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

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State: Serval
Version: Final published version
Serval ID
serval:BIB_F415BF94B601
Type
Article: article from journal or magazin.
Collection
Publications
Title
Loss of the RNA polymerase III repressor MAF1 confers obesity resistance.
Journal
Genes and Development
Author(s)
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.
ISSN
1549-5477 (Electronic)
ISSN-L
0890-9369
Publication state
Published
Issued date
2015
Volume
29
Number
9
Pages
934-947
Language
english
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.
Pubmed
Web of science
Open Access
Yes
Create date
21/05/2015 9:19
Last modification date
09/05/2019 3:27
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