DEPTOR Cell-Autonomously Promotes Adipogenesis, and Its Expression Is Associated with Obesity

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-gamma axis by dampening mTORC1-mediated feedback inhibition of insulin signaling. These results establish DEPTOR as a new regulator of adipogenesis.Canadian Institutes of Health Research (CIHR)Canadian Institutes of Health Research (CIHR)Les Fonds de la Recherche en Sante du Quebec (FRSQ)Les Fonds de la Recherche en Sante du Quebec (FRSQ)Slovenian Research Agency [P4-0220]Slovenian Research AgencySao Paulo Research FoundationSao Paulo Research Foundation [FAPESP 2009/15354-7, FAPESP 2010/10909-8]Young researcher scholarship (Slovenian Research Agency)Young researcher scholarship (Slovenian Research Agency)NIH [CA103866, CA129105, AI47389]NIHJane Coffin Childs Memorial Fund for Medical ResearchJane Coffin Childs Memorial Fund for Medical ResearchHuman Frontier Science ProgramHuman Frontier Science Progra