Loss of the RNA polymerase III repressor MAF1 confers obesity resistance

Nicolas Bonhoure, Ashlee Byrnes, Robyn D. Moir, Wassim Hodroj, Frédéric Preitner, Viviane Praz, Genevieve Marcelin, Streamson C. Chua, Nuria Martinez-Lopez, Rajat Singh, Norman Moullan, Johan Auwerx, Gilles Willemin, Hardik Shah, Kirsten Hartil, Bhavapriya Vaitheesvaran, Irwin Kurland, Nouria Hernandez, Ian M. Willis

Research output: Contribution to journalArticle

47 Scopus citations

Abstract

MAF1 is a global repressor of RNA polymerase III transcription that regulates the expression of highly abundant noncoding RNAs in response to nutrient availability and cellular stress. Thus, MAF1 function is thought to be important for metabolic economy. Here we show that a whole-body knockout of Maf1 in mice confers resistance to diet-induced obesity and nonalcoholic fatty liver disease by reducing food intake and increasing metabolic inefficiency. Energy expenditure in Maf1−/− mice is increased by several mechanisms. Precursor tRNA synthesis was increased in multiple tissues without significant effects on mature tRNA levels, implying increased turnover in a futile tRNA cycle. Elevated futile cycling of hepatic lipids was also observed. Metabolite profiling of the liver and skeletal muscle revealed elevated levels of many amino acids and spermidine, which links the induction of autophagy in Maf1−/− mice with their extended life span. The increase in spermidine was accompanied by reduced levels of nicotinamide N-methyltransferase, which promotes polyamine synthesis, enables nicotinamide salvage to regenerate NAD+, and is associated with obesity resistance. Consistent with this, NAD+ levels were increased in muscle. The importance of MAF1 for metabolic economy reveals the potential for MAF1 modulators to protect against obesity and its harmful consequences.

Original languageEnglish (US)
Pages (from-to)934-947
Number of pages14
JournalGenes and Development
Volume29
Issue number9
DOIs
StatePublished - May 1 2015

Keywords

  • Autophagy
  • Futile cycling
  • MAF1
  • Metabolic efficiency
  • Obesity
  • Polyamines
  • RNA polymerase III

ASJC Scopus subject areas

  • Genetics
  • Developmental Biology

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  • Cite this

    Bonhoure, N., Byrnes, A., Moir, R. D., Hodroj, W., Preitner, F., Praz, V., Marcelin, G., Chua, S. C., Martinez-Lopez, N., Singh, R., Moullan, N., Auwerx, J., Willemin, G., Shah, H., Hartil, K., Vaitheesvaran, B., Kurland, I., Hernandez, N., & Willis, I. M. (2015). Loss of the RNA polymerase III repressor MAF1 confers obesity resistance. Genes and Development, 29(9), 934-947. https://doi.org/10.1101/gad.258350.115