title: DEPTOR cell-autonomously promotes adipogenesis, and its expression is associated with obesity.
abstract: DEP domain-containing mTOR-interacting protein (DEPTOR) inhibits the mechanistic target of rapamycin (mTOR), but its in vivo functions are unknown. Previous work indicates that Deptor is part of the Fob3a quantitative trait locus (QTL) linked to obesity/leanness in mice, with Deptor expression being elevated in white adipose tissue (WAT) of obese animals. This relation is unexpected, considering the positive role of mTOR in adipogenesis. Here, we dissected the Fob3a QTL and show that Deptor is the highest-priority candidate promoting WAT expansion in this model. Consistently, transgenic mice overexpressing DEPTOR accumulate more WAT. Furthermore, in humans, DEPTOR expression in WAT correlates with the degree of obesity. We show that DEPTOR is induced by glucocorticoids during adipogenesis and that its overexpression promotes, while its suppression blocks, adipogenesis. DEPTOR activates the proadipogenic Akt/PKB-PPAR-γ axis by dampening mTORC1-mediated feedback inhibition of insulin signaling. These results establish DEPTOR as a new regulator of adipogenesis.
authors.affiliation: Whitehead Institute for Biomedical Research, Nine Cambridge Center, Cambridge, MA 02142, USA.
authors.forename: Mathieu
authors.initials: M
authors.lastname: Laplante
authors.forename: Simon
authors.initials: S
authors.lastname: Horvat
authors.forename: William T
authors.initials: WT
authors.lastname: Festuccia
authors.forename: Kivanç
authors.initials: K
authors.lastname: Birsoy
authors.forename: Zala
authors.initials: Z
authors.lastname: Prevorsek
authors.forename: Alejo
authors.initials: A
authors.lastname: Efeyan
authors.forename: David M
authors.initials: DM
authors.lastname: Sabatini
mesh_terms: D016475:3T3 Cells; D050156:Adipogenesis / Q000502:physiology*; D052436:Adipose Tissue, White / Q000378:metabolism*; D000818:Animals; D002874:Chromosome Mapping; D005938:Glucocorticoids / Q000378:metabolism*; D015151:Immunoblotting; D007328:Insulin / Q000378:metabolism; D047908:Intracellular Signaling Peptides and Proteins / Q000235:genetics / Q000378:metabolism* / Q000502:physiology; D000076222:Mechanistic Target of Rapamycin Complex 1; D051379:Mice; D008822:Mice, Transgenic; D046912:Multiprotein Complexes; D009765:Obesity / Q000378:metabolism*; D011506:Proteins / Q000378:metabolism; D040641:Quantitative Trait Loci / Q000235:genetics; D060888:Real-Time Polymerase Chain Reaction; D058570:TOR Serine-Threonine Kinases
chemical_list: D005938:Glucocorticoids; D007328:Insulin; D047908:Intracellular Signaling Peptides and Proteins; D046912:Multiprotein Complexes; D011506:Proteins; C570841:deptor protein, mouse; D000076222:Mechanistic Target of Rapamycin Complex 1; D058570:TOR Serine-Threonine Kinases