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

The oxidative phosphorylation (OXPHOS) system in mammalian mitochondria plays a key role in harvesting energy from ingested nutrients[1][1], [2][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][3], [4][4]. Rewiring of mitochondrial metabolism is intricately linked to metabolic diseases[5][5], [6][6] and is also necessary to promote tumour growth[7][7]–[11][8]. Here, we demonstrate that per oral treatment with an inhibitor of mitochondrial transcription (IMT)[11][8] 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. ### Competing Interest Statement NGL is a scientific founder and holds stock in Pretzel Therapeutics, Inc. TB, AU and RDL are employees of Lead Discovery Center GmbH and co-inventors of the patent application WO 2019/057821. [1]: #ref-1 [2]: #ref-2 [3]: #ref-3 [4]: #ref-4 [5]: #ref-5 [6]: #ref-6 [7]: #ref-7 [8]: #ref-11