Re-examination of Dietary Amino Acid Sensing Reveals a GCN2-Independent Mechanism

Leib, David E.; Knight, Zachary A.

doi:10.1016/j.celrep.2015.09.055

Cited by 35 publications

(40 citation statements)

References 32 publications

(59 reference statements)

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“…We note that the initial proposal that GCN2 controls the ability of mice to sense (and avoid) meals depleted of essential amino acids have recently been revisited (Leib and Knight, 2015; Maurin et al, 2005). Newer findings suggest mice cannot immediately discriminate between food lacking or replete with essential amino acids.…”

Section: Discussionmentioning

confidence: 97%

Stress Kinase GCN2 Controls the Proliferative Fitness and Trafficking of Cytotoxic T Cells Independent of Environmental Amino Acid Sensing

et al. 2016

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Summary GCN2 is one of four ‘stress kinases’ that block translation by phosphorylating eIF2α. GCN2 is thought to bind uncharged tRNAs to ‘sense’amino acids availability. In mammals, myeloid cells expressing indoleamine dioxygenases locally deplete tryptophan, which is detected by GCN2 in T cells to cause proliferative arrest. GCN2-deficient T cells were reported to ectopically enter the cell cycle when tryptophan was limiting. Using GCN2-deficient strains crossed to TCR transgenic backgrounds, we found GCN2 is essential for induction of stress target genes such as CHOP. However, GCN2-deficient CD8+ T cells fail to proliferate in limiting tryptophan, arginine, leucine, lysine or asparagine, the opposite of what previous studies concluded. In vitro and in vivo proliferation experiments show that GCN2-deficient CD8+ T cells have T cell-intrinsic proliferative and trafficking defects not observed in CD4+ T cells. Thus GCN2 is required for normal cytotoxic T cell function.

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Section: Discussionmentioning

confidence: 97%

Stress Kinase GCN2 Controls the Proliferative Fitness and Trafficking of Cytotoxic T Cells Independent of Environmental Amino Acid Sensing

et al. 2016

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“…However, a recent study challenged these findings and failed to observe a rapid GCN2-dependent hypophagic response to threonine and leucine deficient diets (74, 75). Mice switched from a control to a leucine or threonine-devoid diet did not display a rapid hypophagic response during the first 3 h of feeding the novel diet but did show a hypophagic response after this time point.…”

Section: Central Detection Of Essential Amino Acid Devoid or Unbalancmentioning

confidence: 99%

Central Amino Acid Sensing in the Control of Feeding Behavior

Heeley

Blouet

2016

Front. Endocrinol.

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Dietary protein quantity and quality greatly impact metabolic health via evolutionary-conserved mechanisms that ensure avoidance of amino acid imbalanced food sources, promote hyperphagia when dietary protein density is low, and conversely produce satiety when dietary protein density is high. Growing evidence supports the emerging concept of protein homeostasis in mammals, where protein intake is maintained within a tight range independently of energy intake to reach a target protein intake. The behavioral and neuroendocrine mechanisms underlying these adaptations are unclear. While peripheral factors are able to signal amino acid deficiency and abundance to the brain, the brain itself is exposed to and can detect changes in amino acid concentrations, and subsequently engages acute and chronic responses modulating feeding behavior and food preferences. In this review, we will examine the literature describing the mechanisms by which the brain senses changes in amino acids concentrations, and how these changes modulate feeding behavior.

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“…It appears that either some of the sensors of nutrients and energy status do not detect the lack of methionine nor the change in energy status or that mRNA and protein levels of these sensors are not indicative of their action suggesting that the effects of methionine restriction are complex. Recently, Leib and Knight (2015) showed that the proposed amino acid sensor, GCN2, plays no role in dietary essential amino acid sensing, contrary to earlier reports.…”

Section: 5 Rodent Studies Of Methionine Restrictionmentioning

confidence: 75%

Cutting back on the essentials: Can manipulating intake of specific amino acids modulate health and lifespan?

Brown‐Borg

Buffenstein

2017

Ageing Research Reviews

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With few exceptions, nutritional and dietary interventions generally impact upon both old-age quality of life and longevity. The life prolonging effects, commonly observed with dietary restriction reportedly are linked to alterations in protein intake and specifically limiting the dietary intake of certain essential amino acids. There is however a paucity of data methodically evaluating the various essential amino acids on health- and lifespan and the mechanisms involved. Rodent diets containing either lower methionine content, or tryptophan, than that found in commercially available chow, appear to elicit beneficial effects. It is unclear whether all of these favorable effects associated with restricted intake of methionine and tryptophan are due to their specific unique properties or if restriction of other essential amino acids, or proteins in general, may produce similar results. Considerably more work remains to be done to elucidate the mechanisms by which limiting these vital molecules may delay the onset of age-associated diseases and improve quality of life at older ages.

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Re-examination of Dietary Amino Acid Sensing Reveals a GCN2-Independent Mechanism

Cited by 35 publications

References 32 publications

Stress Kinase GCN2 Controls the Proliferative Fitness and Trafficking of Cytotoxic T Cells Independent of Environmental Amino Acid Sensing

Stress Kinase GCN2 Controls the Proliferative Fitness and Trafficking of Cytotoxic T Cells Independent of Environmental Amino Acid Sensing

Central Amino Acid Sensing in the Control of Feeding Behavior

Cutting back on the essentials: Can manipulating intake of specific amino acids modulate health and lifespan?

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