Role of adipose dysfunction in genetic susceptibility to abdominal obesity and type 2 diabetes

The purpose of this project is to utilize our genomewide association study (GWAS) of abdominal subcutaneous adipose tissue (SAT) phenotypes and enhancer map to couple risk-alleles for central obesity and type 2 diabetes (T2D) to adipose phenotypes and functional elements of the genome.

The GENiAL cohort comprises n~930 adults that have undergone SAT biopsy and detailed characterization of adipose morphology and metabolism. We will complete a GWAS of basal and insulin stimulated lipogenesis in GENiAL.

By in silico analyses we will evaluate whether lipogenesis-associated alleles influence the risk of developing central obesity or T2D.

Next, we will map overlap between enhancers and their RNA (eRNA), and alleles associated with adipocyte lipogenesis, number, size or lipolysis in GENiAL.

Finally, significant alleles, enhancers, and genes identified in the above analyses will be evaluated for impact on adipocytes in vitro.

The first gene to study is RREB1 where we have identified an allele associated with fewer fat cells and increased risk of T2D.

Candidate genes will undergo screening by siRNA mediated knockdown in human adipose derived stem cells, and eRNA by antisense knockdown.

Allelic specific effects can subsequently be studied by Lentivirus transfection or CRISPR/Cas9.This project can lead to the identification of novel targets for treating obesity and T2D, and to increase the informativeness of genetic risk scores that can be used to guide treatment decisions in T2D.