Review
mTOR couples cellular nutrient sensing to organismal metabolic homeostasis

https://doi.org/10.1016/j.tem.2010.12.003Get rights and content

The mammalian target of rapamycin complex 1 (mTORC1) has the ability to sense a variety of essential nutrients and respond by altering cellular metabolic processes. Hence, this protein kinase complex is poised to influence adaptive changes to nutrient fluctuations toward the maintenance of whole-body metabolic homeostasis. Defects in mTORC1 regulation, arising from either physiological or genetic conditions, are believed to contribute to the metabolic dysfunction underlying a variety of human diseases, including type 2 diabetes. We are just now beginning to gain insights into the complex tissue-specific functions of mTORC1. In this review, we detail the current knowledge of the physiological functions of mTORC1 in controlling systemic metabolism, with a focus on advances obtained through genetic mouse models.

Section snippets

mTOR complex 1: sensing local and systemic nutrient status

The ability of organisms to adapt to fluctuations in nutrient availability is fundamental to the fitness of a species. Organisms respond to nutrient fluctuations by altering the balance between energy-producing catabolic processes and energy-consuming anabolic processes. In eukaryotes, the metabolic response to nutrients is tightly coordinated by nutrient- and energy-sensing signaling pathways. Much progress has been made in our understanding of the cell-intrinsic wiring of these key signaling

Downstream of mTORC1: protein synthesis and beyond

In mammals, two main classes of direct mTORC1 substrates have emerged [13]: the ribosomal S6 kinases (S6K1 and S6K2) and the eukaryotic initiation factor 4E (eIF4E)-binding proteins (4EBP1 and 4EBP2). mTORC1 phosphorylates the hydrophobic motif on the S6Ks (T389 on the 70-kDa isoform of S6K1), which is essential for subsequent activating phosphorylation events. The S6Ks phosphorylate a number of downstream targets, the best characterized of which is the ribosomal protein S6. Although our

mTORC1-dependent feedback mechanisms and cell intrinsic insulin resistance

A crucial element of mTORC1 signaling is its feedback effects on upstream pathways. Both mTORC1 and its downstream target S6K1 can exert negative regulatory inputs into upstream signaling molecules (Figure 2). The best characterized of these are the insulin receptor substrate (IRS) proteins, which are required to activate the PI3K-Akt pathway downstream of the insulin receptor. There are a number of rapamycin-sensitive phosphorylation sites on IRS1, and several of these serine residues appear

Pharmacological versus genetic manipulation of mTORC1 signaling in rodent models

Given the defined roles of mTORC1 in nutrient sensing and control of cellular physiology, there is a real push to understand the functions of mTORC1 in regulating the physiological state of mammals. To this end, gain- and loss-of-function models have been developed to delineate the role of mTORC1 signaling in rodents. One limitation of these models comes from the finding that null alleles of the mTORC1 components (mTOR or RAPTOR 41, 42, 43) or its key upstream regulators (TSC1 and TSC2 44, 45)

Pancreas

The endocrine pancreas functions as a sensor and regulator of circulating glucose levels, and alterations in the physiological function of the pancreas often reflect changes in islet mass [52]. Given its function as both a nutrient sensor and a regulator of cell growth, it is not surprising that mTORC1 has been shown to play a major role in the pancreatic control of insulin secretion and glucose homeostasis, largely through the regulation of β-cell size. Mouse models with constitutive

Conclusions and outstanding questions

The function of mTORC1 as a nutrient sensor and regulator of anabolic processes has been well established in cell culture models. However, we are just beginning to understand how its cell-intrinsic regulation and function translate into the control of systemic metabolism. From the rodent models discussed here, it appears that in response to food intake, mTORC1 activation enhances nutrient mobilization into peripheral tissues through increased insulin secretion from the pancreas, while also

Acknowledgments

Research on the regulation and metabolic function of mTORC1 in the Manning laboratory is supported by grants to B.D.M. from the National Institutes of Health (CA122617) and the American Diabetes Association.

References (103)

  • T. Porstmann

    SREBP activity is regulated by mTORC1 and contributes to Akt-dependent cell growth

    Cell Metab.

    (2008)
  • L.S. Harrington

    Restraining PI3K: mTOR signalling goes back to the membrane

    Trends Biochem. Sci.

    (2005)
  • O.J. Shah

    Inappropriate activation of the TSC/Rheb/mTOR/S6K cassette induces IRS1/2 depletion, insulin resistance and cell survival deficiencies

    Curr. Biol.

    (2004)
  • D.A. Guertin

    Ablation in Mice of the mTORC components raptor, rictor, or mLST8 reveals that mtorc2 is required for signaling to Akt-FOXO and PKC[alpha], but not S6K1

    Dev. Cell

    (2006)
  • G.-R. Chang

    Rapamycin protects against high fat diet-induced obesity in C57BL/6J mice

    J. Pharmacol. Sci.

    (2009)
  • H. Mori

    Critical role for hypothalamic mTOR activity in energy balance

    Cell Metab.

    (2009)
  • C.F. Bentzinger

    Skeletal muscle-specific ablation of raptor, but not of rictor, causes metabolic changes and results in muscle dystrophy

    Cell Metab.

    (2008)
  • V. Aguilar

    S6 Kinase deletion suppresses muscle growth adaptations to nutrient availability by activating AMP kinase

    Cell Metab.

    (2007)
  • H.J. Cho

    Regulation of adipocyte differentiation and insulin action with rapamycin

    Biochem. Biophys. Res. Commun.

    (2004)
  • L.S. Carnevalli

    S6K1 plays a critical role in early adipocyte differentiation

    Dev. Cell

    (2010)
  • P. Polak

    Adipose-specific knockout of raptor results in lean mice with enhanced mitochondrial respiration

    Cell Metab.

    (2008)
  • M. Laplante et al.

    An Emerging role of mTOR in lipid biosynthesis

    Curr. Biol.

    (2009)
  • S. Mordier et al.

    Activation of mammalian target of rapamycin complex 1 and insulin resistance induced by palmitate in hepatocytes

    Biochem. Biophys. Res. Commun.

    (2007)
  • N.F. Brown

    The mammalian target of rapamycin regulates lipid metabolism in primary cultures of rat hepatocytes

    Metabolism

    (2007)
  • C. Blouet

    Mediobasal hypothalamic p70 S6 Kinase 1 modulates the control of energy homeostasis

    Cell Metabolism.

    (2008)
  • J. Huang et al.

    The TSC1-TSC2 complex: a molecular switchboard controlling cell growth

    Biochem. J.

    (2008)
  • K. Inoki

    TSC2 is phosphorylated and inhibited by Akt and suppresses mTOR signalling

    Nat. Cell Biol.

    (2002)
  • D.G. Hardie

    AMP-activated/SNF1 protein kinases: conserved guardians of cellular energy

    Nat. Rev. Mol. Cell Biol.

    (2007)
  • Y. Sancak

    The Rag GTPases bind Raptor and mediate amino acid signaling to mTORC1

    Science

    (2008)
  • E. Kim

    Regulation of TORC1 by Rag GTPases in nutrient response

    Nat. Cell Biol.

    (2008)
  • X.M. Ma et al.

    Molecular mechanisms of mTOR-mediated translational control

    Nat. Rev. Mol. Cell Biol.

    (2009)
  • C. Mayer et al.

    Ribosome biogenesis and cell growth: mTOR coordinates transcription by all three classes of nuclear RNA polymerases

    Oncogene

    (2006)
  • T. Peng

    The immunosuppressant rapamycin mimics a starvation-like signal distinct from amino acid and glucose deprivation

    Mol. Cell. Biol.

    (2002)
  • J.T. Cunningham

    mTOR controls mitochondrial oxidative function through a YY1-PGC-1α transcriptional complex

    Nature

    (2007)
  • H. Zhong

    Modulation of hypoxia-inducible factor 1î± expression by the epidermal growth factor/phosphatidylinositol 3-kinase/PTEN/AKT/FRAP pathway in human prostate cancer cells: implications for tumor angiogenesis and therapeutics

    Cancer Res.

    (2000)
  • E. Laughner

    HER2 (neu) Signaling increases the rate of hypoxia-inducible factor 1{alpha} (HIF-1{alpha}) synthesis: novel mechanism for hif-1-mediated vascular endothelial growth factor expression

    Mol. Cell. Biol.

    (2001)
  • C.C. Hudson

    Regulation of hypoxia-inducible factor 1{alpha} expression and function by the mammalian target of rapamycin

    Mol. Cell. Biol.

    (2002)
  • C.-J. Hu

    Differential roles of hypoxia-inducible factor 1{alpha} (HIF-1{alpha}) and HIF-2{alpha} in hypoxic gene regulation

    Mol. Cell. Biol.

    (2003)
  • B.D. Manning

    Balancing Akt with S6K

    J. Cell Biol.

    (2004)
  • A. Tzatsos et al.

    Nutrients suppress phosphatidylinositol 3-kinase/Akt signaling via raptor-dependent mTOR-mediated insulin receptor substrate 1 phosphorylation

    Mol. Cell. Biol.

    (2006)
  • O.J. Shah et al.

    Turnover of the active fraction of IRS1 involves Raptor-mTOR- and S6K1-dependent serine phosphorylation in cell culture models of tuberous sclerosis

    Mol. Cell. Biol.

    (2006)
  • F.d.r. Tremblay

    Identification of IRS-1 Ser-1101 as a target of S6K1 in nutrient- and obesity-induced insulin resistance

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

    (2007)
  • C.C. Dibble

    Characterization of Rictor phosphorylation sites reveals direct regulation of mTOR Complex 2 by S6K1

    Mol. Cell. Biol.

    (2009)
  • L.-A. Julien

    mTORC1-activated S6K1 phosphorylates Rictor on threonine 1135 and regulates mTORC2 signaling

    Mol. Cell. Biol.

    (2010)
  • T. Radimerski

    Lethality of Drosophila lacking TSC tumor suppressor function rescued by reducing dS6K signaling

    Genes Dev.

    (2002)
  • D.D. Sarbassov

    Phosphorylation and regulation of Akt/PKB by the Rictor-mTOR complex

    Science

    (2005)
  • L.S. Harrington

    The TSC1-2 tumor suppressor controls insulin-PI3K signaling via regulation of IRS proteins

    J. Cell Biol.

    (2004)
  • J. Huang

    The TSC1-TSC2 complex is required for proper activation of mTOR complex 2

    Mol. Cell. Biol.

    (2008)
  • S.H. Um

    Absence of S6K1 protects against age- and diet-induced obesity although enhancing insulin sensitivity

    Nature

    (2004)
  • L. Khamzina

    Increased activation of the mammalian target of rapamycin pathway in liver and skeletal muscle of obese rats: possible involvement in obesity-linked insulin resistance

    Endocrinology

    (2005)
  • Cited by (274)

    • The role and regulation of phospholipase D in infectious and inflammatory diseases

      2023, Phospholipases in Physiology and Pathology: Volumes 1-7
    View all citing articles on Scopus
    View full text