An m7G tRNA-derived fragment mediated thermogenic activation of brown adipose tissue through post-transcriptional repression of Uqcr10.

Obesity, diabetes, and related metabolic disorders have become global epidemics driven mainly by an imbalance between energy intake and energy expenditure. Brown adipose tissue (BAT), the principal site of non-shivering thermogenesis, can be activated to mitigate obesity and its metabolic sequelae. RNA modification is as important regulators of obesity. The N7-methylguanosine (m7G) modification broadly influences RNA stability, enhances translational efficiency, and helps determine cell fate. However, the specific mechanisms by which m7G regulates adipose thermogenesis remain unclear. Using untargeted metabolomics, we found that cold exposure activates thermogenic metabolism in BAT and that 7-Methylguanosine is elevated in thermogenically activated BAT. METTL1-mediated m7G modification correlates positively with adipose thermogenic activation. Loss of METTL1 reduces m7G levels and impairs adipocyte thermogenic capacity. At the same time, METTL1 deficiency alters tRNA cleavage patterns and generates regulatory tRNA-derived fragments that modulate gene expression. Overexpression of tRF-Lys-CTT, which derives from an m7G-modified tRNA, inhibits brown adipocyte differentiation and thermogenic activation; conversely, inhibiting tRF-Lys-CTT produces the opposite effects. Mechanistically, tRF-Lys-CTT associates with AGO2 to form a functional RISC complex that binds the 3'UTR of Uqcr10 mRNA and directly represses Uqcr10 post-transcriptionally. Under basal conditions, elevated tRF-Lys-CTT may constrain mitochondrial function by repressing Uqcr10 expression; upon cold stimulation, downregulation of tRF-Lys-CTT relieves this repression and promotes respiratory chain supercomplex assembly and UCP1-mediated thermogenesis. In summary, our study indicates that tRF-Lys-CTT functions as a post-transcriptional regulator of metabolism that suppresses thermogenesis, and provides new insights into the regulatory relationship among the METTL1/m7G/tRF axis and thermogenic control.