Hormonal
The FTO obesity-risk allele (rs1421085) promotes obesity by disrupting ARID5B binding, which derepresses IRX3/IRX5 expression in adipocyte progenitors, shifting them from energy-dissipating beige adipocytes to energy-storing white adipocytes and reducing mitochondrial thermogenesis.
This research identifies a specific genetic variant (FTO rs1421085) that causes fat cells to store more energy and burn less as heat. While you cannot change your DNA, this finding highlights a biological target (IRX3/IRX5) for future therapies. For now, standard energy balance principles apply, but this mechanism explains why some individuals may have a biological predisposition to store fat more efficiently.
Our data indicate that the FTO allele associated with obesity represses mitochondrial thermogenesis in adipocyte precursor cells in a tissue-autonomous manner. The rs1421085 T-to-C single-nucleotide variant 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. This results in a 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, as well as an increase in lipid storage.
Why this rating
High-quality human genetics, CRISPR editing, and mouse models with consistent findings.
Source
<i>FTO</i> Obesity Variant Circuitry and Adipocyte Browning in Humans
Melina Claussnitzer et al. · New England Journal of Medicine · 2015
DOI 10.1056/nejmoa1502214
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