Researchers at the Beijing Institute of Stem Cells and Regeneration (BISCRM) and the Institute of Zoology (IOZ) have cracked the code of the notorious FTO gene, reconciling its dual role in obesity and muscle growth. The revelation could improve obesity and diabetes treatments, potentially offering an alternative to popular GLP-1 receptor agonists that may cause undesirable muscle wasting.
"We've solved a long-standing puzzle in obesity genetics," announced Dr Ng Shyh-Chang, the study's lead author. "We now understand how a single genetic variant can be Jekyll and Hyde - accelerating muscle growth in youth but also accelerating aging-related decay later in life."
The study zeroes in on the FTO gene variant rs9939609-A, a common genetic quirk linked to increased obesity risk in ~45% of Europeans, ~24% of Africans, ~30% of East Asians, and ~35% of South Asians. This A variant, the researchers discovered, sets off a cellular chain reaction involving H19 and IGF2 genes to accelerate development, initially boosting muscle growth but eventually exhausting the stem cells, leading to premature aging.
In a startling twist, the team found that stem cells carrying this variant rapidly turned into skeletal muscles, but also rapidly developed insulin resistance when exposed to high-fat conditions. This suggests that skeletal muscle could be the first domino to fall in the FTO variant's influence on accelerated development and aging.
"This study rewrites our understanding of how type 2 diabetes develops," Ng Shyh-Chang explained. "We've known that reduced glucose clearance and high insulin levels appear decades before diagnosis of type 2 diabetes. Now using CRISPR genome editing, we have a new human tissue avatar that explains how it all starts in the muscles for humans with rs9939609-A."
According to the researchers, this paradigm-shifting research not only deepens our grasp of obesity genetics but also provides a platform to screen for better CRISPR-based drugs or small molecules for the millions grappling with overweight issues and muscle wasting from current treatments.
As the race for better obesity therapies intensifies, this breakthrough could be the key to unlocking new therapeutic strategies that finely control FTO to trim fat while boosting muscle growth.
The findings were reported in the paper, ‘An obesogenic FTO allele causes accelerated development, growth and insulin resistance in human skeletal muscle cells’, published in Nature Communications. To access this paper, please click here
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