Abstract
Dietary methionine restriction (MR) produces a coordinated series of transcriptional responses in peripheral tissues that limit fat accretion, remodel lipid metabolism in liver and adipose tissue, and improve overall insulin sensitivity. Hepatic sensing of reduced methionine leads to induction and release of fibroblast growth factor 21 (FGF21), which acts centrally to increase sympathetic tone and activate thermogenesis in adipose tissue. FGF21 also has direct effects in adipose to enhance glucose uptake and oxidation. However, an understanding of how the liver senses and translates reduced dietary methionine into these transcriptional programs remains elusive. A comprehensive systems biology approach integrating transcriptomic and metabolomic readouts in MR-treated mice confirmed that three interconnected mechanisms (fatty acid transport and oxidation, tricarboxylic acid cycle, and oxidative phosphorylation) were activated in MR-treated inguinal adipose tissue. In contrast, the effects of MR in liver involved up-regulation of anti-oxidant responses driven by the nuclear factor, erythroid 2 like 2 transcription factor, NFE2L2. Metabolomic analysis provided evidence for redox imbalance, stemming from large reductions in the master anti-oxidant molecule glutathione coupled with disproportionate increases in ophthalmate and its precursors, glutamate and 2-aminobutyrate. Thus, cysteine and its downstream product, glutathione, emerge as key early hepatic signaling molecules linking dietary MR to its metabolic phenotype.
Highlights
fibroblast growth factor 21 (FGF21) appears to be a key mediator of a number of the indirect effects of methionine restriction (MR) in adipose tissue, the transcriptional effects of the diet in liver are most likely linked to MRdependent effects on sulfur amino acid metabolism
We first determined the extent of differential gene expression induced by MR treatment in brown adipose tissue (BAT), inguinal white adipose tissue (IWAT), liver, and skeletal muscle by comparing the proportion of total genes that were significantly differentially expressed at different nominal p-value cutoffs
The top 10 genes showing the largest fold-changes in MR vs. Control (FDR < 5% for all genes) are shown in Fig 2C
Summary
Restriction of dietary methionine intake by 80% produces a coordinated series of transcriptional, endocrine, and biochemical changes across multiple tissues, but the underlying. FGF21 appears to be a key mediator of a number of the indirect effects of MR in adipose tissue, the transcriptional effects of the diet in liver are most likely linked to MRdependent effects on sulfur amino acid metabolism. These mechanisms remain poorly understood recent work has argued that the downstream metabolite, glutathione has a previously unappreciated role in both hepatic insulin signaling [6] and protein kinase R-like endoplasmic reticulum kinase (PERK) signaling [1]. Since all biological processes queried by the transcriptome do not have metabolomic measurements (e.g. inflammationrelated pathways), and many metabolomic outcomes arise from post-transcriptional processes, this strategy ensures a more comprehensive assessment of the molecular landscapes and provides an excellent discovery platform to guide future studies
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