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

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2015

Genes Dev. 2015 May 1;29(9):934-47. doi: 10.1101/gad.258350.115.

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

N Bonhoure;A Byrnes;RD Moir;W Hodroj;F Preitner;V Praz;G Marcelin;SC Jr Chua;N Martinez-Lopez;R Singh;N Moullan;J Auwerx;G Willemin;H Shah;K Hartil;B Vaitheesvaran;I Kurland;N Hernandez;IM Willis

Albert Einstein College of Medicine, Bronx, New York 10461, USA; Center for Integrative Genomics, Faculty of Biology and Medicine, University of Lausanne, 1015 Lausanne, Switzerland; Swiss Institute of Bioinformatics, 1015 Lausanne, Switzerland; Ecole Polytechnique Fédérale de Lausanne (EPFL), 1015 Lausanne, Switzerland.

Service type: Knockout mice

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.

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