Metabolic programming a lean phenotype by deregulation of RNA polymerase III

Ian M. Willis, Robyn D. Moir, Nouria Hernandez

Research output: Contribution to journalArticle

3 Citations (Scopus)

Abstract

As a master negative regulator of RNA polymerase (Pol) III, Maf1 modulates transcription in response to nutrients and stress to balance the production of highly abundant tRNAs, 5S rRNA, and other small noncoding RNAs with cell growth and maintenance. This regulation of Pol III transcription is important for energetic economy as mice lacking Maf1 are lean and resist weight gain on normal and high fat diets. The lean phenotype of Maf1 knockout (KO) mice is attributed in part to metabolic inefficiencies which increase the demand for cellular energy and elevate catabolic processes, including autophagy/lipophagy and lipolysis. A futile RNA cycle involving increased synthesis and turnover of Pol III transcripts has been proposed as an important driver of these changes. Here, using targeted metabolomics, we find changes in the liver of fed and fasted Maf1 KO mice consistent with the function of mammalian Maf1 as a chronic Pol III repressor. Differences in long-chain acylcarnitine levels suggest that energy demand is higher in the fed state of Maf1 KO mice versus the fasted state. Quantitative metabolite profiling supports increased activity in the TCA cycle, the pentose phosphate pathway, and the urea cycle and reveals changes in nucleotide levels and the creatine system. Metabolite profiling also confirms key predictions of the futile RNA cycle hypothesis by identifying changes in many metabolites involved in nucleotide synthesis and turnover. Thus, constitutively high levels of Pol III transcription in Maf1 KO mice reprogram central metabolic pathways and waste metabolic energy through a futile RNA cycle.

Original languageEnglish (US)
Pages (from-to)12182-12187
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume115
Issue number48
DOIs
StatePublished - Nov 27 2018

Fingerprint

RNA Polymerase III
Substrate Cycling
Knockout Mice
Phenotype
RNA
Nucleotides
Small Untranslated RNA
Pentose Phosphate Pathway
Metabolomics
Creatine
Lipolysis
Autophagy
High Fat Diet
Transfer RNA
Metabolic Networks and Pathways
Weight Gain
Urea
Maintenance
Food
Liver

Keywords

  • Futile cycle
  • Maf1
  • Metabolic inefficiency
  • Metabolomics
  • RNA polymerase III

ASJC Scopus subject areas

  • General

Cite this

Metabolic programming a lean phenotype by deregulation of RNA polymerase III. / Willis, Ian M.; Moir, Robyn D.; Hernandez, Nouria.

In: Proceedings of the National Academy of Sciences of the United States of America, Vol. 115, No. 48, 27.11.2018, p. 12182-12187.

Research output: Contribution to journalArticle

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