Obesity, particularly abdominal obesity, increases the risk for chronic illnesses such as type 2 diabetes, heart disease, and neurodegenerative diseases, but not equally in all. This suggests genetic variants act in concert with obesity to trigger disease.

“We think about obesity as a primary disease or the source of morbidity, but what obesity actually does is that it favors the appearance of cardiovascular and metabolic diseases like diabetes, heart attacks, and hypertension,” said Marcelo Nobrega, MD, PhD, professor of human genetics at the University of Chicago. “These are all related, but the baffling part is that not all obese people develop these kinds of complications.”

A new study from Norbega’s team identified genes and variants that underlie abdominal obesity, measured by waist-to-hip ratio adjusted body mass index (WHRadjBMI). The researchers determined regulatory properties of candidate genetic variants and demonstrated the sex-specific effects of the gene SNX10 on fat cell differentiation and diet-induced obesity in a mouse model.

The findings were published in Nature Genetics in an article titled, “Genetics of sexually dimorphic adipose distribution in humans.”

The study, led by investigators at the University of Chicago, identified a variant located in a noncoding region (intron) of SNX10 (rs1534696) that strongly regulates the expression of SNX10 in subcutaneous adipose tissue in both sexes and is robustly linked to WHRadjBMI and higher cholesterol and triglyceride blood levels in women but not men. The researchers conducted experiments on mice where SNX10 was selectively knocked out in adipose tissue, and found the gene contributes to excess diet-induced fat accumulation in female mice, but not males. This suggests similar genes might lead to different patterns of fat distribution and obesity-related disease risk in women.

Control mice of both sexes gain weight when fed a high fat diet (top row). When fat cells lack SNX10, females do not gain weight on a high fat diet but males do (bottom row). [Hansen GT, et al., Nature Genetics, 2023]
Fat distribution matters

Fat deposited in the abdomen and around vital organs has been linked to increased insulin resistance and inflammation, and predicts a higher risk of cardiovascular disease, kidney failure, and stroke. Nobrega’s team conducted several transcriptome-wide association studies (TWAS) that compared the genomes of hundreds of individuals to identify genes that are linked with obesity and higher WHRadjBMI. Ensuing genetic analyses revealed 91 genes that regulate fat distribution, primarily in women.

Interestingly, most of the identified variants associated with these genes don’t alter coding sequences of genes but noncoding regions (introns) that control where and how much a gene is expressed. Most of these intronic variants are in a family of sequences called Alu repeats or retrotransposons—remnants of ancient viral infections that were integrated into the human genome and maintain hundreds of thousands of copies today, making up almost half of the noncoding 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. But over the years, people started to realize that a lot of these DNA sequences that came from viruses have become functional in the human genome,” said Nobrega.

Jumping genes

Retrotransposons, also called “jumping genes” owing to their mobility across different sites in the genome, appear to have wired fat distribution patterns in humans, affecting metabolic health, particularly in women.

Norbega’s team searched the UK Biobank, a GWAS database of more than 700,000 genomes, and found SNX10 was linked to higher waist-to-hip ratio and higher levels of cholesterol and triglycerides in women, commonly associated with cardiovascular 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,” said Nobrega. “We have too many genes associated with diseases, and one of the challenges is to sift through those and find ones that are most likely to be credible targets. The road that led us to find SNX10 is a good way to identify other genes that are likely to be amenable to therapeutic development.”

In future experiments, Norbega’s team intends to explore the biology of SNX10 and similar genes that regulate metabolism, in their quest for targeted treatments for obesity and associated chronic illnesses.

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