Common RNA modification linked to obesity
MedWire News: A ubiquitous RNA base, N6-methyladenenosine, is a major physiologic substrate of the fat mass and obesity-associated protein (FTO), findings from an animal study show.
The discovery offers new insights into the genetic underpinnings of obesity and diabetes, say the researchers, as well as opening up the field of research into RNA epigenetics.
The study was led by Chuan He (University of Chicago, Illinois, USA) and aimed to elucidate the target of FTO, which in 2007 was identified as the major genetic factor associated with obesity and Type 2 diabetes.
"FTO has become a prominent target of research," the researchers explain. "However, the physiological substrate and function of FTO remains unknown, preventing molecular level understanding of the mechanism and pathway of FTO-mediated regulation."
He's team focused on N6-methyladenenosine, the dominant methylated base in messenger RNA (mRNA), which has been proposed to affect mRNA processing and export from nucleus to cytoplasm.
In a series of experiments in mice, He's team showed that FTO efficiently demethylates N6-methyladenenosine in vitro and that the amount of N6-methyladenenosine in cellular mRNA is affected by the oxidation activity of FTO in vivo.
"FTO partially localizes with nuclear speckles [a model for nuclear organelles]," the team writes in Nature Chemical Biology.
Furthermore, FTO showed a "dynamic interaction" with the nuclear speckles, indicating that N6-methyladenenosine in nuclear RNA "is the physiological substrate of FTO and that the function of FTO likely affects the processing of pre-mRNA, other nuclear RNAs, or both."
Taken together, their observations suggest that a portion or subclass of N6-methyladenenosine in mRNA is affected by the activity of FTO in vivo, say the researchers.
Noting that methylation of DNA and histones is established as a major regulator of epigenetics in mammalian cells, they conclude: "There is a previously uncharacterized, reversible regulatory mechanism present in mammalian cells."
In a press statement accompanying the research, Stephen O'Rahilly (University of Cambridge, UK), a leading researcher in obesity and metabolic disease, said that a better understanding of how FTO functions "could aid the development of novel antiobesity therapies."
"Variants around the FTO gene have consistently been associated with human obesity and artificial manipulation of the fto gene in mice clearly demonstrates that FTO plays a crucial role in the regulation of body weight," O'Rahilly explained. "However, the development of a deeper understanding of the normal biological role of FTO has been challenging."
By Joanna Lyford