title: Acute mTOR inhibition induces insulin resistance and alters substrate utilization in vivo.
abstract: The effect of acute inhibition of both mTORC1 and mTORC2 on metabolism is unknown. A single injection of the mTOR kinase inhibitor, AZD8055, induced a transient, yet marked increase in fat oxidation and insulin resistance in mice, whereas the mTORC1 inhibitor rapamycin had no effect. AZD8055, but not rapamycin reduced insulin-stimulated glucose uptake into incubated muscles, despite normal GLUT4 translocation in muscle cells. AZD8055 inhibited glycolysis in MEF cells. Abrogation of mTORC2 activity by SIN1 deletion impaired glycolysis and AZD8055 had no effect in SIN1 KO MEFs. Re-expression of wildtype SIN1 rescued glycolysis. Glucose intolerance following AZD8055 administration was absent in mice lacking the mTORC2 subunit Rictor in muscle, and in vivo glucose uptake into Rictor-deficient muscle was reduced despite normal Akt activity. Taken together, acute mTOR inhibition is detrimental to glucose homeostasis in part by blocking muscle mTORC2, indicating its importance in muscle metabolism in vivo.
authors.affiliation: Molecular Physiology Group, Department of Nutrition, Exercise and Sports, August Krogh Centre, University of Copenhagen, Copenhagen, Denmark.
authors.forename: Maximilian
authors.initials: M
authors.lastname: Kleinert
authors.affiliation: Molecular Physiology Group, Department of Nutrition, Exercise and Sports, August Krogh Centre, University of Copenhagen, Copenhagen, Denmark.
authors.forename: Lykke
authors.initials: L
authors.lastname: Sylow
authors.affiliation: Diabetes and Obesity Program, Garvan Institute of Medical Research, Darlinghurst, New South Wales 2010, Australia.
authors.forename: Daniel J
authors.initials: DJ
authors.lastname: Fazakerley
authors.affiliation: Diabetes and Obesity Program, Garvan Institute of Medical Research, Darlinghurst, New South Wales 2010, Australia ; School of Biotechnology and Biomolecular Sciences, The University of New South Wales, Sydney, Australia.
authors.forename: James R
authors.initials: JR
authors.lastname: Krycer
authors.affiliation: Diabetes and Obesity Program, Garvan Institute of Medical Research, Darlinghurst, New South Wales 2010, Australia.
authors.forename: Kristen C
authors.initials: KC
authors.lastname: Thomas
authors.affiliation: Molecular Physiology Group, Department of Nutrition, Exercise and Sports, August Krogh Centre, University of Copenhagen, Copenhagen, Denmark.
authors.forename: Anne-Julie
authors.initials: AJ
authors.lastname: Oxbøll
authors.affiliation: Molecular Physiology Group, Department of Nutrition, Exercise and Sports, August Krogh Centre, University of Copenhagen, Copenhagen, Denmark.
authors.forename: Andreas B
authors.initials: AB
authors.lastname: Jordy
authors.affiliation: Molecular Physiology Group, Department of Nutrition, Exercise and Sports, August Krogh Centre, University of Copenhagen, Copenhagen, Denmark.
authors.forename: Thomas E
authors.initials: TE
authors.lastname: Jensen
authors.affiliation: Diabetes and Obesity Program, Garvan Institute of Medical Research, Darlinghurst, New South Wales 2010, Australia.
authors.forename: Guang
authors.initials: G
authors.lastname: Yang
authors.affiliation: Institute of Sports Medicine, Department of Orthopedic Surgery, Bispebjerg Hospital and Center for Healthy Aging, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark.
authors.forename: Peter
authors.initials: P
authors.lastname: Schjerling
authors.affiliation: Molecular Physiology Group, Department of Nutrition, Exercise and Sports, August Krogh Centre, University of Copenhagen, Copenhagen, Denmark.
authors.forename: Bente
authors.initials: B
authors.lastname: Kiens
authors.affiliation: Diabetes and Obesity Program, Garvan Institute of Medical Research, Darlinghurst, New South Wales 2010, Australia ; Charles Perkins Centre, School of Molecular Bioscience, The University of Sydney, Sydney, Australia.
authors.forename: David E
authors.initials: DE
authors.lastname: James
authors.affiliation: Biozentrum, University of Basel, Basel, Switzerland.
authors.forename: Markus A
authors.initials: MA
authors.lastname: Ruegg
authors.affiliation: Molecular Physiology Group, Department of Nutrition, Exercise and Sports, August Krogh Centre, University of Copenhagen, Copenhagen, Denmark.
authors.forename: Erik A
authors.initials: EA
authors.lastname: Richter
keywords: Glucose uptake; Glycolysis; Metabolism; Rictor; Skeletal muscle; mTORC2