Ribosomal modification by BUD23 drives selective translational control over energy state and metabolic health

Efficient energy metabolism is essential for health and its dysregulation drives cardiometabolic disease. Delivery of regulatory control through translation and ribosome function is emerging as important. Here, we identify the rRNA methyltransferase BUD23 as a potent regulator of cellular and systemic energy homeostasis. Adipocyte-specific deletion of BUD23 in mice regulates lipid and mitochondrial metabolism resulting in a pronounced lean phenotype and resistance to diet-induced obesity. Mechanistically, BUD23 modulates translation initiation and efficiency of mRNAs with specific features - including short 5 UTR length and GC-rich post-initiation codon usage - characteristic of mitochondrial and lipogenic proteins. Genetic analyses and Mendelian randomisation support a role for BUD23 in human cardiometabolic traits and disease burden. Together, our findings uncover a conserved translational control mechanism that regulates energy state, from cellular metabolism through to human cardiometabolic health.