Dietary Methionine Restriction Regulates Liver Protein Synthesis and Gene Expression Independently of Eukaryotic Initiation Factor 2 Phosphorylation in Mice

Pettit, Ashley P.; Jonsson, William; Bargoud, Albert; Mirek, Emily T.; Peelor, Frederick F.; Wang, Yongping; Gettys, Thomas W.; Kimball, Scot R.; Miller, Benjamin F.; Hamilton, Karyn L.; Wek, Ronald C.; Anthony, Tracy G.

doi:10.3945/jn.116.246710

Cited by 42 publications

(65 citation statements)

References 65 publications

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“…Although we are not the first to examine the metabolic effects of dietary methionine in both male and female mice (52), to our knowledge, our study is the first to show that sex‐dependent mechanisms may be involved in mediating the effects of dietary methionine on metabolic health. As outlined in Fig.…”

Section: Discussionmentioning

confidence: 87%

Short‐term methionine deprivation improves metabolic health via sexually dimorphic, mTORCI‐independent mechanisms

Yang

Miller

et al. 2018

FASEB j.

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Obesity and diabetes are major challenges to global health, and there is an urgent need for interventions that promote weight loss. Dietary restriction of methionine promotes leanness and improves metabolic health in mice and humans. However, poor long-term adherence to this diet limits its translational potential. In this study, we develop a short-term methionine deprivation (MD) regimen that preferentially reduces fat mass, restoring normal body weight and glycemic control to diet-induced obese mice of both sexes. The benefits of MD do not accrue from calorie restriction, but instead result from increased energy expenditure. MD promotes increased energy expenditure in a sex-specific manner, inducing the fibroblast growth factor (Fgf)-21-uncoupling protein (Ucp)-1 axis only in males. Methionine is an agonist of the protein kinase mechanistic target of rapamycin complex (mTORC)-1, which has been proposed to play a key role in the metabolic response to amino acid-restricted diets. In our study, we used a mouse model of constitutive hepatic mTORC1 activity and demonstrate that suppression of hepatic mTORC1 signaling is not required for the metabolic effects of MD. Our study sheds new light on the mechanisms by which dietary methionine regulates metabolic health and demonstrates the translational potential of MD for the treatment of obesity and type 2 diabetes.-Yu, D., Yang, S. E., Miller, B. R., Wisinski, J. A., Sherman, D. S., Brinkman, J. A., Tomasiewicz, J. L., Cummings, N. E., Kimple, M. E., Cryns, V. L., Lamming, D. W. Short-term methionine deprivation improves metabolic health via sexually dimorphic, mTORC1-independent mechanisms.

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Section: Discussionmentioning

confidence: 87%

Short‐term methionine deprivation improves metabolic health via sexually dimorphic, mTORCI‐independent mechanisms

Yang

Miller

et al. 2018

FASEB j.

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“…The expected result of either too little ternary complex or an ineffective ternary complex is that the 48S complex would be unable to form or to recognize the correct start site. Another possibility is that a decrease in ternary complex formation occurs due to a decrease in eIF2B guanine nucleotide exchange that is not dependent on eIF2 phosphorylation, as has been reported in liver of Gcn2 -null mice fed a methionine-restricted, cysteine-free diet 36 .…”

Section: Discussionmentioning

confidence: 88%

“…Despite a number of studies looking at the effects of starvation of total amino acids, few studies have compared the effects of deficiencies of different single essential amino acids on protein synthesis. In rats and mice, single essential amino acid deprivation can affect hepatic polysome profiles 27 – 30 , rates of hepatic protein synthesis 30 , 31 , and the phosphorylation status of 4EBP1 27 , 30 – 32 and eIF2 29 – 31 , 33 – 36 . Studies in hepatocytes or HeLa cells demonstrated effects of short-term starvation of single amino acids on protein synthesis, polysome formation, and PIC formation 37 , 38 .…”

Section: Introductionmentioning

confidence: 99%

Effects of single amino acid deficiency on mRNA translation are markedly different for methionine versus leucine

Mazor

Dong

Mao

et al. 2018

Sci Rep

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Although amino acids are known regulators of translation, the unique contributions of specific amino acids are not well understood. We compared effects of culturing HEK293T cells in medium lacking either leucine, methionine, histidine, or arginine on eIF2 and 4EBP1 phosphorylation and measures of mRNA translation. Methionine starvation caused the most drastic decrease in translation as assessed by polysome formation, ribosome profiling, and a measure of protein synthesis (puromycin-labeled polypeptides) but had no significant effect on eIF2 phosphorylation, 4EBP1 hyperphosphorylation or 4EBP1 binding to eIF4E. Leucine starvation suppressed polysome formation and was the only tested condition that caused a significant decrease in 4EBP1 phosphorylation or increase in 4EBP1 binding to eIF4E, but effects of leucine starvation were not replicated by overexpressing nonphosphorylatable 4EBP1. This suggests the binding of 4EBP1 to eIF4E may not by itself explain the suppression of mRNA translation under conditions of leucine starvation. Ribosome profiling suggested that leucine deprivation may primarily inhibit ribosome loading, whereas methionine deprivation may primarily impair start site recognition. These data underscore our lack of a full understanding of how mRNA translation is regulated and point to a unique regulatory role of methionine status on translation initiation that is not dependent upon eIF2 phosphorylation.

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“…In this case, the inhibition of protein synthesis also could be explained by the lack of the building blocks for making more protein in plasma, specifically methionine ( Tables 1 and 2 ), because it can be the main limiting one to start all translation processes, but it also can act through a mechanism independent of the Met–transfer RNA charging, the activation of a transcriptionally regulated mechanism via the activating transcription factor-4. 106 , 107 , 108 It is worth noting that when all the AAs from the diet were removed, insulin levels were not affected ( Figure 7 ). The amino acid imbalance created by the No Leu diet seems to be the main event that triggers the inhibition of digestive enzyme synthesis after feeding the No Leu diet, and not the lower insulin levels.…”

Section: Discussionmentioning

confidence: 97%

Dietary Protein and Amino Acid Deficiency Inhibit Pancreatic Digestive Enzyme mRNA Translation by Multiple Mechanisms

Sans

Crozier

Vogel

et al. 2021

Cellular and Molecular Gastroenterology and Hepatology

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Background & Aims Chronic amino acid (AA) deficiency, as in kwashiorkor, reduces the size of the pancreas through an effect on mammalian target of rapamycin complex 1 (mTORC1). Because of the physiological importance of AAs and their role as a substrate, a stimulant of mTORC1, and protein synthesis, we studied the effect of acute protein and AA deficiency on the response to feeding. Methods ICR/CD-1 mice were fasted overnight and refed for 2 hours with 4 different isocaloric diets: control (20% Prot); Protein-free (0% Prot); control (AA-based diet), and a leucine-free (No Leu). Protein synthesis, polysomal profiling, and the activation of several protein translation factors were analyzed in pancreas samples. Results All diets stimulated the Protein Kinase-B (Akt)/mTORC1 pathway, increasing the phosphorylation of the kinase Akt, the ribosomal protein S6 (S6) and the formation of the eukaryotic initiation factor 4F (eIF4F) complex. Total protein synthesis and polysome formation were inhibited in the 0% Prot and No Leu groups to a similar extent, compared with the 20% Prot group. The 0% Prot diet partially reduced the Akt/mTORC1 pathway and the activity of the guanine nucleotide exchange factor eIF2B, without affecting eIF2α phosphorylation. The No Leu diet increased the phosphorylation of eIF2α and general control nonderepressible 2, and also inhibited eIF2B activity, without affecting mTORC1. Essential and nonessential AA levels in plasma and pancreas indicated a complex regulation of their cellular transport mechanisms and their specific effect on the synthesis of digestive enzymes. Conclusions These studies show that dietary AAs are important regulators of postprandial digestive enzyme synthesis, and their deficiency could induce pancreatic insufficiency and malnutrition.

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Dietary Methionine Restriction Regulates Liver Protein Synthesis and Gene Expression Independently of Eukaryotic Initiation Factor 2 Phosphorylation in Mice

Cited by 42 publications

References 65 publications

Short‐term methionine deprivation improves metabolic health via sexually dimorphic, mTORCI‐independent mechanisms

Short‐term methionine deprivation improves metabolic health via sexually dimorphic, mTORCI‐independent mechanisms

Effects of single amino acid deficiency on mRNA translation are markedly different for methionine versus leucine

Dietary Protein and Amino Acid Deficiency Inhibit Pancreatic Digestive Enzyme mRNA Translation by Multiple Mechanisms

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