The Critical Role of MAF1 in Repression of RNA Polymerase III Impacts Metabolic Efficiency in Mice

• Published in: The FASEB journal Vol. 30; no. S1
• Main Authors: Willis, Ian M, Bonhoure, Nicolas, Moir, Robyn D, Byrnes, Ashlee, Hodroj, Wassim, Praz, Viviane, Preitner, Frederic, Marcelin, Genevieve, Chua, Streamson, Martinez‐Lopez, Nuria, Singh, Rajat, Auwerx, Johan, Willemin, Gilles, Shah, Hardik, Hartil, Kirsten, Vaitheesvaran, Bhavapriya, Kurland, Irwin, Hernandez, Nouria
• Format: Journal Article
• Language: English
• Published: 01-04-2016
• ISSN: 0892-6638; 1530-6860
• DOI: 10.1096/fasebj.30.1_supplement.1054.4

Abstract only
MAF1 functions to promote metabolic economy by repressing RNA polymerase (pol) III transcription of highly abundant cellular RNAs, most notably tRNAs, under conditions of nutrient limitation and cellular stress. This function of MAF1, along with its phosphoregulation in response to TOR kinase activity and its interactions with the RNA pol III transcription machinery, is conserved from yeast to humans. In addition to its effect on RNA pol III, the mammalian MAF1 protein has been shown to repress several genes transcribed by RNA pol II. However, the scope of MAF1 in repressing transcription at the genome level is not well defined in mammalian systems and studies on the impact of ablating MAF1 in metazoans have only just begun. To address these questions, we generated a whole body
Maf1
knockout (KO) mouse.
Maf1
KO mice are unconditionally viable and demonstrate a striking resistance to diet‐induced obesity and non‐alcoholic fatty liver disease. These phenotypes result from reduced food intake and increased metabolic inefficiency. Gene expression profiling of adipose tissue indicates that the pol II transcriptome is not significantly affected and together with other experiments, show that the increased energy expenditure of
Maf1
KO mice does not result from induction of adaptive thermogenesis. Instead the data indicate that the obesity resistance of
Maf1
KO mice is achieved by novel mechanisms of energy expenditure. These include the increased synthesis and turnover (futile cycling) of tRNAs in the whole animal and increased futile cycling of hepatic lipids. Metabolism in
Maf1
KO mice is altered to meet the increased demand for metabolic energy: Lipolysis is increased in eWAT; polyamine synthesis is affected in liver and skeletal muscle via down‐regulation of nicotinamide N‐methyltransferase and autophagy is activated in the liver. These changes are supported by metabolite profiling which reveal elevated levels of many amino acids and spermidine in both liver and muscle and increased levels of NAD+ in muscle. The importance of MAF1 for metabolic economy reveals the potential for MAF1 modulators to protect against obesity and its harmful consequences.
Support or Funding Information
The work was supported by National Institutes of Health grants GM085177 (I.M.W.), AG043930 (J.A.), and T32 GM07491 (A.B.); the University of Lausanne, Swiss National Science Foundation grants 31003A_132958 (N.H.) and 31003A‐140780 (J.A.) and funds from the Albert Einstein College of Medicine.