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Team Describes Apparent Mechanism for Obesity Risk Variant in FTO

NEW YORK (GenomeWeb) – In a study appearing online last night in the New England Journal of Medicine, an international team led by investigators at the Massachusetts Institute of Technology, Broad Institute, and Beth Israel Deaconess Medical Center outlined a potential mechanism by which obesity-related variants in the FTO gene influence obesity.

Starting from existing epigenetic data generated by members of the Roadmap Epigenomics Project, the researchers found evidence that an obesity-linked FTO allele called rs1421085 upends a conserved binding site used by the ARID5B repressor, which normally regulates thermogenesis in fat precursor cells.

In the absence of this interaction, their results suggest, the fat cell differentiation balance shifts from the production of energy-using "brown" fat that boosts mitochondrial thermogenesis to energy-storing white fat — a transition aided by IRX3 and IRX5 gene expression.

"We found a strong difference for both IRX3 and IRX5 in pre-adipocytes, revealing the target genes, cell type, and developmental stage where the genetic variant acts, thus enabling us to begin dissecting its mechanism of action," senior author Manolis Kellis, a computer science and artificial intelligence researcher at MIT, said in a statement.

"By altering the expression of either gene in human pre-adipoctyes, we could alter adipocyte metabolism between energy storage and energy dissipation," Kellis explained, "providing a direct link between IRX3 and IRX5 expression and energy balance."

Although genetic and environmental contributors to obesity are complex, past genome-wide association studies suggest the FTO locus contains the strongest genetic ties to obesity detected to date. Even so, the mechanistic ties between variants in FTO and obesity risk remain murky, despite efforts to tie it to various biological factors that can impact body weight.

"Many studies attempted to link the FTO region with brain circuits that control appetite or propensity to exercise," explained first author and co-corresponding author Melina Claussnitzer, a gerontology researcher affiliated with the Broad Institute, BIDMC, MIT, and Hebrew SeniorLife, said in a statement. "Our results indicate that the obesity-associated region acts primarily in adipocyte progenitor cells in a brain-independent way."

To begin teasing apart this mechanism, Kellis, Claussnitzer, and colleagues collected subcutaneous fat samples provided by 100 healthy Europeans between 20 and 50 years old who had body mass index measurements in the normal range, using these samples to generate primary human adipose-derived progenitor cell cultures.

More than half of the individuals carried obesity-related alleles at FTO variants such as rs9930506, rs1558902, or rs1421085, they noted, which are part of a risky haplotype identified in past GWAS.

With the help of Roadmap Epigenetics Project data, coupled with their own haplotype-specific enhancer assays and expression quantitative trait locus analyses, the researchers predicted that the rs1421085 variant — a thymine-to-cytosine swap in FTO — would alter a conserved binding site for the ARID5B regulator in fat cell progenitor tissue.

As suspected from the team's target analyses, this regulatory shift eased IRX3 and IRX5 repression, leading to higher levels of these genes in adipose tissue from those with the obesity-associated FTO haplotype.

Likewise, the researchers found that elevated expression of these genes dampened thermogenesis in pre-adipocyte cells. On the other hand, mice became slimmer when missing these genes or when Irx3 protein activity was impaired in their primary fat cells.

Moreover, the team noted that the animals had seven-fold higher thermogenesis levels when the obesity-related FTO variant was restored to the major allele with CRISPR-Cas9 gene editing — a shift that was accompanied by diminished IRX3 and IRX5 expression.

"These mice were 50 percent thinner than the control mice," Claussnitzer noted, "and they did not gain any weight on a high-fat diet. Instead they dissipated more energy, even in their sleep, suggesting a dramatic shift in their global metabolism."

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