title: Rictor/mTORC2 loss in the Myf5 lineage reprograms brown fat metabolism and protects mice against obesity and metabolic disease.
abstract: The in vivo functions of mechanistic target of rapamycin complex 2 (mTORC2) and the signaling mechanisms that control brown adipose tissue (BAT) fuel utilization and activity are not well understood. Here, by conditionally deleting Rictor in the Myf5 lineage, we provide in vivo evidence that mTORC2 is dispensable for skeletal muscle development and regeneration but essential for BAT growth. Furthermore, deleting Rictor in Myf5 precursors shifts BAT metabolism to a more oxidative and less lipogenic state and protects mice from obesity and metabolic disease at thermoneutrality. We additionally find that Rictor is required for brown adipocyte differentiation in vitro and that the mechanism specifically requires AKT1 hydrophobic motif phosphorylation but is independent of pan-AKT signaling and is rescued with BMP7. Our findings provide insights into the signaling circuitry that regulates brown adipocytes and could have important implications for developing therapies aimed at increasing energy expenditure as a means to combat human obesity.
authors.affiliation: Program in Molecular Medicine, University of Massachusetts Medical School, Worcester, MA 01605, USA.
authors.forename: Chien-Min
authors.initials: CM
authors.lastname: Hung
authors.affiliation: Program in Molecular Medicine, University of Massachusetts Medical School, Worcester, MA 01605, USA.
authors.forename: Camila Martinez
authors.initials: CM
authors.lastname: Calejman
authors.affiliation: Program in Molecular Medicine, University of Massachusetts Medical School, Worcester, MA 01605, USA.
authors.forename: Joan
authors.initials: J
authors.lastname: Sanchez-Gurmaches
authors.affiliation: Program in Molecular Medicine, University of Massachusetts Medical School, Worcester, MA 01605, USA.
authors.forename: Huawei
authors.initials: H
authors.lastname: Li
authors.affiliation: Broad Institute, Cambridge, MA 02142, USA.
authors.forename: Clary B
authors.initials: CB
authors.lastname: Clish
authors.affiliation: Howard Hughes Medical Institute, USA; Department of Stem Cell and Regenerative Biology, Harvard Stem Cell Institute, 7 Divinity Avenue, Cambridge, MA 01238, USA; Joslin Diabetes Center, One Joslin Place, Boston, MA 02215, USA; Department of Pediatric Oncology, Dana Farber Cancer Institute, Boston, MA 02155, USA; Division of Pediatric Hematology/Oncology, Children's Hospital, Boston, MA 02155, USA.
authors.forename: Simone
authors.initials: S
authors.lastname: Hettmer
authors.affiliation: Howard Hughes Medical Institute, USA; Department of Stem Cell and Regenerative Biology, Harvard Stem Cell Institute, 7 Divinity Avenue, Cambridge, MA 01238, USA; Joslin Diabetes Center, One Joslin Place, Boston, MA 02215, USA; Department of Pediatric Oncology, Dana Farber Cancer Institute, Boston, MA 02155, USA.
authors.forename: Amy J
authors.initials: AJ
authors.lastname: Wagers
authors.affiliation: Program in Molecular Medicine, University of Massachusetts Medical School, Worcester, MA 01605, USA. Electronic address: david.guertin@umassmed.edu.
authors.forename: David A
authors.initials: DA
authors.lastname: Guertin
mesh_terms: D052437:Adipocytes, Brown / Q000378:metabolism*; D050156:Adipogenesis; D000818:Animals; D055419:Bone Morphogenetic Protein 7 / Q000378:metabolism; D002352:Carrier Proteins / Q000235:genetics / Q000378:metabolism*; D019070:Cell Lineage; D002478:Cells, Cultured; D004734:Energy Metabolism; D000076225:Mechanistic Target of Rapamycin Complex 2; D051379:Mice; D046912:Multiprotein Complexes / Q000378:metabolism*; D018482:Muscle, Skeletal / Q000254:growth & development / Q000378:metabolism; D051787:Myogenic Regulatory Factor 5 / Q000235:genetics / Q000378:metabolism*; D009765:Obesity / Q000378:metabolism*; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D000076226:Rapamycin-Insensitive Companion of mTOR Protein; D015398:Signal Transduction; D058570:TOR Serine-Threonine Kinases / Q000378:metabolism*; D022722:Thermogenesis
chemical_list: D055419:Bone Morphogenetic Protein 7; D002352:Carrier Proteins; D046912:Multiprotein Complexes; C497418:Myf5 protein, mouse; D051787:Myogenic Regulatory Factor 5; D000076226:Rapamycin-Insensitive Companion of mTOR Protein; C525820:bmp7 protein, mouse; C525637:rictor protein, mouse; C514862:Akt1 protein, mouse; D000076225:Mechanistic Target of Rapamycin Complex 2; D051057:Proto-Oncogene Proteins c-akt; D058570:TOR Serine-Threonine Kinases