Martinez-Sanchez, N.; Brümmer, A.; Barron, N. J.; Rosoff, D. B.; Liechti, A.; Voronkov, M.; Hayter, E. A.; Chamois, S.; Dreos, R.; Guex, N.; Johnson, E.; Baxter, M.; Smith, K.; Northeast, R. C.; Galli, G.; Hodson, L.; Gatfield, D.; Ray, D.; Bechtold, D.

Efficient energy metabolism is essential for health, and its dysregulation drives conditions like cardiometabolic disease and obesity. 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. Human genetic analyses and drug-target Mendelian Randomisation support a role for BUD23 in cardiometabolic traits and diseases. Together, our findings uncover a conserved translational control mechanism that regulates energy metabolism and offers a potential therapeutic target.