title: Small‑molecule COH-SR4 inhibits adipocyte differentiation via AMPK activation.
abstract: 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 AMPKα1/α2 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.
authors.affiliation: Division of Diabetes, Endocrinology and Metabolism, Beckman Research Institute, City of Hope National Medical Center, Duarte, CA 91010, USA. jfigarola@coh.org
authors.forename: James L
authors.initials: JL
authors.lastname: Figarola
authors.forename: Samuel
authors.initials: S
authors.lastname: Rahbar
mesh_terms: D041721:3T3-L1 Cells; D055372:AMP-Activated Protein Kinases / Q000378:metabolism*; D017667:Adipocytes / Q000166:cytology* / Q000187:drug effects / Q000201:enzymology*; D050156:Adipogenesis / Q000187:drug effects; D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D020134:Catalytic Domain; D002454:Cell Differentiation / Q000187:drug effects*; D002470:Cell Survival / Q000187:drug effects; D002999:Clone Cells; D004789:Enzyme Activation / Q000187:drug effects; D055785:Gene Knockdown Techniques; D006801:Humans; D000076222:Mechanistic Target of Rapamycin Complex 1; D000076225:Mechanistic Target of Rapamycin Complex 2; D051379:Mice; D008938:Mitosis / Q000187:drug effects; D046912:Multiprotein Complexes / Q000378:metabolism; D010671:Phenylurea Compounds / Q000737:chemistry / Q000494:pharmacology*; D034741:RNA, Small Interfering / Q000378:metabolism; D054852:Small Molecule Libraries / Q000737:chemistry / Q000494:pharmacology*; D058570:TOR Serine-Threonine Kinases / Q000378:metabolism
chemical_list: C577482:1,3-bis(3,5-dichlorophenyl)urea; D046912:Multiprotein Complexes; D010671:Phenylurea Compounds; D034741:RNA, Small Interfering; D054852:Small Molecule Libraries; D000076222:Mechanistic Target of Rapamycin Complex 1; D000076225:Mechanistic Target of Rapamycin Complex 2; D058570:TOR Serine-Threonine Kinases; D055372:AMP-Activated Protein Kinases