Variants in the FTO gene have been associated with obesity and metabolic disease, but little is known about the function of its product. Researchers now show how this gene regulates body weight.
FTO encodes a nuclear protein of the AlkB related non-heme iron and 2-oxoglutarate-dependent oxygenase superfamily.
In the NIH Directors Blog, Francis Collins explained that a variant in an intron of the FTO gene (rs1421085) has been associated with increased body mass and a risk of obesity. People born with 2 copies of the risk variant (1 in every 6 people of European descent) carry an average of 7 pounds more weight.
The high-risk variant does not, as many had suspected, affect regions of the brain that control appetite, but rather progenitor cells that produce white and beige fat.
In the 3 September issue of the New England Journal of Medicine, Melina Claussnitzer et al report that the obesity-risk variant disrupts binding at the FTO locus by ARID5B; this leads to derepression of a potent preadipocyte super-enhancer and activation of IRX3 and IRX5 during early differentiation of mesenchymal progenitors into adipocyte subtypes.
The authors found that increased expression of IRX3 and IRX5 resulted in a cell-autonomous shift from white adipocyte browning to lipid-storage gene expression programs and to repression of basal mitochondrial respiration, reduced thermogenesis in response to stimuli, and an increase in adipocyte size.
Collins says that the discovery may yield new approaches to intervene in obesity with treatments designed to change the way fat cells handle calories.
Claussnitzer et al collected their data from several public databases, including the Roadmap Epigenomics Project, in a search for epigenetic modifications and chromatin state maps of the FTO obesity region in 127 cell types. Although the FTO gene is expressed in the human brain, the team couldn’t connect any differences there with obesity.
However, they found that FTO had an unusually long enhancer (12.8 kb) in mesenchymal adipocyte progenitors, indicating a major regulatory locus. They examined large domains that had long-range 3-dimensional chromatin interactions with areas around FTO, and found the genes encoding the developmental regulators IRX3 and IRX5.
Claussnitzer et al showed that fat tissues from people with the obesity risk variant expressed higher levels of IRX3 and IRX5 than individuals without the variant, and contained fewer beige cells. This genotype-associated expression was not observed in whole-adipose tissue, indicating that the effect was restricted to preadipocytes—a minority of the cells in adipose tissue.
Analyses of genome-wide expression patterns from brown adipocyte-containing peri-renal adipose tissue from people without the obesity risk variant showed that IRX3 and IRX5 downregulated genes associated with mitochondrial activity and upregulated genes with FXR and RXR lipid-metabolism functions. IRX3 and IRX5 therefore have important roles in energy dissipation and storage.
In preadipocytes from carriers of obesity-risk alleles, knockdown of IRX3 and IRX5 restored oxygen consumption and thermogenesis response levels to those of cells from people who did not carry the risk alleles, increasing thermogenesis 7-fold.
Collins explained that beige cells, which were discovered just 3 years ago, are produced by fat cell progenitors to burn rather than stockpile energy. He proposes that beige fat could have an unexpectedly important role in protecting against obesity.
Claussnitzer et al used CRISPR-Cas genome editing system to switch between this obesity risk variant and the non-risk variant in primary preadipocytes. In doing so, they were able to turn energy-burning heat production off and back on again.
They also showed in mice that the shift toward energy-burning beige cells led to weight loss. Mice that expressed a dominant-negative form of IRX3 in adipose tissue had reduced body size, body weight, fat mass, white and brown fat depots, and adipocyte size with no change in their eating or exercise habits. In fact, the mice had resistance to weight gain on a high-fat diet, increased energy expenditure at night and during the day, increased mitochondrial activity, and increased oxygen consumption at room temperature, but did not have significant differences from control mice in food intake or locomotor activity.
Collins says that treatments designed to program fat cells to burn more energy (such as antagonists of IRX3 or IRX5) might be developed to reduce obesity.
The Daily Mail wrote that the breakthrough could force people to question traditional perceptions, such as as over-eating causing obesity, and that discovery challenges the notion that “when people get obese it was basically their own choice because they choose to eat too much or not exercise”.
However, in his Blog, Collins reminds readers that genes are only part of the story: “It’s still important to eat healthy, limit your portions, and maintain a regular exercise program. Leading an active lifestyle keeps weight down and improves the overall sense of well being,” he says.