Summary The oxidative phosphorylation (OXPHOS) system in mammalian mitochondria plays a key role in harvesting energy from ingested nutrients 1, 2 . Mitochondrial metabolism is very dynamic and can be reprogrammed to support both catabolic and anabolic reactions, depending on physiological demands or disease states 3, 4 . Rewiring of mitochondrial metabolism is intricately linked to metabolic diseases 5, 6 and is also necessary to promote tumour growth 7–11 . Here, we demonstrate that per oral treatment with an inhibitor of mitochondrial transcription (IMT) 11 shifts whole animal metabolism towards fatty acid oxidation, which, in turn, leads to rapid normalization of body weight, reversal of hepatosteatosis and restoration of glucose tolerance in mice on high-fat diet. Paradoxically, the IMT treatment causes a severe reduction of OXPHOS capacity concomitant with a marked upregulation of fatty acid oxidation in the liver, as determined by proteomics and non-targeted metabolomics analyses. The IMT treatment leads to a marked reduction of complex I, the main dehydrogenase that feeds electrons into the ubiquinone (Q) pool, whereas the levels of electron transfer flavoprotein dehydrogenase (ETF-DH) and other dehydrogenases connected to the Q pool are increased. This rewiring of metabolism caused by reduced mtDNA expression in the liver provides a novel principle for drug treatment of obesity and obesity-related pathology.

Inhibition of mammalian mtDNA transcription paradoxically activates liver fatty acid oxidation to reverse diet-induced hepatosteatosis and obesity