J. Anim Sci. 2008. 86:E36-E50. doi:10.2527/jas.2007-0567
© 2008 American Society of Animal Science
The mammalian target of rapamycin-signaling pathway in regulating metabolism and growth1,2
X. Yang3,
C. Yang,
A. Farberman,
T. C. Rideout,
C. F. M. de Lange,
J. France and
M. Z. Fan
Center for Nutrition Modeling, Department of Animal and Poultry Science, University of Guelph, Guelph, Ontario, Canada N1G 2W1
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Abstract
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The mammalian target of rapamycin (mTOR) plays key roles in cellular metabolism and hypertrophic-hyperplasic growth, and it acts as a central regulator of protein synthesis and ribosome biogenesis at the transcriptional and translational levels by sensing and integrating signals from mitogens and nutrients. Hormonal and stress factors can affect the mTOR-signaling pathway via their receptors and signal transduction pathways. Nutritional regulation of the mTOR-signaling pathway is mediated by their corresponding plasma membrane transporters, other unknown mechanisms, or both. Adenine monophosphate-activated protein kinase, an important cellular energy sensor, can interact with the mTOR-signaling pathway to maintain cellular energy homeostasis. Interactions of mTOR with regulatory-associated protein of TOR or rapamycin-insensitive companion of mTOR result in 2 mTOR complexes, with the former (mTOR complex-1) being the primary controller of cell growth and the latter (mTOR complex-2) mediating effects that are insensitive to rapamycin, such as cytoskeletal organization. Upstream elements of the mTOR-signaling pathway include Ras-homolog enriched in brain, and tuberous sclerosis complex 1 and 2, with tuberous sclerosis complex 2 as the linker between phosphatidylinositol 3-kinase/protein kinase B or Ras-Raf-mitogen-activated protein kinase-extracellular signal-regulated protein kinase pathways and the mTOR pathway. Ribosomal protein S6 protein kinase 1 and eukaryotic initiation factor 4E binding protein 1 are currently the 2 best-known downstream effectors of mTOR signaling. Hormonal factors, stressors, and nutrients can differentially mediate cellular metabolism and growth via the mTOR pathway with effectors specific to the organ or tissue types involved.
Key Words: growth • mammalian target of rapamycin • metabolism
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INTRODUCTION
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Cellular metabolism is essentially carried out by proteins regulated at the levels of gene transcription, protein translation, and protein degradation. Growth of cells into organs, tissue, and animals is, in essence, cellular hypertrophy and hyperplasia (Lawrence and Fowler, 1997
). Hypertrophy refers to enlargement of cell size mainly caused by increases in protein and RNA contents (Figure 1), whereas hyperplasia is the increase in cell numbers, resulting from the balance between cell proliferation and apoptosis (Figure 2).
The cellular protein metabolism process, including protein synthesis and degradation, is essential to both hypertrophic and hyperplasic growth. The cellular protein synthetic activity is regulated by its synthetic machinery efficiency and capacity (Burrin et al., 1997). The protein synthesis pathway is conventionally divided into 3 stages (i.e., initiation, elongation, and termination), as summarized in Figure 3. The efficiency of the entire protein translational synthesis pathway is affected by activity associated with each of the steps illustrated in Figure 3. Although rate-limiting steps are not clearly identified for the pathway, sufficient evidence points to the importance of mammalian target of rapamycin (mTOR) signaling in regulation of the pathway via direct stimuli on ribosomal protein S6 kinase 1 (S6K1), eukaryotic initiation factor (eIF) 4B, eIF4G, dissociation of S6K1 from eIF3, indirectly stimulating eukaryotic elongation factor 2, and stimulation of the formation of eIF4F by inhibition of eIF4E-binding protein 1 (eIF4E-BP1) complex (Figure 3). Furthermore, cellular protein translational machinery capacity is influenced by the number of ribosomes in cells (Burrin et al., 1997). The eukaryotic ribosome consists of rRNA, including 5S, 5.8S, 18S, and 28S, and approximately 80 ribosomal proteins and 3 RNA polymerases play pivotal roles in ribosome biogenesis (Mayer and Grummt, 2006). On the other hand, 4 major pathways are responsible for intracellular protein degradation: lysosome, ubiquitin-proteasome, calpain, and caspase systems (Goll et al., 2008). Although less elucidated, mTOR is known to be involved in the regulation of ribosome biogenesis (Mayer and Grummt, 2006) and protein degradation (Dennis et al., 1999).
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Figure 3. Summary of the mammalian protein synthetic pathway reaction steps, with emphasis on the established regulatory roles of the mammalian target of rapamycin (mTOR; based on the concepts reviewed by Proud, 2004, and Lee et al., 2007). + = up-regulation; AAi = intracellular free amino acids; ATS = aminoacyl-tRNA synthetases; eEF = eukaryotic elongation factors, including 1A, 1B, and 2; eIF = eukaryotic initiation factors, including 1, 1A, 2, 2B, 3, 4A, 4B, 4E, 4F, 4G, 5, and 5B; eIF4E-BP1 = eukaryotic initiation factor 4E binding protein 1; eRF = eukaryotic release factors, including 1 and 3; mTORC1 = mTOR complex 1; Pi = phosphate; 40S = ribosomal subunit 40S; 60S = ribosomal subunit 60S; S6 = ribosomal protein S6; and S6K1 = ribosomal protein S6 kinase 1.
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The cell cycle comprises 4 phases, G1, S, G2, and M, as shown in Figure 2
. Cellular DNA replicates in the S phase, and the M phase is composed of mitosis and cytokinesis, which are 2 closely coupled processes. Mitotic cell division is mainly controlled by cyclins, cyclin-dependent kinases, and cyclin-dependent kinase inhibitors (Ford et al., 2004; Rhoads, 2004). When cells exit the cell cycle, they enter the resting state, called the G0 phase. Caspases and cytochrome c are involved in the process of apoptosis, one of the main types of programmed cell death. Recent research suggests that the mTOR-signaling pathway plays roles in cell division and apoptosis (Fingar et al., 2004; Ruvinsky and Meyuhas, 2006).
Therefore, the mTOR-signaling pathway has emerged as a central mediator of metabolism and growth. The objectives of this paper are 1) to review the mTOR-signaling network components, and 2) to compile literature reports on the regulation of metabolism and growth mediated by the mTOR-signaling pathway in sensing stimuli exerted by hormonal factors, environmental stress factors, and nutrients.
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RAPAMYCIN AND mTOR
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Rapamycin, a bacterial and lipophilic macrolide with the chemical formula of C51H79NO13, was originally isolated in the soil of Easter Island in the 1970s (Vézina et al., 1975). It has potent antifungal, immunosuppressive, and anticancer activities. Research on the mechanisms of rampamycin activities led to the discovery of TOR in the early 1990s (Brown et al., 1994). In complex with intracellular protein FK506-binding protein (FKBP), rapamycin can bind to TOR and block its functions. Although TOR is highly conserved from yeast to mammalian species (Lorberg and Hall, 2004), 2 homologous TOR genes exist in yeast and fungi, whereas higher eukaryotes have only 1 TOR gene (Lorberg and Hall, 2004).
Other names for mTOR include FKBP-rapamycin-associated protein (FRAP), rapamycin and FKBP target, and rapamycin target. By displaying Ser-Thr protein kinase activity, mTOR belongs to the phosphoinosi-tol-3-kinase-related kinase family (Hay and Sonenberg, 2004). With a molecular weight of 289 kDa, mTOR contains 2,549 AA and has several structurally conserved domains. The direct binding site on mTOR to the FKBP-rapamycin complex is the FKBP-rapamycin binding (FRB) domain. Next to the FRB domain is the catalytic kinase domain at the C terminus. The N terminus possesses 2 clusters of HEAT (abbreviation for Huntington, elongation factor 3, the A subunit of protein phosphatase 2A, and TOR1) repeats. The HEAT repeats, FAT [abbreviation for FRAP, ATM (ataxia telangiectasia mutated), TRRAP (transformation/transcription domain-associated protein)], and FATC (abbreviation for FAT C terminus) are speculated to be involved in protein-protein interactions (Hay and Sonenberg, 2004; Lorberg and Hall, 2004). Nevertheless, the negative regulatory domain is only putative (Hay and Sonenberg, 2004).
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SIGNALING NETWORK of mTOR
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As the intracellular central kinase sensor, mTOR integrates metabolic signals exerted by hormonal factors, stress factors, nutrient availability, and energy status, and regulates various physiological functions, including gene transcription, protein metabolism, cell cycle, and cytoskeleton organization (Schmelzle and Hall, 2000; Guertin et al., 2004; Kahn and Myers, 2006). The existence of mTOR in the 2 complexes (mTORC1 and mTORC2) has been established (Figure 4), and both mTORC1 and mTORC2 may be multimeric (Wullschleger et al., 2006).
Complex Components of mTOR and Their Functions
The upstream regulatory components of mTORC2 are not clear at present (Wullschleger et al., 2006). Activation of protein kinase B (PKB, also known as Akt) by mTORC2 has been established (Figure 4). The components of mTORC2 include mammalian lethal with SEC13 protein 8 [mLST8, also known as G protein beta subunit-like protein (GβL)], rapamycin-insensitive companion of mTOR (rictor; also known as mammalian AVO3), and mTOR (Wullschleger et al., 2006). Recently proposed binding components of mTORC2 include stress-activated protein kinase-interacting protein 1 [previously known as MIP1 (i.e., MEKK2-interacting protein 1) or AVO1; Jacinto et al., 2006; Wullschleger et al., 2006], proline-rich protein 5 (Woo et al., 2007), and protein observed with rictor (protor; Pearce et al., 2007). Although its related signaling mechanism is little understood, mTORC2 is insensitive to rapamycin, and its primary known function is in the actin cytoskeleton organization (Wullschleger et al., 2006). Roles of the components of GβL, rictor, stress-activated protein kinase-interacting protein 1, proline-rich protein 5, and protor associated with mTORC2 and other possible downstream functions of mTORC2 are not clear at present (Wullschleger et al., 2006).
As illustrated in Figure 4, mTORC1 consists of mLST8, regulatory-associated protein of TOR (raptor), and mTOR (Wullschleger et al., 2006). The proline-rich PKB substrate of 40 kDa (PRAS40) is believed to bind to mTORC1 via raptor and inhibits its activity, or it is regarded as a substrate to mTORC1 (Sancak et al., 2007; Figure 4). Being sensitive to rapamycin, mTORC1 is largely responsible for the regulation of cellular metabolism and growth. Acting as a positive upstream regulator of mTORC1, PKB connects the phosphatidyl-inositol 3-kinase (PI3K) pathway to mTORC1 via tuberous sclerosis complex 1 (TSC1), TSC2, and Ras homolog enriched in brain (Rheb; Corradetti and Guan, 2006). The 2 best-characterized downstream effectors of mTORC1 are S6K1 and eIF4E-BP1, which are important factors in the protein synthetic pathway (Hay and Sonenberg, 2004). Cooperation between 3-phosphoinositide-dependent protein kinase-1 (PDK1) and mTORC1 plays critical roles in full activation of S6K1, which has several biological targets such as S6, eIF4B, eukaryotic elongation factor 2 kinase, and insulin receptor substrate-1 (IRS-1; Ruvinsky and Meyuhas, 2006). In addition, TSC2-mediated S6K1 inhibition by PI3K is mTORC1 independent (Jaeschke et al., 2002). The notion that phosphorylation of S6 may be involved in translational control of mRNA with a 5' terminal oligopyrimidine tract (5' TOP mRNA) has been challenged recently (Proud, 2007). Ordered phosphorylation of eIF4E-BP1 activated by mTORC1 and other protein kinases leads to dissociation of eIF4E from the eIF4E-BP1-eIF4E complex, thereby providing free eIF4E for formation of the eIF4F complex in enhancing global protein synthesis efficiency (Proud, 2007).
Hormones and Growth Factors
The mTORC1-signaling network, with emphasis on stimuli by hormones and growth factors, is shown in Figure 4. Insulin and IGF-I can stimulate the mTORC1-signaling pathway via the PI3K cascade. Interactions of Janus kinase 2 with the PI3K and Ras-Raf-MEK [MEK, abbreviation for mitogen-activated protein kinase (MAP)-extracellular signal-regulated protein kinase (ERK) kinase] pathway components can sense growth hormone stimulus to the mTORC1-signaling pathway (Lanning and Carter-Su, 2006; Hayashi and Proud, 2007). Approximately 40 different cytokine receptors signal through the Janus kinase-STAT (signal transducers and activators of transcription) system (Murray, 2007), which can interact with the PI3K and Ras-Raf-MEK pathways (Rawlings et al., 2004), indicating that cytokines may positively or negatively regulate the mTORC1-signaling pathway (Abraham, 1998). Stimulatory signals, such as insulin and IGF-I, can inactivate TSC2 by PKB-dependent phosphorylation of TSC2 (Inoki et al., 2002). Inactivation of TSC2 associated with TSC1 inhibits activity of Rheb, and Rheb is a small guanosine 5-triphosphatase and an activator of mTORC1 (Tee et al., 2002). Activity of TSC2 can also be negatively regulated via phosphorylation of TSC2 by ERK1 and 2 and its downstream target, p90 ribosomal S6 kinase (p90RSK; Roux et al., 2004; Proud, 2007). Thus, the PI3K and Ras-Raf-MEK-ERK pathways converge on TSC2 (Figure 4). On the other hand, activation of the mTORC1 substrate S6K1 feedback inhibits IRS-1 and PI3K activities (Wullschleger et al., 2006). Therefore, hormonal factors that stimulate mTORC1 signaling can also potentially decrease the sensitivity of the insulin-IRS-1- and PI3K-signaling cascade (Figure 4).
β-Adrenergic agonists are widely used in modulating cellular functions and hypertrophic growth in animals (Bergen and Merkel, 1991). It has been reported that the actions of β-agonists are mediated by the MEK-ERK pathway (Gelinas et al., 2007) and, in part, by PKB (Kline et al., 2007) in connecting to mTORC1 signaling. Transforming growth factor-β (TGF-β) family members regulate a wide range of cellular metabolism and organ and tissue growth (Song et al., 2003). It has been shown that with TGF-β, including myostatin, a negative muscle growth regulator, associated regulations are mediated, in part, by affecting the intracellular PI3K-PKB cascade in further linking to the mTORC1-signaling pathway (Song et al., 2003; Qureshi et al., 2007). Glucagon-like peptide-2 (GLP-2), a nutrient-responsive gut trophic neuropeptide, is shown to transduce its effects via the GLP-2 receptor through PI3K-PKB in activating mTORC1 signaling (Li et al., 2007). Epidermal growth factor exerts its stimulatory effects via PI3K-PKB and MEK-ERK in activating mTORC1 signaling in mammary gland epithelial cells (Galbaugh et al., 2006). Regulatory roles of FSH in ovarian follicles, prolactin in lymphoma cells, and serotonin in pulmonary artery smooth muscle have been shown to activate the mTORC1-signaling pathway via the PI3K-PKB cascade (Alam et al., 2004; Bishop et al., 2006; Liu and Fanburg, 2006), whereas PGF2
stimulates the mTORC1-signaling pathway via the Ras-Raf-MEK-ERK cascade in ste-roidogenic luteal cells (Arvisais et al., 2006). Stimulatory roles of thyroid-stimulating hormone and thyroid hormone in thyrocytes, fibroblasts, and cardiomyocytes are shown to activate the mTORC1-signaling pathway via the PI3K-PKB cascade (Suh et al., 2003; Cao et al., 2005; Kenessey and Ojamaa, 2006). Therefore, hormonal stimulus cascades leading to mTORC1 signaling are programmed to be specific to the tissues and organs involved and are being further investigated through ongoing research in this area.
Stress Factors
Sensing of various stress factors by the mTORC1-signaling pathway is illustrated in Figure 5. Hypoxia stimulates the expression of REDD1 (i.e., the regulated in development and DNA damage responses protein 1, also called RTP801) via the action by hypoxia-inducible factor 1, and REDD1 enhances TSC2, leading to inhibition of Rheb, mTORC1-signaling, and protein translational efficiency (Ellisen, 2005; Reiling and Sabatini, 2006). Meanwhile, hypoxia can independently inhibit protein translational efficiency by depressing eIF2-guanosine 5-triphosphate with the participation of PERK (i.e., protein kinase R-like endoplasmic reticulum kinase, also called pancreatic eIF2 kinase; Reiling and Sabatini, 2006). Glucocorticoids, including the stress hormone cortisol, are negative muscle protein regulators contributing to the whole-body catabolic state. Studies by Wang et al. (2006) demonstrated that glucocorticoids inhibit mTORC1 signaling by stimulating REDD1 but not REDD2 (Figure 5). As illustrated in Figure 5, the stress of low energy status can inhibit mTORC1 signaling by stimulating both REDD1 (Ellisen, 2005; Sofer et al., 2005) and adenine monophosphate (AMP)-activated protein kinase (AMPK; Reiling and Sabatini, 2006). Damage to cellular DNA can stimulate the tumor suppressor p53 protein (p53) and activate AMPK, whereas AMPK activation stimulates the TSC2-TSC1 complex, leading to the depression of Rheb and mTORC1 signaling (Reiling and Sabatini, 2006). Hyperosmolarity has been documented to inhibit mTORC1, but its associated mechanisms are not very clear (Fumarola et al., 2005; Reiling and Sabatini, 2006). Studies by Naegele and Morley (2004) indicated that hyperosmotic stress for the inhibition of mTORC1 signaling might be mediated via the PI3K-PKB cascade. Oxidative stress and heat shock are known to impair mTORC1, although its associated mechanisms are not very clear (Reiling and Sabatini, 2006). Various mechanostress conditions stimulate mTORC1 signaling (Figure 5). Mechanical stimuli elicited by exercise and involved in phospholipase D for producing the lipid messenger phosphatidic acid, which binds to the FRB domain of TOR, increase mTORC1 signaling and S6K1 activity in skeletal muscle (Reiling and Sabatini, 2006). Cyclic strain and fluid flow shear stress are also reported to activate mTORC1 signaling in endothelial cells lining the interior of blood vessels (Kraiss et al., 2000; Reiling and Sabatini, 2006). However, mechanisms associated with mechanostress-stimulated mTORC1 signaling are not very clear.
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Figure 5. Schematic illustration of the mammalian target of rapamycin (mTOR)-signaling pathway in mediating metabolism and growth, with emphasis on its sensing of various stress factors (adapted from the concepts reviewed by Levine et al., 2006, Reiling and Sabatini, 2006, and Wang et al., 2006). Lines with end arrows indicate activation, whereas those with perpendicular bars at the end indicate inhibition. AMPK = AMP (adenosine monophosphate)-activated protein kinase; CaMKK = calcium- and calmodulin-dependent protein kinase kinases and β; eEF2 = eukaryotic elongation factor 2; eEF2K = eukaryotic elongation factor 2 kinase; eIF = eukaryotic initiation factors, including 4E and 4B; eIF4E-BP1 = eukaryotic initiation factor 4E-binding protein 1; HIF1 = hypoxia-inducible factor 1; p53 = protein 53; LKB1 = STK11, Ser/Thr-protein kinase 11, in complex with sterile 20 protein-related adaptor and mouse protein 25 to activate AMPK; mTORC1 = mTOR complex 1; PERK = protein kinase R-like endoplasmic reticulum kinase (also called pancreatic eIF2 kinase, PEK); Rheb = Ras homolog enriched in brain; REDD1 = regulated in development and DNA damage responses protein 1; TSC1 = tuberous sclerosis complex 1; TSC2 = tuberous sclerosis complex 2; and eIF2-GTP = eukaryotic initiation factor 2-guanosine 5-triphosphate.
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Cellular Energy Status
Cellular energy status is tightly connected to the mTORC1-signaling pathway through several major mechanisms, as illustrated in Figure 5. As shown in Figure 5, low energy status can inhibit mTORC1 signaling by stimulating the REDD1-TSC2 cascade (Ellisen, 2005; Sofer et al., 2005). Changes in intracellular ATP concentration can be directly sensed by mTORC1; thus, fluctuations of ATP concentration below or above a set homeostatic level would stimulate or inhibit mTORC1 signaling (Sofer et al., 2005; Kimball, 2006). Changes in both the AMP-to-ATP ratio and AMP concentration can be sensed by AMPK (Kimball, 2006). A low cellular AMP-to-ATP ratio can lead to increased AMP binding to AMPK and subsequent phosphorylation of AMPK by the tumor suppressor Ser/Thrprotein kinase 11 (LKB1) in complex with STRAD (i.e., sterile 20 protein-related adaptor) and mouse protein 25 (Alessi et al., 2006). Furthermore, AMPK can be activated by a Ca2+-dependent and AMP-independent process involving phosphorylation by Ca2+- and calmodulin-dependent protein kinase kinase (CaMKK)- and CaMKKβ, leading to the activation of AMPK (Hong et al., 2005; Towler and Hardie, 2007). Activation of AMPK can phosphorylate TSC2, resulting in depression of mTORC1 signaling (Inoki et al., 2003; Kimball, 2006) and improvement in sensitivity of the insulin-IRS-1-PI3K-signaling cascade (Um et al., 2006). Recently, it was proposed that glucose 6-phosphate and glucosamine 6-phosphate also likely participate in mTOR signaling in cardiac muscle (Sharma et al., 2007). Therefore, energy substrates, including AA, sugars, and fatty acids, may indirectly modulate mTORC1 signaling through their catabolism in affecting cellular AMP-to-ATP ratios and glucose-phosphate metabolite levels. On the other hand, activation of the mTORC1 substrate S6K1 by overloading of energy feedback inhibits IRS-1 and PI3K activities (Wullschleger et al., 2006). Therefore, intracellular energy status, which affects mTORC1 signaling, can also influence the sensitivity of the insulin-IRS-1-PI3K-signaling cascade.
AA
A number of experiments have been conducted to examine the effect of availability of AA, especially the branched-chain AA, on mTOR signaling and protein metabolism (Kimball and Jefferson, 2006). The proposed mechanisms of AA availability in regulating the mTORC1-signaling pathway for mediating metabolism and growth are illustrated in Figure 6. How AA availability is sensed by the mTOR-signaling pathway is still poorly understood. Currently, there is disagreement among researchers concerning whether the mTOR-signaling pathway senses changes from extracellular or intracellular AA levels. It has been reported that intracellular AA availability regulates phosphorylation of S6K1, eIF4E-BP1, or both in vitro in Xenopus laevis oocytes (Christie et al., 2002) and in CHO cells (Beugnet et al., 2003). On the other hand, an in vivo study indicated that extracellular rather than intramuscular AA availability modulates the protein synthesis rate in human muscle (Bohe et al., 2003). Some members of the class 3 G-protein-coupled receptors, such as extracellular Ca2+-sensing receptors and heterodimeric taste receptors, may function as extracellular AA sensors (Conigrave and Hampson, 2006). The molecular identity of an L-AA sensor mainly for sensing the aromatic AA has been established as being an extracellular Ca2+-sensing receptor (Conigrave and Brown, 2006). However, the Ca2+-sensing receptor-AA sensor is involved in the regulation of Ca and the transport of a number of other ions with no apparent role in mTOR signaling. On the other hand, several lines of recent evidence indicate that plasma membrane AA transporters function as transceptors in transducing AA stimuli to the mTORC1-signaling pathway (Fuchs et al., 2007; Hyde et al., 2007).
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Figure 6. The proposed mechanisms of AA availability in regulating the mammalian target of rapamycin (mTOR)-signaling pathway for mediating metabolism and growth (based on the concepts reviewed by Erbay et al., 2005, Conigrave and Hampson, 2006, Kimball and Jefferson, 2006, Findlay et al., 2007, and Nobukuni et al., 2007). Lines with end arrows indicate activation, whereas those with perpendicular bars at the end indicate inhibition. Question marks imply that the steps are unclear or poorly defined. FYVE = Fab1p, YOTB, Vac1p, and EEA1 (early endosome antigen 1) domain-containing proteins; eEF2 = eukaryotic elongation factor 2; eEF2K = eukaryotic elongation factor 2 kinase; eIF = eukaryotic initiation factors, including 4E and 4B; eIF4E-BP1 = eukaryotic initiation factor 4E-binding protein 1; IRS = insulin receptor substrate; MAP4K3 = MAP (mitogen-activated protein) kinase kinase kinase kinase 3, a sterile 20-protein family protein kinase (also referred to as germinal center-like kinase, GLK); mTORC1 = mTOR complex 1; PI = phosphatidylinositol; PI3K = phosphatidylinositol 3-kinase; PI3P = phosphatidylinositol-3-phosphate; PX = phox homology domain-containing proteins; Rheb = Ras homolog enriched in brain; S6 = ribosomal protein S6; S6K1 = ribosomal protein S6 kinase 1; TSC1 = tuberous sclerosis complex 1; and TSC2 = tuberous sclerosis complex 2.
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The intracellular cascades through which AA signal to mTORC1 differ from those controlled by insulin (Pham et al., 2000). It was demonstrated that AA regulation of mTORC1 signaling is via interactions with its kinase domain, but not the FRB domain used for binding by rapamycin (Edinger et al., 2003). Thus, direct inhibition by rapamycin may have little effect on AA-related regulations on metabolism and growth mediated by mTOR signaling. Four mechanisms of AA stimulation, as shown in Figure 6, are now described. First, AA can stimulate the TSC1-TSC2 complex directly or indirectly (Kimball and Jefferson, 2006) with the reduced TSC2 inhibition of Rheb, leading to increased phosphorylation of mTORC1 (Long et al., 2005). Second, it also was demonstrated that class 3 PI3K, also called Vps34, the oldest member of the PI3K family, can act through FYVE (abbreviation for Fab1p, YOTB, Vac1p, and early endosome antigen 1 domain-containing proteins) and phox homology domain-containing proteins, and FYVE or phox homology domain-containing proteins can then directly or indirectly activate mTORC1 signaling (Nobukuni et al., 2007). Third, tRNA aminoacylation (Iiboshi et al., 1999) and eIF4G phosphorylation (Bolster et al., 2004) are also proposed as being involved in AA regulation of mTOR signaling. Fourth, a recent study by Findlay et al. (2007) demonstrated that the protein kinase mitogen-activated protein kinase kinase kinase kinase 3 (MAP4K3), also known as germinal center-like kinase, is an upstream AA-sensitive regulator of mTORC1 signaling. However, how MAP4K3 or germinal center-like kinase activates mTORC1 is not clear at this time. On the other hand, activation of mTORC1 substrate S6K1 feedback inhibits IRS-1 and PI3K activities (Wullschleger et al., 2006), as shown in Figure 6. Thus, overloading cells with AA can also potentially decrease the sensitivity of the insulin-IRS-1-PI3K-signaling cascade.
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THE mTOR-SIGNALING PATHWAY IN REGULATION OF METABOLISM AND GROWTH
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The bioavailability of energy and AA provided by dietary ingredients for meeting the requirements of animals for optimal physiological functions and growth has been an important nutritional research topic for many years (NRC, 1998). Recently, it became clear that energy and AA not only serve as metabolic substrates, but also function as essential metabolic-signaling stimuli (Um et al., 2006). At the cellular level, the sufficiency status of energy and AA supply, as affected by genetic programming and environmental stress factors, can regulate metabolism and growth through distinctive molecular regulatory mechanisms via the cellular master regulator mTOR signaling, as illustrated in Figures 5 and 6. At the whole-body level, inadequate supply of these nutrients limits growth and performance in animal production (NRC, 1998), whereas nutrient overload contributes to the development of fatal chronic diseases, such as metabolic syndromes, cardiovascular disease, and cancers in humans (Um et al., 2006).
Regulation of Metabolism by the mTOR Pathway
Signaling by the mTOR pathway is essential in the control of feeding behavior and voluntary feed intake in several ways. Leucine can increase hypothalamic mTOR phosphorylation and contribute to the regulation of food intake (Cota et al., 2006). Leucine stimulates adipocyte differentiation and lipogenesis, and induces leptin secretion from adipose tissue, exerting leptin-specific anorectic effects (Lynch et al., 2006). Amino acids have been shown to inhibit feed intake by mTOR-dependent inhibition of hypothalamic Agouti-related protein gene expression (Morrison et al., 2007). Nutrients, including AA and glucose, are important in the regulation of food intake through hypothalamic neural fuel sensors such as AMPK and mTOR (Cota et al., 2007). Thus, mTOR signaling contributes to the regulation of whole-body energy metabolism and homeostasis.
Plasma membrane substrate transporters are gatekeepers to cellular metabolism, and evidence indicates they may also serve as the cellular surface transceptors for sensing stimuli exerted by nutrients such as AA (Edinger, 2007). Leucine availability regulates the expression of Na+-dependent system-A-neutral AA transporter protein via the mTOR pathway in muscle cells (Peyrollier et al., 2000). Expression of both creatine transporter SLC6A8 and intestinal Na+-phosphate co-transporter SLC34A2 protein is regulated via the mTOR pathway (Shojaiefard and Lang, 2006; Shojaiefard et al., 2006). The expression of aquaporin 3, a membrane protein to permeabilize water, glycerol, and urea, in Caco-2 cells is regulated via mTOR signaling (Asai et al., 2006). There is dissociation between the expression of mRNA and protein in the intestinal Na+-neutral AA cotransporter B0 gene along the crypt-villus axis in the neonate, and the abundance of this transporter protein is associated with mTOR and protein translational pathway efficiency (Yang et al., 2007). Thus, it can be concluded that nutrient-dependent expression of membrane transporters is regulated, in part, via mTOR-mediated protein translational processing.
Hormonal and nutritional factors directly regulate tissue or organ cellular metabolism by way of the established mTORC1 signaling. Two major regulatory effects on metabolism by mTORC1 signaling include interactions with the FRB rapamycin-binding domain and interference with the kinase domain on the TOR (Edinger et al., 2003). Administration of a high dose of rapamycin, the mTORC1 inhibitor, for immunosuppressive and antiproliferative purposes in vivo in guinea pigs disrupted triglyceride metabolism, causing hypertriglyceridemia, hyperglycemia, and hypercholesterolemia, likely by affecting the normal expression of enzymes involved in glucose and lipoprotein metabolism through insulin-PI3K-mTORC1 signaling (Aggarwal et al., 2006). However, in vitro culture of muscle cells with rapamycin decreased the baseline level of mTORC1 phosphorylation and almost completely abolished S6K1 phosphorylation, shifting cellular metabolism from glucose to fatty acid oxidation (Sipula et al., 2006).
As illustrated in Figures 4 and 6, overstimulation by hormones, such as insulin, and overload of nutrients, such as AA, result in feedback phosphorylation and inhibition of IRS-1 activity and the development of insulin resistance mediated by the mTORC1-S6K1 signaling. Studies with S6K1-deficient mice blocked by RNA interference of S6K1 protein demonstrated S6K1 phosphorylation of IRS-1 on the sites of Ser307 and Ser636/639, being responsible for age- and high-fat diet-induced insulin resistance (Um et al., 2004). Tremblay et al. (2005a) showed that insulin activated mTORC1-S6K1 signaling and increased IRS-1 phosphorylation on the sites of Ser636/Ser639, decreasing glucose uptake in human adipocytes. Tremblay et al. (2005b) demonstrated that activation of S6K1 by increasing AA availability caused insulin resistance in humans. Activation of S6K1 by AA caused insulin resistance in mice and humans, in part by phosphorylation of IRS-1 on the site of Ser1101 (Tremblay et al., 2005b; Krebs et al., 2007). On the other hand, ingestion of fish protein has been documented as preventing skeletal muscle insulin resistance induced by high-fat feeding in rats (Lavigne et al., 2001; Tremblay et al., 2007). Furthermore, increasing Leu intake alone has been shown to reduce obesity from feeding high-fat diets and hyperglycemia, presumably by improving IRS-1 sensitivity (Zhang et al., 2007). Therefore, protein quality, including the composition and possible existence of bioactive peptides, rather than just protein quantity, may be associated with its potential for inducing or preventing insulin resistance through the mTORC1-S6K1-IRS-1 signaling cascade.
As well as the principles illustrated in Figures 4 and 6, several other therapy strategies are being explored to attenuate insulin resistance mediated by mTORC1-S6K1 signaling, as induced by typical high-fat and high animal protein-based Western diets in animal models and with cell lines. Activation of AMPK can, in principle, inhibit mTORC1-S6K1 signaling, as shown in Figure 5, leading to reduced feedback inhibition of IRS-1 activity. Studies by Cool et al. (2006) in rats demonstrated that activation of AMPK decreased mTORC1-S6K1 signaling, stimulated glucose metabolism, and treated key components of type 2 diabetes and metabolic syndrome. Work by Zhao et al. (2005) showed that transgenic mice expressing propeptide for blocking myostatin activity do not develop obesity and insulin resistance when fed a high-fat diet. Hyperosmotic dehydration has been documented to inhibit mTORC1 signaling and may be developed to be a fluid therapy for treating insulin resistance (Schliess et al., 2006). Dietary soluble fiber for management of metabolic syndrome has been well recognized (Delzenne and Cani, 2005); however, relevant biological mechanisms are still not very clear. Future work should continue to investigate the effect of dietary soluble fiber on mTORC1-S6K1-IRS-1 signaling in insulin-responsive tissues such as liver, muscle, and adipose tissue in animals fed high-fat diets.
Dietary soluble fiber components are traditionally regarded as a group of antinutritive factors in nonruminant nutrition (Mosenthin et al., 1994), whereas these fiber components are widely used as dietary modulators for attenuating chronic diseases such as type 2 diabetes and cardiovascular disease in human nutrition (Delzenne and Cani, 2005; Rideout et al., 2007). Dietary supplementation of guar gum has been reported to reduce gut digestive enzyme activity and sugar transport in rats (Johnson et al., 1984) and reduce cholesterol absorption in pigs fed a high-fat diet (Rideout, 2007). Studies by Pirman et al. (2007) showed that pectin stimulated protein synthesis rates in all parts of the intestinal tract. However, it is unclear at this time whether soluble fiber in the gut lumen affects mTOR expression and regulates cellular protein translational processing through the mTORC1-signaling pathway.
In summary, hormonal factors, environmental stressors, and nutrients can affect tissue and organ cellular metabolism and functions through mTOR signaling as an intracellular metabolic sensor and master regulator unique to each effector and cell type involved.
Regulation of Hypertrophic Growth by the mTOR Pathway
The cellular and biochemical nature of hypertrophic growth is illustrated in Figure 1. It is generally accepted that hypertrophic growth primarily occurs during postnatal development in the central nervous system, skeletal and cardiac muscles, and adipose tissue, whereas both the hypertrophic and hyperplasic nature of growth occur in some other tissues or organs, such as the visceral organs, skin, lymph tissue, and blood vascular system (Lawrence and Fowler, 1997). A large part of tissue or organ cellular hypertrophic growth is mediated by the mTOR-signaling network. Cellular mechanisms of hormonal, environmental stress, and nutritional factors in regulating hypertrophic growth via the mTOR-signaling pathway are illustrated in Figures 4, 5, and 6, with much work emphasizing and reporting on skeletal muscle in the literature.
Expression of the human mTOR-signaling pathway upstream inhibitor TSC1-TSC2 complex in mice was shown to develop muscle atrophy in these animals (Wan et al., 2006). Administration of rapamycin, the inhibitor to mTOR, effectively reduced rates of protein synthesis in vivo in both cardiac and skeletal muscles (Vary et al., 2007a,b). It has been well recognized that energy availability is the first-limiting factor to hypertrophic growth at the whole-organism level. Whereas cellular and molecular mechanisms in regulating hypertrophic growth via the AMPK-TSC2-mTORC1-signaling cascade have now been well established (Inoki et al., 2003), the relationship between energy intake levels and AMPK activity has not been established in animal studies (Du et al., 2005).
There is a rapid decline in whole-body N efficiency from newborn suckling to postweaning transition in animals (Reeds et al., 1993; Fan et al., 2006). This rapid postnatal decline in N efficiency is largely due to reductions in skeletal muscle protein synthesis activity (Reeds et al., 1993). Positive hormonal regulators, including growth hormone, insulin, and IGF-I, are shown to stimulate hypertrophic muscle protein synthesis via the mTOR-signaling pathway (Rommel et al., 2001; Bush et al., 2003; Hayashi and Proud, 2007). Negative hormonal factors such as glucocorticoids, proinflammatory cytokines, and the TGF-β superfamily member myostatin are known to inhibit hypertrophic muscle protein synthesis via the mTOR-signaling pathway (Kimball et al., 2003; Suryawan et al., 2006). Amino acids, especially Leu, have been documented to stimulate muscle protein synthesis via the mTOR-signaling pathway (Bolster et al., 2004; Escobar et al., 2006; Kimball and Jefferson, 2006). Surprisingly, glucose was shown to stimulate the muscle protein synthesis rate through an AMPK- and mTOR-independent process (Jeyapalan et al., 2007). Developmental decline in the hormonal- and nutrient-dependent mTOR-signaling components is partly responsible for the postnatal reduction in muscle protein synthetic activity (Kimball et al., 2002). However, factors and their relative contributions to postnatal decline in mTOR-signaling components and muscle protein translational efficiency, capacity, or both are yet to be established. Several strategies have been developed to improve muscle protein synthesis via the mTOR-signaling pathway in several animal species, including the use of n-3 long-chain fatty acids (Gingras et al., 2007), administration of the exogenous growth hormone (Bush et al., 2003), oral feeding of the synthetic β-adrenergic agonist ractopamine hydrochloride or Paylean (Bergen and Merkel, 1991), and overexpression of myostatin pro domain through transgenesis (Yang et al., 2001).
Leucine is primarily responsible for stimulating mTOR-mediated protein synthesis and hypertrophic growth and morphogenesis in adipose tissue (Fox et al., 1998). Insulin and AA are the key stimuli in preadipocyte differentiation via the mTOR-signaling pathway (Lynch et al., 2000; Kim and Chen, 2004).
Stoll et al. (1997) showed preferential utilization of dietary AA for hepatic protein synthesis in pigs. Studies by Anand and Gruppuso (2006) demonstrated that feeding stimulated mTOR-dependent hypertrophic hepatic protein synthesis, with an enhanced protein translation efficiency and capacity. Davis et al. (2002) showed that infusion of AA rather than insulin increased hepatic protein synthesis in neonatal pigs. Bush et al. (2003) demonstrated that administration of exogenous growth hormone increased hepatic protein synthesis with an enhanced protein translation efficiency and capacity via the mTOR-signaling pathway. Feeding, insulin, and cholecystokinin increased PI3K-mTOR-mediated exocrine pancreatic acinar cell hypertrophic growth (Crozier et al., 2006). Intragastric infusion of Leu independently enhanced mTOR-signaled acinar cell hypertrophic growth (Sans et al., 2006).
The small intestinal enterocytes are polarized, and enteral, rather than intravenous, supply of nutrients is essential to maintain gut mucosal growth, especially in the neonate (Burrin et al., 2000). Luminal nutrients stimulate gut mucosal growth primarily through nutrient-dependent and gut hormone-associated growth (Guan et al., 2003). Whereas the signal cascade responsible for AA- and GLP-2-stimulated mTOR signaling has been reported in gut mucosal cells (Rhoads et al., 2006), nutrient- and GLP-2-dependent stimulation of gut mucosal growth via the mTOR-signaling pathway has not been examined in vivo.
Regulation of Hyperplasic Growth by the mTOR Pathway
The cellular and biochemical nature of hyperplasic growth is illustrated in Figure 2. It is generally accepted that hyperplasic growth occurs primarily in the central nervous system, cardiac and skeletal muscles, and adipose tissue during prenatal development, whereas the hyperplasic nature of growth also occurs in some other tissues or organs, such as the visceral organs, skin, lymph tissue, and blood vascular system, during postnatal growth (Lawrence and Fowler, 1997).
Signaling by the mTOR pathway is essential to cellular hyperplasic growth. Disruption of the mouse mTOR gene caused early postimplantation lethality and inhibited embryonic stem cell development (Gangloff et al., 2004). Maternal nutrient restriction reduced fetal mTOR abundance in muscle, leading to reduced muscle fiber numbers (Zhu et al., 2004). However, insulin-mTOR signaling was shown to have little effect on lategestation liver development in the rat (Anand et al., 2002).
Glucose was demonstrated to increase cellular DNA synthesis via mTOR signaling in rodent islets (Kwon et al., 2006). Secretion of cholecystokinin can stimulate exocrine pancreatic acinar cell hyperplasic growth via the PI3K-mTOR-mediated pathway in mice (Crozier et al., 2006). Silencing of the AA exchanger, ASCT2, has been shown to depress hepatoma cell apoptosis and increase cell survival via the mTORC2-signaling pathway (Fuchs et al., 2007). Thus, manipulation of plasma AA exchangers and transporters, such as ASCT2 and LAT1, may be effective in treating cancers (Fuchs and Bode, 2005).
Both nutrient- and GLP-2-dependent stimulation of gut mucosal hyperplasic growth has been reported in neonates (Burrin et al., 2000, 2005). Sodium-neutral AA cotransporter B0 and mTOR are extensively expressed along the intestinal crypt-villus axis in the neonate (Yang et al., 2007). However, the quantitative relationship between luminal AA loading and mTOR expression and hyperplasic gut mucosal growth is not clear and should be explored in future studies in the neonate to improve neonatal gut growth and functions.
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CONCLUSIONS
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The mTOR-signaling pathway integrates metabolic signals, hormonal factors, stressors, and nutrients, and regulates physiological functions, such as metabolism and hypertrophic-hyperplasic growth. The underlying signaling mechanisms emphasized in this review include the AMPK pathway and crosstalk among the mTOR, PI3K-PKB, and Ras-Raf-MEK-ERK pathways. Nevertheless, how mTOR senses AA is still poorly understood and worthy of further investigation. In addition, the roles of mTOR signaling in protein degradation as well as in cell apoptosis and division require further exploration.
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Footnotes
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1 Presented at the Nonruminant Nutrition symposium, "Understanding protein synthesis and degradation and their pathway regulations for improving monogastric production efficiency and product quality", at the annual meeting of the American Society of Animal Science, San Antonio, TX, July 8 to 12, 2007. 
2 Related research activities have been supported by grants to M. Z. Fan from the Natural Sciences and Engineering Research Council of Canada Discovery Program (Ottawa, Ontario, Canada), and the Ontario Ministry of Agriculture, Food and Rural Affairs, University of Guelph Animal Research Program (Guelph, Ontario, Canada).
3 Corresponding author: yang{at}uoguelph.ca
Received for publication September 6, 2007.
Accepted for publication October 30, 2007.
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Abstract
INTRODUCTION
