New clues to the genetic origins of obesity

Like many other conditions, obesity is caused by an interplay between genetic and environmental factors. While efforts to combat the obesity epidemic will need to include changes in diet and exercise, insights into the genes involved may also help with prevention and treatment.

Now a research team led by investigators at Beth Israel Deaconess Medical Center (BIDMC) and the Massachusetts Institute of Technology (MIT) reveals the mechanistic explanation behind the strongest genetic association with obesity. The findings, published online today in the New England Journal of Medicine, uncover a genetic circuit that controls whether our bodies burn or store fat. Manipulating that genetic circuit may offer a new approach for obesity treatments.

The strongest genetic association with obesity lies within an unexpressed region of the FTO gene and contains 89 common variants in a region of 47,000 nucelotides. The obesity-risk version of the region that predisposes individuals to increased body weight is found in 44 percent of individuals in European populations, but its mechanistic basis has until now remained unknown, despite extensive investigation.

To identify the cell types in which the FTO obesity-risk region might exert its effects, the researchers analyzed information from the Roadmap Epigenomics project, which assesses chemical or "epigenetic" modifications within chromosomes that switch genes on or off. The project's data revealed that the strongest epigenetic signal was found in "preadipocyte" cells, the progenitor cells that go on to become fat cells.

"Previous studies attempted to uncover a link between FTO and the regulation of appetite or propensity to exercise controlled by the brain," said the study's lead and corresponding author Melina Claussnitzer, PhD, an investigator in the Division of Gerontology at BIDMC and Hebrew SeniorLife, visiting professor at MIT's Computer Science and Artificial Intelligence Laboratory (CSAIL) and member of the Broad Institute. "But an unbiased look across more than one hundred human tissues and cell types indicated that the obesity-associated region acts primarily in adipocyte progenitor cells - not the brain."

The researchers collected fat, or adipose, tissue samples from individuals who carried the genetic obesity risk variant and compared it with tissue samples of individuals who did not carry the variant; they found increased expression of two distant genes, IRX3 and IRX5, indicating that these genes are under genetic control by the obesity risk variant.

"Despite years of investigating the FTO obesity region, no substantial expression differences were found between obesity-risk and non-risk individuals in brain or other tissue types, making it difficult to trace its mechanism of action," said Manolis Kellis, PhD, professor at MIT's CSAIL. "We found a strong difference for both IRX3 and IRX5 in preadipocytes, revealing the target genes, cell type and developmental stage where the genetic variant acts, thus enabling us to begin dissecting its mechanism of action."