scholarly journals Amino acid-sensing mTOR signaling is involved in modulation of lipolysis by chronic insulin treatment in adipocytes

2009 ◽  
Vol 296 (4) ◽  
pp. E862-E868 ◽  
Author(s):  
Chongben Zhang ◽  
Mee-Sup Yoon ◽  
Jie Chen
Keyword(s):  
Amino Acid ◽  
Mammalian Target Of Rapamycin ◽  
Mtor Pathway ◽  
Phosphatidylinositol 3 Kinase ◽  
Insulin Effect ◽  
Triacylglycerol Hydrolase ◽  
High Insulin ◽  
Amino Acid Sensing ◽  
The Relationship ◽  
Stimulation Of

Chronically high insulin levels and increased circulating free fatty acids released from adipose tissue through lipolysis are two features associated with insulin resistance. The relationship between chronic insulin exposure and adipocyte lipolysis has been unclear. In the present study we found that chronic insulin exposure in 3T3-L1 adipocytes, as well as in mouse primary adipocytes, increased basal lipolysis rates. This effect of insulin on lipolysis was only observed when the mammalian target of rapamycin (mTOR) pathway was inhibited by rapamycin in the adipocytes. In addition, amino acid deprivation in adipocytes phenocopied the effect of rapamycin in permitting the stimulation of lipolysis by chronic insulin exposure. The phosphatidylinositol 3-kinase-Akt pathway does not appear to be involved in this insulin effect. Furthermore, we found that triacylglycerol hydrolase (TGH) activity was required for the stimulation of lipolysis by combined exposure to insulin and rapamycin. Therefore, we propose that nutrient sufficiency, mediated by an mTOR pathway, suppresses TGH-dependent lipolysis stimulated by chronic insulin exposure in adipocytes.

Insulin stimulus of leucine incorporation into frog liver protein

1962 ◽  
Vol 203 (4) ◽  
pp. 687-689 ◽  
Author(s):  
J. C. Penhos ◽  
M. E. Krahl
Keyword(s):  
Amino Acid ◽  
Rat Liver ◽  
Leucine Incorporation ◽  
Liver Protein ◽  
Amino Acid Incorporation ◽  
Insulin Effect ◽  
Acid Incorporation ◽  
Liver Slices ◽  
Stimulation Of

Slices prepared from livers of bull frogs ( Rana catesbiana), pancreatectomized and/or hypophysectomized 7 days before, were incubated 2 hr in frog Ringer-bicarbonate solution at 25 C. Incorporation of leucine-1-C14 into protein was subnormal in the pancreatectomized series. The addition of insulin in vitro, with glucose also present in the medium, produced a significant ( P < 0.01) stimulation of amino acid incorporation in the following series: livers from normal fed animals; livers from animals pancreatectomized 7 days before; and livers from animals pancreatectomized and hypophysectomized 7 days before. Neither insulin nor glucose alone gave a significant effect. These results therefore confirm and extend those obtained with rat liver slices showing that insulin can stimulate amino acid incorporation into protein when added directly to liver. The effect is relatively greatest with livers from animals pancreatectomized 7 days before; the insulin effect does not depend on the presence of the pituitary, as it is obtainable with livers from animals hypophysectomized and pancreatectomized 7 days previously.

scholarly journals Identification and characterization of two types of amino acid-regulated acetyltransferases in actinobacteria

2017 ◽  
Vol 37 (4) ◽  
Author(s):  
Yu-Xing Lu ◽  
Xin-Xin Liu ◽  
Wei-Bing Liu ◽  
Bang-Ce Ye
Keyword(s):  
Amino Acid ◽  
Feedback Regulation ◽  
Protein Acetylation ◽  
Post Translational Modifications ◽  
Act Domain ◽  
Amino Acid Binding ◽  
Amino Acid Sensing ◽  
And Function ◽  
Future Work ◽  
The Relationship

Abstract One hundred and fifty GCN5-like acetyltransferases with amino acid-binding (ACT)-GCN5-related N-acetyltransferase (GNAT) domain organization have been identified in actinobacteria. The ACT domain is fused to the GNAT domain, conferring amino acid-induced allosteric regulation to these protein acetyltransferases (Pat) (amino acid sensing acetyltransferase, (AAPatA)). Members of the AAPatA family share similar secondary structure and are divided into two groups based on the allosteric ligands of the ACT domain: the asparagine (Asn)-activated PatA and the cysteine (Cys)-activated PatA. The former are mainly found in Streptomyces; the latter are distributed in other actinobacteria. We investigated the effect of Asn and Cys on the acetylation activity of Sven_0867 (SvePatA, from Streptomyces venezuelae DSM 40230) and Amir_5672 (AmiPatA, from Actinosynnema mirum strain DSM 43827), respectively, as well as the relationship between the structure and function of these enzymes. These findings indicate that the activity of PatA and acetylation level of proteins may be closely correlated with intracellular concentrations of Asn and Cys in actinobacteria. Amino acid-sensing signal transduction in acetyltransferases may be a mechanism that regulates protein acetylation in response to nutrient availability. Future work examining the relationship between protein acetylation and amino acid metabolism will broaden our understanding of post-translational modifications (PTMs) in feedback regulation.

scholarly journals A complex interplay between Akt, TSC2 and the two mTOR complexes

2009 ◽  
Vol 37 (1) ◽  
pp. 217-222 ◽  
Author(s):  
Jingxiang Huang ◽  
Brendan D. Manning
Keyword(s):  
Growth Factor ◽  
Kinase Activity ◽  
Mammalian Target Of Rapamycin ◽  
Inhibitory Effects ◽  
Complex Interplay ◽  
Additional Level ◽  
Phosphoinositide 3 Kinase ◽  
The Relationship ◽  
Stimulation Of ◽  
In Cells

Akt/PKB (protein kinase B) both regulates and is regulated by the TSC (tuberous sclerosis complex) 1–TSC2 complex. Downstream of PI3K (phosphoinositide 3-kinase), Akt phosphorylates TSC2 directly on multiple sites. Although the molecular mechanism is not well understood, these phosphorylation events relieve the inhibitory effects of the TSC1–TSC2 complex on Rheb and mTORC1 [mTOR (mammalian target of rapamycin) complex] 1, thereby activating mTORC1 in response to growth factors. Through negative-feedback mechanisms, mTORC1 activity inhibits growth factor stimulation of PI3K. This is particularly evident in cells and tumours lacking the TSC1–TSC2 complex, where Akt signalling is severely attenuated due, at least in part, to constitutive activation of mTORC1. An additional level of complexity in the relationship between Akt and the TSC1–TSC2 complex has recently been uncovered. The growth-factor-stimulated kinase activity of mTORC2 [also known as the mTOR–rictor (rapamycin-insensitive companion of mTOR) complex], which normally enhances Akt signalling by phosphorylating its hydrophobic motif (Ser473), was found to be defective in cells lacking the TSC1–TSC2 complex. This effect on mTORC2 can be separated from the inhibitory effects of the TSC1–TSC2 complex on Rheb and mTORC1. The present review discusses our current understanding of the increasingly complex functional interactions between Akt, the TSC1–TSC2 complex and mTOR, which are fundamentally important players in a large variety of human diseases.

scholarly journals Distinct amino acid–sensing mTOR pathways regulate skeletal myogenesis

2013 ◽  
Vol 24 (23) ◽  
pp. 3754-3763 ◽  
Author(s):  
Mee-Sup Yoon ◽  
Jie Chen
Keyword(s):  
Amino Acid ◽  
Growth Regulation ◽  
Myogenic Differentiation ◽  
Mammalian Target Of Rapamycin ◽  
Acid Activation ◽  
Class Iii ◽  
Independent Manner ◽  
Inhibitory Function ◽  
Amino Acid Availability ◽  
Amino Acid Sensing

Signaling through the mammalian target of rapamycin (mTOR) in response to amino acid availability controls many cellular and developmental processes. mTOR is a master regulator of myogenic differentiation, but the pathways mediating amino acid signals in this process are not known. Here we examine the Rag GTPases and the class III phosphoinositide 3-kinase (PI3K) Vps34, two mediators of amino acid signals upstream of mTOR complex 1 (mTORC1) in cell growth regulation, for their potential involvement in myogenesis. We find that, although both Rag and Vps34 mediate amino acid activation of mTORC1 in C2C12 myoblasts, they have opposing functions in myogenic differentiation. Knockdown of RagA/B enhances, whereas overexpression of active RagB/C mutants impairs, differentiation, and this inhibitory function of Rag is mediated by mTORC1 suppression of the IRS1-PI3K-Akt pathway. On the other hand, Vps34 is required for myogenic differentiation. Amino acids activate a Vps34-phospholipase D1 (PLD1) pathway that controls the production of insulin-like growth factor II, an autocrine inducer of differentiation, through the Igf2 muscle enhancer. The product of PLD, phosphatidic acid, activates the enhancer in a rapamycin-sensitive but mTOR kinase–independent manner. Our results uncover amino acid–sensing mechanisms controlling the homeostasis of myogenesis and underline the versatility and context dependence of mTOR signaling.

Deletion of the amino acid transporter Slc6a14 suppresses tumour growth in spontaneous mouse models of breast cancer

2015 ◽  
Vol 469 (1) ◽  
pp. 17-23 ◽  
Author(s):  
Ellappan Babu ◽  
Yangzom D. Bhutia ◽  
Sabarish Ramachandran ◽  
Jaya P. Gnanaprakasam ◽  
Puttur D. Prasad ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Amino Acid ◽  
Mouse Models ◽  
Therapeutic Target ◽  
Tumour Growth ◽  
Mammalian Target Of Rapamycin ◽  
Amino Acid Transporter ◽  
Mtor Pathway ◽  
Target Of Rapamycin ◽  
Acid Transporter

Deletion of the amino acid transporter Slc6a14 in mice suppresses tumour growth in spontaneous models of breast cancer via interference with mammalian target of rapamycin (mTOR) pathway; this indicates an obligatory role for SLC6A14 in breast cancer, highlighting its potential as a therapeutic target.

scholarly journals Amino acid sensing and mTOR regulation: inside or out?

2009 ◽  
Vol 37 (1) ◽  
pp. 248-252 ◽  
Author(s):  
Deborah C.I. Goberdhan ◽  
Margret H. Ögmundsdóttir ◽  
Shubana Kazi ◽  
Bruno Reynolds ◽  
Shivanthy M. Visvalingam ◽  
...  
Keyword(s):  
Amino Acids ◽  
Amino Acid ◽  
Growth Factor ◽  
Environmental Conditions ◽  
Detection System ◽  
Mammalian Target Of Rapamycin ◽  
Target Of Rapamycin ◽  
Amino Acid Sensing ◽  
The Impact ◽  
Mtor Signalling

mTOR (mammalian target of rapamycin) plays a key role in determining how growth factor, nutrient and oxygen levels modulate intracellular events critical for the viability and growth of the cell. This is reflected in the impact of aberrant mTOR signalling on a number of major human diseases and has helped to drive research to understand how TOR (target of rapamycin) is itself regulated. While it is clear that amino acids can affect TOR signalling, how these molecules are sensed by TOR remains controversial, perhaps because cells use different mechanisms as environmental conditions change. Even the question of whether they have an effect inside the cell or at its surface remains unresolved. The present review summarizes current ideas and suggests ways in which some of the models proposed might be unified to produce an amino acid detection system that can adapt to environmental change.

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