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How the FTO Gene Contributes to Obesity



sharma-obesity-dna_molecule9While I took a month off from blogging, an international group of researchers published what may well become a landmark paper on the genetics of obesity in the New England Journal of Medicine.

As regular readers may be well aware, a number of previous genetic studies have pointed to the importance of the FTO gene for human obesity – however, what exactly this gene does to effect body weight was largely unclear.

The rs1421085 single-nucleotide variant of this gene has both a high frequency and a strong effect size, which suggests positive selection or bottlenecks (e.g., 44% frequency in European populations vs. 5% in African populations).

In the present paper, that included examination of epigenomic data, allelic activity, motif conservation, regulator expression, and gene coexpression patterns in mice and humans, the researchers showed that the FTO allele associated with obesity represses mitochondrial energy production in adipocyte precursor cells in a tissue-autonomous manner.

To be precise, the rs1421085 variant of this gene apparently disrupts a conserved motif for the ARID5B repressor, which leads to derepression of a potent preadipocyte enhancer and a doubling of IRX3 and IRX5 expression during early adipocyte differentiation. These molecules play key roles in thermogenic dissipation both through UCP-1 and UCP-1-independent pathways.

This change leads to a persistent and cell-autonomous developmental shift from energy-dissipating beige (brite) adipocytes to energy-storing white adipocytes, with a reduction in mitochondrial thermogenesis by a factor of 5. It is also associated with an increase in lipid storage and adipocyte cell size.

Inhibition of Irx3 in adipose tissue in mice reduced body weight and increased energy dissipation without a change in physical activity or appetite.

Knockdown of IRX3 or IRX5 in primary adipocytes from human subjects with the risk allele restored thermogenesis, increasing it by a factor of 7, and overexpression of these genes had the opposite effect in adipocytes from nonrisk-allele carriers.

 

Finally, repair of the ARID5B motif in primary cultured adipocytes from a patient with the risk allele restored IRX3 and IRX5 repression, activated browning expression programs, and restored thermogenesis, increasing it by a factor of 7.

These deep insights into the function of what is apparently a key pathway in human susceptibility (or resistance) to obesity, offers a number of potential targets for pharmacological interventions for obesity – something that we desperately need for patients struggling with this issue.

However, as an accompanying editorial is quick to point out,

“As yet, there is still no simple path to an anti-obesity drug that can be derived from this research.”

Then again, who expects finding new treatments for obesity to be simple?

@DrSharma
Edmonton, AB

1 Comment

  1. But it’s a start. There is hope. Thanks for sharing, Dr. Sharma.

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