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Large-scale Human Genetics Study of Fat Depots Identifies Gene Regions Associated with Depot- and Gender-specific Fat Cell Development

In the largest-scale human genetics study of its kind, researchers have identified seven new gene regions associated with individual variability in body fat traits. In addition, genetic analysis in a mouse model suggests an important physiological role for two of these genes in fat cell development.

Differences in fat tissue (adipose tissue) distribution affect disease risk, including diabetes and heart disease. Mammals store different kinds of adipose tissue in various repositories, or depots, in the body. Subcutaneous adipose tissue (SAT) is found just beneath the skin, while visceral adipose tissue (VAT) surrounds abdominal organs, and pericardial adipose tissue (PAT) surrounds the heart. Research has shown that various traits, such as the volume, density, and relative distribution of adipose tissue have an associated genetic component and are important predictors of disease risk. To gain new insights into the genetic contribution to adipose tissue traits, investigators searched the genomes of 18,332 ethnically diverse men and women to identify small, common variants in their DNA. Then, using non-invasive imaging techniques, they analyzed adipose tissue traits of study participants; each trait was examined in all or a large number (several thousand) of the participants. They found that these traits were associated with common genetic variants in seven gene regions. Of these, three gene regions were associated with SAT and VAT volume, two were associated with PAT volume, one with SAT density, and one with the relative distribution between VAT and SAT depots. In some cases, associations were gender specific. Further evaluation found that genetic variations associated with PAT volume and a higher amount of VAT relative to SAT were also significantly associated with different metabolic conditions, including type 2 diabetes and levels of cholesterol and circulating fat in both men and women.

To examine the functional significance of these findings, they turned to an animal model. They measured activity of four analogous mouse genes in different fat depots in male mice and found variable activity for two genes: the Ube2e2 gene was more highly activated in VAT than in SAT or PAT during fat cell development. The Atxn1 gene was more active in the SAT of mice with diet-induced obesity than in lean mice. These data suggested a potential regulatory role for the genes in adipose tissue development. To explore this possibility, the team isolated early-stage cells from SAT and VAT depots of mice and allowed them to differentiate into (become) fat cells in the laboratory. Both Atxn1 and Ube2e2 showed evidence of dynamic regulation of activity at different timepoints. When they used a molecular technique to silence the activity of either of these genes in the cells, they observed impaired fat cell formation in SAT, whereas only Ube2e2 disruption impaired adipose tissue development in VAT.

Through a combined approach of a large-scale human genetics study coupled with experiments in a mouse model, this research provides new insight into the genetics of body fat distribution and supports physiological roles for specific genes in fat cell development. Future studies are necessary to determine the mechanism by which ATXN1 and UBE2E2 affect adipose tissue formation in humans and if they influence the development of cardiometabolic disease.