title: The novel anti-adipogenic effect and mechanisms of action of SGI-1776, a Pim-specific inhibitor, in 3T3-L1 adipocytes.
abstract: The proviral integration site for moloney murine leukemia virus (Pim) kinases, consisting of Pim-1, Pim-2 and Pim-3, belongs to a family of serine/threonine kinases that are involved in controlling cell growth and differentiation. Pim kinases are emerging as important mediators of adipocyte differentiation. SGI-1776, an inhibitor of Pim kinases, is widely used to assess the physiological roles of Pim kinases, particularly cell functions. In the present study, we examined the effects of SGI-1776 on adipogenesis. The anti‑adipogenic effect of SGI‑1776 was measured by Oil Red O staining and AdipoRed assays. The effect of SGI‑1776 on the growth of 3T3‑L1 adipocytes was determined by cell count analysis. The effects of SGI‑1776 on the protein and mRNA expression of adipogenesis-related proteins and adipokines in 3T3‑L1 adipocytes were also evaluated by western blot analysis and RT‑PCR, respectively. Notably, SGI-1776 markedly inhibited lipid accumulation during the differentiation of 3T3-L1 preadipocytes into adipocytes. On a mechanistic level, SGI-1776 inhibited not only the expression of CCAAT/enhancer-binding protein-α (C/EBP-α), peroxisome proliferator-activated receptor-γ (PPAR-γ) and fatty acid synthase (FAS), but also the phosphorylation of signal transducer and activator of transcription-3 (STAT-3). Moreover, SGI-1776 decreased the expression of adipokines, including the expression of leptin and regulated on activation, normal T cell expressed and secreted (RANTES) during adipocyte differentiation. These findings demonstrate that SGI-1776 inhibits adipogenesis by downregulating the expression and/or phosphorylation levels of C/EBP-α, PPAR-γ, FAS and STAT-3.
authors.affiliation: Department of Molecular Medicine, College of Medicine, Keimyung University, Daegu 704-701, Republic of Korea.
authors.forename: Yu-Kyoung
authors.initials: YK
authors.lastname: Park
authors.affiliation: Department of Chemistry, College of Natural Sciences, Keimyung University, Daegu 704-701, Republic of Korea.
authors.forename: Victor Sukbong
authors.initials: VS
authors.lastname: Hong
authors.affiliation: Department of Microbiology, College of Medicine, Yeungnam University, Daegu 705‑717, Republic of Korea.
authors.forename: Tae-Yoon
authors.initials: TY
authors.lastname: Lee
authors.affiliation: Department of Chemistry, College of Natural Sciences, Keimyung University, Daegu 704-701, Republic of Korea.
authors.forename: Jinho
authors.initials: J
authors.lastname: Lee
authors.affiliation: Division of Life Science, Korea Basic Science Institute, Daejeon 305-333, Republic of Korea.
authors.forename: Jong-Soon
authors.initials: JS
authors.lastname: Choi
authors.affiliation: Department of Rehabilitation Medicine, Catholic University of Daegu School of Medicine, Daegu 705-718, Republic of Korea.
authors.forename: Dong-Soon
authors.initials: DS
authors.lastname: Park
authors.affiliation: Department of Rehabilitation Medicine, Catholic University of Daegu School of Medicine, Daegu 705-718, Republic of Korea.
authors.forename: Gi-Young
authors.initials: GY
authors.lastname: Park
authors.affiliation: Department of Molecular Medicine, College of Medicine, Keimyung University, Daegu 704-701, Republic of Korea.
authors.forename: Byeong-Churl
authors.initials: BC
authors.lastname: Jang
mesh_terms: D041721:3T3-L1 Cells; D017667:Adipocytes / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D050156:Adipogenesis / Q000187:drug effects*; D000818:Animals; D022763:CCAAT-Enhancer-Binding Protein-alpha / Q000235:genetics; D005786:Gene Expression Regulation / Q000187:drug effects; D007093:Imidazoles / Q000494:pharmacology*; D050356:Lipid Metabolism / Q000187:drug effects; D051379:Mice; D047495:PPAR gamma / Q000235:genetics; D047428:Protein Kinase Inhibitors / Q000494:pharmacology*; D051573:Proto-Oncogene Proteins c-pim-1 / Q000037:antagonists & inhibitors*; D011724:Pyridazines / Q000494:pharmacology*; D050796:STAT3 Transcription Factor / Q000235:genetics
chemical_list: D022763:CCAAT-Enhancer-Binding Protein-alpha; D007093:Imidazoles; D047495:PPAR gamma; D047428:Protein Kinase Inhibitors; D011724:Pyridazines; C545188:SGI 1776; D050796:STAT3 Transcription Factor; C494087:Stat3 protein, mouse; D051573:Proto-Oncogene Proteins c-pim-1; C406031:proto-oncogene proteins pim