Leucine Deprivation Increases Hepatic Insulin Sensitivity via GCN2/mTOR/S6K1 and AMPK Pathways

Xiao, Fei; Huang, Zhiyu; Li, Houkai; Yu, Junjie; Wang, Chunxia; Chen, Shanghai; Meng, Qingshu; Cheng, Ying; Gao, Xiang; Li, Jia; Liu, Yong; Guo, Feifan

doi:10.2337/db10-1246

Cited by 256 publications

(279 citation statements)

References 47 publications

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“…Interestingly, BCAAs, leucine in particular, are potent activators of the target of rapamycin (TOR) kinase. Leucine deprivation has previously been associated with reduced TOR signaling (52), which can in turn prolong lifespan and is required for DR-mediated lifespan extension (53). However, it remains unclear whether the drop in BCAA levels is necessary for metformin-induced lifespan extension.…”

Section: Discussionmentioning

confidence: 99%

Metformin promotes lifespan through mitohormesis via the peroxiredoxin PRDX-2

Haes

Frooninckx

Assche

et al. 2014

Proc. Natl. Acad. Sci. U.S.A.

305

212

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The antiglycemic drug metformin, widely prescribed as first-line treatment of type II diabetes mellitus, has lifespan-extending properties. Precisely how this is achieved remains unclear. Via a quantitative proteomics approach using the model organism Caenorhabditis elegans, we gained molecular understanding of the physiological changes elicited by metformin exposure, including changes in branched-chain amino acid catabolism and cuticle maintenance. We show that metformin extends lifespan through the process of mitohormesis and propose a signaling cascade in which metformin-induced production of reactive oxygen species increases overall life expectancy. We further address an important issue in aging research, wherein so far, the key molecular link that translates the reactive oxygen species signal into a prolongevity cue remained elusive. We show that this beneficial signal of the mitohormetic pathway is propagated by the peroxiredoxin PRDX-2. Because of its evolutionary conservation, peroxiredoxin signaling might underlie a general principle of prolongevity signaling.

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Section: Discussionmentioning

confidence: 99%

Metformin promotes lifespan through mitohormesis via the peroxiredoxin PRDX-2

Haes

Frooninckx

Assche

et al. 2014

Proc. Natl. Acad. Sci. U.S.A.

305

212

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“…Although Gcn2 À / À mice have been characterized in other experimental approaches such as their response to amino acid deficiency, [10][11][12] to our knowledge this is the first study evaluating the ability of these mice to react to stress not directly related to nutritional conditions. After acute and chronic CCl 4 -treatment, Gcn2 À / À mice exhibited increased ALT and AST activities, more necrotic areas and, in the case of chronic treatment, enhanced inflammatory cell infiltration and collagen type I production.…”

Section: Discussionmentioning

confidence: 99%

“…12 Gcn2 À / À mice are more sensitive to oxidative stress induced in the liver by an imbalanced diet and present decreased levels of glutathione peroxidase in the liver. 13 Most of the studies have focused on stress caused by amino acid deprivation, yet the role of GCN2 in liver injury and fibrogenesis has not been studied.…”

mentioning

confidence: 99%

GCN2 kinase is a key regulator of fibrogenesis and acute and chronic liver injury induced by carbon tetrachloride in mice

Arriazu

López-Zabalza

Leung

et al. 2013

Laboratory Investigation

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General control nonderepresible 2 (GCN2) is a highly conserved cytosolic kinase that modulates a complex response for coping with the stress owing to lack of amino acids. GCN2 has been recently shown to be involved in the regulation of metabolic balance and lipid degradation rate in the liver. We hypothesized that GCN2 could have a role in in hepatic fibrogenesis and in the response to acute or chronic liver injury. Activation of GCN2 in primary or immortalized human hepatic stellate cells by incubation with medium lacking the essential amino acid histidine correlated with decreased levels of collagen type I protein and mRNA, suggesting an antifibrogenic effect of GCN2. In vivo studies with Gcn2 knockout mice (Gcn2 À / À ) showed increased susceptibility to both acute or chronic liver damage induced by CCl 4 , as shown by higher alanine aminotransferase and aspartate aminotransferase activities, increased necrosis and higher inflammatory infiltrates compared with wild-type mice (WT). Chronic CCl 4 treatment increased deposition of interstitial collagen type I more in Gcn2 À / À mice than in WT mice. Col1a1 and col1a2 mRNA levels also increased in CCl 4 -treated Gcn2 À / À mice compared with WT mice. These results suggest that GCN2 is a key regulator of the fibrogenic response to liver injury.

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“…In 2007, Guo identified a novel function of GCN2 in regulating lipid metabolism during leucine deprivation. Knockout of the Gcn2 gene in mice results in fatty liver, mediated by high expression of FAS, when the animals are fed a leucine-deficient diet for 7 d [16] and results in insulin resistance following leucine deprivation [27]. Furthermore, Xiao et al [27] found that GCN2 also plays a critical role in the regulation of insulin sensitivity and glucose metabolism via the mTOR pathway.…”

Section: Gcn2mentioning

confidence: 99%

“…In contrast, dietary leucine deprivation decreases serum insulin levels 3-fold in mice with normal glucose levels, suggesting that increased insulin sensitivity may occur in response to leucine deprivation [16]. Further work has shown that leucine deprivation improves hepatic insulin sensitivity by sequentially activating general control nonderepressible 2 (GCN2) and decreasing mammalian target of rapamycin (mTOR) signaling, as well as activating AMP-activated protein kinase (AMPK) in the context of leucine deprivation [27]. Moreover, leucine deprivation also improves insulin sensitivity in nutritionally or genetically induced insulin resistance models, which provides hope to patients with diabetes.…”

Section: Amino Acids and Diabetesmentioning

confidence: 99%

Branched chain amino acids and metabolic regulation

Wang

Guo

2013

Chin. Sci. Bull.

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Amino acids are fundamental nutrients required for protein synthesis. The branched chain amino acids (BCAAs) leucine, isoleucine, and valine are the most abundant of the essential amino acids. BCAAs have recently been recognized as having functions in processes other than simple nutrition. For example, metabolic diseases are characterized by higher levels of circulating BCAAs. Moreover, supplementation with or deficiency in BCAAs is closely related to the regulation of metabolic homeostasis. Indeed, leucine deprivation induces increased lipolysis and thermogenesis, which result in fat loss, as well as suppressed lipogenesis and enhanced insulin sensitivity in the liver. Accumulating evidence has indicated that several amino acid sensors, including GCN2, ATF4, mTOR, and AMPK, play pivotal roles in the regulation of lipid metabolism, glucose metabolism, and energy homeostasis. Furthermore, the hypothalamus is critical for sensing amino acid levels and mediates the metabolic adaptation of the body upon limitation of essential amino acids (EAAs) through regulating expression of the S6K1, MC4R, and CRH. In this review, we highlight recent studies investigating the cellular mechanisms linking amino acids, amino acid sensors, metabolic regulation, and metabolic diseases. Amino acid sensing and metabolic regulation have become research hotspots in the metabolic field.branched chain amino acids, amino acid sensor, lipid metabolism, glucose metabolism, energy homeostasis, obesity, diabetes Citation:Wang C X, Guo F F. Branched chain amino acids and metabolic regulation.

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Leucine Deprivation Increases Hepatic Insulin Sensitivity via GCN2/mTOR/S6K1 and AMPK Pathways

Cited by 256 publications

References 47 publications

Metformin promotes lifespan through mitohormesis via the peroxiredoxin PRDX-2

Metformin promotes lifespan through mitohormesis via the peroxiredoxin PRDX-2

GCN2 kinase is a key regulator of fibrogenesis and acute and chronic liver injury induced by carbon tetrachloride in mice

Branched chain amino acids and metabolic regulation

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