PMID- 23740969
OWN - NLM
STAT- MEDLINE
DCOM- 20140224
LR  - 20230618
IS  - 1539-7262 (Electronic)
IS  - 0022-2275 (Print)
IS  - 0022-2275 (Linking)
VI  - 54
IP  - 8
DP  - 2013 Aug
TI  - Mechanistic target of rapamycin controls homeostasis of adipogenesis.
PG  - 2166-2173
LID - S0022-2275(20)37532-5 [pii]
LID - 10.1194/jlr.M037705 [doi]
AB  - 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 alpha (C/EBPalpha) and peroxisome 
      proliferator-activated receptor gamma (PPARgamma). 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 PPARgamma 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.
FAU - Yoon, Mee-Sup
AU  - Yoon MS
AD  - Department of Cell and Developmental Biology, University of Illinois at 
      Urbana-Champaign, Urbana, IL 61801.
FAU - Zhang, Chongben
AU  - Zhang C
AD  - Department of Cell and Developmental Biology, University of Illinois at 
      Urbana-Champaign, Urbana, IL 61801.
FAU - Sun, Yuting
AU  - Sun Y
AD  - Department of Cell and Developmental Biology, University of Illinois at 
      Urbana-Champaign, Urbana, IL 61801.
FAU - Schoenherr, Christopher J
AU  - Schoenherr CJ
AD  - Department of Cell and Developmental Biology, University of Illinois at 
      Urbana-Champaign, Urbana, IL 61801.
FAU - Chen, Jie
AU  - Chen J
AD  - Department of Cell and Developmental Biology, University of Illinois at 
      Urbana-Champaign, Urbana, IL 61801. Electronic address: jiechen@illinois.edu.
LA  - eng
GR  - R01 GM089771/GM/NIGMS NIH HHS/United States
GR  - AR-048914/AR/NIAMS NIH HHS/United States
GR  - GM-089771/GM/NIGMS NIH HHS/United States
GR  - R56 AR048914/AR/NIAMS NIH HHS/United States
GR  - R01 AR048914/AR/NIAMS NIH HHS/United States
PT  - Journal Article
PT  - Research Support, N.I.H., Extramural
DEP - 20130605
PL  - United States
TA  - J Lipid Res
JT  - Journal of lipid research
JID - 0376606
RN  - EC 2.7.11.1 (Ribosomal Protein S6 Kinases, 90-kDa)
RN  - EC 2.7.11.1 (Rps6ka1 protein, mouse)
RN  - W36ZG6FT64 (Sirolimus)
SB  - IM
MH  - 3T3-L1 Cells
MH  - Adipogenesis/*drug effects
MH  - Animals
MH  - Cell Differentiation/drug effects
MH  - Homeostasis/*drug effects
MH  - Mice
MH  - Ribosomal Protein S6 Kinases, 90-kDa/metabolism
MH  - Sirolimus/*pharmacology
MH  - Structure-Activity Relationship
PMC - PMC3708366
OTO - NOTNLM
OT  - CCAAT/enhancer-binding protein alpha
OT  - adipocytes
OT  - mechanistic target of rapamycin complex 1
OT  - peroxisome proliferator-activated receptor gamma
EDAT- 2013/06/07 06:00
MHDA- 2014/02/25 06:00
PMCR- 2014/08/01
CRDT- 2013/06/07 06:00
PHST- 2013/06/07 06:00 [entrez]
PHST- 2013/06/07 06:00 [pubmed]
PHST- 2014/02/25 06:00 [medline]
PHST- 2014/08/01 00:00 [pmc-release]
AID - S0022-2275(20)37532-5 [pii]
AID - m037705 [pii]
AID - 10.1194/jlr.M037705 [doi]
PST - ppublish
SO  - J Lipid Res. 2013 Aug;54(8):2166-2173. doi: 10.1194/jlr.M037705. Epub 2013 Jun 5.