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

  1. Shan Jiang
  2. Taolin Yuan
  3. Laura S Kremer
  4. Florian A Rosenberger
  5. Fynn M Hansen
  6. Melissa Borg
  7. Diana Rubalcava-Gracia
  8. Mara Mennuni
  9. Roberta Filograna
  10. David Alsina
  11. Jelena Misic
  12. Camilla Koolmeister
  13. Lipeng Ren
  14. Olov Andersson
  15. Anke Unger
  16. Tim Bergbrede
  17. Raffaella Di Lucrezia
  18. Rolf Wibom
  19. Juleen R Zierath
  20. Anna Krook
  21. Patrick Giavalisco
  22. Matthias Mann
  23. Nils-Göran Larsson

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Abstract

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.

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  1. PREreview

    This Zenodo record is a permanently preserved version of a PREreview. You can view the complete PREreview at https://prereview.org/reviews/10119001.

    This review reflects comments and contributions from Marina Schernthanner, Shaunak Deota and Pablo Ranea-Robles. Review synthesized by Jonny Coates.

    In this preprint, the authors investigate the rewiring of mitochondrial metabolism using an oral treatment with an inhibitor of mitochondrial transcription. The authors demonstrate that this treatment shifts whole animal metabolism to fatty acid oxidation. This led to normalisation of body weight and restoration of glucose tolerance in high-fat diet mice. The authors argue that this study provides evidence for drug treatment of obesity and obesity-related pathology. Overall, we only had minor comments.

    Minor comments:

    • What was the rationale for the IMT (LDC4857, 30 mg/kg) dosage?

    • The lower RER in IMT may also indicate reduced/slower metabolic switching from fatty-acid oxidation in the fasting phase to glucose utilization during the refeeding phase. The authors should confirm higher fatty acid utilization using oral gavage of labeled fatty acids.

    • Interestingly, after the refeeding experiment, HFD-IMT mice have lower RER (fig-1e) but the GTT shows improved glucose clearance (fig-2c, d). Does this mean that glucose uptake is better but it is not preferentially utilized? The authors should check for liver and muscle glycogen levels upon refeeding.

    • Were isolated islets still treated with IMT in vitro? Perhaps sustained IMT treatment would be necessary to observe a decrease in insulin levels?

    • Did the authors look at the concentration of IMT in the gastrointestinal tract as well? Where orally delivered drugs should be taken up preferentially in the proximal small intestine?

    • Have the authors looked at transcriptional levels of fatty acid transporters in the mitochondrial membrane (if those are affected by IMT)? As I understand it the authors propose that increased FAO is due to metabolic rewiring in OXPHOS, but have they completely ruled out the possibility of increased FAO via increased FA uptake through f.e. an upregulation of FA transporters?

    • The authors should mention the time of day (ZT) at which the IMT is administered.

    Comments on reporting:

    • Fig 5C is a very nice visual presentation of proteomics/metabolomics data - easy-to-understand but detailed

    Suggestions for future studies:

    • Although the authors measure IMT concentrations 24 hr after the last dose in plasma and tissues, they should identify the half-life of the drug, the major tissue which detoxifies the drug (liver, kidney, gut) and excretion (urine, feces). This information is critical to understand the results from fig-4c. If the drug has a smaller life, it is possible that the levels may be different 3-5 hr after dosing but might have reached equilibrium after 24 hr. Additionally, if the half-life is smaller, the time of day (ZT) at which the drug is administered is important because of daily rhythms in metabolism.

    Competing interests

    The author declares that they have no competing interests.

  2. Version published to 10.1101/2023.09.22.558955v1 on bioRxiv