PMID- 23525347
OWN - NLM
STAT- MEDLINE
DCOM- 20131029
LR  - 20211203
IS  - 1791-244X (Electronic)
IS  - 1107-3756 (Linking)
VI  - 31
IP  - 5
DP  - 2013 May
TI  - Small‑molecule COH-SR4 inhibits adipocyte differentiation via AMPK activation.
PG  - 1166-76
LID - 10.3892/ijmm.2013.1313 [doi]
AB  - Obesity is a chronic metabolic disorder caused by an imbalance between energy 
      intake and expenditure. It is one of the principal causative factors involved in 
      the development of metabolic syndrome and cancer. Inhibition of adipocyte 
      differentiation has often been a target of anti-obesity strategies since obesity 
      is caused not only by hypertrophy but also by adipocyte hyperplasia. In this 
      study, we investigated the effects of COH-SR4, a novel compound with anticancer 
      properties, on the adipogenesis in 3T3-L1 cells. Treatment with COH-SR4 
      significantly inhibited adipocyte differentiation in a dose-dependent manner. 
      This inhibitory effect mainly occurred at the early phase of differentiation 
      through inhibition of mitotic clonal expansion and cell cycle arrest at the G1/S 
      phase transition. In differentiating adipocytes, COH-SR4 significantly reduced 
      intracellular lipid accumulation and downregulated the expression of key 
      adipogenesis-related transcription factors and lipogenic proteins. COH-SR4 
      exhibited no cytotoxic effects in 3T3-L1 cells, but indirectly activated 
      AMP-activated protein kinase (AMPK). AMPK activation by COH-SR4 also resulted in 
      the phosphorylation of raptor and tuberous sclerosis protein 2 (TSC2), two 
      proteins involved in the mammalian target of rapamycin (mTOR) signaling pathways. 
      Additionally, COH-SR4 decreased the phosphorylation of p70 kDa ribosomal protein 
      S6 kinase (S6K) and initiation factor 4E (eIF4E) binding protein 1 (4EB‑P1), two 
      downstream effectors of mTOR that regulate protein synthesis. Interestingly, 
      knockdown of AMPKalpha1/alpha2 prevented the ability of COH-SR4 to inhibit cell cycle 
      arrest and overall adipogenesis and lipid accumulation in the differentiating 
      3T3-L1 cells. Taken together, these results suggest that COH-SR4 inhibits 3T3-L1 
      adipogenesis via AMPK activation. COH-SR4 may be a promising compound for the 
      treatment of obesity and related metabolic disorders.
FAU - Figarola, James L
AU  - Figarola JL
AD  - Division of Diabetes, Endocrinology and Metabolism, Beckman Research Institute, 
      City of Hope National Medical Center, Duarte, CA 91010, USA. jfigarola@coh.org
FAU - Rahbar, Samuel
AU  - Rahbar S
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20130321
PL  - Greece
TA  - Int J Mol Med
JT  - International journal of molecular medicine
JID - 9810955
RN  - 0 (1,3-bis(3,5-dichlorophenyl)urea)
RN  - 0 (Multiprotein Complexes)
RN  - 0 (Phenylurea Compounds)
RN  - 0 (RNA, Small Interfering)
RN  - 0 (Small Molecule Libraries)
RN  - EC 2.7.11.1 (Mechanistic Target of Rapamycin Complex 1)
RN  - EC 2.7.11.1 (Mechanistic Target of Rapamycin Complex 2)
RN  - EC 2.7.11.1 (TOR Serine-Threonine Kinases)
RN  - EC 2.7.11.31 (AMP-Activated Protein Kinases)
SB  - IM
MH  - 3T3-L1 Cells
MH  - AMP-Activated Protein Kinases/*metabolism
MH  - Adipocytes/*cytology/drug effects/*enzymology
MH  - Adipogenesis/drug effects
MH  - Animals
MH  - Apoptosis/drug effects
MH  - Catalytic Domain
MH  - Cell Differentiation/*drug effects
MH  - Cell Survival/drug effects
MH  - Clone Cells
MH  - Enzyme Activation/drug effects
MH  - Gene Knockdown Techniques
MH  - Humans
MH  - Mechanistic Target of Rapamycin Complex 1
MH  - Mechanistic Target of Rapamycin Complex 2
MH  - Mice
MH  - Mitosis/drug effects
MH  - Multiprotein Complexes/metabolism
MH  - Phenylurea Compounds/chemistry/*pharmacology
MH  - RNA, Small Interfering/metabolism
MH  - Small Molecule Libraries/chemistry/*pharmacology
MH  - TOR Serine-Threonine Kinases/metabolism
EDAT- 2013/03/26 06:00
MHDA- 2013/10/30 06:00
CRDT- 2013/03/26 06:00
PHST- 2013/01/02 00:00 [received]
PHST- 2013/02/18 00:00 [accepted]
PHST- 2013/03/26 06:00 [entrez]
PHST- 2013/03/26 06:00 [pubmed]
PHST- 2013/10/30 06:00 [medline]
AID - 10.3892/ijmm.2013.1313 [doi]
PST - ppublish
SO  - Int J Mol Med. 2013 May;31(5):1166-76. doi: 10.3892/ijmm.2013.1313. Epub 2013 Mar 
      21.