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Loss of the RNA polymerase III repressor MAF1 confers obesity resistance.

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.
AuthorsNicolas Bonhoure, Ashlee Byrnes, Robyn D Moir, Wassim Hodroj, Frédéric Preitner, Viviane Praz, Genevieve Marcelin, Streamson C Chua Jr, Nuria Martinez-Lopez, Rajat Singh, Norman Moullan, Johan Auwerx, Gilles Willemin, Hardik Shah, Kirsten Hartil, Bhavapriya Vaitheesvaran, Irwin Kurland, Nouria Hernandez, Ian M Willis
JournalGenes & development (Genes Dev) Vol. 29 Issue 9 Pg. 934-47 (May 01 2015) ISSN: 1549-5477 [Electronic] United States
PMID25934505 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
Copyright© 2015 Bonhoure et al.; Published by Cold Spring Harbor Laboratory Press.
Chemical References
  • Maf1 protein, mouse
  • Repressor Proteins
  • RNA, Transfer
  • Spermidine
Topics
  • Animals
  • Autophagy (genetics)
  • Eating (genetics)
  • Energy Metabolism (genetics)
  • Lipid Metabolism (genetics)
  • Longevity (genetics)
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Non-alcoholic Fatty Liver Disease (genetics)
  • Obesity (genetics)
  • RNA, Transfer (metabolism)
  • Repressor Proteins (genetics)
  • Spermidine (metabolism)

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