title: mTORC2 sustains thermogenesis via Akt-induced glucose uptake and glycolysis in brown adipose tissue.
abstract: Activation of non-shivering thermogenesis (NST) in brown adipose tissue (BAT) has been proposed as an anti-obesity treatment. Moreover, cold-induced glucose uptake could normalize blood glucose levels in insulin-resistant patients. It is therefore important to identify novel regulators of NST and cold-induced glucose uptake. Mammalian target of rapamycin complex 2 (mTORC2) mediates insulin-stimulated glucose uptake in metabolic tissues, but its role in NST is unknown. We show that mTORC2 is activated in brown adipocytes upon β-adrenergic stimulation. Furthermore, mice lacking mTORC2 specifically in adipose tissue (AdRiKO mice) are hypothermic, display increased sensitivity to cold, and show impaired cold-induced glucose uptake and glycolysis. Restoration of glucose uptake in BAT by overexpression of hexokinase II or activated Akt2 was sufficient to increase body temperature and improve cold tolerance in AdRiKO mice. Thus, mTORC2 in BAT mediates temperature homeostasis via regulation of cold-induced glucose uptake. Our findings demonstrate the importance of glucose metabolism in temperature regulation.
authors.affiliation: Biozentrum, University of Basel, Basel, Switzerland.
authors.forename: Verena
authors.initials: V
authors.lastname: Albert
authors.affiliation: Biozentrum, University of Basel, Basel, Switzerland.
authors.forename: Kristoffer
authors.initials: K
authors.lastname: Svensson
authors.affiliation: Biozentrum, University of Basel, Basel, Switzerland.
authors.forename: Mitsugu
authors.initials: M
authors.lastname: Shimobayashi
authors.affiliation: Biozentrum, University of Basel, Basel, Switzerland.
authors.forename: Marco
authors.initials: M
authors.lastname: Colombi
authors.affiliation: Center of Animal Biotechnology and Gene Therapy and Department of Biochemistry and Molecular Biology, School of Veterinary Medicine, Universitat Autònoma de Barcelona, Bellaterra, Spain Centro de Investigación Biomédica en Red de Diabetes y Enfermedades Metabólicas Asociadas (CIBERDEM), Madrid, Spain.
authors.forename: Sergio
authors.initials: S
authors.lastname: Muñoz
authors.affiliation: Center of Animal Biotechnology and Gene Therapy and Department of Biochemistry and Molecular Biology, School of Veterinary Medicine, Universitat Autònoma de Barcelona, Bellaterra, Spain Centro de Investigación Biomédica en Red de Diabetes y Enfermedades Metabólicas Asociadas (CIBERDEM), Madrid, Spain.
authors.forename: Veronica
authors.initials: V
authors.lastname: Jimenez
authors.affiliation: Biozentrum, University of Basel, Basel, Switzerland.
authors.forename: Christoph
authors.initials: C
authors.lastname: Handschin
authors.affiliation: Center of Animal Biotechnology and Gene Therapy and Department of Biochemistry and Molecular Biology, School of Veterinary Medicine, Universitat Autònoma de Barcelona, Bellaterra, Spain Centro de Investigación Biomédica en Red de Diabetes y Enfermedades Metabólicas Asociadas (CIBERDEM), Madrid, Spain.
authors.forename: Fatima
authors.initials: F
authors.lastname: Bosch
authors.affiliation: Biozentrum, University of Basel, Basel, Switzerland m.hall@unibas.ch.
authors.forename: Michael N
authors.initials: MN
authors.lastname: Hall
mesh_terms: D002001:Adipose Tissue, Brown / Q000378:metabolism*; D000818:Animals; D005947:Glucose / Q000378:metabolism*; D006019:Glycolysis; D000076225:Mechanistic Target of Rapamycin Complex 2; D051379:Mice; D046912:Multiprotein Complexes / Q000378:metabolism*; D051058:Oncogene Protein v-akt / Q000378:metabolism*; D058570:TOR Serine-Threonine Kinases / Q000378:metabolism*; D022722:Thermogenesis
chemical_list: D046912:Multiprotein Complexes; D000076225:Mechanistic Target of Rapamycin Complex 2; D051058:Oncogene Protein v-akt; D058570:TOR Serine-Threonine Kinases; D005947:Glucose
keywords: brown adipose tissue; glucose uptake; mTORC2; thermogenesis