Loss of the RNA polymerase III repressor MAF1 confers obesity resistance.
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.
Center for Integrative Genomics, Faculty of Biology and Medicine, University of Lausanne, 1015 Lausanne, Switzerland;
Nicolas
N
Bonhoure
Department of Biochemistry, Albert Einstein College of Medicine, Bronx, New York 10461, USA;
Ashlee
A
Byrnes
Department of Biochemistry, Albert Einstein College of Medicine, Bronx, New York 10461, USA;
Robyn D
RD
Moir
Center for Integrative Genomics, Faculty of Biology and Medicine, University of Lausanne, 1015 Lausanne, Switzerland;
Wassim
W
Hodroj
Mouse Metabolic Evaluation Facility, Center for Integrative Genomics, University of Lausanne, 1015 Lausanne, Switzerland;
Frédéric
F
Preitner
Center for Integrative Genomics, Faculty of Biology and Medicine, University of Lausanne, 1015 Lausanne, Switzerland; Swiss Institute of Bioinformatics, 1015 Lausanne, Switzerland;
Viviane
V
Praz
Division of Endocrinology, Department of Medicine, Albert Einstein College of Medicine, Bronx, New York 10461, USA;
Genevieve
G
Marcelin
Division of Endocrinology, Department of Medicine, Albert Einstein College of Medicine, Bronx, New York 10461, USA; Diabetes Research Center, Albert Einstein College of Medicine, Bronx, New York 10461, USA;
Streamson C
SC
Chua
Division of Endocrinology, Department of Medicine, Albert Einstein College of Medicine, Bronx, New York 10461, USA;
Nuria
N
Martinez-Lopez
Division of Endocrinology, Department of Medicine, Albert Einstein College of Medicine, Bronx, New York 10461, USA; Diabetes Research Center, Albert Einstein College of Medicine, Bronx, New York 10461, USA;
Rajat
R
Singh
Laboratory for Integrative and Systems Physiology, Ecole Polytechnique Fédérale de Lausanne (EPFL), 1015 Lausanne, Switzerland.
Norman
N
Moullan
Laboratory for Integrative and Systems Physiology, Ecole Polytechnique Fédérale de Lausanne (EPFL), 1015 Lausanne, Switzerland.
Johan
J
Auwerx
Center for Integrative Genomics, Faculty of Biology and Medicine, University of Lausanne, 1015 Lausanne, Switzerland; Mouse Metabolic Evaluation Facility, Center for Integrative Genomics, University of Lausanne, 1015 Lausanne, Switzerland;
Gilles
G
Willemin
Division of Endocrinology, Department of Medicine, Albert Einstein College of Medicine, Bronx, New York 10461, USA;
Hardik
H
Shah
Division of Endocrinology, Department of Medicine, Albert Einstein College of Medicine, Bronx, New York 10461, USA;
Kirsten
K
Hartil
Division of Endocrinology, Department of Medicine, Albert Einstein College of Medicine, Bronx, New York 10461, USA;
Bhavapriya
B
Vaitheesvaran
Division of Endocrinology, Department of Medicine, Albert Einstein College of Medicine, Bronx, New York 10461, USA; Diabetes Research Center, Albert Einstein College of Medicine, Bronx, New York 10461, USA;
Irwin
I
Kurland
Center for Integrative Genomics, Faculty of Biology and Medicine, University of Lausanne, 1015 Lausanne, Switzerland; nouria.hernandez@unil.ch ian.willis@einstein.yu.edu.
Nouria
N
Hernandez
Department of Biochemistry, Albert Einstein College of Medicine, Bronx, New York 10461, USA; Diabetes Research Center, Albert Einstein College of Medicine, Bronx, New York 10461, USA; nouria.hernandez@unil.ch ian.willis@einstein.yu.edu.
Ian M
IM
Willis
D000818:Animals; D001343:Autophagy / Q000235:genetics; D004435:Eating / Q000235:genetics; D004734:Energy Metabolism / Q000235:genetics; D050356:Lipid Metabolism / Q000235:genetics; D008136:Longevity / Q000235:genetics; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D065626:Non-alcoholic Fatty Liver Disease / Q000235:genetics; D009765:Obesity / Q000235:genetics; D012343:RNA, Transfer / Q000378:metabolism; D012097:Repressor Proteins / Q000235:genetics*; D013095:Spermidine / Q000378:metabolism
C529453:Maf1 protein, mouse; D012097:Repressor Proteins; D012343:RNA, Transfer; D013095:Spermidine
MAF1; RNA polymerase III; autophagy; futile cycling; metabolic efficiency; obesity; polyamines