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.

Human MAF1 targets and represses active RNA polymerase III genes by preventing recruitment rather than inducing long-term transcriptional arrest

“…The tags were then mapped in three sequential steps and categorized as either mature or precursors as previously described (Bonhoure et al 2015). Each tag contribution to the gene score was weighted according to its length, its number of matches on the transcriptome, and the number of times it was sequenced.…”

NAD+ Metabolism and the Control of Energy Homeostasis: A Balancing Act between Mitochondria and the Nucleus

“…Coming from a totally different angle, a germline mouse model deficient in Maf1, a repressor of RNA polymerase III transcription of highly abundant cellular RNAs (Upadhya et al, 2002), also underscored the importance of NNMT in NAD + homeostasis. Maf1 -/- mice are resistant to obesity due to metabolic inefficiency as a consequence of futile tRNA production, which led to extreme reductions of NNMT levels, boosting NAM salvage to regenerate NAD + (Bonhoure et al, 2015). In combination, these independent studies in widely different mouse models support that NNMT inhibition enhances NAD + -dependent SIRT1 activity and protects mice against obesity and type 2 diabetes.…”

Emerging Roles for Maf1 beyond the Regulation of RNA Polymerase III Activity

“…In C. elegans , Maf1 levels can also influence TBP expression in addition to canonical RNA pol III targets [16]. In contrast, a whole-body knockout of Maf1 in mice showed no significant changes in the steady state transcript levels of TBP in liver [41]. At the present time we can only speculate about the reasons for the differences in these results.…”

“…This finding functionally links Maf1 levels with lipogenesis from excess sugars. Importantly, studies of the Maf1 knockout mouse revealed a significant increase in the levels of newly synthesized palmitate in Maf1(−/−) livers [41], which suggests the negative regulation of de novo lipogenesis by Maf1 is functionally conserved. However, Acc1 and Fasn transcripts were unaltered, and surprisingly the Maf1(−/−) animals were phenotypically lean.…”

“…The increased expression of Maf1 – specifically in the intestine – was causal for reproductive decline, which points to the necessity of investigating the tissue-specific differences in Maf1 activity and regulation in mammals. Interestingly, ablation of Maf1 in mice also results reduced fecundity [41] by a currently unknown mechanism. These findings raise an intriguing question of whether Maf1 could play a role in mammalian reproductive diseases, including polycystic ovarian syndrome (PCOS), premature ovarian aging (POA) and testicular dysgenesis (TDS), which are also influenced by metabolism [49-51].…”