title: Mechanistic target of rapamycin controls homeostasis of adipogenesis.
abstract: Signaling mediated by the mechanistic target of rapamycin (mTOR) is believed to play a critical and positive role in adipogenesis, based on pharmacological evidence and genetic manipulation of mTOR regulators and targets. However, there is no direct genetic evidence for an autonomous role of mTOR itself in preadipocyte differentiation. To seek such evidence, we employed a conditional knockdown approach to deplete mTOR in preadipocytes. Surprisingly, while knockdown of S6K1, a target of mTOR, impairs 3T3-L1 preadipocyte differentiation, reduction of mTOR levels leads to increased differentiation. This enhanced adipogenesis requires the remaining mTOR activity, as mTOR inhibitors abolish differentiation in the mTOR knockdown cells. We also found that mTOR knockdown elevates the levels of CCAAT/enhancer-binding protein α (C/EBPα) and peroxisome proliferator-activated receptor γ (PPARγ). Furthermore, partial reduction of mTOR levels alleviates inhibition of Akt by mTORC1 via IRS1, while at the same time maintaining its positive input through mTORC1 into the adipogenic program. The greater sensitivity of the IRS1-Akt pathway to mTOR levels provides a mechanism that explains the net outcome of enhanced adipogenesis through PPARγ upon mTOR knockdown. Our observations reveal an unexpected role of mTOR in suppressing adipogenesis and suggest that mTOR governs the homeostasis of the adipogenic process by modulating multiple signaling pathways.
authors.affiliation: Department of Cell and Developmental Biology, University of Illinois at Urbana-Champaign, Urbana, IL 61801.
authors.forename: Mee-Sup
authors.initials: MS
authors.lastname: Yoon
authors.affiliation: Department of Cell and Developmental Biology, University of Illinois at Urbana-Champaign, Urbana, IL 61801.
authors.forename: Chongben
authors.initials: C
authors.lastname: Zhang
authors.affiliation: Department of Cell and Developmental Biology, University of Illinois at Urbana-Champaign, Urbana, IL 61801.
authors.forename: Yuting
authors.initials: Y
authors.lastname: Sun
authors.affiliation: Department of Cell and Developmental Biology, University of Illinois at Urbana-Champaign, Urbana, IL 61801.
authors.forename: Christopher J
authors.initials: CJ
authors.lastname: Schoenherr
authors.affiliation: Department of Cell and Developmental Biology, University of Illinois at Urbana-Champaign, Urbana, IL 61801. Electronic address: jiechen@illinois.edu.
authors.forename: Jie
authors.initials: J
authors.lastname: Chen
mesh_terms: D041721:3T3-L1 Cells; D050156:Adipogenesis / Q000187:drug effects*; D000818:Animals; D002454:Cell Differentiation / Q000187:drug effects; D006706:Homeostasis / Q000187:drug effects*; D051379:Mice; D038744:Ribosomal Protein S6 Kinases, 90-kDa / Q000378:metabolism; D020123:Sirolimus / Q000494:pharmacology*; D013329:Structure-Activity Relationship
chemical_list: D038744:Ribosomal Protein S6 Kinases, 90-kDa; C512964:Rps6ka1 protein, mouse; D020123:Sirolimus
keywords: CCAAT/enhancer-binding protein α; adipocytes; mechanistic target of rapamycin complex 1; peroxisome proliferator-activated receptor γ