancient viral infections that were incorporated into the human genome and still exist in hundreds of thousands of copies today, making up nearly half of the non-coding human genome.
“We once assumed that most of these were archaeological sites of battles that happened in the past between our genome and that of viruses,” adds Nobrega.
“But then over the years, people started to realize that a lot of these DNA sequences that came from viruses have actually become functional in the human genome.”
Jumping genes for good health
Fat distribution patterns in humans may have been hardwired by these “jumping genes,” with potential consequences for metabolic health in women. Next, the researchers looked at SNX10, a gene that was strongly linked to the waist-to-hip ratio in women but not in men.
They discovered that SNX10 regulates how well adipocytes, or fat cells, can store lipids and fat deposits. In a mouse model, the researchers found that male mice developed obesity when given a high-fat diet, but not female mice when SNX10 in the adipocytes was knocked out.
The team also looked at the UK Biobank, which is a GWAS database with more than 700,000 genomes. They found that SNX10 is linked to both a higher waist-to-hip ratio in women and higher levels of cholesterol and triglycerides, which are often linked to heart disease.
“We have now identified a gene, out of the hundreds of genes that are involved in fat accumulation or obesity, that may be more likely to cause disease complications and, interestingly, it does so primarily in women” adds prof. Nobrega. “That’s what we were aiming for.”
The next step, according to Nobrega, is to investigate the biology of SNX10 and related genes to learn how they affect metabolism and potentially one day develop a therapeutic target.
There are “too many” genes that have been linked to diseases, and one of the difficulties is “to sift through those and find ones that are most likely to be credible targets.”
It seems the path that helped them discover SNX10 is a good strategy to locate additional genes that are probably suitable for therapeutic development.
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